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The MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss >= 5% and analysed using a binary logistic regression (LR) model.\n\nNR: Subjects with missing week 68 response are considered as non-responders. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:28 - tstatsens.sas/tsensbw5.txt\n\nAnalysis of data from on-treatment period, A time-point is considered as on-treatment if any dose of trial product has been administered within the prior 14 days., MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline value of the endpoint as covariate, all nested within visit, The MMRM was performed on week 68 value of the endpoint and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for the response threshold of the endpoint and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline value of the endpoint as covariate. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:18 - tstatlogregx.sas/tmmrmxresp.txt\n\nMMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit. The MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss >= 10% and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline body weight as covariate.\n\nMMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit. The MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss >= 15% and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline body weight as covariate.\n\nMMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit. The MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss >= 20% and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline body weight as covariate. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:21 - tstatlogreg.sas/tmmrmbw20.txt\n\nMMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline waist circumference as covariate, all nested within visit. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:22 - tstatmmrm.sas/tmmrmwc.txt\n\nMMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline pulse as covariate, all nested within visit. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:23 - tstatmmrm.sas/tmmrmpulse.txt\n\n78,79,80 According to the guidance document, an estimand is defined by four inter-related attributes: the population of interest, the variable (endpoint) of interest, the way intercurrent events are handled and the population level summary. The two estimands in this trial address the same population of interest (i.e. adults with overweight or obesity), cover the same endpoints (i.e. all efficacy-related endpoints) and are based on the same population level summary (the estimated mean treatment contrast between semaglutide and placebo), although the statistical methods applied to estimate the treatment effects differ. The largest difference between the two estimands is in the handling of intercurrent events, which in this trial comprised any off-treatment periods and initiation of other anti-obesity therapies (i.e. weight management drugs or bariatric surgery).\n\nThe treatment policy estimand is the primary estimand and is used for the confirmatory, multiplicity-controlled statistical evaluations. It estimates the population level treatment effect of semaglutide regardless of treatment adherence and/or other anti-obesity therapies and does not exclude data collected after discontinuation of treatment (e.g. due to tolerability issues) or after initiation of alternative treatment (e.g. due to lack of efficacy). The treatment policy estimand is relevant when evaluating the overall treatment impact for the indicated patient population.\n\nThe hypothetical estimand excludes the effects of any other anti-obesity therapies and any effects after first treatment discontinuation, and provides a clinically relevant estimate of the average treatment effect of semaglutide, as an adjunct to a reduced-calorie diet and increased physical activity, if all subjects adhered to the treatment regimen as described in the protocol. The hypothetical estimand is of interest when evaluating the potential achievable effects of treatment for the patient, if treatment is taken as intended.\n\nThe treatment policy estimand and the hypothetical estimand were applied to the efficacy analyses in order to address two different aspects of the treatment effect of semaglutide (Section 8.4). Different observation periods (in-trial period and the period until first treatment discontinuation without use of other anti-obesity therapies, respectively) and different statistical analysis methods were used for the two estimands resulting in different point estimates and CIs.\n\nThe efficacy evaluation is based on the full analysis set.\n\nThe text explaining how to handle missing baseline values has been changed to make it clear that if no eligible observation at or before randomisation is available then the mean of baseline values across all subjects is used as baseline value.\n\nIt is clarified that RD-MI imputation was performed according to the timing of last available observation during the on-treatment period (LAO-OT) for all endpoints. Furthermore, it is clarified that the LAO-OT must be prior to the landmark visit (week 68).\n\nIn grouping of retrieved subjects by timing of LAO-OT in the RD-MI procedure, it was clarified that timing by quarters or halves is defined as too restrictive if the imputation model cannot be fit due to inadequate numbers of retrieved subjects in 1 or more groups.\n\nIt is clarified that if no post-baseline LAO-OT exist, then LAO-OT were to be the baseline value and the timing of LAO-OT were to be the first interval.\n\nTo clarify the definition of the last available observation during the on-treatment period In all multiple imputation procedures, in addition to the seed number, it was specified that the dataset is sorted by subject ID.\n\nThe TP-MI procedure was updated to be a 2-way tipping point analysis in which penalties are applied to\n\nChange to planned statistical analysis Rationale for change and possible implications A description was included of the sensitivity analysis of the 5% responder endpoint (primary estimand) using MMRM. To clarify precisely how the MMRM will be parameterized, and how missing values will be imputed.\n\nIt has been clarified that the non-responder analysis includes subjects with missing body weight assessment at week 68 as non-responders.\n\nIt has been clarified that the 5% responder analysis using MMRM for the secondary estimand is predicting individual values for % weight change only when % weight change is missing at week 68. Furthermore, it is clarified that the logistic regression includes both randomised treatment as a factor and baseline body weight as covariate.\n\nThe pre-specified sensitivity analyses confirmed the robustness of the primary statistical analysis.\n\nAE adverse event ALT alanine aminotransferase AST aspartate aminotransferase BMI body mass index CFR US Code of Federal Regulations CI confidence interval CKD-EPI Chronic Kidney Disease Epidemiology Collaboration Cmax maximum concentration COVID-19 Coronavirus disease 2019 CRF case report form C-SSRS Columbia\u2013Suicide Severity Rating Scale CS clinically significant CT computerised tomography CV coefficient of variation DBL database lock DEXA Dual-energy X-ray absorptiometry DUN dispensing unit number DXA DEXA analysis set EAC event adjudication committee ECG electrocardiogram eCRF electronic case report form eGFR estimated glomerular filtration rate EMA European Medicines Agency EOT end of text ETD estimated treatment difference ETR estimated treatment ratio FAS full analysis set FDA US Food and Drug Administration FPFV first patient first visit FPG fasting plasma glucose GCP Good Clinical Practice GI gastrointestinal GLP-1 glucagon-like peptide-1 GLP-1 RA glucagon-like peptide-1 receptor agonist HbA1c glycated haemoglobin HDL high density lipoprotein HLGT high-level group term CRP C-reactive protein ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICIQ-UI-SF International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form IEC independent ethics committee IgE Immunoglobulin E IMP investigational medicinal product IND investigational new drug INR international normalized ratio IRB institutional review board ISO International Organization for Standardization IT in-trial IWQOL-Lite-CT Impact of Weight on Quality of Life-Lite for Clinical Trials IWRS interactive voice/web response system J2R-MI jump to reference multiple imputation KDIGO Kidney Disease: Improving Global Outcomes LAO-OT last available observation during the on-treatment period LDL low density lipoprotein MedDRA Medical Dictionary for Regulatory Activities MMRM mixed model for repeated measurements MRI magnetic resonance imaging NCS not clinically significant ND not done NR sensitivity analysis setting subjects with missing week 68 value as non-responders OR odds ratio OT on-treatment PAI-1 plasminogen activator inhibitor-1 PD protocol deviation PGI-C Patient Global Impression of Change PGI-S Patient Global Impression of Status PHQ-9 Patient Health Questionnaire-9 PK pharmacokinetic PRO patient-reported outcome PT preferred term PYE patient years of exposure PYO patient years of observation RD-MI multiple imputation using retrieved subjects S1-SI Sacks single imputation approach 1 S2-SI Sacks single imputation approach 2 SAE serious adverse event SAP statistical analysis plan SAS safety analysis set s.c. subcutaneous(ly) SD standard deviation SF-36 Short Form 36 v2.0 acute SOC system organ class SPS-6 Stanford Presenteeism Scale STEP Semaglutide Treatment Effect in People with obesity SUSAR suspected unexpected serious adverse reaction T2D type 2 diabetes TEAE treatment emergent adverse event TEE total energy expenditure TP-MI tipping-point multiple imputation TSH thyroid stimulating hormone UK United Kingdom ULN upper limit of normal range US United States of America UTN universal trial number VLDL", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "LR: Week 68 responses were analysed using a binary logistic regression model with randomised treatment as factor and baseline body weight as covariate.\n\nJ2R-MI: Missing observations multiple (x1000) imputed from placebo subjects based on a jump to reference approach.\n\nS1-SI: Missing observations imputed by adding a body weight regain rate of 0.3 kg per month to the last available observation (LAO) until baseline is reached.\n\nS2-SI: Missing observations imputed by adding a body weight regain rate of 0.3 kg per month to the last available observation (LAO) until baseline is reached for sema 2.4 mg only.\n\nMMRM: All responses were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit. The MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss >= 5% and analysed using a binary logistic regression (LR) model.\n\nNR: Subjects with missing week 68 response are considered as non-responders. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:28 - tstatsens.sas/tsensbw5.txt", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 346, "section": "14.2.24 Proportion of subjects achieving body weight loss response criteria since baseline by week - summary - in-trial - full analysis set"}}, {"excerpt": "Analysis of data from on-treatment period, A time-point is considered as on-treatment if any dose of trial product has been administered within the prior 14 days., MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline value of the endpoint as covariate, all nested within visit, The MMRM was performed on week 68 value of the endpoint and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for the response threshold of the endpoint and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline value of the endpoint as covariate. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:18 - tstatlogregx.sas/tmmrmxresp.txt", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 515, "section": "14.2.152 Odds of achieving response in non-weight-related endpoints since baseline at week 68 -"}}, {"excerpt": "MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit. The MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss >= 10% and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline body weight as covariate.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 353, "section": "14.2.36 Odds of achieving body weight loss response criteria since baseline at week 68 - forest plot -"}}, {"excerpt": "MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit. The MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss >= 15% and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline body weight as covariate.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 353, "section": "14.2.36 Odds of achieving body weight loss response criteria since baseline at week 68 - forest plot -"}}, {"excerpt": "MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit. The MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss >= 20% and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline body weight as covariate. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:21 - tstatlogreg.sas/tmmrmbw20.txt", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 354, "section": "14.2.36 Odds of achieving body weight loss response criteria since baseline at week 68 - forest plot -"}}, {"excerpt": "MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline waist circumference as covariate, all nested within visit. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:22 - tstatmmrm.sas/tmmrmwc.txt", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 376, "section": "14.2.60 Waist circumference change from baseline to week 68 - statistical analysis - hypothetical"}}, {"excerpt": "MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline pulse as covariate, all nested within visit. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:23 - tstatmmrm.sas/tmmrmpulse.txt", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 4096, "section": "14.3.6.5 Pulse change from baseline to week 68 - statistical analysis - hypothetical estimand - safety"}}, {"excerpt": "78,79,80 According to the guidance document, an estimand is defined by four inter-related attributes: the population of interest, the variable (endpoint) of interest, the way intercurrent events are handled and the population level summary. The two estimands in this trial address the same population of interest (i.e. adults with overweight or obesity), cover the same endpoints (i.e. all efficacy-related endpoints) and are based on the same population level summary (the estimated mean treatment contrast between semaglutide and placebo), although the statistical methods applied to estimate the treatment effects differ. The largest difference between the two estimands is in the handling of intercurrent events, which in this trial comprised any off-treatment periods and initiation of other anti-obesity therapies (i.e. weight management drugs or bariatric surgery).\n\nThe treatment policy estimand is the primary estimand and is used for the confirmatory, multiplicity-controlled statistical evaluations. It estimates the population level treatment effect of semaglutide regardless of treatment adherence and/or other anti-obesity therapies and does not exclude data collected after discontinuation of treatment (e.g. due to tolerability issues) or after initiation of alternative treatment (e.g. due to lack of efficacy). The treatment policy estimand is relevant when evaluating the overall treatment impact for the indicated patient population.\n\nThe hypothetical estimand excludes the effects of any other anti-obesity therapies and any effects after first treatment discontinuation, and provides a clinically relevant estimate of the average treatment effect of semaglutide, as an adjunct to a reduced-calorie diet and increased physical activity, if all subjects adhered to the treatment regimen as described in the protocol. The hypothetical estimand is of interest when evaluating the potential achievable effects of treatment for the patient, if treatment is taken as intended.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 34, "section": "68 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in all"}}, {"excerpt": "The treatment policy estimand and the hypothetical estimand were applied to the efficacy analyses in order to address two different aspects of the treatment effect of semaglutide (Section 8.4). Different observation periods (in-trial period and the period until first treatment discontinuation without use of other anti-obesity therapies, respectively) and different statistical analysis methods were used for the two estimands resulting in different point estimates and CIs.\n\nThe efficacy evaluation is based on the full analysis set.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 86, "section": "11.1 Introduction to the efficacy evaluation"}}, {"excerpt": "The text explaining how to handle missing baseline values has been changed to make it clear that if no eligible observation at or before randomisation is available then the mean of baseline values across all subjects is used as baseline value.\n\nIt is clarified that RD-MI imputation was performed according to the timing of last available observation during the on-treatment period (LAO-OT) for all endpoints. Furthermore, it is clarified that the LAO-OT must be prior to the landmark visit (week 68).\n\nIn grouping of retrieved subjects by timing of LAO-OT in the RD-MI procedure, it was clarified that timing by quarters or halves is defined as too restrictive if the imputation model cannot be fit due to inadequate numbers of retrieved subjects in 1 or more groups.\n\nIt is clarified that if no post-baseline LAO-OT exist, then LAO-OT were to be the baseline value and the timing of LAO-OT were to be the first interval.\n\nTo clarify the definition of the last available observation during the on-treatment period In all multiple imputation procedures, in addition to the seed number, it was specified that the dataset is sorted by subject ID.\n\nThe TP-MI procedure was updated to be a 2-way tipping point analysis in which penalties are applied to", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 62, "section": "9.7.2 Changes in planned analyses prior to trial unblinding"}}, {"excerpt": "Change to planned statistical analysis Rationale for change and possible implications A description was included of the sensitivity analysis of the 5% responder endpoint (primary estimand) using MMRM. To clarify precisely how the MMRM will be parameterized, and how missing values will be imputed.\n\nIt has been clarified that the non-responder analysis includes subjects with missing body weight assessment at week 68 as non-responders.\n\nIt has been clarified that the 5% responder analysis using MMRM for the secondary estimand is predicting individual values for % weight change only when % weight change is missing at week 68. Furthermore, it is clarified that the logistic regression includes both randomised treatment as a factor and baseline body weight as covariate.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 63, "section": "9.7.2 Changes in planned analyses prior to trial unblinding"}}, {"excerpt": "The pre-specified sensitivity analyses confirmed the robustness of the primary statistical analysis.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 188, "section": "13.1 Discussion"}}, {"excerpt": "AE adverse event ALT alanine aminotransferase AST aspartate aminotransferase BMI body mass index CFR US Code of Federal Regulations CI confidence interval CKD-EPI Chronic Kidney Disease Epidemiology Collaboration Cmax maximum concentration COVID-19 Coronavirus disease 2019 CRF case report form C-SSRS Columbia\u2013Suicide Severity Rating Scale CS clinically significant CT computerised tomography CV coefficient of variation DBL database lock DEXA Dual-energy X-ray absorptiometry DUN dispensing unit number DXA DEXA analysis set EAC event adjudication committee ECG electrocardiogram eCRF electronic case report form eGFR estimated glomerular filtration rate EMA European Medicines Agency EOT end of text ETD estimated treatment difference ETR estimated treatment ratio FAS full analysis set FDA US Food and Drug Administration FPFV first patient first visit FPG fasting plasma glucose GCP Good Clinical Practice GI gastrointestinal GLP-1 glucagon-like peptide-1 GLP-1 RA glucagon-like peptide-1 receptor agonist HbA1c glycated haemoglobin HDL high density lipoprotein HLGT high-level group term CRP C-reactive protein ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICIQ-UI-SF International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form IEC independent ethics committee IgE Immunoglobulin E IMP investigational medicinal product IND investigational new drug INR international normalized ratio IRB institutional review board ISO International Organization for Standardization IT in-trial IWQOL-Lite-CT Impact of Weight on Quality of Life-Lite for Clinical Trials IWRS interactive voice/web response system J2R-MI jump to reference multiple imputation KDIGO Kidney Disease: Improving Global Outcomes LAO-OT last available observation during the on-treatment period LDL low density lipoprotein MedDRA Medical Dictionary for Regulatory Activities MMRM mixed model for repeated measurements MRI magnetic resonance imaging NCS not clinically significant ND not done NR sensitivity analysis setting subjects with missing week 68 value as non-responders OR odds ratio OT on-treatment PAI-1 plasminogen activator inhibitor-1 PD protocol deviation PGI-C Patient Global Impression of Change PGI-S Patient Global Impression of Status PHQ-9 Patient Health Questionnaire-9 PK pharmacokinetic PRO patient-reported outcome PT preferred term PYE patient years of exposure PYO 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The subjects in the FAS will contribute to evaluation \u201cas randomised\u201d. \uf0b7 The safety analysis set (SAS) includes all randomised subjects exposed to at least one dose of randomised treatment. Subjects in the SAS will contribute to evaluation \u201cas treated\u201d. \uf0b7 The DEXA analysis set (DXA) includes subjects in the sub-population of FAS that have had a DEXA scan performed at baseline and where the DEXA scan was found to be of an acceptable quality by the imaging laboratory. Two observation periods were defined for the efficacy and safety evaluations: \uf0b7 The in-trial period defined as the uninterrupted time interval from randomisation to last contact with trial site. \uf0b7 The in-trial period was used for: o Efficacy \u2013 observed values o Safety \u2013 death and events with potential long latency to diagnosis \uf0b7 The on-treatment period defined as the interval from first to last trial product administration plus 2 or 7 weeks of follow-up and excluding any period of temporary treatment interruption defined as >2 or >7 consecutive missed doses (corresponding to >2 or >7 weeks off-treatment). \uf0b7 The on-treatment period (+2 weeks) was used for: o Efficacy \u2013 observed values and hypothetical estimand o Safety \u2013 ECG, laboratory assessments, physical examination and pulse \uf0b7 The on-treatment period (+7 weeks) was used for: o Safety \u2013 adverse events and adjudicated events\n\nThe text explaining how to handle missing baseline values has been changed to make it clear that if no eligible observation at or before randomisation is available then the mean of baseline values across all subjects is used as baseline value. To clarify how missing baseline values are handled.\n\nIt is clarified that RD-MI imputation was performed according to the timing of last available observation during the on-treatment period (LAO-OT) for all endpoints. Furthermore, it is clarified that the LAO-OT must be prior to the landmark visit (week 68). To clarify that the grouping of subjects according to timing is as in the publication by McEvoy.98 In grouping of retrieved subjects by timing of LAO-OT in the RD-MI procedure, it was clarified that timing by quarters or halves is defined as too restrictive if the imputation model cannot be fit due to inadequate numbers of retrieved subjects in 1 or more groups. To clarify the criteria on which a decision to reduce the imputation model will be based. It is clarified that if no post-baseline LAO-OT exist, then LAO-OT were to be the baseline value and the timing of LAO-OT were to be the first interval.\n\nTo clarify the definition of the last available observation during the on-treatment period In all multiple imputation procedures, in addition to the seed number, it was specified that the dataset is sorted by subject ID. To ensure reproducibility of the imputed datasets.\n\nFigure 11-4 Body weight (%) change from baseline by week \u2013 missing data pattern plot Cross-reference: EOT Figure 14.2.7 Sensitivity analyses For the treatment policy estimand, four pre-specified sensitivity analyses using different imputation methods (SAP; Appendix 16.1.9) were performed to evaluate the robustness of the conclusions based on the primary analysis towards any impact of the assumptions regarding missing data. Across the primary analysis and the four sensitivity analyses, the ETDs for semaglutide 2.4 mg vs placebo and the associated 95% CIs were similar (Figure 11-5, EOT Table 14.2.11). The alignment across the four sensitivity analyses supported the robustness of the conclusions based on the primary analysis for the treatment policy estimand.\n\nFigure 11-7 Odds of achieving \u22655% weight loss at week 68 \u2212 primary and sensitivity statistical analyses \u2013 treatment policy estimand Cross-reference: EOT Figure 14.2.28 Furthermore, a 2-way tipping point analysis in which penalties are applied to both treatment groups (semaglutide 2.4 mg and placebo) was performed for the primary analysis for the treatment policy estimand. The purpose of the tipping point analysis was to identify the penalties required to tip the conclusion from superiority to not being able to confirm superiority based on the primary analysis. For both treatments, no penalty could be added to reverse the conclusion of the primary analysis in the range explored (from -30% to 30% by 1%). Hence, the tipping point sensitivity analysis supported the robustness of the conclusions based on the primary analysis for the treatment policy estimand (EOT Table 14.2.29).\n\nThe primary estimand was a treatment policy estimand, which was used for the confirmatory, multiplicity-controlled statistical evaluations. The treatment policy estimand was used to estimate the treatment effect of semaglutide 2.4 mg in all patients regardless of treatment adherence or initiation of other anti-obesity therapies. 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To ensure reproducibility of the imputed datasets.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 62, "section": "9.7.2 Changes in planned analyses prior to trial unblinding"}}, {"excerpt": "Figure 11-4 Body weight (%) change from baseline by week \u2013 missing data pattern plot Cross-reference: EOT Figure 14.2.7 Sensitivity analyses For the treatment policy estimand, four pre-specified sensitivity analyses using different imputation methods (SAP; Appendix 16.1.9) were performed to evaluate the robustness of the conclusions based on the primary analysis towards any impact of the assumptions regarding missing data. Across the primary analysis and the four sensitivity analyses, the ETDs for semaglutide 2.4 mg vs placebo and the associated 95% CIs were similar (Figure 11-5, EOT Table 14.2.11). 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A treatment duration of 68 weeks (including 52 weeks on maintenance dose) was considered sufficient to assess weight loss, safety and tolerability in the phase 3 weight management development programme in accordance with regulatory guidelines.81, 82 The 7-week follow-up period was included to account for the long half-life of semaglutide.\n\nThe two estimands in this trial address the same population of interest (i.e. adults with overweight or obesity), cover the same endpoints (i.e. all efficacy-related endpoints) and are based on the same population level summary (the estimated mean treatment contrast between semaglutide and placebo), although the statistical methods applied to estimate the treatment effects differ. 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A treatment duration of 68 weeks (including 52 weeks on maintenance dose) was considered sufficient to assess weight loss, safety and tolerability in the phase 3 weight management development programme in accordance with regulatory guidelines.81, 82 The 7-week follow-up period was included to account for the long half-life of semaglutide.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 36, "section": "9.2 Rationale for trial design"}}, {"excerpt": "The two estimands in this trial address the same population of interest (i.e. adults with overweight or obesity), cover the same endpoints (i.e. all efficacy-related endpoints) and are based on the same population level summary (the estimated mean treatment contrast between semaglutide and placebo), although the statistical methods applied to estimate the treatment effects differ. 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Furthermore, it is clarified that the LAO-OT must be prior to the landmark visit (week 68).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 62, "section": "9.7.2 Changes in planned analyses prior to trial unblinding"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "298910876", "title": "Systematic review \u2014 overview of safety", "value": "Safety findings The present trial was the largest trial in the STEP programme and the primary trial for the evaluation of safety of treatment with semaglutide 2.4 mg. The trial included standard safety assessments including systematic collection of AEs and regular measurements of vital signs, standard biochemistry and haematology parameters, antibodies, ECG and physical examination.\n\nBased on the extensive amount of safety data collected in the trial, semaglutide 2.4 mg administered once weekly, as an adjunct to a reduced-calorie diet and increased physical activity, was overall well tolerated in the intended patient population of subjects with overweight or obesity. The safety and tolerability profile of semaglutide 2.4 mg was as expected with a GLP-1 RA and there were no new or unexpected findings.\n\nThe proportion of subjects with AEs was similar with semaglutide 2.4 mg and placebo (89.7% vs 86.4%); but event rates were higher with semaglutide (566.1 vs 398.0 events per 100 PYE), driven primarily by gastrointestinal AEs (see Section 12.5.3). Gastrointestinal disorders are well-known AEs associated with GLP-1 RA treatment. The proportion of subjects with SAEs and the rate of SAEs were also higher with semaglutide 2.4 mg than with placebo (9.8% vs 6.4% and 9.6 vs 6.4 events per 100 PYE), driven by AEs within the SOCs: infections and infestations, gastrointestinal disorders and hepatobiliary disorders (see Section 12.3.2).\n\nFor most of the predefined safety focus areas there were no differences between semaglutide 2.4 mg and placebo (Table 12-2). The areas showing treatment differences were: gastrointestinal disorders and gallbladder disorders for which the proportion of subjects with events and the event rates were higher with semaglutide 2.4 mg than with placebo; and cardiovascular disorders, injection site reactions and psychiatric disorders for which the proportion of subjects with events and the event rates were lower with semaglutide 2.4 mg than with placebo.\n\nSema 2.4 mg Placebo\nN (%) E R N (%) E R\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 1306 655\nPatient years of exposure (PYE) 1706.1 829.6\nPatient years of observation (PYO) 1856.4 918.5\nAdverse Events (OT) 1171 (89.7) 9658 566.1 566 (86.4) 3302 398.0\nAdverse Events (IT) 1173 (89.8) 9977 537.4 570 (87.0) 3424 372.8\nSerious\nYes (OT) 128 ( 9.8) 164 9.6 42 ( 6.4) 53 6.4\nYes (IT) 137 (10.5) 183 9.9 48 ( 7.3) 62 6.7\nNo (OT) 1169 (89.5) 9494 556.5 560 (85.5) 3249 391.7\nNo (IT) 1171 (89.7) 9794 527.6 564 (86.1) 3362 366.0\nSeverity\nSevere (OT) 143 (10.9) 242 14.2 44 ( 6.7) 68 8.2\nSevere (IT) 152 (11.6) 262 14.1 45 ( 6.9) 71 7.7\nModerate (OT) 723 (55.4) 2612 153.1 311 (47.5) 863 104.0\nModerate (IT) 729 (55.8) 2743 147.8 317 (48.4) 901 98.1\nMild (OT) 1079 (82.6) 6804 398.8 507 (77.4) 2371 285.8\nMild (IT) 1086 (83.2) 6972 375.6 510 (77.9) 2452 266.9\nRelationship to trial product\nProbable (OT) 571 (43.7) 2148 125.9 147 (22.4) 330 39.8\nProbable (IT) 573 (43.9) 2156 116.1 147 (22.4) 330 35.9\nPossible (OT) 726 (55.6) 2700 158.3 223 (34.0) 555 66.9\nPossible (IT) 727 (55.7) 2710 146.0 223 (34.0) 559 60.9\nUnlikely (OT) 1032 (79.0) 4780 280.2 536 (81.8) 2409 290.4\nUnlikely (IT) 1050 (80.4) 5073 273.3 542 (82.7) 2520 274.3\nMissing (OT) 24 ( 1.8) 30 1.8 7 ( 1.1) 8 1.0\nMissing (IT) 32 ( 2.5) 38 2.0 13 ( 2.0) 15 1.6\nOutcome\nFatal (OT) 0 1 ( 0.2) 1 0.1\nFatal (IT) 1 ( 0.1) 1 0.1 1 ( 0.2) 3 0.3\nRecovered (OT) 1140 (87.3) 8439 494.6 545 (83.2) 2710 326.7\nRecovered (IT) 1143 (87.5) 8654 466.2 547 (83.5) 2785 303.2\nRecovering (OT) 59 ( 4.5) 91 5.3 25 ( 3.8) 37 4.5\nRecovering (IT) 65 ( 5.0) 100 5.4 26 ( 4.0) 38 4.1\nRecovered With Sequelae (OT) 11 ( 0.8) 19 1.1 4 ( 0.6) 5 0.6\nRecovered With Sequelae (IT) 11 ( 0.8) 19 1.0 4 ( 0.6) 5 0.5\nNot Recovered (OT) 513 (39.3) 1106 64.8 265 (40.5) 548 66.1\nNot Recovered (IT) 541 (41.4) 1200 64.6 281 (42.9) 592 64.5\nUnknown (OT) 2 ( 0.2) 3 0.2 1 ( 0.2) 1 0.1\nUnknown (IT) 2 ( 0.2) 3 0.2 1 ( 0.2) 1 0.1", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Safety findings The present trial was the largest trial in the STEP programme and the primary trial for the evaluation of safety of treatment with semaglutide 2.4 mg. 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The safety and tolerability profile of semaglutide 2.4 mg was as expected with a GLP-1 RA and there were no new or unexpected findings.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 189, "section": "13.1 Discussion"}}, {"excerpt": "The proportion of subjects with AEs was similar with semaglutide 2.4 mg and placebo (89.7% vs 86.4%); but event rates were higher with semaglutide (566.1 vs 398.0 events per 100 PYE), driven primarily by gastrointestinal AEs (see Section 12.5.3). Gastrointestinal disorders are well-known AEs associated with GLP-1 RA treatment. The proportion of subjects with SAEs and the rate of SAEs were also higher with semaglutide 2.4 mg than with placebo (9.8% vs 6.4% and 9.6 vs 6.4 events per 100 PYE), driven by AEs within the SOCs: infections and infestations, gastrointestinal disorders and hepatobiliary disorders (see Section 12.3.2).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 127, "section": "12.2.1 Brief summary of adverse events"}}, {"excerpt": "For most of the predefined safety focus areas there were no differences between semaglutide 2.4 mg and placebo (Table 12-2). The areas showing treatment differences were: gastrointestinal disorders and gallbladder disorders for which the proportion of subjects with events and the event rates were higher with semaglutide 2.4 mg than with placebo; and cardiovascular disorders, injection site reactions and psychiatric disorders for which the proportion of subjects with events and the event rates were lower with semaglutide 2.4 mg than with placebo.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 129, "section": "12.2.1 Brief summary of adverse events"}}, {"excerpt": "Sema 2.4 mg Placebo\nN (%) E R N (%) E R\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 1306 655\nPatient years of exposure (PYE) 1706.1 829.6\nPatient years of observation (PYO) 1856.4 918.5\nAdverse Events (OT) 1171 (89.7) 9658 566.1 566 (86.4) 3302 398.0\nAdverse Events (IT) 1173 (89.8) 9977 537.4 570 (87.0) 3424 372.8\nSerious\nYes (OT) 128 ( 9.8) 164 9.6 42 ( 6.4) 53 6.4\nYes (IT) 137 (10.5) 183 9.9 48 ( 7.3) 62 6.7\nNo (OT) 1169 (89.5) 9494 556.5 560 (85.5) 3249 391.7\nNo (IT) 1171 (89.7) 9794 527.6 564 (86.1) 3362 366.0\nSeverity\nSevere (OT) 143 (10.9) 242 14.2 44 ( 6.7) 68 8.2\nSevere (IT) 152 (11.6) 262 14.1 45 ( 6.9) 71 7.7\nModerate (OT) 723 (55.4) 2612 153.1 311 (47.5) 863 104.0\nModerate (IT) 729 (55.8) 2743 147.8 317 (48.4) 901 98.1\nMild (OT) 1079 (82.6) 6804 398.8 507 (77.4) 2371 285.8\nMild (IT) 1086 (83.2) 6972 375.6 510 (77.9) 2452 266.9\nRelationship to trial product\nProbable (OT) 571 (43.7) 2148 125.9 147 (22.4) 330 39.8\nProbable (IT) 573 (43.9) 2156 116.1 147 (22.4) 330 35.9\nPossible (OT) 726 (55.6) 2700 158.3 223 (34.0) 555 66.9\nPossible (IT) 727 (55.7) 2710 146.0 223 (34.0) 559 60.9\nUnlikely (OT) 1032 (79.0) 4780 280.2 536 (81.8) 2409 290.4\nUnlikely (IT) 1050 (80.4) 5073 273.3 542 (82.7) 2520 274.3\nMissing (OT) 24 ( 1.8) 30 1.8 7 ( 1.1) 8 1.0\nMissing (IT) 32 ( 2.5) 38 2.0 13 ( 2.0) 15 1.6\nOutcome\nFatal (OT) 0 1 ( 0.2) 1 0.1\nFatal (IT) 1 ( 0.1) 1 0.1 1 ( 0.2) 3 0.3\nRecovered (OT) 1140 (87.3) 8439 494.6 545 (83.2) 2710 326.7\nRecovered (IT) 1143 (87.5) 8654 466.2 547 (83.5) 2785 303.2\nRecovering (OT) 59 ( 4.5) 91 5.3 25 ( 3.8) 37 4.5\nRecovering (IT) 65 ( 5.0) 100 5.4 26 ( 4.0) 38 4.1\nRecovered With Sequelae (OT) 11 ( 0.8) 19 1.1 4 ( 0.6) 5 0.6\nRecovered With Sequelae (IT) 11 ( 0.8) 19 1.0 4 ( 0.6) 5 0.5\nNot Recovered (OT) 513 (39.3) 1106 64.8 265 (40.5) 548 66.1\nNot Recovered (IT) 541 (41.4) 1200 64.6 281 (42.9) 592 64.5\nUnknown (OT) 2 ( 0.2) 3 0.2 1 ( 0.2) 1 0.1\nUnknown (IT) 2 ( 0.2) 3 0.2 1 ( 0.2) 1 0.1", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 516, "section": "14.3.1.1 Adverse events - overview - safety analysis set"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "302260809", "title": "Patient exposure \u2014 adherence \u2014 Study 1 treatment 2", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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Review it closely before accepting."}, {"code": "citations_unsupported", "severity": "warning", "blocksApply": false, "message": "Autofill found related passages, but they did not support a fillable answer for this field."}, {"code": "content_inferred", "severity": "required", "blocksApply": true, "message": "This content was inferred rather than stated in the source material, so it cannot be applied as an Autofill suggestion."}, {"code": "missing_recommended_evidence", "severity": "warning", "blocksApply": false, "message": "Estimated prevalence \u2014 Alberta \u2014 best estimate."}, {"code": "evidence_scope_note", "severity": "warning", "blocksApply": false, "message": "No supporting evidence found in this document."}], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "400911679", "title": "Long-term : Harms", "value": "AEs with onset during the on-treatment period correspond to treatment-emergent AEs.\n\nAdverse Events (OT) 1171 (89.7) 9658 566.1 566 (86.4) 3302 398.0\nAdverse Events (IT) 1173 (89.8) 9977 537.4 570 (87.0) 3424 372.8\nSerious\nYes (OT) 128 ( 9.8) 164 9.6 42 ( 6.4) 53 6.4\nYes (IT) 137 (10.5) 183 9.9 48 ( 7.3) 62 6.7\nNo (OT) 1169 (89.5) 9494 556.5 560 (85.5) 3249 391.7\nNo (IT) 1171 (89.7) 9794 527.6 564 (86.1) 3362 366.0\nSeverity\nSevere (OT) 143 (10.9) 242 14.2 44 ( 6.7) 68 8.2\nSevere (IT) 152 (11.6) 262 14.1 45 ( 6.9) 71 7.7\nModerate (OT) 723 (55.4) 2612 153.1 311 (47.5) 863 104.0\nModerate (IT) 729 (55.8) 2743 147.8 317 (48.4) 901 98.1\nMild (OT) 1079 (82.6) 6804 398.8 507 (77.4) 2371 285.8\nMild (IT) 1086 (83.2) 6972 375.6 510 (77.9) 2452 266.9\nRelationship to trial product\nProbable (OT) 571 (43.7) 2148 125.9 147 (22.4) 330 39.8\nProbable (IT) 573 (43.9) 2156 116.1 147 (22.4) 330 35.9\nPossible (OT) 726 (55.6) 2700 158.3 223 (34.0) 555 66.9\nPossible (IT) 727 (55.7) 2710 146.0 223 (34.0) 559 60.9\nUnlikely (OT) 1032 (79.0) 4780 280.2 536 (81.8) 2409 290.4\nUnlikely (IT) 1050 (80.4) 5073 273.3 542 (82.7) 2520 274.3\nMissing (OT) 24 ( 1.8) 30 1.8 7 ( 1.1) 8 1.0\nMissing (IT) 32 ( 2.5) 38 2.0 13 ( 2.0) 15 1.6\nOutcome\nFatal (OT) 0 1 ( 0.2) 1 0.1\nFatal (IT) 1 ( 0.1) 1 0.1 1 ( 0.2) 3 0.3\nRecovered (OT) 1140 (87.3) 8439 494.6 545 (83.2) 2710 326.7\nRecovered (IT) 1143 (87.5) 8654 466.2 547 (83.5) 2785 303.2\nRecovering (OT) 59 ( 4.5) 91 5.3 25 ( 3.8) 37 4.5\nRecovering (IT) 65 ( 5.0) 100 5.4 26 ( 4.0) 38 4.1\nRecovered With Sequelae (OT) 11 ( 0.8) 19 1.1 4 ( 0.6) 5 0.6\nRecovered With Sequelae (IT) 11 ( 0.8) 19 1.0 4 ( 0.6) 5 0.5\nNot Recovered (OT) 513 (39.3) 1106 64.8 265 (40.5) 548 66.1\nNot Recovered (IT) 541 (41.4) 1200 64.6 281 (42.9) 592 64.5\nUnknown (OT) 2 ( 0.2) 3 0.2 1 ( 0.2) 1 0.1\nUnknown (IT) 2 ( 0.2) 3 0.2 1 ( 0.2) 1 0.1\n\nAdverse events of special interest\nGastrointestinal disorders (OT) 969 (74.2) 4309 252.6 314 (47.9) 739 89.1\nGallbladder-related disorders (OT) 34 ( 2.6) 42 2.5 8 ( 1.2) 8 1.0\nAcute pancreatitis (OT)# 3 ( 0.2) 3 0.2 0\nCardiovascular disorders (IT) 107 ( 8.2) 134 7.2 75 (11.5) 96 10.5\nAll neoplasms (IT) 93 ( 7.1) 112 6.0 49 ( 7.5) 56 6.1\nMalignant neoplasms (IT) 14 ( 1.1) 14 0.8 7 ( 1.1) 7 0.8\nHepatic events (OT) 31 ( 2.4) 37 2.2 20 ( 3.1) 24 2.9\nAcute renal failure (OT) 3 ( 0.2) 4 0.2 2 ( 0.3) 2 0.2\nHypoglycaemia (OT) 8 ( 0.6) 15 0.9 5 ( 0.8) 7 0.8\nInjection site reactions (OT) 65 ( 5.0) 99 5.8 44 ( 6.7) 82 9.9\nAllergic reactions (OT) 96 ( 7.4) 108 6.3 54 ( 8.2) 63 7.6\nPsychiatric disorders (OT) 124 ( 9.5) 160 9.4 83 (12.7) 113 13.6\nRare events (OT) 7 ( 0.5) 7 0.4 5 ( 0.8) 6 0.7\nMedication errors (OT) 15 ( 1.1) 15 0.9 5 ( 0.8) 6 0.7\nOverdose (OT) 11 ( 0.8) 11 0.6 5 ( 0.8) 6 0.7\nAbuse or misuse (OT) 0 1 ( 0.2) 1 0.1\nSuspected transmission of infectious agent (IT) 0 0\n\nThe proportion of subjects with AEs was similar with semaglutide 2.4 mg and placebo (89.7% vs 86.4%); but event rates were higher with semaglutide (566.1 vs 398.0 events per 100 PYE), driven primarily by gastrointestinal AEs (see Section 12.5.3). Gastrointestinal disorders are well-known AEs associated with GLP-1 RA treatment. The proportion of subjects with SAEs and the rate of SAEs were also higher with semaglutide 2.4 mg than with placebo (9.8% vs 6.4% and 9.6 vs 6.4 events per 100 PYE), driven by AEs within the SOCs: infections and infestations, gastrointestinal disorders and hepatobiliary disorders (see Section 12.3.2). A similar pattern was seen for severe AEs (see Section 12.2.2.3). One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo) (see Section 12.3.1). In both treatment groups, the majority of the AEs were non-serious, of mild or moderate severity, and reported as recovered. There was no difference between the treatment groups with respect to the relative distribution of AEs with respect to seriousness, severity and outcome. However, relatively more events were considered probably or possibly related to trial product by the investigator with semaglutide 2.4 mg than with placebo, predominantly driven by gastrointestinal AEs (see Section 12.2.2.2). A higher proportion of subjects permanently discontinued treatment due to AEs in the semaglutide 2.4 mg group than in the placebo group (7.0% vs 3.1%), again driven predominantly by gastrointestinal AEs (see Section 12.4.2).\n\nThe evaluation of AEs showed: \uf0b7 Similar overall proportion of subjects with AEs with semaglutide 2.4 mg and placebo (89.7% vs 86.4%), but higher event rates with semaglutide 2.4 mg (566.1 vs 398.0 events/100 PYE), driven primarily by gastrointestinal AEs \uf0b7 Higher proportion of subjects with SAEs for semaglutide 2.4 mg vs placebo (9.8% vs 6.4%), driven by AEs within the SOCs: gastrointestinal disorders (primarily the PTs: vomiting and abdominal pain); infections and infestations (primarily the PT: gastroenteritis); and hepatobiliary disorders (primarily the PTs: cholelithiasis) \uf0b7 Higher proportion of subjects who permanently discontinued treatment due to AEs with semaglutide 2.4 mg vs placebo (7.0% vs 3.1%), again mostly driven by gastrointestinal AEs \uf0b7 One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo), corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group \uf0b7 The majority of the AEs in both treatment groups were of mild or moderate severity and reported as recovered Gastrointestinal AEs were more frequent with semaglutide 2.4 mg than with placebo (74.2% vs 47.9% and 252.6 vs 89.1 events per 100 PYE): \uf0b7 The difference was driven by nausea, diarrhoea, vomiting, constipation and different kinds of abdominal pain or discomfort \uf0b7 The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered \uf0b7 The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it started to decrease The results of the other safety focus areas showed that: \uf0b7 The proportion of subjects with events was higher with semaglutide 2.4 mg than placebo for: \uf0b7 Gallbladder disorders (2.6% vs 1.2%), driven by the PT cholelithiasis (1.8% vs 0.6%); but a low proportion of semaglutide-treated subjects reported complications to cholelithiasis such\n\nOne subject in each treatment group died during the trial, corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group (EOT Table 14.3.1.62). The death in the semaglutide 2.4 mg group was adjudicated as sudden cardiac death and the death in the placebo group as malignancy (related to the reported AE of (Adverse event)). Details on the two deaths are provided in Table 12-4.\n\nIn addition to the 2 subjects who died (1 subject in each treatment group), an additional 4 subjects withdrew or were withdrawn from the trial due to reasons indicating AEs (Table 12-7). The 5 subjects (4 in the semaglutide 2.4 mg group and 1 in the placebo group) withdrew consent (withdrawal by subject) for reasons that included mentioning of AEs.\n\nBased on the therapeutic experience with GLP-1 RAs and regulatory feedback and requirements, a number of safety focus areas were predefined as being of special interest in the safety evaluation. An overview of these safety focus areas is provided in Table 12-9. Each area was evaluated based on a combination of methods and data sources as relevant for the area. The on-treatment period was used for most areas, except safety focus areas with potential long latency to diagnosis of an event, for which the in-trial period was used. The PTs included in the MedDRA searches for each of the safety focus areas are listed in Appendix 16.1.9. General methodology for additional data collection and event adjudication is described in Section 9.5.4.1. Table 12-9 Overview of safety focus areas including methodology Safety focus area Adjudication/Add. data collection Basis for the evaluation Observation period used for evaluation Gastrointestinal disorders Section 12.5.3 No/No MedDRA search (gastrointestinal disorders SOC) On-treatment Gallbladder-related disorders Section 12.5.4 No/Yes MedDRA search On-treatment Acute pancreatitis Section 12.5.5 Yes/Yes AE reporting Adjudication outcome Laboratory assessments of amylase and lipase On-treatment Cardiovascular disorders Section 12.5.6 Yes/No MedDRA search Adjudication outcome Pulse rate measurements Electrocardiogram In-trial On-treatment Neoplasms Section 12.5.7 No/Yes MedDRA search: \uf0b7 neoplasms \uf0b7 malignant neoplasms Laboratory assessment of calcitonin In-trial On-treatment Hepatic events Section 12.5.8 No/Yes MedDRA search Laboratory assessment of ALT, AST, total bilirubin (potential Hy\u2019s law) and alkaline phosphatase On-treatment Acute renal failure Section 12.5.9 No/No MedDRA search Laboratory assessment of eGFR and creatinine On-treatment Hypoglycaemia Section 12.5.10 No/No MedDRA search On-treatment Immunogenicity Section 12.5.11 No/No MedDRA search: \uf0b7 allergic reactions \uf0b7 injection site reactions Anti-semaglutide antibodies On-treatment In-trial", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "AEs with onset during the on-treatment period correspond to treatment-emergent AEs.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 127, "section": "12.1 Introduction to the safety evaluation"}}, {"excerpt": "Adverse Events (OT) 1171 (89.7) 9658 566.1 566 (86.4) 3302 398.0\nAdverse Events (IT) 1173 (89.8) 9977 537.4 570 (87.0) 3424 372.8\nSerious\nYes (OT) 128 ( 9.8) 164 9.6 42 ( 6.4) 53 6.4\nYes (IT) 137 (10.5) 183 9.9 48 ( 7.3) 62 6.7\nNo (OT) 1169 (89.5) 9494 556.5 560 (85.5) 3249 391.7\nNo (IT) 1171 (89.7) 9794 527.6 564 (86.1) 3362 366.0\nSeverity\nSevere (OT) 143 (10.9) 242 14.2 44 ( 6.7) 68 8.2\nSevere (IT) 152 (11.6) 262 14.1 45 ( 6.9) 71 7.7\nModerate (OT) 723 (55.4) 2612 153.1 311 (47.5) 863 104.0\nModerate (IT) 729 (55.8) 2743 147.8 317 (48.4) 901 98.1\nMild (OT) 1079 (82.6) 6804 398.8 507 (77.4) 2371 285.8\nMild (IT) 1086 (83.2) 6972 375.6 510 (77.9) 2452 266.9\nRelationship to trial product\nProbable (OT) 571 (43.7) 2148 125.9 147 (22.4) 330 39.8\nProbable (IT) 573 (43.9) 2156 116.1 147 (22.4) 330 35.9\nPossible (OT) 726 (55.6) 2700 158.3 223 (34.0) 555 66.9\nPossible (IT) 727 (55.7) 2710 146.0 223 (34.0) 559 60.9\nUnlikely (OT) 1032 (79.0) 4780 280.2 536 (81.8) 2409 290.4\nUnlikely (IT) 1050 (80.4) 5073 273.3 542 (82.7) 2520 274.3\nMissing (OT) 24 ( 1.8) 30 1.8 7 ( 1.1) 8 1.0\nMissing (IT) 32 ( 2.5) 38 2.0 13 ( 2.0) 15 1.6\nOutcome\nFatal (OT) 0 1 ( 0.2) 1 0.1\nFatal (IT) 1 ( 0.1) 1 0.1 1 ( 0.2) 3 0.3\nRecovered (OT) 1140 (87.3) 8439 494.6 545 (83.2) 2710 326.7\nRecovered (IT) 1143 (87.5) 8654 466.2 547 (83.5) 2785 303.2\nRecovering (OT) 59 ( 4.5) 91 5.3 25 ( 3.8) 37 4.5\nRecovering (IT) 65 ( 5.0) 100 5.4 26 ( 4.0) 38 4.1\nRecovered With Sequelae (OT) 11 ( 0.8) 19 1.1 4 ( 0.6) 5 0.6\nRecovered With Sequelae (IT) 11 ( 0.8) 19 1.0 4 ( 0.6) 5 0.5\nNot Recovered (OT) 513 (39.3) 1106 64.8 265 (40.5) 548 66.1\nNot Recovered (IT) 541 (41.4) 1200 64.6 281 (42.9) 592 64.5\nUnknown (OT) 2 ( 0.2) 3 0.2 1 ( 0.2) 1 0.1\nUnknown (IT) 2 ( 0.2) 3 0.2 1 ( 0.2) 1 0.1", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 516, "section": "14.3.1.1 Adverse events - overview - safety analysis set"}}, {"excerpt": "Adverse events of special interest\nGastrointestinal disorders (OT) 969 (74.2) 4309 252.6 314 (47.9) 739 89.1\nGallbladder-related disorders (OT) 34 ( 2.6) 42 2.5 8 ( 1.2) 8 1.0\nAcute pancreatitis (OT)# 3 ( 0.2) 3 0.2 0\nCardiovascular disorders (IT) 107 ( 8.2) 134 7.2 75 (11.5) 96 10.5\nAll neoplasms (IT) 93 ( 7.1) 112 6.0 49 ( 7.5) 56 6.1\nMalignant neoplasms (IT) 14 ( 1.1) 14 0.8 7 ( 1.1) 7 0.8\nHepatic events (OT) 31 ( 2.4) 37 2.2 20 ( 3.1) 24 2.9\nAcute renal failure (OT) 3 ( 0.2) 4 0.2 2 ( 0.3) 2 0.2\nHypoglycaemia (OT) 8 ( 0.6) 15 0.9 5 ( 0.8) 7 0.8\nInjection site reactions (OT) 65 ( 5.0) 99 5.8 44 ( 6.7) 82 9.9\nAllergic reactions (OT) 96 ( 7.4) 108 6.3 54 ( 8.2) 63 7.6\nPsychiatric disorders (OT) 124 ( 9.5) 160 9.4 83 (12.7) 113 13.6\nRare events (OT) 7 ( 0.5) 7 0.4 5 ( 0.8) 6 0.7\nMedication errors (OT) 15 ( 1.1) 15 0.9 5 ( 0.8) 6 0.7\nOverdose (OT) 11 ( 0.8) 11 0.6 5 ( 0.8) 6 0.7\nAbuse or misuse (OT) 0 1 ( 0.2) 1 0.1\nSuspected transmission of infectious agent (IT) 0 0", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 129, "section": "12.2.1 Brief summary of adverse events"}}, {"excerpt": "The proportion of subjects with AEs was similar with semaglutide 2.4 mg and placebo (89.7% vs 86.4%); but event rates were higher with semaglutide (566.1 vs 398.0 events per 100 PYE), driven primarily by gastrointestinal AEs (see Section 12.5.3). Gastrointestinal disorders are well-known AEs associated with GLP-1 RA treatment. The proportion of subjects with SAEs and the rate of SAEs were also higher with semaglutide 2.4 mg than with placebo (9.8% vs 6.4% and 9.6 vs 6.4 events per 100 PYE), driven by AEs within the SOCs: infections and infestations, gastrointestinal disorders and hepatobiliary disorders (see Section 12.3.2). A similar pattern was seen for severe AEs (see Section 12.2.2.3). One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo) (see Section 12.3.1). In both treatment groups, the majority of the AEs were non-serious, of mild or moderate severity, and reported as recovered. There was no difference between the treatment groups with respect to the relative distribution of AEs with respect to seriousness, severity and outcome. However, relatively more events were considered probably or possibly related to trial product by the investigator with semaglutide 2.4 mg than with placebo, predominantly driven by gastrointestinal AEs (see Section 12.2.2.2). A higher proportion of subjects permanently discontinued treatment due to AEs in the semaglutide 2.4 mg group than in the placebo group (7.0% vs 3.1%), again driven predominantly by gastrointestinal AEs (see Section 12.4.2).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 127, "section": "12.2.1 Brief summary of adverse events"}}, {"excerpt": "The evaluation of AEs showed: \uf0b7 Similar overall proportion of subjects with AEs with semaglutide 2.4 mg and placebo (89.7% vs 86.4%), but higher event rates with semaglutide 2.4 mg (566.1 vs 398.0 events/100 PYE), driven primarily by gastrointestinal AEs \uf0b7 Higher proportion of subjects with SAEs for semaglutide 2.4 mg vs placebo (9.8% vs 6.4%), driven by AEs within the SOCs: gastrointestinal disorders (primarily the PTs: vomiting and abdominal pain); infections and infestations (primarily the PT: gastroenteritis); and hepatobiliary disorders (primarily the PTs: cholelithiasis) \uf0b7 Higher proportion of subjects who permanently discontinued treatment due to AEs with semaglutide 2.4 mg vs placebo (7.0% vs 3.1%), again mostly driven by gastrointestinal AEs \uf0b7 One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo), corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group \uf0b7 The majority of the AEs in both treatment groups were of mild or moderate severity and reported as recovered Gastrointestinal AEs were more frequent with semaglutide 2.4 mg than with placebo (74.2% vs 47.9% and 252.6 vs 89.1 events per 100 PYE): \uf0b7 The difference was driven by nausea, diarrhoea, vomiting, constipation and different kinds of abdominal pain or discomfort \uf0b7 The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered \uf0b7 The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it started to decrease The results of the other safety focus areas showed that: \uf0b7 The proportion of subjects with events was higher with semaglutide 2.4 mg than placebo for: \uf0b7 Gallbladder disorders (2.6% vs 1.2%), driven by the PT cholelithiasis (1.8% vs 0.6%); but a low proportion of semaglutide-treated subjects reported complications to cholelithiasis such", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 186, "section": "12.8.1 Adverse events including adverse events within safety focus areas"}}, {"excerpt": "One subject in each treatment group died during the trial, corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group (EOT Table 14.3.1.62). The death in the semaglutide 2.4 mg group was adjudicated as sudden cardiac death and the death in the placebo group as malignancy (related to the reported AE of (Adverse event)). Details on the two deaths are provided in Table 12-4.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 133, "section": "12.3.1 Deaths"}}, {"excerpt": "In addition to the 2 subjects who died (1 subject in each treatment group), an additional 4 subjects withdrew or were withdrawn from the trial due to reasons indicating AEs (Table 12-7). The 5 subjects (4 in the semaglutide 2.4 mg group and 1 in the placebo group) withdrew consent (withdrawal by subject) for reasons that included mentioning of AEs.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 136, "section": "12.4.1 Adverse events leading to withdrawal from the trial"}}, {"excerpt": "Based on the therapeutic experience with GLP-1 RAs and regulatory feedback and requirements, a number of safety focus areas were predefined as being of special interest in the safety evaluation. An overview of these safety focus areas is provided in Table 12-9. Each area was evaluated based on a combination of methods and data sources as relevant for the area. The on-treatment period was used for most areas, except safety focus areas with potential long latency to diagnosis of an event, for which the in-trial period was used. The PTs included in the MedDRA searches for each of the safety focus areas are listed in Appendix 16.1.9. General methodology for additional data collection and event adjudication is described in Section 9.5.4.1. Table 12-9 Overview of safety focus areas including methodology Safety focus area Adjudication/Add. data collection Basis for the evaluation Observation period used for evaluation Gastrointestinal disorders Section 12.5.3 No/No MedDRA search (gastrointestinal disorders SOC) On-treatment Gallbladder-related disorders Section 12.5.4 No/Yes MedDRA search On-treatment Acute pancreatitis Section 12.5.5 Yes/Yes AE reporting Adjudication outcome Laboratory assessments of amylase and lipase On-treatment Cardiovascular disorders Section 12.5.6 Yes/No MedDRA search Adjudication outcome Pulse rate measurements Electrocardiogram In-trial On-treatment Neoplasms Section 12.5.7 No/Yes MedDRA search: \uf0b7 neoplasms \uf0b7 malignant neoplasms Laboratory assessment of calcitonin In-trial On-treatment Hepatic events Section 12.5.8 No/Yes MedDRA search Laboratory assessment of ALT, AST, total bilirubin (potential Hy\u2019s law) and alkaline phosphatase On-treatment Acute renal failure Section 12.5.9 No/No MedDRA search Laboratory assessment of eGFR and creatinine On-treatment Hypoglycaemia Section 12.5.10 No/No MedDRA search On-treatment Immunogenicity Section 12.5.11 No/No MedDRA search: \uf0b7 allergic reactions \uf0b7 injection site reactions Anti-semaglutide antibodies On-treatment In-trial", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 139, "section": "12.5.1 Methods used for safety focus areas"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "415487437", "title": "Patient disposition \u2014 Study 1 treatment 1 sample size", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. Review it closely before accepting."}, {"code": "content_inferred", "severity": "required", "blocksApply": true, "message": "This content was inferred rather than stated in the source material, so it cannot be applied as an Autofill suggestion."}, {"code": "citations_partially_unsupported", "severity": "warning", "blocksApply": false, "message": "Some citations do not support this field answer."}, {"code": "missing_recommended_evidence", "severity": "warning", "blocksApply": false, "message": "Field asks for clinical product, efficacy, or safety evidence, but the extracted answer is submission methodology or procedural guidance."}], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "425283575", "title": "Long-term extension \u2014 sponsor summary and conclusion", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. Review it closely before accepting."}, {"code": "citations_unsupported", "severity": "warning", "blocksApply": false, "message": "Autofill found related passages, but they did not support a fillable answer for this field."}, {"code": "content_inferred", "severity": "required", "blocksApply": true, "message": "This content was inferred rather than stated in the source material, so it cannot be applied as an Autofill suggestion."}, {"code": "missing_recommended_evidence", "severity": "warning", "blocksApply": false, "message": "Long term extension \u2014 sponsor summary and conclusion."}, {"code": "evidence_scope_note", "severity": "warning", "blocksApply": false, "message": "No supporting evidence found in this document."}], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "432304059", "title": "Patient disposition \u2014 discontinuation due to adverse events \u2014 Study 2 treatment 2", "value": "Events 92 ( 7.0) 123 7.2 20 ( 3.1) 23 2.8", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Events 92 ( 7.0) 123 7.2 20 ( 3.1) 23 2.8", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 605, "section": "14.3.1.20 Adverse events leading to permanent trial product discontinuation - overview - on-treatment"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "433728940", "title": "Long-term extension \u2014 harms \u2014 treatment 2", "value": "Subject: 610888 Subject information Subject ID NN9536-4373/610888 Age (years) (Age) Gender Female Body mass index (kg/m2) (BMI) Actual trial product Sema 2.4 mg Trial day of first dosing 1 Trial day of last dosing 374 Trial day of permanent discontinuation 389 Narrative for event number 2: 'Affective disorder' Reason for narrative: Other (permanent discontinuation of trial product; safety focus area: psychiatric disorders).\n\nOn trial day 295, the subject had an event of 'affective disorder'. Due to the event and an AE of constipation, the subject permanently discontinued trial product on trial day 389. As judged by the investigator, the severity of the event was moderate and the relationship with the trial product was unlikely. The outcome of the event was reported as not recovered. Preferred term Affective disorder Adverse event number 2 System organ class Psychiatric disorders Trial product at event onset Sema 2.4 mg Observation period at event onset On-treatment Serious event No Severity Moderate All adverse events Preferred term Reference ID Serious event Observation period at event onset Event onset (trial day) Duration (days) Constipation 1 No On-treatment 229 Unknown Affective disorder 2 No On-treatment 295 Unknown\n\nAll adverse events\nPreferred term Reference ID Serious event Observation period\nat event onset\nEvent onset\n(trial day)\nDuration\n(days)\nNausea 1 No On-treatment 2 84\nDecreased appetite 2 No On-treatment 2 198\nTaste disorder 3 No On-treatment 2 30\nSinusitis 4 No On-treatment 43 14\nInjection site pain 5 No On-treatment 30 35\nAbdominal pain 6 No On-treatment 80 2\nConjunctivitis 7 No On-treatment 77 4\nAnxiety 8 No On-treatment 94 379\nNausea 9 No On-treatment 86 114\nAbdominal pain 10 No On-treatment 92 72\nFatigue 11 No On-treatment 149 305\nInjection site pain 12 No On-treatment 135 50\nInjection site bruising 13 No On-treatment 150 49\nDiarrhoea 14 No On-treatment 143 57\nNail discolouration 15 No On-treatment 147 330\nHaemorrhoids 16 No On-treatment 209 13\nSinusitis 17 No On-treatment 221 36\nDiarrhoea 18 No On-treatment 297 157\nHeadache 19 No On-treatment 324 130\nSinusitis 20 No On-treatment 372 14\nNausea 21 No On-treatment 200 254\nVomiting 22 No On-treatment 430 24\nPanic attack 23 No On-treatment 430 24\n\nAll adverse events\nPreferred term Reference ID Serious event Observation period\nat event onset\nEvent onset\n(trial day)\nDuration\n(days)\nNausea 1 No On-treatment 2 3\nDiarrhoea 2 No On-treatment 2 1\nDysgeusia 3 No On-treatment 2 Unknown\nHeadache 4 No On-treatment 10 1\nHeadache 5 No On-treatment 24 2\nNausea 6 No On-treatment 29 6\nOverdose 7 No On-treatment 57 15\nNausea 8 No On-treatment 57 25\nVomiting 9 No On-treatment 58 2\nConstipation 10 No On-treatment 58 48\nDiarrhoea 11 No On-treatment 106 88\n\nDyspepsia 12 No On-treatment 130 Unknown\nAsthenia 13 No On-treatment 57 Unknown\nAbdominal distension 14 No On-treatment 140 Unknown\nVomiting 15 No On-treatment 127 2\nNausea 16 No On-treatment 130 180\nLipase increased 17 Yes On-treatment 260 14\nCholelithiasis 18 No On-treatment 260 60\nAbdominal pain upper 19 No On-treatment 260 1\nAbdominal pain 20 No On-treatment 276 1\nDiarrhoea 21 No On-treatment 253 1\nVomiting 22 No On-treatment 253 1\nPelvic pain 23 No In-trial 304 4\nDiarrhoea 24 No In-trial 335 16\n\nUrinary tract infection 5 No On-treatment 275 8\nThrombocytopenia 6 No On-treatment 476 44\nAnaemia 7 No On-treatment 476 44\n\n(Age)/F/(BMI) Severe 225/3 Dose Not Changed/Sema 2.4 mg Recovered\ntissue disorders/Osteoarthritis/10 Psychiatric disorders/ Y/ 02Dec2018/ Y Unlikely/ N/N\n47/M/>=40.0 Severe Dose Not Changed/Sema 2.4 mg\nSuicidal Ideation/ 97/1\nSuicidal Ideations Recovered\n\nNovo Nordisk Note: The preferred term displayed in this report is ONLY for the primary event. On 16-Sep-2019 the patient had onset of Paroxysmal atrial fibrillation again. On 24-Sep-2019 the patient was seen in outpatient clinic. Planned CT (computerized tomography)-angiogram and possibly new medication. ECG with sinus rhythm. On 05-Nov-2019 the patient was admitted to hospital for planned start of treatment for paroxysmal atrial fibrillation; Flecainide under cardiac monitoring. Was monitored for 48 hours. Normal sinus rhythm during the stay at hospital. On 07-Nov-2019 the patient was discharged from hospital with panned follow-up in outpatient clinic in 1 month. On 08-Nov-2019 the patient had paroxysmal atrial fibrillation (reported as a non-serious event). On 06-Dec-2019 the patient was seen in an outpatient clinic for the planned visit. Since start of (Con. Med) treatment 2 episodes with atrial fibrillation, both after . Otherwise the patient tolerated treatment well. Planned for control at the outpatient clinic 6 months later. Action taken to Blinded Semaglutide was reported as No Change for both events. On 01-Jul-2019 the outcome for the event \"Paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation)\" was Recovered. On 07-Nov-2019 the outcome for the event \"paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation)\" was Recovered. Investigator's causality (Blinded Semaglutide) - Paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation) : Unlikely paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation) : Unlikely Sponsor's causality (Blinded Semaglutide) - Paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation) : Unlikely paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation) : Unlikely", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Subject: 610888 Subject information Subject ID NN9536-4373/610888 Age (years) (Age) Gender Female Body mass index (kg/m2) (BMI) Actual trial product Sema 2.4 mg Trial day of first dosing 1 Trial day of last dosing 374 Trial day of permanent discontinuation 389 Narrative for event number 2: 'Affective disorder' Reason for narrative: Other (permanent discontinuation of trial product; safety focus area: psychiatric disorders).\n\nOn trial day 295, the subject had an event of 'affective disorder'. Due to the event and an AE of constipation, the subject permanently discontinued trial product on trial day 389. As judged by the investigator, the severity of the event was moderate and the relationship with the trial product was unlikely. The outcome of the event was reported as not recovered. Preferred term Affective disorder Adverse event number 2 System organ class Psychiatric disorders Trial product at event onset Sema 2.4 mg Observation period at event onset On-treatment Serious event No Severity Moderate All adverse events Preferred term Reference ID Serious event Observation period at event onset Event onset (trial day) Duration (days) Constipation 1 No On-treatment 229 Unknown Affective disorder 2 No On-treatment 295 Unknown", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1422, "section": "410580 Disclosed by Health Canada for non-commercial purposes and subject to the Terms of Use"}}, {"excerpt": "All adverse events\nPreferred term Reference ID Serious event Observation period\nat event onset\nEvent onset\n(trial day)\nDuration\n(days)\nNausea 1 No On-treatment 2 84\nDecreased appetite 2 No On-treatment 2 198\nTaste disorder 3 No On-treatment 2 30\nSinusitis 4 No On-treatment 43 14\nInjection site pain 5 No On-treatment 30 35\nAbdominal pain 6 No On-treatment 80 2\nConjunctivitis 7 No On-treatment 77 4\nAnxiety 8 No On-treatment 94 379\nNausea 9 No On-treatment 86 114\nAbdominal pain 10 No On-treatment 92 72\nFatigue 11 No On-treatment 149 305\nInjection site pain 12 No On-treatment 135 50\nInjection site bruising 13 No On-treatment 150 49\nDiarrhoea 14 No On-treatment 143 57\nNail discolouration 15 No On-treatment 147 330\nHaemorrhoids 16 No On-treatment 209 13\nSinusitis 17 No On-treatment 221 36\nDiarrhoea 18 No On-treatment 297 157\nHeadache 19 No On-treatment 324 130\nSinusitis 20 No On-treatment 372 14\nNausea 21 No On-treatment 200 254\nVomiting 22 No On-treatment 430 24\nPanic attack 23 No On-treatment 430 24", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1446, "section": "1445 of 6980"}}, {"excerpt": "All adverse events\nPreferred term Reference ID Serious event Observation period\nat event onset\nEvent onset\n(trial day)\nDuration\n(days)\nNausea 1 No On-treatment 2 3\nDiarrhoea 2 No On-treatment 2 1\nDysgeusia 3 No On-treatment 2 Unknown\nHeadache 4 No On-treatment 10 1\nHeadache 5 No On-treatment 24 2\nNausea 6 No On-treatment 29 6\nOverdose 7 No On-treatment 57 15\nNausea 8 No On-treatment 57 25\nVomiting 9 No On-treatment 58 2\nConstipation 10 No On-treatment 58 48\nDiarrhoea 11 No On-treatment 106 88", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1338, "section": "1326 of 6980"}}, {"excerpt": "Dyspepsia 12 No On-treatment 130 Unknown\nAsthenia 13 No On-treatment 57 Unknown\nAbdominal distension 14 No On-treatment 140 Unknown\nVomiting 15 No On-treatment 127 2\nNausea 16 No On-treatment 130 180\nLipase increased 17 Yes On-treatment 260 14\nCholelithiasis 18 No On-treatment 260 60\nAbdominal pain upper 19 No On-treatment 260 1\nAbdominal pain 20 No On-treatment 276 1\nDiarrhoea 21 No On-treatment 253 1\nVomiting 22 No On-treatment 253 1\nPelvic pain 23 No In-trial 304 4\nDiarrhoea 24 No In-trial 335 16", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1338, "section": "1326 of 6980"}}, {"excerpt": "Urinary tract infection 5 No On-treatment 275 8\nThrombocytopenia 6 No On-treatment 476 44\nAnaemia 7 No On-treatment 476 44", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1336, "section": "1326 of 6980"}}, {"excerpt": "(Age)/F/(BMI) Severe 225/3 Dose Not Changed/Sema 2.4 mg Recovered\ntissue disorders/Osteoarthritis/10 Psychiatric disorders/ Y/ 02Dec2018/ Y Unlikely/ N/N\n47/M/>=40.0 Severe Dose Not Changed/Sema 2.4 mg\nSuicidal Ideation/ 97/1\nSuicidal Ideations Recovered", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 688, "section": "408950 4 Musculoskeletal and connective Y/ (Date)/ Y Unlikely/ N/N"}}, {"excerpt": "Novo Nordisk Note: The preferred term displayed in this report is ONLY for the primary event. On 16-Sep-2019 the patient had onset of Paroxysmal atrial fibrillation again. On 24-Sep-2019 the patient was seen in outpatient clinic. Planned CT (computerized tomography)-angiogram and possibly new medication. ECG with sinus rhythm. On 05-Nov-2019 the patient was admitted to hospital for planned start of treatment for paroxysmal atrial fibrillation; Flecainide under cardiac monitoring. Was monitored for 48 hours. Normal sinus rhythm during the stay at hospital. On 07-Nov-2019 the patient was discharged from hospital with panned follow-up in outpatient clinic in 1 month. On 08-Nov-2019 the patient had paroxysmal atrial fibrillation (reported as a non-serious event). On 06-Dec-2019 the patient was seen in an outpatient clinic for the planned visit. Since start of (Con. Med) treatment 2 episodes with atrial fibrillation, both after . Otherwise the patient tolerated treatment well. Planned for control at the outpatient clinic 6 months later. Action taken to Blinded Semaglutide was reported as No Change for both events. On 01-Jul-2019 the outcome for the event \"Paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation)\" was Recovered. On 07-Nov-2019 the outcome for the event \"paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation)\" was Recovered. Investigator's causality (Blinded Semaglutide) - Paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation) : Unlikely paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation) : Unlikely Sponsor's causality (Blinded Semaglutide) - Paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation) : Unlikely paroxysmal atrial fibrillation(Paroxysmal atrial fibrillation) : Unlikely", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1116, "section": "1115 of 6980"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "437025929", "title": "Patient disposition \u2014 Study 2 treatment 2 sample size", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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Thus, the potential of semaglutide 2.4 mg for weight management was confirmed.\n\nThe superiority of semaglutide 2.4 mg vs placebo on body weight was also supported by the weight-related secondary confirmatory endpoints. Thus, superiority of semaglutide 2.4 mg vs placebo was confirmed for body weight reduction \u226510% and \u226515% and change in waist circumference at week 68. A greater proportion of subjects achieved weight reduction \u226520% with semaglutide 2.4 mg vs placebo at week 68, and the decrease in mean BMI was greater with semaglutide 2.4 mg vs placebo.\n\nFinally, in a planned sub-population of subjects undergoing DEXA whole body scans, semaglutide 2.4 mg-induced weight loss was accompanied by greater reduction in fat mass than in lean body mass, leading to an improvement in body composition supporting a healthy weight loss.\n\nWith respect to cardiovascular risk factors, superiority of semaglutide 2.4 mg vs placebo was confirmed for change in systolic blood pressure. In addition, the decrease in mean diastolic blood pressure was greater with semaglutide 2.4 mg vs placebo, and beneficial effects in favour of semaglutide 2.4 mg vs placebo were seen in all fasting blood lipids (total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, free fatty acids and triglycerides) and for the cardiovascular risk-related biomarkers (CRP and PAI-1 activity).\n\nFor the treatment policy estimand, the estimated decreases in body weight (kg) from baseline at week 68 were \u221215.33 kg with semaglutide 2.4 mg and \u22122.61 kg with placebo and the decrease was greater for semaglutide 2.4 mg vs placebo. The ETD was \u221212.71 [\u221213.68; \u221211.74]95% CI (EOT Figures 14.2.14 and 14.2.15).\n\nFor the treatment policy estimand, the estimated decrease in body weight (%) from baseline to week 68 was \u221214.98% with semaglutide 2.4 mg and \u22123.55% with placebo. The decrease in body weight (%) was greater for semaglutide 2.4 mg vs placebo. The ETD was \u221211.43% [\u221215.06 ; \u22127.81]95% CI (EOT Table 14.2.69).\n\nOverall, the body composition sub-study showed that the semaglutide 2.4 mg-induced weight loss was accompanied by greater reduction in fat mass than in lean body mass leading to an improvement in body composition compared to placebo at week 68. For the in-trial observation period, with semaglutide 2.4 mg treatment, there was a numerical reduction in absolute fat mass (kg) as well as in the proportion of mean total fat mass relative to total body mass (%-point). In contrast, the proportion of lean body mass (%-point) increased with semaglutide 2.4 mg, with a numerical reduction observed in absolute mean lean body mass (kg). A reduction in absolute lean body mass is expected to occur in connection with weight loss.99 With placebo, there was almost no change in the proportion of mean total fat mass and lean body mass (%-point), whereas absolute total fat mass and lean body mass (kg) decreased. For the in-trial observation period, the proportion of visceral fat mass relative to total fat mass in the selected abdominal regions (%-point) decreased. Absolute mean visceral fat mass (kg) also slightly decreased with semaglutide 2.4 mg. With placebo there was no change in absolute mean visceral fat mass (kg) or in the proportion of mean visceral fat mass (%-points).\n\nFrom baseline to week 68, mean CRP decreased in both treatment groups. For the treatment policy estimand, the estimated ratio to baseline at week 68 was 0.47 for semaglutide 2.4 mg, corresponding to a 53% decrease, whereas the ratio to baseline was 0.85 with placebo, corresponding to a 15% decrease. The decrease was greater for semaglutide 2.4 mg vs placebo. The treatment ratio was 0.56 [0.51; 0.61] 95% CI (Figure 11-21; EOT Tables 14.2.99 and 14.2.100).", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Efficacy findings Superiority of semaglutide 2.4 mg vs placebo was confirmed for the two primary endpoints, body weight change (%) from baseline to week 68 and body weight reduction \u22655% at week 68. Thus, the potential of semaglutide 2.4 mg for weight management was confirmed.\n\nThe superiority of semaglutide 2.4 mg vs placebo on body weight was also supported by the weight-related secondary confirmatory endpoints. Thus, superiority of semaglutide 2.4 mg vs placebo was confirmed for body weight reduction \u226510% and \u226515% and change in waist circumference at week 68. A greater proportion of subjects achieved weight reduction \u226520% with semaglutide 2.4 mg vs placebo at week 68, and the decrease in mean BMI was greater with semaglutide 2.4 mg vs placebo.\n\nFinally, in a planned sub-population of subjects undergoing DEXA whole body scans, semaglutide 2.4 mg-induced weight loss was accompanied by greater reduction in fat mass than in lean body mass, leading to an improvement in body composition supporting a healthy weight loss.\n\nWith respect to cardiovascular risk factors, superiority of semaglutide 2.4 mg vs placebo was confirmed for change in systolic blood pressure. In addition, the decrease in mean diastolic blood pressure was greater with semaglutide 2.4 mg vs placebo, and beneficial effects in favour of semaglutide 2.4 mg vs placebo were seen in all fasting blood lipids (total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, free fatty acids and triglycerides) and for the cardiovascular risk-related biomarkers (CRP and PAI-1 activity).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 188, "section": "13.1 Discussion"}}, {"excerpt": "For the treatment policy estimand, the estimated decreases in body weight (kg) from baseline at week 68 were \u221215.33 kg with semaglutide 2.4 mg and \u22122.61 kg with placebo and the decrease was greater for semaglutide 2.4 mg vs placebo. The ETD was \u221212.71 [\u221213.68; \u221211.74]95% CI (EOT Figures 14.2.14 and 14.2.15).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 98, "section": "11.3.4 Other body weight-related endpoints"}}, {"excerpt": "For the treatment policy estimand, the estimated decrease in body weight (%) from baseline to week 68 was \u221214.98% with semaglutide 2.4 mg and \u22123.55% with placebo. The decrease in body weight (%) was greater for semaglutide 2.4 mg vs placebo. The ETD was \u221211.43% [\u221215.06 ; \u22127.81]95% CI (EOT Table 14.2.69).\n\nOverall, the body composition sub-study showed that the semaglutide 2.4 mg-induced weight loss was accompanied by greater reduction in fat mass than in lean body mass leading to an improvement in body composition compared to placebo at week 68. For the in-trial observation period, with semaglutide 2.4 mg treatment, there was a numerical reduction in absolute fat mass (kg) as well as in the proportion of mean total fat mass relative to total body mass (%-point). In contrast, the proportion of lean body mass (%-point) increased with semaglutide 2.4 mg, with a numerical reduction observed in absolute mean lean body mass (kg). A reduction in absolute lean body mass is expected to occur in connection with weight loss.99 With placebo, there was almost no change in the proportion of mean total fat mass and lean body mass (%-point), whereas absolute total fat mass and lean body mass (kg) decreased. For the in-trial observation period, the proportion of visceral fat mass relative to total fat mass in the selected abdominal regions (%-point) decreased. Absolute mean visceral fat mass (kg) also slightly decreased with semaglutide 2.4 mg. 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infections and infestations (primarily the PT: gastroenteritis); and hepatobiliary disorders (primarily the PTs: cholelithiasis) \uf0b7 Higher proportion of subjects who permanently discontinued treatment due to AEs with semaglutide 2.4 mg vs placebo (7.0% vs 3.1%), again mostly driven by gastrointestinal AEs \uf0b7 One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo), corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group \uf0b7 The majority of the AEs in both treatment groups were of mild or moderate severity and reported as recovered Gastrointestinal AEs were more frequent with semaglutide 2.4 mg than with placebo (74.2% vs 47.9% and 252.6 vs 89.1 events per 100 PYE): \uf0b7 The difference was driven by nausea, diarrhoea, vomiting, constipation and different kinds of abdominal pain or discomfort \uf0b7 The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered \uf0b7 The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it started to decrease The results of the other safety focus areas showed that: \uf0b7 The proportion of subjects with events was higher with semaglutide 2.4 mg than placebo for: \uf0b7 Gallbladder disorders (2.6% vs 1.2%), driven by the PT cholelithiasis (1.8% vs 0.6%); but a low proportion of semaglutide-treated subjects reported complications to cholelithiasis such", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "The evaluation of AEs showed: \uf0b7 Similar overall proportion of subjects with AEs with semaglutide 2.4 mg and placebo (89.7% vs 86.4%), but higher event rates with semaglutide 2.4 mg (566.1 vs 398.0 events/100 PYE), driven primarily by gastrointestinal AEs \uf0b7 Higher proportion of subjects with SAEs for semaglutide 2.4 mg vs placebo (9.8% vs 6.4%), driven by AEs within the SOCs: gastrointestinal disorders (primarily the PTs: vomiting and abdominal pain); infections and infestations (primarily the PT: gastroenteritis); and hepatobiliary disorders (primarily the PTs: cholelithiasis) \uf0b7 Higher proportion of subjects who permanently discontinued treatment due to AEs with semaglutide 2.4 mg vs placebo (7.0% vs 3.1%), again mostly driven by gastrointestinal AEs \uf0b7 One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo), corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group \uf0b7 The majority of the AEs in both treatment groups were of mild or moderate severity and reported as recovered Gastrointestinal AEs were more frequent with semaglutide 2.4 mg than with placebo (74.2% vs 47.9% and 252.6 vs 89.1 events per 100 PYE): \uf0b7 The difference was driven by nausea, diarrhoea, vomiting, constipation and different kinds of abdominal pain or discomfort \uf0b7 The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered \uf0b7 The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it started to decrease The results of the other safety focus areas showed that: \uf0b7 The proportion of subjects with events was higher with semaglutide 2.4 mg than placebo for: \uf0b7 Gallbladder disorders (2.6% vs 1.2%), driven by the PT cholelithiasis (1.8% vs 0.6%); but a low proportion of semaglutide-treated subjects reported complications to cholelithiasis such", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 186, "section": "12.8.1 Adverse events including adverse events within safety focus areas"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "451938502", "title": "Comparators \u2014 data sources", "value": "Each area was evaluated based on a combination of methods and data sources as relevant for the area.\n\nMedDRA version 22.1 Cross-reference: based on EOT Tables 14.3.1.42 and 14.3.1.14 The cholelithiasis and cholecystitis (including cholecystitis acute) events in the semaglutide 2.4 mg group were assessed in more details based on the investigator reported information collected on the AE form and the additional data collection form for acute gallbladder disease.\n\nThe risk of acute pancreatitis was evaluated based on the outcome of the adjudication of suspected cases of acute pancreatitis supplemented with the investigator reported information from the AE form and the additional data collection form for acute pancreatitis (see Section 9.5.4.1).\n\nThe trial included standard safety assessments including systematic collection of AEs and regular measurements of vital signs, standard biochemistry and haematology parameters, antibodies, ECG and physical examination. The trial included two questionnaires for assessment of mental health (PHQ-9 and C-SSRS). Adjudication was performed for potential events of acute pancreatitis, for specific predefined types of cardiovascular disorders, and for death. 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The trial included two questionnaires for assessment of mental health (PHQ-9 and C-SSRS). Adjudication was performed for potential events of acute pancreatitis, for specific predefined types of cardiovascular disorders, and for death. 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infections and infestations (primarily the PT: gastroenteritis); and hepatobiliary disorders (primarily the PTs: cholelithiasis) \uf0b7 Higher proportion of subjects who permanently discontinued treatment due to AEs with semaglutide 2.4 mg vs placebo (7.0% vs 3.1%), again mostly driven by gastrointestinal AEs \uf0b7 One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo), corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group \uf0b7 The majority of the AEs in both treatment groups were of mild or moderate severity and reported as recovered Gastrointestinal AEs were more frequent with semaglutide 2.4 mg than with placebo (74.2% vs 47.9% and 252.6 vs 89.1 events per 100 PYE): \uf0b7 The difference was driven by nausea, diarrhoea, vomiting, constipation and different kinds of abdominal pain or discomfort \uf0b7 The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered \uf0b7 The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it started to decrease The results of the other safety focus areas showed that: \uf0b7 The proportion of subjects with events was higher with semaglutide 2.4 mg than placebo for: \uf0b7 Gallbladder disorders (2.6% vs 1.2%), driven by the PT cholelithiasis (1.8% vs 0.6%); 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infections and infestations (primarily the PT: gastroenteritis); and hepatobiliary disorders (primarily the PTs: cholelithiasis) \uf0b7 Higher proportion of subjects who permanently discontinued treatment due to AEs with semaglutide 2.4 mg vs placebo (7.0% vs 3.1%), again mostly driven by gastrointestinal AEs \uf0b7 One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo), corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group \uf0b7 The majority of the AEs in both treatment groups were of mild or moderate severity and reported as recovered Gastrointestinal AEs were more frequent with semaglutide 2.4 mg than with placebo (74.2% vs 47.9% and 252.6 vs 89.1 events per 100 PYE): \uf0b7 The difference was driven by nausea, diarrhoea, vomiting, constipation and different kinds of abdominal pain or discomfort \uf0b7 The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered \uf0b7 The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it started to decrease The results of the other safety focus areas showed that: \uf0b7 The proportion of subjects with events was higher with semaglutide 2.4 mg than placebo for: \uf0b7 Gallbladder disorders (2.6% vs 1.2%), driven by the PT cholelithiasis (1.8% vs 0.6%); 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59.2 weeks vs 57.4 weeks for semaglutide 2.4 mg vs placebo) and mean observation time (in-trial; 74.1 weeks vs 73.1 weeks).\n\nThe total exposure time (on-treatment) was 1480.8 vs 720.9 PYE and the total observation time (in-trial) was 1855.4 vs 918.1 PYO for semaglutide 2.4 mg vs placebo, respectively, and reflected the 2:1 randomisation (EOT Table 14.1.23).", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "All 1961 randomised subjects were exposed to trial product.\n\nThe treatment groups were similar with respect to mean exposure time (on-treatment; 59.2 weeks vs 57.4 weeks for semaglutide 2.4 mg vs placebo) and mean observation time (in-trial; 74.1 weeks vs 73.1 weeks).\n\nThe total exposure time (on-treatment) was 1480.8 vs 720.9 PYE and the total observation time (in-trial) was 1855.4 vs 918.1 PYO for semaglutide 2.4 mg vs placebo, respectively, and reflected the 2:1 randomisation (EOT Table 14.1.23).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 73, "section": "10.4.1 Exposure"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "476826638", "title": "Systematic review \u2014 harms \u2014 patients with \u2265 1 SAE \u2014 treatment 1", "value": "Number of subjects 1306 655\n\nYes 18 ( 1.4) 23 1.3 5 ( 0.8) 5 0.6", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Number of subjects 1306 655\n\nYes 18 ( 1.4) 23 1.3 5 ( 0.8) 5 0.6", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 605, "section": "14.3.1.20 Adverse events leading to permanent trial product discontinuation - overview - on-treatment"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "486984095", "title": "PICO table - Abbreviations", "value": "FAS: Full analysis set, N: Number of subjects with an observation at the visit, OR: Odds ratio, CI: Confidence interval, SF-36: Short Form 36 v2.0 acute, IWQOL-Lite-CT: Impact of Weight on Quality of Life-Lite for Clinical Trials.\n\nSema 2.4 mg / Placebo 19.26 [ 12.89; 28.76] <.0001 0.05 Superiority Confirmed Waist circumference (cm) change from baseline to week 68 Sema 2.4 mg - Placebo -9.42 [-10.30; -8.53] <.0001 0.05 Superiority Confirmed Systolic blood pressure (mmHg) change from baseline to week 68 Sema 2.4 mg - Placebo -5.10 [ -6.34; -3.87] <.0001 0.05 Superiority Confirmed SF-36 Physical Functioning score change from baseline to week 68 Sema 2.4 mg - Placebo 1.80 [ 1.18; 2.42] <.0001 0.05 Superiority Confirmed IWQOL-Lite-CT Physical Function score change from baseline to week 68 Sema 2.4 mg - Placebo 9.43 [ 7.50; 11.35] <.0001 0.05 Superiority Confirmed \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 Est.: Estimate, alpha: Local significance level, CI: Confidence interval, p-value: Unadjusted two-sided p-value for test of no difference. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:16 - tstathier.sas/thier.txt Cross-reference: EOT Table 14.2.1\n\nN: Number of subjects experiencing at least one event, %: Percentage of subjects experiencing at least one event, E: Number of events, R: Event rate per 100 years, NEC: Not elsewhere classified PYO: The duration of the in-trial period in years. cond.: condition.\n\nFAS: Full analysis set, N: Number of subjects with an observation at the visit, CI: Confidence interval, HDL: High density lipoprotein, LDL: Low density lipoprotein, VLDL: Very low density lipoprotein.\n\nIWQOL-Lite-CT: Impact of Weight on Quality of Life-Lite for Clinical Trials, FAS: Full analysis set, N: Number of subjects with an observation at the visit, CI: Confidence interval.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "FAS: Full analysis set, N: Number of subjects with an observation at the visit, OR: Odds ratio, CI: Confidence interval, SF-36: Short Form 36 v2.0 acute, IWQOL-Lite-CT: Impact of Weight on Quality of Life-Lite for Clinical Trials.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 515, "section": "14.2.152 Odds of achieving response in non-weight-related endpoints since baseline at week 68 -"}}, {"excerpt": "Sema 2.4 mg / Placebo 19.26 [ 12.89; 28.76] <.0001 0.05 Superiority Confirmed Waist circumference (cm) change from baseline to week 68 Sema 2.4 mg - Placebo -9.42 [-10.30; -8.53] <.0001 0.05 Superiority Confirmed Systolic blood pressure (mmHg) change from baseline to week 68 Sema 2.4 mg - Placebo -5.10 [ -6.34; -3.87] <.0001 0.05 Superiority Confirmed SF-36 Physical Functioning score change from baseline to week 68 Sema 2.4 mg - Placebo 1.80 [ 1.18; 2.42] <.0001 0.05 Superiority Confirmed IWQOL-Lite-CT Physical Function score change from baseline to week 68 Sema 2.4 mg - Placebo 9.43 [ 7.50; 11.35] <.0001 0.05 Superiority Confirmed \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 Est.: Estimate, alpha: Local significance level, CI: Confidence interval, p-value: Unadjusted two-sided p-value for test of no difference. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:16 - tstathier.sas/thier.txt Cross-reference: EOT Table 14.2.1", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 87, "section": "11.2 Summary of results for the primary and confirmatory secondary endpoints"}}, {"excerpt": "N: Number of subjects experiencing at least one event, %: Percentage of subjects experiencing at least one event, E: Number of events, R: Event rate per 100 years, NEC: Not elsewhere classified PYO: The duration of the in-trial period in years. cond.: condition.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 159, "section": "158 of 6980"}}, {"excerpt": "FAS: Full analysis set, N: Number of subjects with an observation at the visit, CI: Confidence interval, HDL: High density lipoprotein, LDL: Low density lipoprotein, VLDL: Very low density lipoprotein.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 441, "section": "14.2.96 Lipids ratio to baseline at week 68 - supportive secondary analysis - treatment policy estimand"}}, {"excerpt": "IWQOL-Lite-CT: Impact of Weight on Quality of Life-Lite for Clinical Trials, FAS: Full analysis set, N: Number of subjects with an observation at the visit, CI: Confidence interval.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 491, "section": "14.2.131 Odds of achieving at least 20-point increase from baseline in IWQOL-Lite-CT Physical"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "488266923", "title": "Systematic review \u2014 harms \u2014 stopped-treatment adverse event 1 \u2014 treatment 2", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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Preferred term/reported term Onset/ (duration) Severity Action Outcome / /F/[35-40[/ (ID) Nausea/Worsening of nausea 228/(8) Moderate Permanent treatment discontinuation Recovered Vomiting/Vomitting 228/(8) Moderate Permanent treatment discontinuation Recovered Colitis/Colitis 232/(5) Moderate Permanent treatment discontinuation Recovered Pancreatitis acute/Idiopathic acute pancreatitis without infection or necrosis 234/(3) Moderate Permanent treatment discontinuation Recovered / /F/[35-40[/ (ID) Volvulus/Volvulus 68/(2) Severe Dose not changed Recovered / /F/>=40.0/ (ID) Duodenal ulcer/Duodenal ulcer 357/(2) Severe Permanent treatment discontinuation Recovered 329676/ (Age)/F/(BMI)/ (ID) Hiatus hernia/Parasophageal hiatal hernia 96/(158) Moderate Temporary interruption of trial product Recovered / /F/[30-35[/ (ID) Enteritis/Enteritis 83/(41) Severe Temporary interruption of trial product Recovered / /M/[35-40[/ (ID) Pancreatitis acute/Acute pancreatitis 508/(3) Mild Not Applicable Recovered F: Female, M: Male, Age: Age in years, BMI: Body mass index (kg/m2). Cross-reference: based on EOT Listing 14.3.2.1 All cases (except the case of vomiting in Subject ID 727323) required hospitalisation (EOT Listing 14.3.2.1). One subject (Subject ID: 887705) had two events: large intestine perforation (onset on trial day 349) and constipation (onset on trial day 350) were considered life-threatening. The cause of the large intestine perforation (stercoral perforation) was due to impacted stool. The subject had and a performed. Both events were assessed as possibly related to trial product by the investigator and both events were reported as recovered. At the time of onset of the events, the subject was treated with the following concomitant medication: atorvastatin, venlafaxine and trazodone which may also cause constipation and thus might have contributed to the severe constipation leading to perforation of colon. Four months after permanent discontinuation of treatment with semaglutide, the subject had a non-serious AE of constipation of moderate severity reported. For details, please see the case narrative (Subject ID: 887705, Case no. (ID)). Timing of gastrointestinal adverse events Gastrointestinal AEs occurred throughout the trial in both treatment groups. In the semaglutide\n\nThe patient decided to suspend the medication under study due to non-serious adverse events she presented with (nausea, vomit, diarrhea).", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "For subjects treated with semaglutide 2.4 mg vs placebo, a higher proportion of subjects permanently discontinued trial product due to AEs and safety concern as judged by the investigator.\n\nGI AEs were the most frequently reported events leading to permanent discontinuation of trial product with semaglutide 2.4 mg (4.5%).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 67, "section": "10.1.1 Subject flow"}}, {"excerpt": "Permanent treatment discontinuation (OT) 92 ( 7.0) 123 7.2 20 ( 3.1) 23 2.8\n\nTemporary interruption of trial product (OT) 126 ( 9.6) 265 15.5 26 ( 4.0) 44 5.3", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 517, "section": "14.3.1.1 Adverse events - overview - safety analysis set"}}, {"excerpt": "Permanent treatment discontinuation (OT) 59 ( 4.5) 78 4.6 5 ( 0.8) 5 0.6\n\nTemporary interruption of trial product (OT) 71 ( 5.4) 134 7.9 8 ( 1.2) 13 1.6", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 617, "section": "14.3.1.25 Gastrointestinal adverse events - pre-defined MedDRA search - overview - safety analysis set"}}, {"excerpt": "Permanent treatment discontinuation (OT) 7 ( 0.5) 7 0.4 3 ( 0.5) 4 0.5\n\nTemporary interruption of trial product (OT) 6 ( 0.5) 9 0.5 3 ( 0.5) 5 0.6", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 654, "section": "14.3.1.56 Psychiatric disorders adverse events - pre-defined MedDRA search - overview - safety"}}, {"excerpt": "Permanent treatment discontinuation (OT) 2 ( 0.2) 2 0.1 2 ( 0.3) 2 0.2\n\nTemporary interruption of trial product (OT) 4 ( 0.3) 4 0.2 1 ( 0.2) 1 0.1", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 632, "section": "14.3.1.38 Allergic reactions adverse events - pre-defined MedDRA search - overview - safety analysis"}}, {"excerpt": "Temporary interruption of trial product (OT) 4 ( 0.3) 4 0.2 0", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 643, "section": "14.3.1.47 Medication error adverse events - pre-defined MedDRA search - overview - safety analysis"}}, {"excerpt": "Due to the event, the subject permanently discontinued trial product on trial day 102.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1353, "section": "1352 of 6980"}}, {"excerpt": "Due to the event, the subject permanently discontinued trial product on trial day 111.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1407, "section": "165908 Disclosed by Health Canada for non-commercial purposes and subject to the Terms of Use"}}, {"excerpt": "Due to the event, the subject permanently discontinued trial product on trial day 177.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1387, "section": "1386 of 6980"}}, {"excerpt": "Due to the event and an AE of constipation, the subject permanently discontinued trial product on trial day 389.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1422, "section": "410580 Disclosed by Health Canada for non-commercial purposes and subject to the Terms of Use"}}, {"excerpt": "Subject ID/Age/Sex/BMI/Case no. Preferred term/reported term Onset/ (duration) Severity Action Outcome / /F/[35-40[/ (ID) Nausea/Worsening of nausea 228/(8) Moderate Permanent treatment discontinuation Recovered Vomiting/Vomitting 228/(8) Moderate Permanent treatment discontinuation Recovered Colitis/Colitis 232/(5) Moderate Permanent treatment discontinuation Recovered Pancreatitis acute/Idiopathic acute pancreatitis without infection or necrosis 234/(3) Moderate Permanent treatment discontinuation Recovered / /F/[35-40[/ (ID) Volvulus/Volvulus 68/(2) Severe Dose not changed Recovered / /F/>=40.0/ (ID) Duodenal ulcer/Duodenal ulcer 357/(2) Severe Permanent treatment discontinuation Recovered 329676/ (Age)/F/(BMI)/ (ID) Hiatus hernia/Parasophageal hiatal hernia 96/(158) Moderate Temporary interruption of trial product Recovered / /F/[30-35[/ (ID) Enteritis/Enteritis 83/(41) Severe Temporary interruption of trial product Recovered / /M/[35-40[/ (ID) Pancreatitis acute/Acute pancreatitis 508/(3) Mild Not Applicable Recovered F: Female, M: Male, Age: Age in years, BMI: Body mass index (kg/m2). Cross-reference: based on EOT Listing 14.3.2.1 All cases (except the case of vomiting in Subject ID 727323) required hospitalisation (EOT Listing 14.3.2.1). One subject (Subject ID: 887705) had two events: large intestine perforation (onset on trial day 349) and constipation (onset on trial day 350) were considered life-threatening. The cause of the large intestine perforation (stercoral perforation) was due to impacted stool. The subject had and a performed. Both events were assessed as possibly related to trial product by the investigator and both events were reported as recovered. At the time of onset of the events, the subject was treated with the following concomitant medication: atorvastatin, venlafaxine and trazodone which may also cause constipation and thus might have contributed to the severe constipation leading to perforation of colon. Four months after permanent discontinuation of treatment with semaglutide, the subject had a non-serious AE of constipation of moderate severity reported. For details, please see the case narrative (Subject ID: 887705, Case no. (ID)). Timing of gastrointestinal adverse events Gastrointestinal AEs occurred throughout the trial in both treatment groups. 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To mitigate the risk of GI side effects, the trial included an initial 16-week dose-escalation period during which the dose was gradually increased to the maintenance dose of 2.4 mg once weekly. Treatment was continued on the maintenance dose of 2.4 mg once weekly for an additional 52 weeks until week 68 (end of treatment). Accounting for the long half-life of semaglutide, a follow-up visit (end of trial) for safety assessments was scheduled 7 weeks after end of treatment to ensure complete wash-out for antibody assessments.\n\nRationale for trial population The trial population consisted of subjects with obesity, or with overweight and at least one weight-related comorbidity (treated or untreated: hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease) in accordance with regulatory guidelines.81, 82 These subjects represent a clinically relevant population for pharmacotherapeutic weight management as they are at significant risk for weight-related comorbidities and increased mortality and are likely to benefit from weight reduction. Subjects with T2D were excluded from the trial. Subjects with T2D and overweight or obesity are addressed in a dedicated trial (NN9536-4374 [STEP 2]). First-line treatment in weight management is lifestyle modification with reduced-calorie diet and increased physical activity, therefore only subjects who had tried but failed a dietary weight loss intervention were included.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "The trial was a multicentre, multinational trial comprising of a 68-week randomised, double-blind, two-armed, placebo-controlled main phase and a 52-week off-treatment extension phase.\n\nMain phase In the main phase, 1950 subjects with overweight or obesity were planned to be randomised 2:1 to blinded treatment with either semaglutide 2.4 mg once weekly or placebo once weekly as an adjunct to a reduced-calorie diet and increased physical activity. To mitigate the risk of GI side effects, the trial included an initial 16-week dose-escalation period during which the dose was gradually increased to the maintenance dose of 2.4 mg once weekly. Treatment was continued on the maintenance dose of 2.4 mg once weekly for an additional 52 weeks until week 68 (end of treatment). 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Subjects with T2D and overweight or obesity are addressed in a dedicated trial (NN9536-4374 [STEP 2]). First-line treatment in weight management is lifestyle modification with reduced-calorie diet and increased physical activity, therefore only subjects who had tried but failed a dietary weight loss intervention were included.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 36, "section": "9.2 Rationale for trial design"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "531843204", "title": "Key efficacy outcomes \u2014 Outcome 4 \u2014 reported result \u2014 Study 2 treatment 2", "value": "Sema 2.4 mg / Placebo 19.26 [ 12.89; 28.76] <.0001 0.05 Superiority Confirmed Waist circumference (cm) change from baseline to week 68 Sema 2.4 mg - Placebo -9.42 [-10.30; -8.53] <.0001 0.05 Superiority Confirmed Systolic blood pressure (mmHg) change from baseline to week 68 Sema 2.4 mg - Placebo -5.10 [ -6.34; -3.87] <.0001 0.05 Superiority Confirmed SF-36 Physical Functioning score change from baseline to week 68 Sema 2.4 mg - Placebo 1.80 [ 1.18; 2.42] <.0001 0.05 Superiority Confirmed IWQOL-Lite-CT Physical Function score change from baseline to week 68 Sema 2.4 mg - Placebo 9.43 [ 7.50; 11.35] <.0001 0.05 Superiority Confirmed \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 Est.: Estimate, alpha: Local significance level, CI: Confidence interval, p-value: Unadjusted two-sided p-value for test of no difference. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:16 - tstathier.sas/thier.txt", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg / Placebo 19.26 [ 12.89; 28.76] <.0001 0.05 Superiority Confirmed Waist circumference (cm) change from baseline to week 68 Sema 2.4 mg - Placebo -9.42 [-10.30; -8.53] <.0001 0.05 Superiority Confirmed Systolic blood pressure (mmHg) change from baseline to week 68 Sema 2.4 mg - Placebo -5.10 [ -6.34; -3.87] <.0001 0.05 Superiority Confirmed SF-36 Physical Functioning score change from baseline to week 68 Sema 2.4 mg - Placebo 1.80 [ 1.18; 2.42] <.0001 0.05 Superiority Confirmed IWQOL-Lite-CT Physical Function score change from baseline to week 68 Sema 2.4 mg - Placebo 9.43 [ 7.50; 11.35] <.0001 0.05 Superiority Confirmed \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 Est.: Estimate, alpha: Local significance level, CI: Confidence interval, p-value: Unadjusted two-sided p-value for test of no difference. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:16 - tstathier.sas/thier.txt", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 319, "section": "14.2.1 Overview of confirmatory analyses (test hierarchy) - treatment policy estimand - full analysis"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "536485881", "title": "Long-term extension \u2014 subsequent treatment \u2014 therapy 2 \u2014 Study 1 treatment 2", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nSubject ID , Case Number (ID) Preferred term Hypersensitivity Narrative category Death No SAE Yes SUSAR No Case unblinded during the trial Yes The case was: Broken by Sponsor AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nSubject ID , Case Number (ID) Preferred term Cellulitis Narrative category Death No SAE Yes SUSAR No Case unblinded during the trial No AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nPatient's BMI: (BMI) This Clinical Trial case from (Country) was reported by an Investigator as \"diarrhea(Diarrhea)\" , and \"vomiting(Vomiting)\" and concerned a 52 Years old Female patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from 13-Nov-2018 to 19-Nov-2018 for \"Obesity\".\n\nPatient's BMI: (BMI) This Clinical Trial case from (Country) was reported by an Investigator as \"atrial fibrillation\" and concerned a 52 Years old Male patient who was treated with Blinded Semaglutide (NN9536-4373) from 27-Nov-2018 and ongoing due to \"Obesity\".\n\nPatient's BMI: (BMI) This Clinical Trial case from the (Country) was reported by an Investigator as \"Allergy adverse reaction (unknown origin)\" and \"Asthma\" and concerned a 21 Years old Female patient who was not started on treatment with Blinded Semaglutide (NN9536-4373) due to \"Obesity\".\n\nSubject ID , Case Number (ID) Preferred term Abortion spontaneous Narrative category Death No SAE Yes SUSAR No Case unblinded during the trial No AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nSubject ID , Case Number (ID) Preferred term Ankle fracture Narrative category Death No SAE Yes SUSAR No Case unblinded during the trial No AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nPatient's BMI: (BMI) This Clinical Trial case from (Country) was reported by an Investigator as \" Cellulitis(Cellulitis of )\" and concerned a 52 Years old Male patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from 09-Dec-2018 and ongoing for \"Obesity\".\n\nPatient's BMI: (BMI) This Clinical Trial case from (Country) was reported by an Investigator as \"bimalleolar fracture of ankle\" and concerned a 32 Years old Female patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from 16-Aug-2018 and ongoing due to \"Obesity\".\n\nPatient's BMI: (BMI) This Clinical Trial case from the (Country) was reported by an Investigator as \"spontaneous abortion\" and \"Drug exposure during pregnancy\" and concerned a 32 Years old Female patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from 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Med) (aluminium hydroxide gel, dried, magnesium carbonate), scopolamine (scopolamine), cefazolin (cefazolin), apixaban (apixaban), sennoside (sennoside a+b), docusate (docusate), bacitracin (bacitracin).\n\nConcomitant medications included - naproxen(naproxen), diclofenac(diclofenac), metaxalone(metaxalone), (Con. Med) (sertraline hydrochloride).\n\nConcomitant medications included - lisinopril(lisinopril), calcium(calcium), (Con. Med) [ascorbic acid;betacarotene;copper;tocofersolan;zinc](ascorbic acid, betacarotene, copper, tocofersolan, zinc), alpha lipoic acid(thioctic acid), (Con. Med) (ubidecarenone), glucosamine chondroitin [chondroitin sulfate sodium;glucosamine](chondroitin sulfate sodium, glucosamine), (Con. Med)(ascorbic acid, cupric oxide, dl-alpha tocopheryl acetate, xantofyl, zeaxanthin, zinc oxide), cod liver oil(cod-liver oil), rosuvastatin(rosuvastatin), metoprolol(metoprolol), (Con. 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infections and infestations (primarily the PT: gastroenteritis); and hepatobiliary disorders (primarily the PTs: cholelithiasis) \uf0b7 Higher proportion of subjects who permanently discontinued treatment due to AEs with semaglutide 2.4 mg vs placebo (7.0% vs 3.1%), again mostly driven by gastrointestinal AEs \uf0b7 One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo), corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group \uf0b7 The majority of the AEs in both treatment groups were of mild or moderate severity and reported as recovered Gastrointestinal AEs were more frequent with semaglutide 2.4 mg than with placebo (74.2% vs 47.9% and 252.6 vs 89.1 events per 100 PYE): \uf0b7 The difference was driven by nausea, diarrhoea, vomiting, constipation and different kinds of abdominal pain or discomfort \uf0b7 The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered \uf0b7 The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it started to decrease The results of the other safety focus areas showed that: \uf0b7 The proportion of subjects with events was higher with semaglutide 2.4 mg than placebo for: \uf0b7 Gallbladder disorders (2.6% vs 1.2%), driven by the PT cholelithiasis (1.8% vs 0.6%); 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Subjects with T2D and overweight or obesity are addressed in a dedicated trial (NN9536-4374 [STEP 2]).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 36, "section": "9.2 Rationale for trial design"}}, {"excerpt": "Cholecystitis or cholecystitis acute A total of 8 AEs of cholecystitis or cholecystitis acute were reported in 8 subjects in the semaglutide 2.4 mg group: \uf0b7 All events seemed to have occurred as complications to cholelithiasis, as all 8 subjects also had cholelithiasis, either as co-reported AEs of cholelithiasis (5 subjects) or according to the SAE narrative (Subject ID and ) or the additional data collection form \uf0b7 All 8 events were reported as recovered \uf0b7 No events led to permanent discontinuation of trial product, but 1 event led to temporary interruption of trial product \uf0b7 3 events were judged as possibly or probably related to trial product by the investigator Additional data was collected for all 8 events and showed that: \uf0b7 7 events were diagnosed by means of ultrasound and 1 by CT scan \uf0b7 The reason for performing the imaging was suspicion of gallbladder disease for all 8 events \uf0b7 The imaging identified: gallstone(s) in the gallbladder for 4 events, gallstone(s) in the common bile duct for 1 event; findings suspicious for acute cholecystitis for 5 events \uf0b7 For 6 subjects, the investigator had indicated that the subjects had gallbladder risk factors: either prior experience with similar pain (4 subjects) and/or weight loss (3 subjects) At baseline, 14.2% of the randomised subjects had a history of gallbladder disease, with no noteworthy differences between treatment groups, showing that gallbladder disorders are common in the investigated population (Section 10.2.1.1).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 147, "section": "12.5.4 Gallbladder-related disorders"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "631054096", "title": "Mechanism of action", "value": "Clinical68-73 and nonclinical 74 data indicate that the weight-reducing effect of semaglutide is mediated mainly by reduced energy intake.\n\nGLP-1 RAs reduce body weight by lowering energy intake via induced feelings of satiety and fullness and by lowering feelings of hunger.73, 75, 76 This is consistent with the normal physiological effect of native GLP-1; GLP-1 is a known physiological regulator of appetite, and GLP-1 receptors are present in several areas of the brain involved in appetite regulation.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Clinical68-73 and nonclinical 74 data indicate that the weight-reducing effect of semaglutide is mediated mainly by reduced energy intake.\n\nGLP-1 RAs reduce body weight by lowering energy intake via induced feelings of satiety and fullness and by lowering feelings of hunger.73, 75, 76 This is consistent with the normal physiological effect of native GLP-1; GLP-1 is a known physiological regulator of appetite, and GLP-1 receptors are present in several areas of the brain involved in appetite regulation.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 32, "section": "7.1 Background"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "631428389", "title": "Baseline characteristics \u2014 Study 2 treatment 2", "value": "Placebo 45 42 95.18", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Placebo 45 42 95.18", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 394, "section": "14.2.70 Body weight (kg) change from baseline to week 68 - supportive secondary analysis - treatment"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "635493110", "title": "Economic evaluation \u2014 utilities sources", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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Table 9-1 Trial products provided by Novo Nordisk ........................................................................... Table 9-2 Treatments including dose escalation .................................................................................. Table 9-3 Investigational medicinal products \u2013 batch numbers and expiry dates................................ Table 9-4 Protocol-required efficacy laboratory assessments (up to visit 25) ..................................... Table 9-5 Adverse events requiring additional data collection ............................................................ Table 9-6 Event types in scope for adjudication .................................................................................. Table 9-7 Laboratory assessments for safety evaluation...................................................................... Table 9-8 List of endpoints for each trial objective ............................................................................. Table 9-9 Major changes made in the statistical analysis plan to the planned statistical analysis in the protocol ........................................................................................................................... Table 9-10 Amendments to the protocol.............................................................................................. Table 10-1 Subject disposition \u2013 all subjects ....................................................................................... Table 10-2 Demographics and baseline characteristics \u2013 categorical variables................................... Table 10-3 Demographics and baseline characteristics \u2013 continuous variables................................... Table 10-4 Summary of important protocol deviations at site and subject level ................................. Table 10-5 Protocol deviations \u2013 informed consent............................................................................. Table 10-6 Protocol deviations \u2013 Inclusion/exclusion criteria ............................................................. Table 10-7 Protocol deviations \u2013 Treatment administration ................................................................ Table 10-8 Protocol deviations \u2013 Trial procedures/assessments .......................................................... Table 10-9 Protocol deviations \u2013 SAE notification/safety procedures................................................. Table 10-10 Cases of intentional unblinding........................................................................................ Table 11-1 Primary and confirmatory secondary endpoints \u2013 primary statistical analyses \u2013 treatment policy estimand ..................................................................................................... Table 11-2 Odds of achieving at least 5% baseline body weight loss at week 68 \u2013 primary analysis \u2013 treatment", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "28 40 40 41 46 49 50 55 59 62 63 65 69 70 77 78 79 79 81 82 83 87 93 103 109 128 129 132 134 135 136 136 137 139 141 142 143 List of in-text tables Page Table 6-1 Trial sites.............................................................................................................................. Table 9-1 Trial products provided by Novo Nordisk ........................................................................... Table 9-2 Treatments including dose escalation .................................................................................. Table 9-3 Investigational medicinal products \u2013 batch numbers and expiry dates................................ Table 9-4 Protocol-required efficacy laboratory assessments (up to visit 25) ..................................... Table 9-5 Adverse events requiring additional data collection ............................................................ Table 9-6 Event types in scope for adjudication .................................................................................. Table 9-7 Laboratory assessments for safety evaluation...................................................................... Table 9-8 List of endpoints for each trial objective ............................................................................. Table 9-9 Major changes made in the statistical analysis plan to the planned statistical analysis in the protocol ........................................................................................................................... Table 9-10 Amendments to the protocol.............................................................................................. Table 10-1 Subject disposition \u2013 all subjects ....................................................................................... Table 10-2 Demographics and baseline characteristics \u2013 categorical variables................................... Table 10-3 Demographics and baseline characteristics \u2013 continuous variables................................... Table 10-4 Summary of important protocol deviations at site and subject level ................................. Table 10-5 Protocol deviations \u2013 informed consent............................................................................. Table 10-6 Protocol deviations \u2013 Inclusion/exclusion criteria ............................................................. Table 10-7 Protocol deviations \u2013 Treatment administration ................................................................ Table 10-8 Protocol deviations \u2013 Trial procedures/assessments .......................................................... Table 10-9 Protocol deviations \u2013 SAE notification/safety procedures................................................. Table 10-10 Cases of intentional unblinding........................................................................................ Table 11-1 Primary and confirmatory secondary endpoints \u2013 primary statistical analyses \u2013 treatment policy estimand ..................................................................................................... Table 11-2 Odds of achieving at least 5% baseline body weight loss at week 68 \u2013 primary analysis \u2013 treatment", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 22, "section": "14.3.6.8 C-SSRS proportion of subjects with suicidal ideation and/or behaviour -"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "667974963", "title": "Key efficacy outcomes \u2014 Outcome 1 \u2014 baseline mean (SD) \u2014 Study 1 treatment 2", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. Review it closely before accepting."}, {"code": "citations_unsupported", "severity": "warning", "blocksApply": false, "message": "Autofill found related passages, but they did not support a fillable answer for this field."}, {"code": "content_inferred", "severity": "required", "blocksApply": true, "message": "This content was inferred rather than stated in the source material, so it cannot be applied as an Autofill suggestion."}, {"code": "missing_recommended_evidence", "severity": "warning", "blocksApply": false, "message": "Key efficacy outcomes \u2014 Outcome 1 \u2014 baseline mean (SD) \u2014 Study 1 treatment 2."}, {"code": "evidence_scope_note", "severity": "warning", "blocksApply": false, "message": "No supporting evidence found in this document."}], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "672981599", "title": "Indirect comparison \u2014 dichotomous outcomes \u2014 comparator 1 name", "value": "Table 9-1 Trial products provided by Novo Nordisk Treatment arm Semaglutide 2.4 mg Placebo Trial product name Semaglutide", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Table 9-1 Trial products provided by Novo Nordisk Treatment arm Semaglutide 2.4 mg Placebo Trial product name Semaglutide", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 40, "section": "9.4.1.1 Investigational medicinal products"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "675561605", "title": "Other-design study \u2014 patient exposure \u2014 total exposure \u2014 Study 1 treatment 1", "value": "The total exposure time (on-treatment) was 1480.8 vs 720.9 PYE and the total observation time (in-trial) was 1855.4 vs 918.1 PYO for semaglutide 2.4 mg vs placebo, respectively, and reflected the 2:1 randomisation (EOT Table 14.1.23).", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "The total exposure time (on-treatment) was 1480.8 vs 720.9 PYE and the total observation time (in-trial) was 1855.4 vs 918.1 PYO for semaglutide 2.4 mg vs placebo, respectively, and reflected the 2:1 randomisation (EOT Table 14.1.23).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 73, "section": "10.4.1 Exposure"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "678192564", "title": "Key efficacy outcomes \u2014 Outcome 1 \u2014 treatment difference versus control \u2014 Study 2 treatment 2", "value": "Sema 2.4 mg - Placebo -12.71 [-13.68;-11.74] <.0001", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg - Placebo -12.71 [-13.68;-11.74] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 336, "section": "14.2.14 Body weight (kg) change from baseline to week 68 - supportive secondary analysis - treatment"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "678809355", "title": "Place in therapy \u2014 impact on currently reimbursed treatments", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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Trial product was administered using a PDS290 pre-filled pen-injector with a 3 mL cartridge containing semaglutide 1.0 mg/mL or 3.0 mg/mL (depending on dose level) or placebo.\n\nTo mitigate GI side effects with GLP-1 RA treatment, dose escalation to the maintenance dose was required. Subjects were initiated at a once weekly dose of 0.25 mg and followed a fixed-dose escalation regimen, with dose increases every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week), aiming at reaching the maintenance dose of 2.4 mg (or the corresponding volume of placebo) after 16 weeks as described in Table 9-2.\n\nDosing instructions and administration Injection once weekly at the same day of the week (to the extent possible). Injections could be administered in the thigh, abdomen or upper arm, and at any time of the day irrespective of meals.\n\n\uf0b7 Subjects\u2019 weight history was recorded, and diet and physical activity counselling was provided \uf0b7 Subjects received training in trial product and pen-handling.\n\n\uf0b7 At all on-site visits, training in trial product pen-handling was performed, and diaries were collected, reviewed and transcribed.\n\nMissed dose If a single dose of trial product was missed, it was to be administered as soon as noticed, provided the time to the next scheduled dose was at least 2 days (48 hours) away. If a dose was missed and the next scheduled dose was less than 2 days (48 hours) away, the subject was not to administer a dose until the next scheduled dose. A missed dose was not to affect the scheduled dosing day of the week. If two or more consecutive doses of trial product were missed, the subject was encouraged to re-commence the treatment if considered safe, as per the investigator\u2019s discretion, and if the subject did not meet any of the discontinuation criteria (Section 9.3.4). Re-commencement of treatment was then to occur as early as the situation allowed. The missed doses were not to affect the scheduled dosing day of the week. The start dose for re-initiation of trial product was at the investigator\u2019s discretion.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Subjects were randomised 2:1 to blinded treatment with either semaglutide s.c 2.4 mg once weekly or placebo once weekly as an adjunct to a reduced-calorie diet and increased physical activity. 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Injections could be administered in the thigh, abdomen or upper arm, and at any time of the day irrespective of meals.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 40, "section": "3.0 mg/mL"}}, {"excerpt": "\uf0b7 Subjects\u2019 weight history was recorded, and diet and physical activity counselling was provided \uf0b7 Subjects received training in trial product and pen-handling.\n\n\uf0b7 At all on-site visits, training in trial product pen-handling was performed, and diaries were collected, reviewed and transcribed.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 44, "section": "9.5.1 Trial plan and flowchart"}}, {"excerpt": "Missed dose If a single dose of trial product was missed, it was to be administered as soon as noticed, provided the time to the next scheduled dose was at least 2 days (48 hours) away. 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In addition, the decrease in mean diastolic blood pressure was greater with semaglutide 2.4 mg vs placebo, and beneficial effects in favour of semaglutide 2.4 mg vs placebo were seen in all fasting blood lipids (total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, free fatty acids and triglycerides) and for the cardiovascular risk-related biomarkers (CRP and PAI-1 activity).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 188, "section": "13.1 Discussion"}}, {"excerpt": "The supportive secondary endpoint \u201cBody weight reduction \u2265 20% from baseline at week 0\u201d was added To be able to assess the proportion of subjects with the greatest weight loss It was clarified that subjects in the FAS/SAS will be evaluated \u201cas randomised\u201d/\u201cas treated\u201d.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 62, "section": "9.7.2 Changes in planned analyses prior to trial unblinding"}}, {"excerpt": "It has been added that the responder definition value is 20 for IWQoL-Lite for CT physical function domain (5-items) score To specify the threshold for the responders for the IWQoL-Lite for CT physical function domain, which was not available at the time of protocol preparation", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 63, "section": "9.7.2 Changes in planned analyses prior to trial unblinding"}}, {"excerpt": "\uf0b7 SF-36 measures the subject\u2019s overall health related quality of life.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 46, "section": "9.5.2.2 Clinical outcome assessments"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "701151610", "title": "Other-design study \u2014 subsequent treatment \u2014 therapy 2 \u2014 Study 2 treatment 1", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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Subjects with T2D and overweight or obesity are addressed in a dedicated trial (NN9536-4374 [STEP 2]).\n\nFirst-line treatment in weight management is lifestyle modification with reduced-calorie diet and increased physical activity, therefore only subjects who had tried but failed a dietary weight loss intervention were included.\n\nIn total 2303 subjects were screened of which 305 subjects were screening failures and 37 subjects withdrew consent before randomisation; thus, 1961 subjects were randomised 2:1 to receive either semaglutide 2.4 mg (1306 subjects) or placebo (655 subjects; Table 10-1). 26 subjects were randomised in violation of the eligibility criteria (Section 9.3).\n\nThe primary reasons were not keeping a food diary without missing more than 2 days of entries (19 subjects) and female subjects being pregnant, breast-feeding or intending to become pregnant or of child-bearing potential and not using highly effective contraception methods (6 subjects) (EOT Table 14.1.9).\n\nExclusion criteria 5 (29.4) 3 (33.3) 8 (30.8)\nA Patient Health Questionnaire-9 (PHQ-9) 1 (20.0) 0 1 (12.5)\nscore of >= 15 at screening\nFemale who is pregnant, breast-feeding or 4 (80.0) 2 (66.7) 6 (75.0)\nintends to become pregnant or is of childbearing potential and not using a highly\neffective contraceptive method\nTreatment with glucose-lowering agent(s) 0 1 (33.3) 1 (12.5)\n\nRandomisation criteria 13 (76.5) 6 (66.7) 19 (73.1)\nHave kept a food diary with at least one 13 ( 100) 6 ( 100) 19 ( 100)\n\nentry per day between screening and randomisation. 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A greater proportion of subjects achieved weight reduction \u226520% with semaglutide 2.4 mg vs placebo at week 68, and the decrease in mean BMI was greater with semaglutide 2.4 mg vs placebo.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 188, "section": "13.1 Discussion"}}, {"excerpt": "From baseline to week 68, superiority of semaglutide 2.4 mg vs placebo was confirmed in the pre-defined fixed-sequence statistical testing hierarchy for the primary endpoints (change in body weight [%] and body weight loss \u22655%) and all confirmatory secondary endpoints (body weight loss \u226510%, body weight loss \u226515%, change in waist circumference, systolic blood pressure, SF-36 physical functioning score and IWQOL-Lite-CT physical function score).\n\nThis trial estimated the efficacy of semaglutide 2.4 mg vs placebo for the treatment policy (primary) and the hypothetical estimands, which were used to address different aspects of the treatment effect (Section 8.4). 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Review it closely before accepting."}, {"code": "citations_unsupported", "severity": "warning", "blocksApply": false, "message": "Autofill found related passages, but they did not support a fillable answer for this field."}, {"code": "content_inferred", "severity": "required", "blocksApply": true, "message": "This content was inferred rather than stated in the source material, so it cannot be applied as an Autofill suggestion."}, {"code": "missing_recommended_evidence", "severity": "warning", "blocksApply": false, "message": "Indirect comparison \u2014 selection criteria \u2014 databases searched."}, {"code": "evidence_scope_note", "severity": "warning", "blocksApply": false, "message": "No supporting evidence found in this document."}], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "880393120", "title": "List of figures", "value": "34 35 48 51 59 67 74 75 88 89 90 91 92 93 94 95 96 97 98 99 100 101 104 106 107 108 110 111 112 113 114 List of in-text figures Page Figure 8-1 Definition of estimands ......................................................................................................\n\nFigure 9-1 Trial design ......................................................................................................................... Figure 9-2 Decision tree for determining the event type and the respective forms to complete with associated timelines .............................................................................................................. Figure 9-3 Overview of event adjudication process............................................................................. Figure 9-4 Observation periods............................................................................................................ Figure 10-1 Time to permanent discontinuation of trial product ......................................................... Figure 10-2 Last dose for treatment completers - bar plot \u2013 observed in-trial data ............................. Figure 10-3 Diet and physical activity by week \u2212 mean plot \u2013 observed in-trial data......................... Figure 11-1 Body weight change from baseline (%) by week \u2013 mean plot \u2013 treatment policy estimand ................................................................................................................................ Figure 11-2 Body weight (%) change from baseline to week 68 \u2013 cumulative distribution plot \u2013 observed in-trial data............................................................................................................. Figure 11-3 Body weight (%) change from baseline to week 68 \u2013 bar plot \u2013 treatment policy estimand ................................................................................................................................ Figure 11-4 Body weight (%) change from baseline by week \u2013 missing data pattern plot.................. Figure 11-5 Body weight (%) change from baseline to week 68 \u2212 primary analysis and sensitivity analyses \u2013 treatment policy estimand.................................................................................... Figure 11-6 Proportion of subjects achieving body weight loss \u22655% at week 68 \u2013 bar plot \u2013 observed in-trial data............................................................................................................. Figure 11-7 Odds of achieving \u22655% weight loss at week 68 \u2212 primary and sensitivity statistical analyses \u2013 treatment policy estimand.................................................................................... Figure 11-8 Proportion of subjects achieving body weight loss response criteria since baseline at week 68 \u2013 bar plot \u2013 observed in-trial data........................................................................... Figure 11-9 Odds of achieving body weight loss response criteria since baseline at week 68 \u2212 forest plot \u2212 treatment policy estimand................................................................................. Figure 11-10 Waist circumference by week \u2013 mean plot \u2013 observed in-trial data", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "34 35 48 51 59 67 74 75 88 89 90 91 92 93 94 95 96 97 98 99 100 101 104 106 107 108 110 111 112 113 114 List of in-text figures Page Figure 8-1 Definition of estimands ......................................................................................................\n\nFigure 9-1 Trial design ......................................................................................................................... Figure 9-2 Decision tree for determining the event type and the respective forms to complete with associated timelines .............................................................................................................. Figure 9-3 Overview of event adjudication process............................................................................. Figure 9-4 Observation periods............................................................................................................ Figure 10-1 Time to permanent discontinuation of trial product ......................................................... Figure 10-2 Last dose for treatment completers - bar plot \u2013 observed in-trial data ............................. Figure 10-3 Diet and physical activity by week \u2212 mean plot \u2013 observed in-trial data......................... Figure 11-1 Body weight change from baseline (%) by week \u2013 mean plot \u2013 treatment policy estimand ................................................................................................................................ Figure 11-2 Body weight (%) change from baseline to week 68 \u2013 cumulative distribution plot \u2013 observed in-trial data............................................................................................................. Figure 11-3 Body weight (%) change from baseline to week 68 \u2013 bar plot \u2013 treatment policy estimand ................................................................................................................................ Figure 11-4 Body weight (%) change from baseline by week \u2013 missing data pattern plot.................. Figure 11-5 Body weight (%) change from baseline to week 68 \u2212 primary analysis and sensitivity analyses \u2013 treatment policy estimand.................................................................................... Figure 11-6 Proportion of subjects achieving body weight loss \u22655% at week 68 \u2013 bar plot \u2013 observed in-trial data............................................................................................................. Figure 11-7 Odds of achieving \u22655% weight loss at week 68 \u2212 primary and sensitivity statistical analyses \u2013 treatment policy estimand.................................................................................... Figure 11-8 Proportion of subjects achieving body weight loss response criteria since baseline at week 68 \u2013 bar plot \u2013 observed in-trial data........................................................................... Figure 11-9 Odds of achieving body weight loss response criteria since baseline at week 68 \u2212 forest plot \u2212 treatment policy estimand................................................................................. 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A treatment duration of 68 weeks (including 52 weeks on maintenance dose) was considered sufficient to assess weight loss, safety and tolerability in the phase 3 weight management development programme in accordance with regulatory guidelines.81, 82 The 7-week follow-up period was included to account for the long half-life of semaglutide.\n\nA multicentre and multinational design was chosen to ensure that the results are applicable in subjects with different race, ethnicity, and other demographic characteristics.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "The trial was a multicentre, multinational trial comprising of a 68-week randomised, double-blind, two-armed, placebo-controlled main phase and a 52-week off-treatment extension phase.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 35, "section": "9.1 Description of trial design"}}, {"excerpt": "A randomised, double-blinded trial design was chosen to minimise bias in the assessment of the efficacy and safety of semaglutide 2.4 mg once weekly versus placebo.\n\nThe treatment duration was 68 weeks with an additional 7 weeks off-treatment follow-up. A treatment duration of 68 weeks (including 52 weeks on maintenance dose) was considered sufficient to assess weight loss, safety and tolerability in the phase 3 weight management development programme in accordance with regulatory guidelines.81, 82 The 7-week follow-up period was included to account for the long half-life of semaglutide.\n\nA multicentre and multinational design was chosen to ensure that the results are applicable in subjects with different race, ethnicity, and other demographic characteristics.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 36, "section": "9.2 Rationale for trial design"}}], "reviewIssues": [{"code": "missing_recommended_evidence", "severity": "warning", "blocksApply": false, "message": "Review protocol PICO Study design."}], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "909304935", "title": "Economic evaluation \u2014 base case results", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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The target was to have approximately 300 subjects from selected countries (Canada, Germany, Japan, UK and US) to continue in the extension phase", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Extension phase The trial further included a 52-week off-treatment extension phase without structured lifestyle intervention in a subset of subjects who had completed the main phase on the maintenance dose of 2.4 mg semaglutide once weekly or placebo. The target was to have approximately 300 subjects from selected countries (Canada, Germany, Japan, UK and US) to continue in the extension phase", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 35, "section": "9.1 Description of trial design"}}], "reviewIssues": [{"code": "missing_recommended_evidence", "severity": "warning", "blocksApply": false, "message": "Long term extension \u2014 patient exposure \u2014 Study 2 treatment 2 sample size."}], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "931854948", "title": "Indirect comparison \u2014 continuous outcomes \u2014 comparator 2 name", "value": "Table 9-1 Trial products provided by Novo Nordisk Treatment arm Semaglutide 2.4 mg Placebo Trial product name Semaglutide", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Table 9-1 Trial products provided by Novo Nordisk Treatment arm Semaglutide 2.4 mg Placebo Trial product name Semaglutide", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 40, "section": "9.4.1.1 Investigational medicinal products"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "932791655", "title": "Statistical analysis \u2014 Study 1 additional endpoints", "value": "The primary endpoints when addressed by the treatment policy estimand (confirmatory endpoints) as well as when addressed by the hypothetical estimand (nonconfirmatory endpoints) are presented in-text. For the confirmatory and supportive secondary endpoints, only the data for the treatment policy estimand are presented in-text, but the results are evaluated for both estimands.\n\n11.3.5.1 Change in body weight (kg and %) \u2013 DEXA sub-population \u2212 supportive secondary endpoint At baseline, mean body weight (kg) in the DEXA sub-population was similar in the semaglutide 2.4 mg and placebo groups (98.4 kg across the total DEXA sub-population). For the in-trial period, observed mean body weight decreased to 82.4 kg and 96.4 kg for semaglutide 2.4 mg and placebo, respectively (EOT Tables 14.2.67 and 14.2.68). For the treatment policy estimand, the estimated decrease in body weight (%) from baseline to week 68 was \u221214.98% with semaglutide 2.4 mg and \u22123.55% with placebo. The decrease in body weight (%) was greater for semaglutide 2.4 mg vs placebo. The ETD was \u221211.43% [\u221215.06 ; \u22127.81]95% CI (EOT Table 14.2.69). The corresponding estimated decrease in body weight (kg) and statistical analysis are presented in EOT Table 14.2.70. The results on change in body weight from baseline to week 68 in the DEXA sub-population were consistent with the results in the total trial population. The results of the statistical analysis of the change from baseline in body weight (kg and %) for the hypothetical estimand are provided in EOT Table 14.2.150.\n\n11.3.5.2 Change in body composition (kg and %) \u2013 DEXA sub-population \u2212 supportive secondary endpoints At baseline, mean body composition (kg and %) was similar in the semaglutide 2.4 mg and placebo groups. Total fat mass and lean body mass comprised 43.8% and 53.5%, respectively, of the total body mass. Visceral fat mass comprised 34.6% of the total fat mass in selected abdominal regions (Table 11-3). Overall, the body composition sub-study showed that the semaglutide 2.4 mg-induced weight loss was accompanied by greater reduction in fat mass than in lean body mass leading to an improvement in body composition compared to placebo at week 68. For the in-trial observation period, with semaglutide 2.4 mg treatment, there was a numerical reduction in absolute fat mass (kg) as well as in the proportion of mean total fat mass relative to total body mass (%-point). In contrast, the proportion of lean body mass (%-point) increased with semaglutide 2.4 mg, with a numerical reduction observed in absolute mean lean body mass (kg). A reduction in absolute lean body mass is expected to occur in connection with weight loss.99 With placebo, there was almost no change in the proportion of mean total fat mass and lean body mass (%-point), whereas absolute total fat mass and lean body mass (kg) decreased. For the in-trial observation period, the proportion of visceral fat mass relative to total fat mass in the selected abdominal regions (%-point) decreased. Absolute mean visceral fat mass (kg) also slightly decreased with semaglutide 2.4 mg. With placebo there was no change in absolute mean visceral fat mass (kg) or in the proportion of mean visceral fat mass (%-points).\n\nFigure 11-10 Waist circumference by week \u2013 mean plot \u2013 observed in-trial data Cross-reference: EOT Figure 14.2.50 The distribution function plots showed a left-shifted treatment effect on waist circumference with a clear separation between semaglutide 2.4 mg and placebo in favour of semaglutide 2.4 mg. From baseline to week 68, waist circumference was reduced in approximately 95% of subjects on semaglutide 2.4 mg and in approximately 70% of subjects on placebo (EOT Figure 14.2.52). For the treatment policy estimand, the estimated decreases in waist circumference from baseline to week 68 were \u221213.54 cm with semaglutide 2.4 mg and \u22124.13 cm with placebo and the ETD was statistically significant in favour of semaglutide 2.4 mg (\u22129.42 cm [\u221210.30; \u22128.53]95% CI; Figure 11-11 and EOT Table 14.2.54). The pre-specified sensitivity analysis for the treatment policy estimand supported the robustness of the superiority conclusion (EOT Table 14.2.56). The results for the hypothetical estimand, as compared with the treatment policy estimand, showed generally greater decreases in waist circumference from baseline for both semaglutide 2.4 mg and placebo, however more pronounced for semaglutide 2.4 mg. Results for the hypothetical estimand are available in EOT Table and Figures 14.2.57 to 14.2.61.\n\nThe analysis of pulse rate was performed using the same data selection and statistical model (MMRM) as for analyses of efficacy endpoints addressing the hypothetical estimand. Mean observed pulse rate at baseline was 72 beats/min in both treatment groups and had increased to 75 beats/min at week 68 in the semaglutide 2.4 mg group while remaining unchanged in the placebo group (EOT Tables 14.3.6.1). The estimated change from baseline at week 68 was 3.52 beats/min for semaglutide 2.4 mg vs -0.74 beats/min for placebo and the treatment difference was: 4.26 beats/min ([3.38; 5.15]95% CI), (EOT Table 14.3.6.5). The increase in pulse rate in the semaglutide 2.4 mg group occurred within the initial 16 weeks of treatment after which a slight decrease was observed. At the follow-up visit (week 75) after the off-treatment period, mean pulse rate had returned to the baseline level (EOT Figure 14.3.6.3). A total of 26.3% of subjects in the semaglutide 2.4 mg group had an increase (from baseline) in pulse rate of \u226520 beats/min at one or more timepoints during the on-treatment period compared to 15.0% in the placebo group (Table 12-20). The proportion of subjects with increases in pulse rate of \u226520 beats/min was highest among subjects with low baseline pulse rate (<60 beats/min) and lowest among subjects with high baseline pulse rate (\u226580 beats/min). Pulse rate is listed by subject and visit for all subjects in EOT Listing 14.3.7.1. Based on the listing, pulse rate generally showed large fluctuations over time. Table 12-20 Pulse rate \u2013 categorical summary of maximum increase from baseline \u2013 on-treatment\n\nestimand - full analysis set\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nEstimated Estimated\nParameter FAS N Mean Ratio ETR [ 95% CI ] p-value\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nMMRM\nRatio to baseline at Visit 24 (week 68)\nFasting serum insulin (pmol/L)\nSema 2.4 mg 1306 928 64.38 0.69 0.77 [ 0.73 ; 0.82] <0.0001\nPlacebo 655 439 83.72 0.90\nFasting serum insulin (mIU/mL)\nSema 2.4 mg 1306 928 8.92 0.69 0.77 [ 0.73 ; 0.82] <0.0001\nPlacebo 655 439 11.60 0.90\nTotal cholesterol (mmol/L)\nSema 2.4 mg 1306 947 4.72 0.96 0.96 [ 0.94 ; 0.97] <0.0001\nPlacebo 655 440 4.94 1.00\nTotal cholesterol (mg/dL)\nSema 2.4 mg 1306 947 182.15 0.96 0.96 [ 0.94 ; 0.97] <0.0001\nPlacebo 655 440 190.61 1.00\nHDL cholesterol (mmol/L)\nSema 2.4 mg 1306 942 1.35 1.05 1.03 [ 1.02 ; 1.05] <0.0001\nPlacebo 655 438 1.31 1.02\nHDL cholesterol (mg/dL)\nSema 2.4 mg 1306 942 52.08 1.05 1.03 [ 1.02 ; 1.05] <0.0001\nPlacebo 655 438 50.47 1.02\nLDL cholesterol (mmol/L)\nSema 2.4 mg 1306 945 2.77 0.96 0.95 [ 0.93 ; 0.98] 0.0001\nPlacebo 655 440 2.90 1.01\nLDL cholesterol (mg/dL)\nSema 2.4 mg 1306 945 106.88 0.96 0.95 [ 0.93 ; 0.98] 0.0001\nPlacebo 655 440 112.09 1.01\nVLDL cholesterol (mmol/L)\nSema 2.4 mg 1306 944 0.48 0.76 0.82 [ 0.79 ; 0.85] <0.0001\nPlacebo 655 440 0.59 0.92\n\nNon-weight-related endpoints ratio to baseline at week 68 - statistical analysis -\nhypothetical estimand - full analysis set\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nEstimated Estimated\nParameter FAS N Mean Ratio ETR [ 95% CI ] p-value\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nMMRM\nRatio to baseline at Visit 24 (week 68)\nVLDL cholesterol (mg/dL)\nSema 2.4 mg 1306 944 18.69 0.76 0.82 [ 0.79 ; 0.85] <0.0001\nPlacebo 655 440 22.70 0.92\nFree fatty acids (mmol/L)\nSema 2.4 mg 1306 928 0.36 0.81 0.88 [ 0.82 ; 0.94] 0.0003\nPlacebo 655 439 0.41 0.92\nFree fatty acids (mg/dL)\nSema 2.4 mg 1306 928 10.11 0.81 0.88 [ 0.82 ; 0.94] 0.0003\nPlacebo 655 439 11.46 0.92\nTriglycerides (mmol/L)\nSema 2.4 mg 1306 946 1.08 0.76 0.82 [ 0.79 ; 0.86] <0.0001\nPlacebo 655 440 1.31 0.92\nTriglycerides (mg/dL)\nSema 2.4 mg 1306 946 96.06 0.76 0.82 [ 0.79 ; 0.86] <0.0001\nPlacebo 655 440 116.57 0.92\nhsCRP (mg/L)\nSema 2.4 mg 1306 948 1.62 0.42 0.52 [ 0.47 ; 0.57] <0.0001\nPlacebo 655 440 3.12 0.80\nLeptin (ng/mL)\nSema 2.4 mg 1306 946 15.90 0.49 0.56 [ 0.52 ; 0.59] <0.0001\nPlacebo 655 441 28.63 0.88\nSoluble leptin receptor (ng/mL)\nSema 2.4 mg 1306 943 19.88 1.07 1.04 [ 1.02 ; 1.07] 0.0009\nPlacebo 655 440 19.03 1.03\nPAI-1 (AU/mL)\nSema 2.4 mg 1306 900 17.29 1.10 0.72 [ 0.68 ; 0.76] <0.0001\nPlacebo 655 427 24.13 1.53", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "The primary endpoints when addressed by the treatment policy estimand (confirmatory endpoints) as well as when addressed by the hypothetical estimand (nonconfirmatory endpoints) are presented in-text. For the confirmatory and supportive secondary endpoints, only the data for the treatment policy estimand are presented in-text, but the results are evaluated for both estimands.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 86, "section": "11.1 Introduction to the efficacy evaluation"}}, {"excerpt": "11.3.5.1 Change in body weight (kg and %) \u2013 DEXA sub-population \u2212 supportive secondary endpoint At baseline, mean body weight (kg) in the DEXA sub-population was similar in the semaglutide 2.4 mg and placebo groups (98.4 kg across the total DEXA sub-population). For the in-trial period, observed mean body weight decreased to 82.4 kg and 96.4 kg for semaglutide 2.4 mg and placebo, respectively (EOT Tables 14.2.67 and 14.2.68). For the treatment policy estimand, the estimated decrease in body weight (%) from baseline to week 68 was \u221214.98% with semaglutide 2.4 mg and \u22123.55% with placebo. The decrease in body weight (%) was greater for semaglutide 2.4 mg vs placebo. The ETD was \u221211.43% [\u221215.06 ; \u22127.81]95% CI (EOT Table 14.2.69). The corresponding estimated decrease in body weight (kg) and statistical analysis are presented in EOT Table 14.2.70. The results on change in body weight from baseline to week 68 in the DEXA sub-population were consistent with the results in the total trial population. The results of the statistical analysis of the change from baseline in body weight (kg and %) for the hypothetical estimand are provided in EOT Table 14.2.150.\n\n11.3.5.2 Change in body composition (kg and %) \u2013 DEXA sub-population \u2212 supportive secondary endpoints At baseline, mean body composition (kg and %) was similar in the semaglutide 2.4 mg and placebo groups. Total fat mass and lean body mass comprised 43.8% and 53.5%, respectively, of the total body mass. Visceral fat mass comprised 34.6% of the total fat mass in selected abdominal regions (Table 11-3). Overall, the body composition sub-study showed that the semaglutide 2.4 mg-induced weight loss was accompanied by greater reduction in fat mass than in lean body mass leading to an improvement in body composition compared to placebo at week 68. For the in-trial observation period, with semaglutide 2.4 mg treatment, there was a numerical reduction in absolute fat mass (kg) as well as in the proportion of mean total fat mass relative to total body mass (%-point). In contrast, the proportion of lean body mass (%-point) increased with semaglutide 2.4 mg, with a numerical reduction observed in absolute mean lean body mass (kg). A reduction in absolute lean body mass is expected to occur in connection with weight loss.99 With placebo, there was almost no change in the proportion of mean total fat mass and lean body mass (%-point), whereas absolute total fat mass and lean body mass (kg) decreased. For the in-trial observation period, the proportion of visceral fat mass relative to total fat mass in the selected abdominal regions (%-point) decreased. Absolute mean visceral fat mass (kg) also slightly decreased with semaglutide 2.4 mg. With placebo there was no change in absolute mean visceral fat mass (kg) or in the proportion of mean visceral fat mass (%-points).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 102, "section": "11.3.5 Body composition (sub-study)"}}, {"excerpt": "Figure 11-10 Waist circumference by week \u2013 mean plot \u2013 observed in-trial data Cross-reference: EOT Figure 14.2.50 The distribution function plots showed a left-shifted treatment effect on waist circumference with a clear separation between semaglutide 2.4 mg and placebo in favour of semaglutide 2.4 mg. From baseline to week 68, waist circumference was reduced in approximately 95% of subjects on semaglutide 2.4 mg and in approximately 70% of subjects on placebo (EOT Figure 14.2.52). For the treatment policy estimand, the estimated decreases in waist circumference from baseline to week 68 were \u221213.54 cm with semaglutide 2.4 mg and \u22124.13 cm with placebo and the ETD was statistically significant in favour of semaglutide 2.4 mg (\u22129.42 cm [\u221210.30; \u22128.53]95% CI; Figure 11-11 and EOT Table 14.2.54). The pre-specified sensitivity analysis for the treatment policy estimand supported the robustness of the superiority conclusion (EOT Table 14.2.56). The results for the hypothetical estimand, as compared with the treatment policy estimand, showed generally greater decreases in waist circumference from baseline for both semaglutide 2.4 mg and placebo, however more pronounced for semaglutide 2.4 mg. Results for the hypothetical estimand are available in EOT Table and Figures 14.2.57 to 14.2.61.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 97, "section": "11.3.4 Other body weight-related endpoints"}}, {"excerpt": "The analysis of pulse rate was performed using the same data selection and statistical model (MMRM) as for analyses of efficacy endpoints addressing the hypothetical estimand. Mean observed pulse rate at baseline was 72 beats/min in both treatment groups and had increased to 75 beats/min at week 68 in the semaglutide 2.4 mg group while remaining unchanged in the placebo group (EOT Tables 14.3.6.1). The estimated change from baseline at week 68 was 3.52 beats/min for semaglutide 2.4 mg vs -0.74 beats/min for placebo and the treatment difference was: 4.26 beats/min ([3.38; 5.15]95% CI), (EOT Table 14.3.6.5). The increase in pulse rate in the semaglutide 2.4 mg group occurred within the initial 16 weeks of treatment after which a slight decrease was observed. At the follow-up visit (week 75) after the off-treatment period, mean pulse rate had returned to the baseline level (EOT Figure 14.3.6.3). A total of 26.3% of subjects in the semaglutide 2.4 mg group had an increase (from baseline) in pulse rate of \u226520 beats/min at one or more timepoints during the on-treatment period compared to 15.0% in the placebo group (Table 12-20). The proportion of subjects with increases in pulse rate of \u226520 beats/min was highest among subjects with low baseline pulse rate (<60 beats/min) and lowest among subjects with high baseline pulse rate (\u226580 beats/min). Pulse rate is listed by subject and visit for all subjects in EOT Listing 14.3.7.1. Based on the listing, pulse rate generally showed large fluctuations over time. Table 12-20 Pulse rate \u2013 categorical summary of maximum increase from baseline \u2013 on-treatment", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 156, "section": "12.5.6.2 Pulse rate"}}, {"excerpt": "estimand - full analysis set\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nEstimated Estimated\nParameter FAS N Mean Ratio ETR [ 95% CI ] p-value\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nMMRM\nRatio to baseline at Visit 24 (week 68)\nFasting serum insulin (pmol/L)\nSema 2.4 mg 1306 928 64.38 0.69 0.77 [ 0.73 ; 0.82] <0.0001\nPlacebo 655 439 83.72 0.90\nFasting serum insulin (mIU/mL)\nSema 2.4 mg 1306 928 8.92 0.69 0.77 [ 0.73 ; 0.82] <0.0001\nPlacebo 655 439 11.60 0.90\nTotal cholesterol (mmol/L)\nSema 2.4 mg 1306 947 4.72 0.96 0.96 [ 0.94 ; 0.97] <0.0001\nPlacebo 655 440 4.94 1.00\nTotal cholesterol (mg/dL)\nSema 2.4 mg 1306 947 182.15 0.96 0.96 [ 0.94 ; 0.97] <0.0001\nPlacebo 655 440 190.61 1.00\nHDL cholesterol (mmol/L)\nSema 2.4 mg 1306 942 1.35 1.05 1.03 [ 1.02 ; 1.05] <0.0001\nPlacebo 655 438 1.31 1.02\nHDL cholesterol (mg/dL)\nSema 2.4 mg 1306 942 52.08 1.05 1.03 [ 1.02 ; 1.05] <0.0001\nPlacebo 655 438 50.47 1.02\nLDL cholesterol (mmol/L)\nSema 2.4 mg 1306 945 2.77 0.96 0.95 [ 0.93 ; 0.98] 0.0001\nPlacebo 655 440 2.90 1.01\nLDL cholesterol (mg/dL)\nSema 2.4 mg 1306 945 106.88 0.96 0.95 [ 0.93 ; 0.98] 0.0001\nPlacebo 655 440 112.09 1.01\nVLDL cholesterol (mmol/L)\nSema 2.4 mg 1306 944 0.48 0.76 0.82 [ 0.79 ; 0.85] <0.0001\nPlacebo 655 440 0.59 0.92", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 513, "section": "14.2.151 Non-weight-related endpoints ratio to baseline at week 68 - statistical analysis - hypothetical"}}, {"excerpt": "Non-weight-related endpoints ratio to baseline at week 68 - statistical analysis -\nhypothetical estimand - full analysis set\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nEstimated Estimated\nParameter FAS N Mean Ratio ETR [ 95% CI ] p-value\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nMMRM\nRatio to baseline at Visit 24 (week 68)\nVLDL cholesterol (mg/dL)\nSema 2.4 mg 1306 944 18.69 0.76 0.82 [ 0.79 ; 0.85] <0.0001\nPlacebo 655 440 22.70 0.92\nFree fatty acids (mmol/L)\nSema 2.4 mg 1306 928 0.36 0.81 0.88 [ 0.82 ; 0.94] 0.0003\nPlacebo 655 439 0.41 0.92\nFree fatty acids (mg/dL)\nSema 2.4 mg 1306 928 10.11 0.81 0.88 [ 0.82 ; 0.94] 0.0003\nPlacebo 655 439 11.46 0.92\nTriglycerides (mmol/L)\nSema 2.4 mg 1306 946 1.08 0.76 0.82 [ 0.79 ; 0.86] <0.0001\nPlacebo 655 440 1.31 0.92\nTriglycerides (mg/dL)\nSema 2.4 mg 1306 946 96.06 0.76 0.82 [ 0.79 ; 0.86] <0.0001\nPlacebo 655 440 116.57 0.92\nhsCRP (mg/L)\nSema 2.4 mg 1306 948 1.62 0.42 0.52 [ 0.47 ; 0.57] <0.0001\nPlacebo 655 440 3.12 0.80\nLeptin (ng/mL)\nSema 2.4 mg 1306 946 15.90 0.49 0.56 [ 0.52 ; 0.59] <0.0001\nPlacebo 655 441 28.63 0.88\nSoluble leptin receptor (ng/mL)\nSema 2.4 mg 1306 943 19.88 1.07 1.04 [ 1.02 ; 1.07] 0.0009\nPlacebo 655 440 19.03 1.03\nPAI-1 (AU/mL)\nSema 2.4 mg 1306 900 17.29 1.10 0.72 [ 0.68 ; 0.76] <0.0001\nPlacebo 655 427 24.13 1.53", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 514, "section": "14.2.151 Non-weight-related endpoints ratio to baseline at week 68 - statistical analysis - hypothetical"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "933644844", "title": "Included studies \u2014 Study 1 enrolment end date", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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"sourceEvidence": [{"excerpt": "Serious adverse events leading to permanent trial product discontinuation by system organ class and preferred term - summary - on-treatment - safety analysis set \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 System organ class Sema 2.4 mg Placebo Preferred term N (%) E R N (%) E R 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\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 N: Number of subjects experiencing at least one event, %: Percentage of subjects experiencing at least one event, E: Number of events, R: Event rate per 100 years, NEC: Not elsewhere classified PYE: The duration of the on-treatment period in years.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 605, "section": "14.3.1.19 Serious adverse events leading to permanent trial product discontinuation by system organ"}}], "reviewIssues": [{"code": "missing_recommended_evidence", "severity": "warning", "blocksApply": false, "message": "Long term extension \u2014 harms \u2014 SAE 2 name."}], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "959984345", "title": "Systematic review \u2014 statistical testing", "value": "From baseline to week 68, superiority of semaglutide 2.4 mg vs placebo was confirmed in the pre-defined fixed-sequence statistical testing hierarchy for the primary endpoints (change in body weight [%] and body weight loss \u22655%) and all confirmatory secondary endpoints (body weight loss \u226510%, body weight loss \u226515%, change in waist circumference, systolic blood pressure, SF-36 physical functioning score and IWQOL-Lite-CT physical function score).\n\nThe tests of superiority of semaglutide 2.4 mg vs placebo for the primary and 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"reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "970765608", "title": "Key efficacy outcomes \u2014 Study 1 treatment 1", "value": "Efficacy findings Superiority of semaglutide 2.4 mg vs placebo was confirmed for the two primary endpoints, body weight change (%) from baseline to week 68 and body weight reduction \u22655% at week 68.\n\nThus, superiority of semaglutide 2.4 mg vs placebo was confirmed for body weight reduction \u226510% and \u226515% and change in waist circumference at week 68. 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Placebo -4.61 [-4.96;-4.27] <.0001\n\nSema 2.4 mg - Placebo -5.33 [-5.65 ; -5.00] <0.0001\n\nSema 2.4 mg - Placebo -9.42 [-10.30;-8.53] <.0001\n\nSema 2.4 mg - Placebo -9.01 [-9.86;-8.16] <.0001\n\nSema 2.4 mg - Placebo -11.47 [-15.12;-7.82] <.0001\n\nSema 2.4 mg - Placebo -11.43 [-15.06;-7.81] <.0001\n\nSema 2.4 mg - Placebo 4.26 [3.38 ; 5.15] <0.0001\n\nSema 2.4 mg - Placebo 1.80 [1.18;2.42] <.0001\n\nSema 2.4 mg - Placebo 1.85 [1.23;2.47] <.0001\n\nSema 2.4 mg - Placebo 1.38 [0.73;2.04] <.0001\n\nSema 2.4 mg - Placebo 1.64 [0.84;2.45] <.0001\n\nSema 2.4 mg - Placebo 2.16 [1.46;2.86] <.0001\n\nSema 2.4 mg - Placebo 1.14 [0.40;1.88] 0.0026\n\nSema 2.4 mg - Placebo 1.96 [1.31;2.61] <.0001\n\nSema 2.4 mg - Placebo 0.92 [0.10;1.73] 0.0274\n\nSema 2.4 mg - Placebo 9.43 [7.50;11.35] <.0001\n\nSema 2.4 mg - Placebo 8.88 [7.04;10.73] <.0001\n\nSema 2.4 mg - Placebo 9.14 [7.31;10.96] <.0001\n\nSema 2.4 mg - Placebo 10.50 [8.81;12.19] <.0001\n\nSema 2.4 mg - Placebo 10.02 [8.42;11.62] <.0001", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg - 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Placebo -11.47 [-15.12;-7.82] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 394, "section": "14.2.70 Body weight (kg) change from baseline to week 68 - supportive secondary analysis - treatment"}}, {"excerpt": "Sema 2.4 mg - Placebo -11.43 [-15.06;-7.81] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 394, "section": "14.2.68 Body weight change from baseline by week - descriptive statistics - in-trial - DEXA"}}, {"excerpt": "Sema 2.4 mg - Placebo 4.26 [3.38 ; 5.15] <0.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 4096, "section": "14.3.6.5 Pulse change from baseline to week 68 - statistical analysis - hypothetical estimand - safety"}}, {"excerpt": "Sema 2.4 mg - Placebo 1.80 [1.18;2.42] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 462, "section": "14.2.111 SF-36 Physical Functioning change from baseline to week 68 - confirmatory secondary"}}, {"excerpt": "Sema 2.4 mg - 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28.76] <.0001 0.05 Superiority Confirmed Waist circumference (cm) change from baseline to week 68 Sema 2.4 mg - Placebo -9.42 [-10.30; -8.53] <.0001 0.05 Superiority Confirmed Systolic blood pressure (mmHg) change from baseline to week 68 Sema 2.4 mg - Placebo -5.10 [ -6.34; -3.87] <.0001 0.05 Superiority Confirmed SF-36 Physical Functioning score change from baseline to week 68 Sema 2.4 mg - Placebo 1.80 [ 1.18; 2.42] <.0001 0.05 Superiority Confirmed IWQOL-Lite-CT Physical Function score change from baseline to week 68 Sema 2.4 mg - Placebo 9.43 [ 7.50; 11.35] <.0001 0.05 Superiority Confirmed \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 Est.: Estimate, alpha: Local significance level, CI: Confidence interval, p-value: Unadjusted two-sided p-value for test of no difference. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:16 - tstathier.sas/thier.txt", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg / Placebo 19.26 [ 12.89; 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\uf0b7 Haematocrit \uf0b7 Haemoglobin \uf0b7 Leucocytes \uf0b7 Lymphocytes \uf0b7 Monocytes \uf0b7 Neutrophils \uf0b7 Thrombocytes Biochemistrya \uf0b7 ALTb \uf0b7 Albumin \uf0b7 Albumin corrected calcium \uf0b7 Alkaline phosphatase \uf0b7 Amylasec \uf0b7 ASTb \uf0b7 Calcitoninc, d \uf0b7 Creatine kinase \uf0b7 Creatinine \uf0b7 Gamma Glutamyl Transferase \uf0b7 Lipasec \uf0b7 Potassium \uf0b7 Sodium \uf0b7 TSHe \uf0b7 Total bilirubin \uf0b7 Urea Pregnancy testing Urine human chorionic gonadotropin pregnancy test (as needed for women of childbearing potential)f Other tests \uf0b7 eGFR calculated by the central laboratory according to CKD-EPI creatinine equation as defined by KDIGO 201294 \uf0b7 Tryptase, in case of severe hypersensitivity \uf0b7 Anti-semaglutide antibodies \uf0b7 Semaglutide plasma concentration a Details of required actions and follow-up assessments for increased liver parameters including any discontinuation criteria are given in the protocol (Appendix 16.1.1 [Protocol, Section 8.1 and Appendix 2]). b If ALT or AST >3 ULN, additional blood sample should be taken from the subject to analyse international normalised ratio (INR) by central laboratory (except at screening visit).\n\nTable 9-6 Event types in scope for adjudication Event type Description Adjudication outcomes Death All-cause death Cardiovascular death (including undetermined cause of death) Non-Cardiovascular death Acute Coronary Syndrome Acute Coronary Syndrome conditions include all types of acute myocardial infarction and hospitalisation for unstable angina pectoris Acute myocardial infarction (including subgroup classifications) Hospitalisation for unstable angina pectoris Cerebrovascular events Episode of focal or global neurological dysfunction that could be caused by brain, spinal cord, or retinal vascular injury as a result of haemorrhage or infarction Ischaemic stroke Haemorrhagic stroke Undetermined stroke Transient ischaemic attack Coronary artery revascularisation A Coronary revascularisation procedure is a catheter-based (percutaneous coronary intervention) or a surgical procedure (coronary artery bypass grafting) designed to improve myocardial blood flow Coronary revascularisation procedure Heart failure Presentation of the patient for an urgent, unscheduled clinic/office/emergency department visit or hospital admission, with a primary diagnosis of heart failure (new episode or worsening of existing heart failure) Heart failure hospitalisation Urgent heart failure visit Acute pancreatitis The diagnosis of acute pancreatitis requires two of the following three features: \uf0b7 abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back) \uf0b7 serum lipase activity (and/or amylase activity) at least three times greater than the upper limit of normal \uf0b7 characteristic findings of acute pancreatitis on imaging Acute pancreatitis \uf0b7 Mild \uf0b7 Moderately severe \uf0b7 Severe Events for adjudication were identified by one of three paths as illustrated in Figure 9-3: \uf0b7 Investigator: When reporting AEs, the investigator was to assess whether an AE matched one of the AE categories defined in the protocol as in scope for adjudication, and if yes, choose the relevant event category on the AE form in the eCRF.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Table 9-7 Laboratory assessments for safety evaluation Laboratory assessments Parameters Haematology \uf0b7 Basophils \uf0b7 Eosinophils \uf0b7 Erythrocytes \uf0b7 Haematocrit \uf0b7 Haemoglobin \uf0b7 Leucocytes \uf0b7 Lymphocytes \uf0b7 Monocytes \uf0b7 Neutrophils \uf0b7 Thrombocytes Biochemistrya \uf0b7 ALTb \uf0b7 Albumin \uf0b7 Albumin corrected calcium \uf0b7 Alkaline phosphatase \uf0b7 Amylasec \uf0b7 ASTb \uf0b7 Calcitoninc, d \uf0b7 Creatine kinase \uf0b7 Creatinine \uf0b7 Gamma Glutamyl Transferase \uf0b7 Lipasec \uf0b7 Potassium \uf0b7 Sodium \uf0b7 TSHe \uf0b7 Total bilirubin \uf0b7 Urea Pregnancy testing Urine human chorionic gonadotropin pregnancy test (as needed for women of childbearing potential)f Other tests \uf0b7 eGFR calculated by the central laboratory according to CKD-EPI creatinine equation as defined by KDIGO 201294 \uf0b7 Tryptase, in case of severe hypersensitivity \uf0b7 Anti-semaglutide antibodies \uf0b7 Semaglutide plasma concentration a Details of required actions and follow-up assessments for increased liver parameters including any discontinuation criteria are given in the protocol (Appendix 16.1.1 [Protocol, Section 8.1 and Appendix 2]). b If ALT or AST >3 ULN, additional blood sample should be taken from the subject to analyse international normalised ratio (INR) by central laboratory (except at screening visit).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 55, "section": "9.5.4.9 Laboratory assessments for safety"}}, {"excerpt": "Table 9-6 Event types in scope for adjudication Event type Description Adjudication outcomes Death All-cause death Cardiovascular death (including undetermined cause of death) Non-Cardiovascular death Acute Coronary Syndrome Acute Coronary Syndrome conditions include all types of acute myocardial infarction and hospitalisation for unstable angina pectoris Acute myocardial infarction (including subgroup classifications) Hospitalisation for unstable angina pectoris Cerebrovascular events Episode of focal or global neurological dysfunction that could be caused by brain, spinal cord, or retinal vascular injury as a result of haemorrhage or infarction Ischaemic stroke Haemorrhagic stroke Undetermined stroke Transient ischaemic attack Coronary artery revascularisation A Coronary revascularisation procedure is a catheter-based (percutaneous coronary intervention) or a surgical procedure (coronary artery bypass grafting) designed to improve myocardial blood flow Coronary revascularisation procedure Heart failure Presentation of the patient for an urgent, unscheduled clinic/office/emergency department visit or hospital admission, with a primary diagnosis of heart failure (new episode or worsening of existing heart failure) Heart failure hospitalisation Urgent heart failure visit Acute pancreatitis The diagnosis of acute pancreatitis requires two of the following three features: \uf0b7 abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back) \uf0b7 serum lipase activity (and/or amylase activity) at least three times greater than the upper limit of normal \uf0b7 characteristic findings of acute pancreatitis on imaging Acute pancreatitis \uf0b7 Mild \uf0b7 Moderately severe \uf0b7 Severe Events for adjudication were identified by one of three paths as illustrated in Figure 9-3: \uf0b7 Investigator: When reporting AEs, the investigator was to assess 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5.15] <0.0001\n\nSema 2.4 mg - Placebo 1.38 [0.73;2.04] <.0001\n\nSema 2.4 mg - Placebo 1.64 [0.84;2.45] <.0001\n\nSema 2.4 mg - Placebo 2.16 [1.46;2.86] <.0001\n\nSema 2.4 mg - Placebo 1.85 [1.23;2.47] <.0001\n\nSema 2.4 mg - Placebo 1.80 [1.18;2.42] <.0001\n\nSema 2.4 mg - Placebo -11.47 [-15.12;-7.82] <.0001\n\nSema 2.4 mg - Placebo -2.41 [-3.25;-1.57] <.0001", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg - Placebo -4.61 [-4.96;-4.27] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 362, "section": "14.2.47 BMI change from baseline to week 68 - supportive secondary analysis - treatment policy"}}, {"excerpt": "Sema 2.4 mg - Placebo -5.33 [-5.65 ; -5.00] <0.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 363, "section": "14.2.48 BMI change from baseline to week 68 - statistical analysis - hypothetical estimand - full"}}, {"excerpt": "Sema 2.4 mg - Placebo -9.42 [-10.30;-8.53] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 371, "section": "14.2.54 Waist circumference change from baseline to week 68 - confirmatory secondary analysis -"}}, {"excerpt": "Sema 2.4 mg - Placebo -9.01 [-9.86;-8.16] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 372, "section": "14.2.56 Waist circumference change from baseline to week 68 - sensitivity analysis - treatment policy"}}, {"excerpt": "Sema 2.4 mg - Placebo 9.43 [7.50;11.35] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 488, "section": "14.2.127 IWQOL-Lite-CT Physical Function change from baseline to week 68 - confirmatory"}}, {"excerpt": "Sema 2.4 mg - Placebo 9.14 [7.31;10.96] <.0001\n\nSema 2.4 mg - Placebo 10.50 [8.81;12.19] <.0001\n\nSema 2.4 mg - Placebo 10.02 [8.42;11.62] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 497, "section": "14.2.136 IWQOL-Lite-CT (all scores except Physical Function) change from baseline to week 68 -"}}, {"excerpt": "Sema 2.4 mg - Placebo 8.88 [7.04;10.73] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 489, "section": "14.2.129 IWQOL-Lite-CT Physical Function change from baseline to week 68 - sensitivity analysis -"}}, {"excerpt": "Sema 2.4 mg - Placebo 4.26 [3.38 ; 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treatment due to AEs in the semaglutide 2.4 mg group than in the placebo group (7.0% vs 3.1%), again driven predominantly by gastrointestinal AEs (see Section 12.4.2).\n\nThe evaluation of AEs showed: \uf0b7 Similar overall proportion of subjects with AEs with semaglutide 2.4 mg and placebo (89.7% vs 86.4%), but higher event rates with semaglutide 2.4 mg (566.1 vs 398.0 events/100 PYE), driven primarily by gastrointestinal AEs \uf0b7 Higher proportion of subjects with SAEs for semaglutide 2.4 mg vs placebo (9.8% vs 6.4%), driven by AEs within the SOCs: gastrointestinal disorders (primarily the PTs: vomiting and abdominal pain); infections and infestations (primarily the PT: gastroenteritis); and hepatobiliary disorders (primarily the PTs: cholelithiasis) \uf0b7 Higher proportion of subjects who permanently discontinued treatment due to AEs with semaglutide 2.4 mg vs placebo (7.0% vs 3.1%), again mostly driven by gastrointestinal AEs \uf0b7 One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo), corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group \uf0b7 The majority of the AEs in both treatment groups were of mild or moderate severity and reported as recovered Gastrointestinal AEs were more frequent with semaglutide 2.4 mg than with placebo (74.2% vs 47.9% and 252.6 vs 89.1 events per 100 PYE): \uf0b7 The difference was driven by nausea, diarrhoea, vomiting, constipation and different kinds of abdominal pain or discomfort \uf0b7 The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered \uf0b7 The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it started to decrease The results of the other safety focus areas showed that: \uf0b7 The proportion of subjects with events was higher with semaglutide 2.4 mg than placebo for: \uf0b7 Gallbladder disorders (2.6% vs 1.2%), driven by the PT cholelithiasis (1.8% vs 0.6%); but a low proportion of semaglutide-treated subjects reported complications to cholelithiasis such\n\nPermanent treatment discontinuation (OT) 92 ( 7.0) 123 7.2 20 ( 3.1) 23 2.8\n\nTemporary interruption of trial product (OT) 126 ( 9.6) 265 15.5 26 ( 4.0) 44 5.3\n\nCholelithiasis A total of 24 AEs of cholelithiasis were reported in 23 subjects in the semaglutide 2.4 mg group: \uf0b7 17 events were reported as recovered and 7 as not recovered \uf0b7 2 events led to permanent discontinuation of trial product, 4 events to temporary interruption of trial product and 1 event to dose reduction \uf0b7 9 events were judged as possibly or probably related to trial product by the investigator Additional data was collected for 17 of the 24 AEs of cholelithiasis and showed that: \uf0b7 16 events were diagnosed by means of ultrasound and 1 by CT scan \uf0b7 The reasons specified for performing the imaging were: suspicion of gallbladder disease (13 events), suspicion of pancreatitis (1 event) and unspecific GI symptoms (1 event)\n\nThe patient decided to suspend the medication under study due to non-serious adverse events she presented with (nausea, vomit, diarrhea).", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "A higher proportion of subjects permanently discontinued treatment due to AEs in the semaglutide 2.4 mg group than in the placebo group (7.0% vs 3.1%), again driven predominantly by gastrointestinal AEs (see Section 12.4.2).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 127, "section": "12.2.1 Brief summary of adverse events"}}, {"excerpt": "The evaluation of AEs showed: \uf0b7 Similar overall proportion of subjects with AEs with semaglutide 2.4 mg and placebo (89.7% vs 86.4%), but higher event rates with semaglutide 2.4 mg (566.1 vs 398.0 events/100 PYE), driven primarily by gastrointestinal AEs \uf0b7 Higher proportion of subjects with SAEs for semaglutide 2.4 mg vs placebo (9.8% vs 6.4%), driven by AEs within the SOCs: gastrointestinal disorders (primarily the PTs: vomiting and abdominal pain); infections and infestations (primarily the PT: gastroenteritis); and hepatobiliary disorders (primarily the PTs: cholelithiasis) \uf0b7 Higher proportion of subjects who permanently discontinued treatment due to AEs with semaglutide 2.4 mg vs placebo (7.0% vs 3.1%), again mostly driven by gastrointestinal AEs \uf0b7 One subject in each treatment group died during the trial, due to sudden cardiac death (semaglutide 2.4 mg) and malignancy (placebo), corresponding to <0.1% of subjects in the semaglutide 2.4 mg group and 0.2% in the placebo group \uf0b7 The majority of the AEs in both treatment groups were of mild or moderate severity and reported as recovered Gastrointestinal AEs were more frequent with semaglutide 2.4 mg than with placebo (74.2% vs 47.9% and 252.6 vs 89.1 events per 100 PYE): \uf0b7 The difference was driven by nausea, diarrhoea, vomiting, constipation and different kinds of abdominal pain or discomfort \uf0b7 The majority of the gastrointestinal AEs were non-serious, mild or moderate in severity and reported as recovered \uf0b7 The prevalence of gastrointestinal AEs was highest during the initial 20 weeks of treatment, after which it started to decrease The results of the other safety focus areas showed that: \uf0b7 The proportion of subjects with events was higher with semaglutide 2.4 mg than placebo for: \uf0b7 Gallbladder disorders (2.6% vs 1.2%), driven by the PT cholelithiasis (1.8% vs 0.6%); but a low proportion of semaglutide-treated subjects reported complications to cholelithiasis such", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 186, "section": "12.8.1 Adverse events including adverse events within safety focus areas"}}, {"excerpt": "Permanent 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events), suspicion of pancreatitis (1 event) and unspecific GI symptoms (1 event)", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 146, "section": "12.5.4 Gallbladder-related disorders"}}, {"excerpt": "The patient decided to suspend the medication under study due to non-serious adverse events she presented with (nausea, vomit, diarrhea).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1141, "section": "1139 of 6980"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1407604333", "title": "Baseline characteristics \u2014 row 2 Study 1 treatment 2 result", "value": "Mean (SD) 46 (13) 47 (12) 46 (13)", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Mean (SD) 46 (13) 47 (12) 46 (13)", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 205, "section": "14.1.6 Demographics and baseline characteristics - descriptive statistics - full analysis set"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1409617373", "title": "Key efficacy outcomes \u2014 outcome 2 name", "value": "Sema 2.4 mg / Placebo 19.26 [ 12.89; 28.76] <.0001 0.05 Superiority Confirmed Waist circumference (cm) change from baseline to week 68 Sema 2.4 mg - Placebo -9.42 [-10.30; -8.53] <.0001 0.05 Superiority Confirmed Systolic blood pressure (mmHg) change from baseline to week 68 Sema 2.4 mg - Placebo -5.10 [ -6.34; -3.87] <.0001 0.05 Superiority Confirmed SF-36 Physical Functioning score change from baseline to week 68 Sema 2.4 mg - Placebo 1.80 [ 1.18; 2.42] <.0001 0.05 Superiority Confirmed IWQOL-Lite-CT Physical Function score change from baseline to week 68 Sema 2.4 mg - Placebo 9.43 [ 7.50; 11.35] <.0001 0.05 Superiority Confirmed \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 Est.: Estimate, alpha: Local significance level, CI: Confidence interval, p-value: Unadjusted two-sided p-value for test of no difference. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:16 - tstathier.sas/thier.txt Cross-reference: EOT Table 14.2.1", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg / Placebo 19.26 [ 12.89; 28.76] <.0001 0.05 Superiority Confirmed Waist circumference (cm) change from baseline to week 68 Sema 2.4 mg - Placebo -9.42 [-10.30; -8.53] <.0001 0.05 Superiority Confirmed Systolic blood pressure (mmHg) change from baseline to week 68 Sema 2.4 mg - Placebo -5.10 [ -6.34; -3.87] <.0001 0.05 Superiority Confirmed SF-36 Physical Functioning score change from baseline to week 68 Sema 2.4 mg - Placebo 1.80 [ 1.18; 2.42] <.0001 0.05 Superiority Confirmed IWQOL-Lite-CT Physical Function score change from baseline to week 68 Sema 2.4 mg - Placebo 9.43 [ 7.50; 11.35] <.0001 0.05 Superiority Confirmed \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 Est.: Estimate, alpha: Local significance level, CI: Confidence interval, p-value: Unadjusted two-sided p-value for test of no difference. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:16 - tstathier.sas/thier.txt Cross-reference: EOT Table 14.2.1", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 87, "section": "11.2 Summary of results for the primary and confirmatory secondary endpoints"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1413108311", "title": "Efficacy outcome sample \u2014 dichotomous outcome name", "value": "From baseline to week 68, superiority of semaglutide 2.4 mg vs placebo was confirmed in the pre-defined fixed-sequence statistical testing hierarchy for the primary endpoints (change in body weight [%] and body weight loss \u22655%) and all confirmatory secondary endpoints (body weight loss \u226510%, body weight loss \u226515%, change in waist circumference, systolic blood pressure, SF-36 physical functioning score and IWQOL-Lite-CT physical function score).\n\nAt week 68, the observed proportion of subjects achieving a weight loss of \u22655% was greater with semaglutide 2.4 mg compared to placebo (Figure 11-6).\n\nthe treatment policy estimand, the odds of achieving the \u226510% and \u226515% 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waist circumference, systolic blood pressure, SF-36 physical functioning score and IWQOL-Lite-CT physical function score).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 125, "section": "11.7 Efficacy conclusions"}}, {"excerpt": "At week 68, the observed proportion of subjects achieving a weight loss of \u22655% was greater with semaglutide 2.4 mg compared to placebo (Figure 11-6).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 92, "section": "11.3.2.1 Treatment policy estimand"}}, {"excerpt": "the treatment policy estimand, the odds of achieving the \u226510% and \u226515% targets included in the testing hierarchy were statistically significantly greater with semaglutide 2.4 mg vs placebo (Figure 11-9 and EOT Tables 14.2.30, 14.2.32, 14.2.34).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 95, "section": "11.3.2.3 Sensitivity analyses"}}, {"excerpt": "The supportive secondary endpoint \u201cBody weight reduction \u2265 20% from baseline at week 0\u201d was added To be able to assess the proportion of subjects with the greatest weight loss It was clarified that subjects in the FAS/SAS will be evaluated \u201cas randomised\u201d/\u201cas treated\u201d.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 62, "section": "9.7.2 Changes in planned analyses prior to trial unblinding"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1415065320", "title": "Patient population: Baseline characteristics", "value": "Sema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 1306 655 1961\nAge (years)\nN 1306 655 1961\nMean (SD) 46 (13) 47 (12) 46 (13)\nMedian 46 48 46\nP5 ; P95 25 ; 68 26 ; 66 25 ; 67\nMin ; Max 18 ; 86 18 ; 82 18 ; 86\nHeight (m)\nN 1306 655 1961\nMean (SD) 1.67 (0.09) 1.66 (0.09) 1.67 (0.09)\nMedian 1.66 1.65 1.66\nP5 ; P95 1.53 ; 1.83 1.52 ; 1.83 1.53 ; 1.83\nMin ; Max 1.42 ; 2.03 1.40 ; 1.93 1.40 ; 2.03\nBody weight (kg)\nN 1306 655 1961\nMean (SD) 105.4 (22.1) 105.2 (21.5) 105.3 (21.9)\nMedian 102.1 101.3 101.8\nP5 ; P95 76.1 ; 144.3 78.1 ; 143.2 76.6 ; 144.2\nMin ; Max 61.8 ; 245.6 66.3 ; 211.0 61.8 ; 245.6\nBMI (kg/m^2)\nN 1306 655 1961\nMean (SD) 37.8 (6.7) 38.0 (6.5) 37.9 (6.7)\nMedian 36.7 36.5 36.7\nP5 ; P95 29.7 ; 51.0 29.8 ; 50.6 29.7 ; 50.8\nMin ; Max 26.5 ; 83.0 27.5 ; 67.0 26.5 ; 83.0\nWaist circumference (cm)\nN 1306 655 1961\nMean (SD) 114.6 (14.8) 114.8 (14.4) 114.7 (14.6)\nMedian 113.0 113.2 113.0\nP5 ; P95 93.5 ; 140.0 94.0 ; 139.5 94.0 ; 139.7\nMin ; Max 85.0 ; 180.0 83.8 ; 182.9 83.8 ; 182.9\nHbA1c (%)\nN 1306 655 1961\nMean (SD) 5.7 (0.3) 5.7 (0.3) 5.7 (0.3)\nMedian 5.7 5.7 5.7\nP5 ; P95 5.2 ; 6.2 5.2 ; 6.3 5.2 ; 6.2\nMin ; Max 4.1 ; 6.6 4.6 ; 6.6 4.1 ; 6.6\nHbA1c (mmol/mol)\nN 1306 655 1961\nMean (SD) 38.9 (3.4) 39.0 (3.6) 39.0 (3.5)\nMedian 38.8 38.8 38.8\nP5 ; P95 33.3 ; 44.3 33.3 ; 45.4 33.3 ; 44.3\nMin ; Max 21.3 ; 48.6 26.8 ; 48.6 21.3 ; 48.6\n\nDemographics and baseline characteristics - descriptive statistics - full analysis\nset\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nFasting plasma glucose (mg/dL)\nN 1291 649 1940\nMean (SD) 95.4 (10.7) 94.7 (10.5) 95.2 (10.6)\nMedian 94.4 93.7 94.2\nP5 ; P95 80.2 ; 114.2 80.5 ; 112.8 80.4 ; 113.5\nMin ; Max 68.1 ; 166.0 66.5 ; 150.5 66.5 ; 166.0\nFasting plasma glucose (mmol/L)\nN 1291 649 1940\nMean (SD) 5.3 (0.6) 5.3 (0.6) 5.3 (0.6)\nMedian 5.2 5.2 5.2\nP5 ; P95 4.5 ; 6.3 4.5 ; 6.3 4.5 ; 6.3\nMin ; Max 3.8 ; 9.2 3.7 ; 8.4 3.7 ; 9.2\n\nDemographics and baseline characteristics - summary - full analysis set\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSmoking habits\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nNever smoked 828 (63.4) 409 (62.4) 1237 (63.1)\nPrevious smoker 318 (24.3) 178 (27.2) 496 (25.3)\nCurrent smoker 160 (12.3) 68 (10.4) 228 (11.6)\n\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 95 45 140\nAge (years)\nN 95 ( 100) 45 ( 100) 140 ( 100)\n18-<65 85 (89.5) 39 (86.7) 124 (88.6)\n65-<75 10 (10.5) 5 (11.1) 15 (10.7)\n75-<85 0 1 ( 2.2) 1 ( 0.7)\n>=85 0 0 0\nSex\nN 95 ( 100) 45 ( 100) 140 ( 100)\nFemale 72 (75.8) 34 (75.6) 106 (75.7)\nMale 23 (24.2) 11 (24.4) 34 (24.3)\nCountry of residence\nN 95 ( 100) 45 ( 100) 140 ( 100)\nArgentina 0 0 0\nBelgium 0 0 0\nBulgaria 0 0 0\nCanada 0 0 0\nGermany 0 0 0\nDenmark 0 0 0\nFinland 0 0 0\nFrance 0 0 0\nUnited Kingdom 0 0 0\nIndia 0 0 0\nJapan 0 0 0\nMexico 0 0 0\nPoland 0 0 0\nRussian Federation 0 0 0\nTaiwan 0 0 0\nUnited States 95 ( 100) 45 ( 100) 140 ( 100)\nEthnic origin\nN 95 ( 100) 45 ( 100) 140 ( 100)\nNot Hispanic or Latino 93 (97.9) 39 (86.7) 132 (94.3)\nHispanic or Latino 2 ( 2.1) 6 (13.3) 8 ( 5.7)\nNot Applicable 0 0 0\nUnknown 0 0 0\nRace\nN 95 ( 100) 45 ( 100) 140 ( 100)\nWhite 75 (78.9) 41 (91.1) 116 (82.9)\nBlack or African American 18 (18.9) 3 ( 6.7) 21 (15.0)\nAsian 1 ( 1.1) 1 ( 2.2) 2 ( 1.4)\nOther 1 ( 1.1) 0 1 ( 0.7)\nAmerican Indian or Alaska Native 0 0 0\nNative Hawaiian or Other Pacific Islander 0 0 0\nNot Applicable 0 0 0\nBMI (kg/m^2)\nN 95 ( 100) 45 ( 100) 140 ( 100)\n<30 7 ( 7.4) 4 ( 8.9) 11 ( 7.9)\n30-<35 41 (43.2) 17 (37.8) 58 (41.4)\n35-<40 43 (45.3) 23 (51.1) 66 (47.1)\n>=40 4 ( 4.2) 1 ( 2.2) 5 ( 3.6)\n\nDemographics and baseline characteristics - summary - DEXA subpopulation\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSmoking habits\nN 95 ( 100) 45 ( 100) 140 ( 100)\nNever smoked 57 (60.0) 28 (62.2) 85 (60.7)\nPrevious smoker 32 (33.7) 13 (28.9) 45 (32.1)\nCurrent smoker 6 ( 6.3) 4 ( 8.9) 10 ( 7.1)\n\nSema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 95 45 140\nAge (years)\nN 95 45 140\nMean (SD) 50 (12) 52 (13) 51 (12)\nMedian 51 56 53\nP5 ; P95 29 ; 69 30 ; 67 30 ; 68\nMin ; Max 22 ; 71 19 ; 82 19 ; 82\nHeight (m)\nN 95 45 140\nMean (SD) 1.68 (0.09) 1.68 (0.08) 1.68 (0.09)\nMedian 1.68 1.68 1.68\nP5 ; P95 1.52 ; 1.83 1.58 ; 1.80 1.55 ; 1.83\nMin ; Max 1.48 ; 1.89 1.57 ; 1.86 1.48 ; 1.89\nBody weight (kg)\nN 95 45 140\nMean (SD) 98.3 (15.9) 98.7 (12.1) 98.4 (14.7)\nMedian 95.1 96.6 96.2\nP5 ; P95 75.6 ; 126.1 79.1 ; 119.6 76.9 ; 124.0\nMin ; Max 67.2 ; 141.7 71.8 ; 121.8 67.2 ; 141.7\nBMI (kg/m^2)\nN 95 45 140\nMean (SD) 34.8 (3.6) 35.0 (3.6) 34.8 (3.6)\nMedian 34.9 35.3 35.1\nP5 ; P95 29.4 ; 39.7 29.0 ; 39.9 29.3 ; 39.8\nMin ; Max 28.1 ; 47.0 28.2 ; 41.1 28.1 ; 47.0\nWaist circumference (cm)\nN 95 45 140\nMean (SD) 109.4 (10.6) 111.0 (10.1) 109.9 (10.4)\nMedian 109.0 111.0 109.4\nP5 ; P95 92.0 ; 130.0 95.3 ; 127.0 92.4 ; 128.0\nMin ; Max 88.3 ; 135.0 89.0 ; 128.0 88.3 ; 135.0\nHbA1c (%)\nN 95 45 140\nMean (SD) 5.7 (0.4) 5.7 (0.3) 5.7 (0.3)\nMedian 5.7 5.7 5.7\nP5 ; P95 5.1 ; 6.2 5.2 ; 6.2 5.2 ; 6.2\nMin ; Max 4.8 ; 6.6 5.0 ; 6.5 4.8 ; 6.6\nHbA1c (mmol/mol)\nN 95 45 140\nMean (SD) 39.3 (3.9) 39.1 (3.4) 39.2 (3.7)\nMedian 38.8 38.8 38.8\nP5 ; P95 32.2 ; 44.3 33.3 ; 44.3 33.3 ; 44.3\nMin ; Max 29.0 ; 48.6 31.2 ; 47.5 29.0 ; 48.6\n\nDemographics and baseline characteristics - descriptive statistics - DEXA\nsubpopulation\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nFasting plasma glucose (mg/dL)\nN 95 45 140\nMean (SD) 96.4 (11.0) 95.6 (11.6) 96.1 (11.2)\nMedian 94.8 94.4 94.6\nP5 ; P95 79.8 ; 115.3 82.4 ; 109.0 81.2 ; 113.8\nMin ; Max 69.4 ; 134.1 75.0 ; 147.9 69.4 ; 147.9\nFasting plasma glucose (mmol/L)\nN 95 45 140\nMean (SD) 5.3 (0.6) 5.3 (0.6) 5.3 (0.6)\nMedian 5.3 5.2 5.3\nP5 ; P95 4.4 ; 6.4 4.6 ; 6.1 4.5 ; 6.3\nMin ; Max 3.9 ; 7.4 4.2 ; 8.2 3.9 ; 8.2\n\nTable 10-2 Demographics and baseline characteristics \u2013 categorical variables\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 1306 655 1961\nAge (years)\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\n18-<65 1198 (91.7) 607 (92.7) 1805 (92.0)\n65-<75 99 ( 7.6) 46 ( 7.0) 145 ( 7.4)\n75-<85 8 ( 0.6) 2 ( 0.3) 10 ( 0.5)\n>=85 1 (<0.1) 0 1 (<0.1)\nSex\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nFemale 955 (73.1) 498 (76.0) 1453 (74.1)\nMale 351 (26.9) 157 (24.0) 508 (25.9)\nCountry of residence\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nArgentina 39 ( 3.0) 26 ( 4.0) 65 ( 3.3)\nBelgium 39 ( 3.0) 21 ( 3.2) 60 ( 3.1)\nBulgaria 32 ( 2.5) 13 ( 2.0) 45 ( 2.3)\nCanada 39 ( 3.0) 24 ( 3.7) 63 ( 3.2)\nGermany 70 ( 5.4) 30 ( 4.6) 100 ( 5.1)\nDenmark 34 ( 2.6) 16 ( 2.4) 50 ( 2.5)\nFinland 38 ( 2.9) 22 ( 3.4) 60 ( 3.1)\nFrance 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nUnited Kingdom 135 (10.3) 83 (12.7) 218 (11.1)\nIndia 82 ( 6.3) 35 ( 5.3) 117 ( 6.0)\nJapan 67 ( 5.1) 33 ( 5.0) 100 ( 5.1)\nMexico 47 ( 3.6) 23 ( 3.5) 70 ( 3.6)\nPoland 42 ( 3.2) 18 ( 2.7) 60 ( 3.1)\nRussian Federation 73 ( 5.6) 27 ( 4.1) 100 ( 5.1)\nTaiwan 26 ( 2.0) 9 ( 1.4) 35 ( 1.8)\nUnited States 505 (38.7) 258 (39.4) 763 (38.9)\nEthnic origin\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nNot Hispanic or Latino 1118 (85.6) 551 (84.1) 1669 (85.1)\nHispanic or Latino 150 (11.5) 86 (13.1) 236 (12.0)\nNot Applicable 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nUnknown 0 1 ( 0.2) 1 (<0.1)\nRace\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nWhite 973 (74.5) 499 (76.2) 1472 (75.1)\nAsian 181 (13.9) 80 (12.2) 261 (13.3)\nBlack or African American 72 ( 5.5) 39 ( 6.0) 111 ( 5.7)\nNot Applicable 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nOther 25 ( 1.9) 8 ( 1.2) 33 ( 1.7)\nAmerican Indian or Alaska Native 17 ( 1.3) 10 ( 1.5) 27 ( 1.4)\nNative Hawaiian or Other Pacific Islander 0 2 ( 0.3) 2 ( 0.1)\nBMI (kg/m^2)\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\n<30 81 ( 6.2) 36 ( 5.5) 117 ( 6.0)\n30-<35 436 (33.4) 207 (31.6) 643 (32.8)\n35-<40 406 (31.1) 208 (31.8) 614 (31.3)\n>=40 383 (29.3) 204 (31.1) 587 (29.9)\n\nTable 10-3 Demographics and baseline characteristics \u2013 continuous variables\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 1306 655 1961\nAge (years)\nN 1306 655 1961\nMean (SD) 46 (13) 47 (12) 46 (13)\nMedian 46 48 46\nP5 ; P95 25 ; 68 26 ; 66 25 ; 67\nMin ; Max 18 ; 86 18 ; 82 18 ; 86\nBody weight (kg)\nN 1306 655 1961\nMean (SD) 105.4 (22.1) 105.2 (21.5) 105.3 (21.9)\nMedian 102.1 101.3 101.8\nP5 ; P95 76.1 ; 144.3 78.1 ; 143.2 76.6 ; 144.2\nMin; Max 61.8 ; 245.6 66.3 ; 211.0 61.8 ; 245.6\nBMI (kg/m^2)\nN 1306 655 1961\nMean (SD) 37.8 (6.7) 38.0 (6.5) 37.9 (6.7)\nMedian 36.7 36.5 36.7\nP5 ; P95 29.7 ; 51.0 29.8 ; 50.6 29.7 ; 50.8\nMin; Max 26.5 ; 83.0 27.5 ; 67.0 26.5 ; 83.0\nWaist circumference (cm)\nN 1306 655 1961\nMean (SD) 114.6 (14.8) 114.8 (14.4) 114.7 (14.6)\nMedian 113.0 113.2 113.0\nP5 ; P95 93.5 ; 140.0 94.0 ; 139.5 94.0 ; 139.7\nMin; Max 85.0 ; 180.0 83.8 ; 182.9 83.8 ; 182.9\nHbA1c (%)\nN 1306 655 1961\nMean (SD) 5.7 (0.3) 5.7 (0.3) 5.7 (0.3)\nMedian 5.7 5.7 5.7\nP5 ; P95 5.2 ; 6.2 5.2 ; 6.3 5.2 ; 6.2\nMin; Max 4.1 ; 6.6 4.6 ; 6.6 4.1 ; 6.6\nFasting plasma glucose (mmol/L)\nN 1291 649 1940\nMean (SD) 5.3 (0.6) 5.3 (0.6) 5.3 (0.6)\nMedian 5.2 5.2 5.2\nP5 ; P95 4.5 ; 6.3 4.5 ; 6.3 4.5 ; 6.3\nMin ; Max 3.8 ; 9.2 3.7 ; 8.4 3.7 ; 9.2\nFasting plasma glucose (mg/dL)\nN 1291 649 1940\nMean (SD) 95.4 (10.7) 94.7 (10.5) 95.2 (10.6)\nMedian 94.4 93.7 94.2\nP5 ; P95 80.2 ; 114.2 80.5 ; 112.8 80.4 ; 113.5\nMin ; Max 68.1 ; 166.0 66.5 ; 150.5 66.5 ; 166.0", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 1306 655 1961\nAge (years)\nN 1306 655 1961\nMean (SD) 46 (13) 47 (12) 46 (13)\nMedian 46 48 46\nP5 ; P95 25 ; 68 26 ; 66 25 ; 67\nMin ; Max 18 ; 86 18 ; 82 18 ; 86\nHeight (m)\nN 1306 655 1961\nMean (SD) 1.67 (0.09) 1.66 (0.09) 1.67 (0.09)\nMedian 1.66 1.65 1.66\nP5 ; P95 1.53 ; 1.83 1.52 ; 1.83 1.53 ; 1.83\nMin ; Max 1.42 ; 2.03 1.40 ; 1.93 1.40 ; 2.03\nBody weight (kg)\nN 1306 655 1961\nMean (SD) 105.4 (22.1) 105.2 (21.5) 105.3 (21.9)\nMedian 102.1 101.3 101.8\nP5 ; P95 76.1 ; 144.3 78.1 ; 143.2 76.6 ; 144.2\nMin ; Max 61.8 ; 245.6 66.3 ; 211.0 61.8 ; 245.6\nBMI (kg/m^2)\nN 1306 655 1961\nMean (SD) 37.8 (6.7) 38.0 (6.5) 37.9 (6.7)\nMedian 36.7 36.5 36.7\nP5 ; P95 29.7 ; 51.0 29.8 ; 50.6 29.7 ; 50.8\nMin ; Max 26.5 ; 83.0 27.5 ; 67.0 26.5 ; 83.0\nWaist circumference (cm)\nN 1306 655 1961\nMean (SD) 114.6 (14.8) 114.8 (14.4) 114.7 (14.6)\nMedian 113.0 113.2 113.0\nP5 ; P95 93.5 ; 140.0 94.0 ; 139.5 94.0 ; 139.7\nMin ; Max 85.0 ; 180.0 83.8 ; 182.9 83.8 ; 182.9\nHbA1c (%)\nN 1306 655 1961\nMean (SD) 5.7 (0.3) 5.7 (0.3) 5.7 (0.3)\nMedian 5.7 5.7 5.7\nP5 ; P95 5.2 ; 6.2 5.2 ; 6.3 5.2 ; 6.2\nMin ; Max 4.1 ; 6.6 4.6 ; 6.6 4.1 ; 6.6\nHbA1c (mmol/mol)\nN 1306 655 1961\nMean (SD) 38.9 (3.4) 39.0 (3.6) 39.0 (3.5)\nMedian 38.8 38.8 38.8\nP5 ; P95 33.3 ; 44.3 33.3 ; 45.4 33.3 ; 44.3\nMin ; Max 21.3 ; 48.6 26.8 ; 48.6 21.3 ; 48.6", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 205, "section": "14.1.6 Demographics and baseline characteristics - descriptive statistics - full analysis set"}}, {"excerpt": "Demographics and baseline characteristics - descriptive statistics - full analysis\nset\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nFasting plasma glucose (mg/dL)\nN 1291 649 1940\nMean (SD) 95.4 (10.7) 94.7 (10.5) 95.2 (10.6)\nMedian 94.4 93.7 94.2\nP5 ; P95 80.2 ; 114.2 80.5 ; 112.8 80.4 ; 113.5\nMin ; Max 68.1 ; 166.0 66.5 ; 150.5 66.5 ; 166.0\nFasting plasma glucose (mmol/L)\nN 1291 649 1940\nMean (SD) 5.3 (0.6) 5.3 (0.6) 5.3 (0.6)\nMedian 5.2 5.2 5.2\nP5 ; P95 4.5 ; 6.3 4.5 ; 6.3 4.5 ; 6.3\nMin ; Max 3.8 ; 9.2 3.7 ; 8.4 3.7 ; 9.2", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 206, "section": "14.1.6 Demographics and baseline characteristics - descriptive statistics - full analysis set"}}, {"excerpt": "Demographics and baseline characteristics - summary - full analysis set\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSmoking habits\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nNever smoked 828 (63.4) 409 (62.4) 1237 (63.1)\nPrevious smoker 318 (24.3) 178 (27.2) 496 (25.3)\nCurrent smoker 160 (12.3) 68 (10.4) 228 (11.6)", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 202, "section": "14.1.4 Demographics and baseline characteristics - summary - full analysis set"}}, {"excerpt": "Sema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 95 45 140\nAge (years)\nN 95 ( 100) 45 ( 100) 140 ( 100)\n18-<65 85 (89.5) 39 (86.7) 124 (88.6)\n65-<75 10 (10.5) 5 (11.1) 15 (10.7)\n75-<85 0 1 ( 2.2) 1 ( 0.7)\n>=85 0 0 0\nSex\nN 95 ( 100) 45 ( 100) 140 ( 100)\nFemale 72 (75.8) 34 (75.6) 106 (75.7)\nMale 23 (24.2) 11 (24.4) 34 (24.3)\nCountry of residence\nN 95 ( 100) 45 ( 100) 140 ( 100)\nArgentina 0 0 0\nBelgium 0 0 0\nBulgaria 0 0 0\nCanada 0 0 0\nGermany 0 0 0\nDenmark 0 0 0\nFinland 0 0 0\nFrance 0 0 0\nUnited Kingdom 0 0 0\nIndia 0 0 0\nJapan 0 0 0\nMexico 0 0 0\nPoland 0 0 0\nRussian Federation 0 0 0\nTaiwan 0 0 0\nUnited States 95 ( 100) 45 ( 100) 140 ( 100)\nEthnic origin\nN 95 ( 100) 45 ( 100) 140 ( 100)\nNot Hispanic or Latino 93 (97.9) 39 (86.7) 132 (94.3)\nHispanic or Latino 2 ( 2.1) 6 (13.3) 8 ( 5.7)\nNot Applicable 0 0 0\nUnknown 0 0 0\nRace\nN 95 ( 100) 45 ( 100) 140 ( 100)\nWhite 75 (78.9) 41 (91.1) 116 (82.9)\nBlack or African American 18 (18.9) 3 ( 6.7) 21 (15.0)\nAsian 1 ( 1.1) 1 ( 2.2) 2 ( 1.4)\nOther 1 ( 1.1) 0 1 ( 0.7)\nAmerican Indian or Alaska Native 0 0 0\nNative Hawaiian or Other Pacific Islander 0 0 0\nNot Applicable 0 0 0\nBMI (kg/m^2)\nN 95 ( 100) 45 ( 100) 140 ( 100)\n<30 7 ( 7.4) 4 ( 8.9) 11 ( 7.9)\n30-<35 41 (43.2) 17 (37.8) 58 (41.4)\n35-<40 43 (45.3) 23 (51.1) 66 (47.1)\n>=40 4 ( 4.2) 1 ( 2.2) 5 ( 3.6)", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 203, "section": "14.1.5 Demographics and baseline characteristics - summary - DEXA subpopulation"}}, {"excerpt": "Demographics and baseline characteristics - summary - DEXA subpopulation\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSmoking habits\nN 95 ( 100) 45 ( 100) 140 ( 100)\nNever smoked 57 (60.0) 28 (62.2) 85 (60.7)\nPrevious smoker 32 (33.7) 13 (28.9) 45 (32.1)\nCurrent smoker 6 ( 6.3) 4 ( 8.9) 10 ( 7.1)", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 204, "section": "14.1.5 Demographics and baseline characteristics - summary - DEXA subpopulation"}}, {"excerpt": "Sema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 95 45 140\nAge (years)\nN 95 45 140\nMean (SD) 50 (12) 52 (13) 51 (12)\nMedian 51 56 53\nP5 ; P95 29 ; 69 30 ; 67 30 ; 68\nMin ; Max 22 ; 71 19 ; 82 19 ; 82\nHeight (m)\nN 95 45 140\nMean (SD) 1.68 (0.09) 1.68 (0.08) 1.68 (0.09)\nMedian 1.68 1.68 1.68\nP5 ; P95 1.52 ; 1.83 1.58 ; 1.80 1.55 ; 1.83\nMin ; Max 1.48 ; 1.89 1.57 ; 1.86 1.48 ; 1.89\nBody weight (kg)\nN 95 45 140\nMean (SD) 98.3 (15.9) 98.7 (12.1) 98.4 (14.7)\nMedian 95.1 96.6 96.2\nP5 ; P95 75.6 ; 126.1 79.1 ; 119.6 76.9 ; 124.0\nMin ; Max 67.2 ; 141.7 71.8 ; 121.8 67.2 ; 141.7\nBMI (kg/m^2)\nN 95 45 140\nMean (SD) 34.8 (3.6) 35.0 (3.6) 34.8 (3.6)\nMedian 34.9 35.3 35.1\nP5 ; P95 29.4 ; 39.7 29.0 ; 39.9 29.3 ; 39.8\nMin ; Max 28.1 ; 47.0 28.2 ; 41.1 28.1 ; 47.0\nWaist circumference (cm)\nN 95 45 140\nMean (SD) 109.4 (10.6) 111.0 (10.1) 109.9 (10.4)\nMedian 109.0 111.0 109.4\nP5 ; P95 92.0 ; 130.0 95.3 ; 127.0 92.4 ; 128.0\nMin ; Max 88.3 ; 135.0 89.0 ; 128.0 88.3 ; 135.0\nHbA1c (%)\nN 95 45 140\nMean (SD) 5.7 (0.4) 5.7 (0.3) 5.7 (0.3)\nMedian 5.7 5.7 5.7\nP5 ; P95 5.1 ; 6.2 5.2 ; 6.2 5.2 ; 6.2\nMin ; Max 4.8 ; 6.6 5.0 ; 6.5 4.8 ; 6.6\nHbA1c (mmol/mol)\nN 95 45 140\nMean (SD) 39.3 (3.9) 39.1 (3.4) 39.2 (3.7)\nMedian 38.8 38.8 38.8\nP5 ; P95 32.2 ; 44.3 33.3 ; 44.3 33.3 ; 44.3\nMin ; Max 29.0 ; 48.6 31.2 ; 47.5 29.0 ; 48.6", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 207, "section": "14.1.7 Demographics and baseline characteristics - descriptive statistics - DEXA subpopulation"}}, {"excerpt": "Demographics and baseline characteristics - descriptive statistics - DEXA\nsubpopulation\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nFasting plasma glucose (mg/dL)\nN 95 45 140\nMean (SD) 96.4 (11.0) 95.6 (11.6) 96.1 (11.2)\nMedian 94.8 94.4 94.6\nP5 ; P95 79.8 ; 115.3 82.4 ; 109.0 81.2 ; 113.8\nMin ; Max 69.4 ; 134.1 75.0 ; 147.9 69.4 ; 147.9\nFasting plasma glucose (mmol/L)\nN 95 45 140\nMean (SD) 5.3 (0.6) 5.3 (0.6) 5.3 (0.6)\nMedian 5.3 5.2 5.3\nP5 ; P95 4.4 ; 6.4 4.6 ; 6.1 4.5 ; 6.3\nMin ; Max 3.9 ; 7.4 4.2 ; 8.2 3.9 ; 8.2", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 208, "section": "14.1.7 Demographics and baseline characteristics - descriptive statistics - DEXA subpopulation"}}, {"excerpt": "Table 10-2 Demographics and baseline characteristics \u2013 categorical variables\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 1306 655 1961\nAge (years)\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\n18-<65 1198 (91.7) 607 (92.7) 1805 (92.0)\n65-<75 99 ( 7.6) 46 ( 7.0) 145 ( 7.4)\n75-<85 8 ( 0.6) 2 ( 0.3) 10 ( 0.5)\n>=85 1 (<0.1) 0 1 (<0.1)\nSex\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nFemale 955 (73.1) 498 (76.0) 1453 (74.1)\nMale 351 (26.9) 157 (24.0) 508 (25.9)\nCountry of residence\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nArgentina 39 ( 3.0) 26 ( 4.0) 65 ( 3.3)\nBelgium 39 ( 3.0) 21 ( 3.2) 60 ( 3.1)\nBulgaria 32 ( 2.5) 13 ( 2.0) 45 ( 2.3)\nCanada 39 ( 3.0) 24 ( 3.7) 63 ( 3.2)\nGermany 70 ( 5.4) 30 ( 4.6) 100 ( 5.1)\nDenmark 34 ( 2.6) 16 ( 2.4) 50 ( 2.5)\nFinland 38 ( 2.9) 22 ( 3.4) 60 ( 3.1)\nFrance 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nUnited Kingdom 135 (10.3) 83 (12.7) 218 (11.1)\nIndia 82 ( 6.3) 35 ( 5.3) 117 ( 6.0)\nJapan 67 ( 5.1) 33 ( 5.0) 100 ( 5.1)\nMexico 47 ( 3.6) 23 ( 3.5) 70 ( 3.6)\nPoland 42 ( 3.2) 18 ( 2.7) 60 ( 3.1)\nRussian Federation 73 ( 5.6) 27 ( 4.1) 100 ( 5.1)\nTaiwan 26 ( 2.0) 9 ( 1.4) 35 ( 1.8)\nUnited States 505 (38.7) 258 (39.4) 763 (38.9)\nEthnic origin\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nNot Hispanic or Latino 1118 (85.6) 551 (84.1) 1669 (85.1)\nHispanic or Latino 150 (11.5) 86 (13.1) 236 (12.0)\nNot Applicable 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nUnknown 0 1 ( 0.2) 1 (<0.1)\nRace\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\nWhite 973 (74.5) 499 (76.2) 1472 (75.1)\nAsian 181 (13.9) 80 (12.2) 261 (13.3)\nBlack or African American 72 ( 5.5) 39 ( 6.0) 111 ( 5.7)\nNot Applicable 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nOther 25 ( 1.9) 8 ( 1.2) 33 ( 1.7)\nAmerican Indian or Alaska Native 17 ( 1.3) 10 ( 1.5) 27 ( 1.4)\nNative Hawaiian or Other Pacific Islander 0 2 ( 0.3) 2 ( 0.1)\nBMI (kg/m^2)\nN 1306 ( 100) 655 ( 100) 1961 ( 100)\n<30 81 ( 6.2) 36 ( 5.5) 117 ( 6.0)\n30-<35 436 (33.4) 207 (31.6) 643 (32.8)\n35-<40 406 (31.1) 208 (31.8) 614 (31.3)\n>=40 383 (29.3) 204 (31.1) 587 (29.9)", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 69, "section": "10.2 Demographics and other baseline characteristics"}}, {"excerpt": "Table 10-3 Demographics and baseline characteristics \u2013 continuous variables\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nNumber of subjects 1306 655 1961\nAge (years)\nN 1306 655 1961\nMean (SD) 46 (13) 47 (12) 46 (13)\nMedian 46 48 46\nP5 ; P95 25 ; 68 26 ; 66 25 ; 67\nMin ; Max 18 ; 86 18 ; 82 18 ; 86\nBody weight (kg)\nN 1306 655 1961\nMean (SD) 105.4 (22.1) 105.2 (21.5) 105.3 (21.9)\nMedian 102.1 101.3 101.8\nP5 ; P95 76.1 ; 144.3 78.1 ; 143.2 76.6 ; 144.2\nMin; Max 61.8 ; 245.6 66.3 ; 211.0 61.8 ; 245.6\nBMI (kg/m^2)\nN 1306 655 1961\nMean (SD) 37.8 (6.7) 38.0 (6.5) 37.9 (6.7)\nMedian 36.7 36.5 36.7\nP5 ; P95 29.7 ; 51.0 29.8 ; 50.6 29.7 ; 50.8\nMin; Max 26.5 ; 83.0 27.5 ; 67.0 26.5 ; 83.0\nWaist circumference (cm)\nN 1306 655 1961\nMean (SD) 114.6 (14.8) 114.8 (14.4) 114.7 (14.6)\nMedian 113.0 113.2 113.0\nP5 ; P95 93.5 ; 140.0 94.0 ; 139.5 94.0 ; 139.7\nMin; Max 85.0 ; 180.0 83.8 ; 182.9 83.8 ; 182.9\nHbA1c (%)\nN 1306 655 1961\nMean (SD) 5.7 (0.3) 5.7 (0.3) 5.7 (0.3)\nMedian 5.7 5.7 5.7\nP5 ; P95 5.2 ; 6.2 5.2 ; 6.3 5.2 ; 6.2\nMin; Max 4.1 ; 6.6 4.6 ; 6.6 4.1 ; 6.6\nFasting plasma glucose (mmol/L)\nN 1291 649 1940\nMean (SD) 5.3 (0.6) 5.3 (0.6) 5.3 (0.6)\nMedian 5.2 5.2 5.2\nP5 ; P95 4.5 ; 6.3 4.5 ; 6.3 4.5 ; 6.3\nMin ; Max 3.8 ; 9.2 3.7 ; 8.4 3.7 ; 9.2\nFasting plasma glucose (mg/dL)\nN 1291 649 1940\nMean (SD) 95.4 (10.7) 94.7 (10.5) 95.2 (10.6)\nMedian 94.4 93.7 94.2\nP5 ; P95 80.2 ; 114.2 80.5 ; 112.8 80.4 ; 113.5\nMin ; Max 68.1 ; 166.0 66.5 ; 150.5 66.5 ; 166.0", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 70, "section": "10.2 Demographics and other baseline characteristics"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1418799728", "title": "Systematic review \u2014 serious adverse events narrative", "value": "Subject ID , Case Number (ID) Preferred term Gastroenteritis Narrative category Death No SAE Yes SUSAR No Case unblinded during the trial No AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nPatient's BMI: (BMI) This Clinical Trial case from the (Country) was reported by an Investigator as \"Acute Gastroenteritis(Acute Gastroenteritis)\" and concerned a 52 Years old Female patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from 16-Dec-2018 and ongoing due to \"Obesity\". Current Condition: Obesity, (Med. History), (Med. History), (Med. History), (Med. History), (Med. History), (Med. History), (Med. History) Historical Condition: (Med. History), (Med. History) (Med. History), (Med. History). Concomitant medications included \u2013 (Con. Med) (iohexol), iodine (iodine) Treatment medication included - isotonic sodium chloride solution (sodium chloride), ondansetron(ondansetron). On 29-Apr-2019 the patient had onset of acute gastroenteritis and was hospitalised on the same day due to dehydration. A computerised tomography (CT) scan was performed. It revealed several non-serious adverse events. On 02-May-2019 the patient was discharged from the hospital once symptoms resolved. Action taken to Blinded Semaglutide was reported as No Change. On 02-May-2019 the outcome for the event \"Acute Gastroenteritis\" was Recovered.\n\nSubject ID 971920, Case Number (ID) Preferred term Death Narrative category Death Yes SAE Yes SUSAR No Case unblinded during the trial No AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nPatient's BMI: (BMI) This Clinical Trial case from (Country) was reported by an Investigator as \"death(Death)\" and concerned a (Age) Years old Male patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from (Date) to (Date) for \"Obesity\". Current Condition: obesity, (Med. History), (Med. History), (Med. History), and (Med. History) Historical Condition: (Med. History). Prior to this event the patient had \u201closs of consciousness\u201d (serious adverse events) on (Date) , (Date) and (Date) , all recovered. (Reflected in linked cases (ID), (ID) and (ID)). On (Date) the patient was found dead in his . No autopsy was performed. The cause of death was unknown. Action taken to Blinded Semaglutide was reported as Not Applicable. On (Date) the outcome for the event \"death(Death)\" was Fatal. Investigator's causality (Blinded Semaglutide) - death(Death) : Unlikely Sponsor's causality (Blinded Semaglutide) -\n\nSubject ID 770960, Case Number (ID) Preferred term Osteoarthritis Narrative category Death No SAE Yes SUSAR No Case unblinded during the trial No AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nPatient's BMI: (BMI) This Clinical Trial case from (Country) was reported by an Investigator as \"worsening of osteoarthritis of the \" and concerned a (Age) Years old Female patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from (Date) to (Date) due to \"Obesity\". Medical history included obesity, (Med. History), (Med. History), (Med. History), (Med. History), and (Med. History). Treatment medications included - diclofenac (diclofenac). On (Date) the patient was admitted to the hospital and had onset of worsening of osteoarthritis of the . On the same day the patient had surgery (arthroscopy) for osteoarthritis of the . The surgery was not planned prior to trial participation. It was reported that no other tests other than the actual surgery were performed. The patient decided to suspend the medication under study due to non-serious adverse events she presented with (nausea, vomit, diarrhea). On the other hand, during the last face-to-face visit, the reintroduction of the medication under study was discussed and it was pending to try to resume it at the next face-to-face visit. Action taken to Blinded Semaglutide was reported as Not Applicable.\n\nThe following tests was performed: - Lab Data Test as Reported: CT abd pelvis without contrast (Test Name: Computerised tomogram abdomen and Computerised tomogram pelvis) Showed New free intraperitoneal air and moderate volume of free fluid in pelvis also present. wall thickening involving the colon was also present. Mesenteric inflammatory changes were present. moderate amount of stool remained present within the more proximal colon. There were multiple fluid containing loops of small bowel present with multiple scattered small bowel air-fluid levels. Small bowel distended up to approximately 2.7cm. Gastric lumen was distended with fluid and gas. cecum was distended up to approximately 7.5cm. - Test as Reported: Urine, (Test Name: Urine analysis) Appear Value Slightly cloudy reference range clear. - Test as Reported: Urine WBC, (Test Name: White blood cells urine) Value 5-10 reference range non seen. - Lab Data Test as Reported: Urine Leuk Est value (Test Name: Urine leukocyte esterase) was 100 u/L, negative. On (Date) the patient had part of the colon removed and had a colostomy bag. Admitted to the ICU (Intensive Care Unit). The cause for the stercoral perforation was due to impacted stool. The patient's history did not yield any predisposing factors. On (Date) the patient was discharged. On (Date) the patient was admitted to hospital for her stoma closure. The patient's stay at the hospital was prolonged due to fluid collection (coded as Peritoneal fluid analysis) (reported as nonserious event), reason unknown. Once drained, fluid was sent for the appropriate testing. Fluid was negative and the patient was released from the hospital (on an unspecified date). The patient had numerous non-serious adverse events reported. They were evaluated by Investigator as not needing to be associated to this case. Action taken to Blinded Semaglutide was reported as Product discontinued for the event, stercoral perforation of colon. Action taken to Blinded Semaglutide was reported as not applicable for the event, constipation. On (Date) the outcome for the event \"stercoral perforation of colon(Perforated colon)\" was Recovered. On (Date) the outcome for the event \"Constipation(Constipation)\" was Recovered. Investigator's causality (Blinded Semaglutide) - stercoral perforation of colon(Perforated colon) : Possible Constipation(Constipation) : Possible Sponsor's causality (Blinded Semaglutide) - stercoral perforation of colon(Perforated colon) : Possible Constipation(Constipation) : Possible Since last submission the case has been updated with the following: - Laboratory tests - Onset date - AE18, constipation, associated to case - Investigator causality updated - Narrative - Sponsor causality changed from unlikely to possible - company comment updated This case was re-classified from double unlikely to possible/possible on (Date) due to follow-up. On (Date) trial product was unblinded according to regulatory requirements. Information on actual treatment can be obtained from Global Safety for regulatory purposes.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Subject ID , Case Number (ID) Preferred term Gastroenteritis Narrative category Death No SAE Yes SUSAR No Case unblinded during the trial No AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nPatient's BMI: (BMI) This Clinical Trial case from the (Country) was reported by an Investigator as \"Acute Gastroenteritis(Acute Gastroenteritis)\" and concerned a 52 Years old Female patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from 16-Dec-2018 and ongoing due to \"Obesity\". Current Condition: Obesity, (Med. History), (Med. History), (Med. History), (Med. History), (Med. History), (Med. History), (Med. History) Historical Condition: (Med. History), (Med. History) (Med. History), (Med. History). Concomitant medications included \u2013 (Con. Med) (iohexol), iodine (iodine) Treatment medication included - isotonic sodium chloride solution (sodium chloride), ondansetron(ondansetron). On 29-Apr-2019 the patient had onset of acute gastroenteritis and was hospitalised on the same day due to dehydration. A computerised tomography (CT) scan was performed. It revealed several non-serious adverse events. On 02-May-2019 the patient was discharged from the hospital once symptoms resolved. Action taken to Blinded Semaglutide was reported as No Change. On 02-May-2019 the outcome for the event \"Acute Gastroenteritis\" was Recovered.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1002, "section": "997 of 6980"}}, {"excerpt": "Subject ID 971920, Case Number (ID) Preferred term Death Narrative category Death Yes SAE Yes SUSAR No Case unblinded during the trial No AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nPatient's BMI: (BMI) This Clinical Trial case from (Country) was reported by an Investigator as \"death(Death)\" and concerned a (Age) Years old Male patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from (Date) to (Date) for \"Obesity\". Current Condition: obesity, (Med. History), (Med. History), (Med. History), and (Med. History) Historical Condition: (Med. History). Prior to this event the patient had \u201closs of consciousness\u201d (serious adverse events) on (Date) , (Date) and (Date) , all recovered. (Reflected in linked cases (ID), (ID) and (ID)). On (Date) the patient was found dead in his . No autopsy was performed. The cause of death was unknown. Action taken to Blinded Semaglutide was reported as Not Applicable. On (Date) the outcome for the event \"death(Death)\" was Fatal. Investigator's causality (Blinded Semaglutide) - death(Death) : Unlikely Sponsor's causality (Blinded Semaglutide) -", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1052, "section": "1050 of 6980"}}, {"excerpt": "Subject ID 770960, Case Number (ID) Preferred term Osteoarthritis Narrative category Death No SAE Yes SUSAR No Case unblinded during the trial No AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.\n\nPatient's BMI: (BMI) This Clinical Trial case from (Country) was reported by an Investigator as \"worsening of osteoarthritis of the \" and concerned a (Age) Years old Female patient who was treated with Blinded Semaglutide (Blinded Semaglutide) from (Date) to (Date) due to \"Obesity\". Medical history included obesity, (Med. History), (Med. History), (Med. History), (Med. History), and (Med. History). Treatment medications included - diclofenac (diclofenac). On (Date) the patient was admitted to the hospital and had onset of worsening of osteoarthritis of the . On the same day the patient had surgery (arthroscopy) for osteoarthritis of the . The surgery was not planned prior to trial participation. It was reported that no other tests other than the actual surgery were performed. The patient decided to suspend the medication under study due to non-serious adverse events she presented with (nausea, vomit, diarrhea). On the other hand, during the last face-to-face visit, the reintroduction of the medication under study was discussed and it was pending to try to resume it at the next face-to-face visit. Action taken to Blinded Semaglutide was reported as Not Applicable.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1141, "section": "1139 of 6980"}}, {"excerpt": "The following tests was performed: - Lab Data Test as Reported: CT abd pelvis without contrast (Test Name: Computerised tomogram abdomen and Computerised tomogram pelvis) Showed New free intraperitoneal air and moderate volume of free fluid in pelvis also present. wall thickening involving the colon was also present. Mesenteric inflammatory changes were present. moderate amount of stool remained present within the more proximal colon. There were multiple fluid containing loops of small bowel present with multiple scattered small bowel air-fluid levels. Small bowel distended up to approximately 2.7cm. Gastric lumen was distended with fluid and gas. cecum was distended up to approximately 7.5cm. - Test as Reported: Urine, (Test Name: Urine analysis) Appear Value Slightly cloudy reference range clear. - Test as Reported: Urine WBC, (Test Name: White blood cells urine) Value 5-10 reference range non seen. - Lab Data Test as Reported: Urine Leuk Est value (Test Name: Urine leukocyte esterase) was 100 u/L, negative. On (Date) the patient had part of the colon removed and had a colostomy bag. Admitted to the ICU (Intensive Care Unit). The cause for the stercoral perforation was due to impacted stool. The patient's history did not yield any predisposing factors. On (Date) the patient was discharged. On (Date) the patient was admitted to hospital for her stoma closure. The patient's stay at the hospital was prolonged due to fluid collection (coded as Peritoneal fluid analysis) (reported as nonserious event), reason unknown. Once drained, fluid was sent for the appropriate testing. Fluid was negative and the patient was released from the hospital (on an unspecified date). The patient had numerous non-serious adverse events reported. They were evaluated by Investigator as not needing to be associated to this case. Action taken to Blinded Semaglutide was reported as Product discontinued for the event, stercoral perforation of colon. Action taken to Blinded Semaglutide was reported as not applicable for the event, constipation. On (Date) the outcome for the event \"stercoral perforation of colon(Perforated colon)\" was Recovered. On (Date) the outcome for the event \"Constipation(Constipation)\" was Recovered. 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0.82] <0.0001\nPlacebo 655 439 83.72 0.90\nFasting serum insulin (mIU/mL)\nSema 2.4 mg 1306 928 8.92 0.69 0.77 [ 0.73 ; 0.82] <0.0001\nPlacebo 655 439 11.60 0.90\nTotal cholesterol (mmol/L)\nSema 2.4 mg 1306 947 4.72 0.96 0.96 [ 0.94 ; 0.97] <0.0001\nPlacebo 655 440 4.94 1.00\nTotal cholesterol (mg/dL)\nSema 2.4 mg 1306 947 182.15 0.96 0.96 [ 0.94 ; 0.97] <0.0001\nPlacebo 655 440 190.61 1.00\nHDL cholesterol (mmol/L)\nSema 2.4 mg 1306 942 1.35 1.05 1.03 [ 1.02 ; 1.05] <0.0001\nPlacebo 655 438 1.31 1.02\nHDL cholesterol (mg/dL)\nSema 2.4 mg 1306 942 52.08 1.05 1.03 [ 1.02 ; 1.05] <0.0001\nPlacebo 655 438 50.47 1.02\nLDL cholesterol (mmol/L)\nSema 2.4 mg 1306 945 2.77 0.96 0.95 [ 0.93 ; 0.98] 0.0001\nPlacebo 655 440 2.90 1.01\nLDL cholesterol (mg/dL)\nSema 2.4 mg 1306 945 106.88 0.96 0.95 [ 0.93 ; 0.98] 0.0001\nPlacebo 655 440 112.09 1.01\nVLDL cholesterol (mmol/L)\nSema 2.4 mg 1306 944 0.48 0.76 0.82 [ 0.79 ; 0.85] <0.0001\nPlacebo 655 440 0.59 0.92\n\nVLDL cholesterol (mg/dL)\nSema 2.4 mg 1306 944 18.69 0.76 0.82 [ 0.79 ; 0.85] <0.0001\nPlacebo 655 440 22.70 0.92\nFree fatty acids (mmol/L)\nSema 2.4 mg 1306 928 0.36 0.81 0.88 [ 0.82 ; 0.94] 0.0003\nPlacebo 655 439 0.41 0.92\nFree fatty acids (mg/dL)\nSema 2.4 mg 1306 928 10.11 0.81 0.88 [ 0.82 ; 0.94] 0.0003\nPlacebo 655 439 11.46 0.92\nTriglycerides (mmol/L)\nSema 2.4 mg 1306 946 1.08 0.76 0.82 [ 0.79 ; 0.86] <0.0001\nPlacebo 655 440 1.31 0.92\nTriglycerides (mg/dL)\nSema 2.4 mg 1306 946 96.06 0.76 0.82 [ 0.79 ; 0.86] <0.0001\nPlacebo 655 440 116.57 0.92\nhsCRP (mg/L)\nSema 2.4 mg 1306 948 1.62 0.42 0.52 [ 0.47 ; 0.57] <0.0001\nPlacebo 655 440 3.12 0.80\nLeptin (ng/mL)\nSema 2.4 mg 1306 946 15.90 0.49 0.56 [ 0.52 ; 0.59] <0.0001\nPlacebo 655 441 28.63 0.88\nSoluble leptin receptor (ng/mL)\nSema 2.4 mg 1306 943 19.88 1.07 1.04 [ 1.02 ; 1.07] 0.0009\nPlacebo 655 440 19.03 1.03\nPAI-1 (AU/mL)\nSema 2.4 mg 1306 900 17.29 1.10 0.72 [ 0.68 ; 0.76] <0.0001\nPlacebo 655 427 24.13 1.53\n\nSF-36 Physical Functioning >= 4.3\nSema 2.4 mg 1306 942 0.32 2.75 [ 2.03; 3.73] <.0001\nPlacebo 655 439 0.12\nIWQOL-Lite-CT Physical Function >= 20\nSema 2.4 mg 1306 940 0.62 3.15 [ 2.43; 4.08] <.0001\nPlacebo 655 439 0.20", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "The pre-specified sensitivity analyses for the treatment policy estimand supported the robustness of the superiority conclusion (EOT Tables 14.2.31 [odds of achieving \u226510% weight loss] and 14.2.33 [odds of achieving \u226515% weight loss]).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 95, "section": "11.3.2.3 Sensitivity analyses"}}, {"excerpt": "Waist circumference (cm)\nANCOVA - J2R-MI\nMean at Visit 24 (week 68)\nSema 2.4 mg 1306 1210 101.26\nPlacebo 655 575 110.27\nChange from baseline to Visit 24 (week 68)\nSema 2.4 mg 1306 1210 -13.41\nPlacebo 655 575 -4.40\nTreatment difference\nSema 2.4 mg - Placebo -9.01 [-9.86;-8.16] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 372, "section": "14.2.56 Waist circumference change from baseline to week 68 - sensitivity analysis - treatment policy"}}, {"excerpt": "Fasting serum insulin (pmol/L)\nSema 2.4 mg 1306 928 64.38 0.69 0.77 [ 0.73 ; 0.82] <0.0001\nPlacebo 655 439 83.72 0.90\nFasting serum insulin (mIU/mL)\nSema 2.4 mg 1306 928 8.92 0.69 0.77 [ 0.73 ; 0.82] <0.0001\nPlacebo 655 439 11.60 0.90\nTotal cholesterol (mmol/L)\nSema 2.4 mg 1306 947 4.72 0.96 0.96 [ 0.94 ; 0.97] <0.0001\nPlacebo 655 440 4.94 1.00\nTotal cholesterol (mg/dL)\nSema 2.4 mg 1306 947 182.15 0.96 0.96 [ 0.94 ; 0.97] <0.0001\nPlacebo 655 440 190.61 1.00\nHDL cholesterol (mmol/L)\nSema 2.4 mg 1306 942 1.35 1.05 1.03 [ 1.02 ; 1.05] <0.0001\nPlacebo 655 438 1.31 1.02\nHDL cholesterol (mg/dL)\nSema 2.4 mg 1306 942 52.08 1.05 1.03 [ 1.02 ; 1.05] <0.0001\nPlacebo 655 438 50.47 1.02\nLDL cholesterol (mmol/L)\nSema 2.4 mg 1306 945 2.77 0.96 0.95 [ 0.93 ; 0.98] 0.0001\nPlacebo 655 440 2.90 1.01\nLDL cholesterol (mg/dL)\nSema 2.4 mg 1306 945 106.88 0.96 0.95 [ 0.93 ; 0.98] 0.0001\nPlacebo 655 440 112.09 1.01\nVLDL cholesterol (mmol/L)\nSema 2.4 mg 1306 944 0.48 0.76 0.82 [ 0.79 ; 0.85] <0.0001\nPlacebo 655 440 0.59 0.92", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 513, "section": "14.2.151 Non-weight-related endpoints ratio to baseline at week 68 - statistical analysis - hypothetical"}}, {"excerpt": "VLDL cholesterol (mg/dL)\nSema 2.4 mg 1306 944 18.69 0.76 0.82 [ 0.79 ; 0.85] <0.0001\nPlacebo 655 440 22.70 0.92\nFree fatty acids (mmol/L)\nSema 2.4 mg 1306 928 0.36 0.81 0.88 [ 0.82 ; 0.94] 0.0003\nPlacebo 655 439 0.41 0.92\nFree fatty acids (mg/dL)\nSema 2.4 mg 1306 928 10.11 0.81 0.88 [ 0.82 ; 0.94] 0.0003\nPlacebo 655 439 11.46 0.92\nTriglycerides (mmol/L)\nSema 2.4 mg 1306 946 1.08 0.76 0.82 [ 0.79 ; 0.86] <0.0001\nPlacebo 655 440 1.31 0.92\nTriglycerides (mg/dL)\nSema 2.4 mg 1306 946 96.06 0.76 0.82 [ 0.79 ; 0.86] <0.0001\nPlacebo 655 440 116.57 0.92\nhsCRP (mg/L)\nSema 2.4 mg 1306 948 1.62 0.42 0.52 [ 0.47 ; 0.57] <0.0001\nPlacebo 655 440 3.12 0.80\nLeptin (ng/mL)\nSema 2.4 mg 1306 946 15.90 0.49 0.56 [ 0.52 ; 0.59] <0.0001\nPlacebo 655 441 28.63 0.88\nSoluble leptin receptor (ng/mL)\nSema 2.4 mg 1306 943 19.88 1.07 1.04 [ 1.02 ; 1.07] 0.0009\nPlacebo 655 440 19.03 1.03\nPAI-1 (AU/mL)\nSema 2.4 mg 1306 900 17.29 1.10 0.72 [ 0.68 ; 0.76] <0.0001\nPlacebo 655 427 24.13 1.53", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 514, "section": "14.2.151 Non-weight-related endpoints ratio to baseline at week 68 - statistical analysis - hypothetical"}}, {"excerpt": "SF-36 Physical Functioning >= 4.3\nSema 2.4 mg 1306 942 0.32 2.75 [ 2.03; 3.73] <.0001\nPlacebo 655 439 0.12\nIWQOL-Lite-CT Physical Function >= 20\nSema 2.4 mg 1306 940 0.62 3.15 [ 2.43; 4.08] <.0001\nPlacebo 655 439 0.20", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 515, "section": "14.2.152 Odds of achieving response in non-weight-related endpoints since baseline at week 68 -"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1510024955", "title": "Long-term extension \u2014 patient exposure \u2014 median duration \u2014 Study 2 treatment 2", "value": "Median 69.1 69.1 69.1", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Median 69.1 69.1 69.1", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 310, "section": "14.1.23 Observation periods - descriptive statistics - full analysis set"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1510114055", "title": "Key efficacy outcomes \u2014 Outcome 2 \u2014 RD (95% CI) \u2014 Study 2 treatment 1", "value": "Sema 2.4 mg - Placebo 1.80 [1.18;2.42] <.0001", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg - Placebo 1.80 [1.18;2.42] <.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 462, "section": "14.2.111 SF-36 Physical Functioning change from baseline to week 68 - confirmatory secondary"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1512039669", "title": "Estimated prevalence \u2014 Non-Insured Health Benefits \u2014 upper estimate", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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Subjects with T2D were excluded from the trial. Subjects with T2D and overweight or obesity are addressed in a dedicated trial (NN9536-4374 [STEP 2]). First-line treatment in weight management is lifestyle modification with reduced-calorie diet and increased physical activity, therefore only subjects who had tried but failed a dietary weight loss intervention were included.\n\nSubjects who fulfilled all inclusion criteria and who did not meet any exclusion criteria, were eligible to be randomised in the trial only if all the following randomisation criteria applied: \uf0b7 Have kept a food diary with at least one entry per day between screening and randomisation. However, missed entries for a maximum of two days were allowed \uf0b7 A PHQ-9 score of <15 at randomisation \uf0b7 No suicidal behaviour in the period between screening and randomisation \uf0b7 No suicidal ideation corresponding to type 4 or 5 on the C-SSRS in the period between screening and randomisation Subjects not fulfilling all randomisation criteria were considered screen failures (see Section 9.3.5).\n\nExclusion criteria 296 (97.0)\nHbA1c >= 48 mmol/mol (6.5%) as measured by the central laboratory at screening 120 (39.3)\nUncontrolled thyroid disease, defined as thyroid stimulating hormone (TSH) > 81 (26.6)\n6.0 mIU/L or < 0.4 mIU/L as measured by the central laboratory at screening\nAny disorder, unwillingness or inability, not covered by any of the other 38 (12.5)\nexclusion criteria, which in the investigators opinion, might jeopardise the\nsubjects safety or compliance with the protocol\nA Patient Health Questionnaire-9 (PHQ-9) score of >= 15 at screening 18 ( 5.9)\nA lifetime history of a suicidal attempt 8 ( 2.6)\nHistory of major depressive disorder within 2 years before screening 6 ( 2.0)\nFemale who is pregnant, breast-feeding or intends to become pregnant or is of 5 ( 1.6)\nchild-bearing potential and not using a highly effective contraceptive method\nHistory of type 1 or type 2 diabetes mellitus 4 ( 1.3)\nA self-reported change in body weight > 5 kg (11 lbs) within 90 days before 3 ( 1.0)\nscreening irrespective of medical records\nDiagnosis of other severe psychiatric disorder (e.g., schizophrenia, bipolar 3 ( 1.0)\ndisorder)\nParticipation in another clinical trial within 90 days before screening 3 ( 1.0)\nSurgery scheduled for the duration of the trial, except for minor surgical 3 ( 1.0)\nprocedures, in the opinion of the investigator\nTreatment with glucose-lowering agent(s) within 90 days before screening 3 ( 1.0)\nCalcitonin >= 100 ng/L as measured by the central laboratory at screening 2 ( 0.7)\nHistory of malignant neoplasms within the past 5 years prior to screening. 2 ( 0.7)\nBasal and squamous cell skin cancer and any carcinoma in-situ are allowed\nKnown or suspected abuse of alcohol or recreational drugs 2 ( 0.7)\nPrevious or planned (during the trial period) obesity treatment with surgery 2 ( 0.7)\nor a weight loss device. 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"Sema 2.4 mg 1306 1212 -15.33", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg 1306 1212 -15.33", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 336, "section": "14.2.14 Body weight (kg) change from baseline to week 68 - supportive secondary analysis - treatment"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1591733779", "title": "Baseline characteristics \u2014 Study 1 treatment 2", "value": "Table 9-1 Trial products provided by Novo Nordisk Treatment arm Semaglutide 2.4 mg Placebo Trial product name Semaglutide", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Table 9-1 Trial products provided by Novo Nordisk Treatment arm Semaglutide 2.4 mg Placebo Trial product name Semaglutide", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 40, "section": "9.4.1.1 Investigational medicinal products"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1592170354", "title": "Indirect comparison \u2014 selection criteria \u2014 exclusion criteria", "value": "The key exclusion criteria are listed below, the complete list is provided in the protocol (Appendix 16.1.1 [Protocol, Section 6.2]): \uf0b7 HbA1c \u226548 mmol/mol (6.5%) as measured by the central laboratory at screening \uf0b7 A self-reported change in body weight >5 kg (11 lbs) within 90 days before screening irrespective of medical records\n\nSubjects with T2D were excluded from the trial.\n\nAt baseline, similar proportions of subjects had a score between 10-14 in the two treatment groups (0.9% in the semaglutide 2.4 mg group and 1.1% in the placebo group) and no subjects had a score of \u226515 (EOT Table 14.3.6.9), as this was an exclusion criteria.\n\nNone of the subjects had reported suicidal behaviour (EOT Table 14.3.6.8), as this was an exclusion criteria.\n\nA Patient Health Questionnaire-9 (PHQ-9) 1 (20.0) 0 1 (12.5)\nscore of >= 15 at screening\n\nFemale who is pregnant, breast-feeding or 4 (80.0) 2 (66.7) 6 (75.0)\nintends to become pregnant or is of childbearing potential and not using a highly\neffective contraceptive method\n\nTreatment with glucose-lowering agent(s) 0 1 (33.3) 1 (12.5)\nwithin 90 days before screening\n\nintragastric balloon, if the balloon has been removed > 1 year before screening or (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed > 1 year before screening Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) 2 ( 0.7) value of eGFR < 15 ml/min/1.73 m^2 as defined by KDIGO 2012 by the central laboratory at screening \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 N: Number of subjects, %: Percentages are based on subjects failing screening.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "The key exclusion criteria are listed below, the complete list is provided in the protocol (Appendix 16.1.1 [Protocol, Section 6.2]): \uf0b7 HbA1c \u226548 mmol/mol (6.5%) as measured by the central laboratory at screening \uf0b7 A self-reported change in body weight >5 kg (11 lbs) within 90 days before screening irrespective of medical records", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 37, "section": "9.3.2 Exclusion criteria"}}, {"excerpt": "Subjects with T2D were excluded from the trial.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 36, "section": "9.2 Rationale for trial design"}}, {"excerpt": "At baseline, similar proportions of subjects had a score between 10-14 in the two treatment groups (0.9% in the semaglutide 2.4 mg group and 1.1% in the placebo group) and no subjects had a score of \u226515 (EOT Table 14.3.6.9), as this was an exclusion criteria.\n\nNone of the subjects had reported suicidal behaviour (EOT Table 14.3.6.8), as this was an exclusion criteria.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 176, "section": "12.5.12.2 Mental health assessments (PHQ-9 and C-SSRS)"}}, {"excerpt": "A Patient Health Questionnaire-9 (PHQ-9) 1 (20.0) 0 1 (12.5)\nscore of >= 15 at screening\n\nFemale who is pregnant, breast-feeding or 4 (80.0) 2 (66.7) 6 (75.0)\nintends to become pregnant or is of childbearing potential and not using a highly\neffective contraceptive method\n\nTreatment with glucose-lowering agent(s) 0 1 (33.3) 1 (12.5)\nwithin 90 days before screening", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 210, "section": "14.1.9 Randomisation in violation of eligibility criteria - summary"}}, {"excerpt": "intragastric balloon, if the balloon has been removed > 1 year before screening or (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed > 1 year before screening Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) 2 ( 0.7) value of eGFR < 15 ml/min/1.73 m^2 as defined by KDIGO 2012 by the central laboratory at screening \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 N: Number of subjects, %: Percentages are based on subjects failing screening.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 209, "section": "14.1.8 Reasons for failing screening - summary"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1598447578", "title": "Other-design study \u2014 baseline characteristics \u2014 characteristic 1 \u2014 Study 1 treatment 2", "value": "18-<65 1198 (91.7) 607 (92.7) 1805 (92.0)\n65-<75 99 ( 7.6) 46 ( 7.0) 145 ( 7.4)\n75-<85 8 ( 0.6) 2 ( 0.3) 10 ( 0.5)\n>=85 1 (<0.1) 0 1 (<0.1)\n\nFemale 955 (73.1) 498 (76.0) 1453 (74.1)\nMale 351 (26.9) 157 (24.0) 508 (25.9)\n\nArgentina 39 ( 3.0) 26 ( 4.0) 65 ( 3.3)\nBelgium 39 ( 3.0) 21 ( 3.2) 60 ( 3.1)\nBulgaria 32 ( 2.5) 13 ( 2.0) 45 ( 2.3)\nCanada 39 ( 3.0) 24 ( 3.7) 63 ( 3.2)\nGermany 70 ( 5.4) 30 ( 4.6) 100 ( 5.1)\nDenmark 34 ( 2.6) 16 ( 2.4) 50 ( 2.5)\nFinland 38 ( 2.9) 22 ( 3.4) 60 ( 3.1)\nFrance 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nUnited Kingdom 135 (10.3) 83 (12.7) 218 (11.1)\nIndia 82 ( 6.3) 35 ( 5.3) 117 ( 6.0)\nJapan 67 ( 5.1) 33 ( 5.0) 100 ( 5.1)\nMexico 47 ( 3.6) 23 ( 3.5) 70 ( 3.6)\nPoland 42 ( 3.2) 18 ( 2.7) 60 ( 3.1)\nRussian Federation 73 ( 5.6) 27 ( 4.1) 100 ( 5.1)\nTaiwan 26 ( 2.0) 9 ( 1.4) 35 ( 1.8)\nUnited States 505 (38.7) 258 (39.4) 763 (38.9)\n\nNot Hispanic or Latino 1118 (85.6) 551 (84.1) 1669 (85.1)\nHispanic or Latino 150 (11.5) 86 (13.1) 236 (12.0)\nNot Applicable 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nUnknown 0 1 ( 0.2) 1 (<0.1)\n\nWhite 973 (74.5) 499 (76.2) 1472 (75.1)\nAsian 181 (13.9) 80 (12.2) 261 (13.3)\nBlack or African American 72 ( 5.5) 39 ( 6.0) 111 ( 5.7)\nNot Applicable 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nOther 25 ( 1.9) 8 ( 1.2) 33 ( 1.7)\nAmerican Indian or Alaska Native 17 ( 1.3) 10 ( 1.5) 27 ( 1.4)\nNative Hawaiian or Other Pacific Islander 0 2 ( 0.3) 2 ( 0.1)\n\n<30 81 ( 6.2) 36 ( 5.5) 117 ( 6.0)\n30-<35 436 (33.4) 207 (31.6) 643 (32.8)\n35-<40 406 (31.1) 208 (31.8) 614 (31.3)\n>=40 383 (29.3) 204 (31.1) 587 (29.9)\n\nMean (SD) 46 (13) 47 (12) 46 (13)\nMedian 46 48 46\nP5 ; P95 25 ; 68 26 ; 66 25 ; 67\nMin ; Max 18 ; 86 18 ; 82 18 ; 86\n\nMean (SD) 105.4 (22.1) 105.2 (21.5) 105.3 (21.9)\nMedian 102.1 101.3 101.8\nP5 ; P95 76.1 ; 144.3 78.1 ; 143.2 76.6 ; 144.2\nMin; Max 61.8 ; 245.6 66.3 ; 211.0 61.8 ; 245.6\n\nMean (SD) 37.8 (6.7) 38.0 (6.5) 37.9 (6.7)\nMedian 36.7 36.5 36.7\nP5 ; P95 29.7 ; 51.0 29.8 ; 50.6 29.7 ; 50.8\nMin; Max 26.5 ; 83.0 27.5 ; 67.0 26.5 ; 83.0\n\nMean (SD) 114.6 (14.8) 114.8 (14.4) 114.7 (14.6)\nMedian 113.0 113.2 113.0\nP5 ; P95 93.5 ; 140.0 94.0 ; 139.5 94.0 ; 139.7\nMin; Max 85.0 ; 180.0 83.8 ; 182.9 83.8 ; 182.9\n\nMean (SD) 5.7 (0.3) 5.7 (0.3) 5.7 (0.3)\nMedian 5.7 5.7 5.7\nP5 ; P95 5.2 ; 6.2 5.2 ; 6.3 5.2 ; 6.2\nMin; Max 4.1 ; 6.6 4.6 ; 6.6 4.1 ; 6.6\n\nMean (SD) 5.3 (0.6) 5.3 (0.6) 5.3 (0.6)\nMedian 5.2 5.2 5.2\nP5 ; P95 4.5 ; 6.3 4.5 ; 6.3 4.5 ; 6.3\nMin ; Max 3.8 ; 9.2 3.7 ; 8.4 3.7 ; 9.2\n\nMean (SD) 95.4 (10.7) 94.7 (10.5) 95.2 (10.6)\nMedian 94.4 93.7 94.2\nP5 ; P95 80.2 ; 114.2 80.5 ; 112.8 80.4 ; 113.5\nMin ; Max 68.1 ; 166.0 66.5 ; 150.5 66.5 ; 166.0", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "18-<65 1198 (91.7) 607 (92.7) 1805 (92.0)\n65-<75 99 ( 7.6) 46 ( 7.0) 145 ( 7.4)\n75-<85 8 ( 0.6) 2 ( 0.3) 10 ( 0.5)\n>=85 1 (<0.1) 0 1 (<0.1)\n\nFemale 955 (73.1) 498 (76.0) 1453 (74.1)\nMale 351 (26.9) 157 (24.0) 508 (25.9)\n\nArgentina 39 ( 3.0) 26 ( 4.0) 65 ( 3.3)\nBelgium 39 ( 3.0) 21 ( 3.2) 60 ( 3.1)\nBulgaria 32 ( 2.5) 13 ( 2.0) 45 ( 2.3)\nCanada 39 ( 3.0) 24 ( 3.7) 63 ( 3.2)\nGermany 70 ( 5.4) 30 ( 4.6) 100 ( 5.1)\nDenmark 34 ( 2.6) 16 ( 2.4) 50 ( 2.5)\nFinland 38 ( 2.9) 22 ( 3.4) 60 ( 3.1)\nFrance 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nUnited Kingdom 135 (10.3) 83 (12.7) 218 (11.1)\nIndia 82 ( 6.3) 35 ( 5.3) 117 ( 6.0)\nJapan 67 ( 5.1) 33 ( 5.0) 100 ( 5.1)\nMexico 47 ( 3.6) 23 ( 3.5) 70 ( 3.6)\nPoland 42 ( 3.2) 18 ( 2.7) 60 ( 3.1)\nRussian Federation 73 ( 5.6) 27 ( 4.1) 100 ( 5.1)\nTaiwan 26 ( 2.0) 9 ( 1.4) 35 ( 1.8)\nUnited States 505 (38.7) 258 (39.4) 763 (38.9)\n\nNot Hispanic or Latino 1118 (85.6) 551 (84.1) 1669 (85.1)\nHispanic or Latino 150 (11.5) 86 (13.1) 236 (12.0)\nNot Applicable 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nUnknown 0 1 ( 0.2) 1 (<0.1)\n\nWhite 973 (74.5) 499 (76.2) 1472 (75.1)\nAsian 181 (13.9) 80 (12.2) 261 (13.3)\nBlack or African American 72 ( 5.5) 39 ( 6.0) 111 ( 5.7)\nNot Applicable 38 ( 2.9) 17 ( 2.6) 55 ( 2.8)\nOther 25 ( 1.9) 8 ( 1.2) 33 ( 1.7)\nAmerican Indian or Alaska Native 17 ( 1.3) 10 ( 1.5) 27 ( 1.4)\nNative Hawaiian or Other Pacific Islander 0 2 ( 0.3) 2 ( 0.1)\n\n<30 81 ( 6.2) 36 ( 5.5) 117 ( 6.0)\n30-<35 436 (33.4) 207 (31.6) 643 (32.8)\n35-<40 406 (31.1) 208 (31.8) 614 (31.3)\n>=40 383 (29.3) 204 (31.1) 587 (29.9)", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 69, "section": "10.2 Demographics and other baseline characteristics"}}, {"excerpt": "Mean (SD) 46 (13) 47 (12) 46 (13)\nMedian 46 48 46\nP5 ; P95 25 ; 68 26 ; 66 25 ; 67\nMin ; Max 18 ; 86 18 ; 82 18 ; 86\n\nMean (SD) 105.4 (22.1) 105.2 (21.5) 105.3 (21.9)\nMedian 102.1 101.3 101.8\nP5 ; P95 76.1 ; 144.3 78.1 ; 143.2 76.6 ; 144.2\nMin; Max 61.8 ; 245.6 66.3 ; 211.0 61.8 ; 245.6\n\nMean (SD) 37.8 (6.7) 38.0 (6.5) 37.9 (6.7)\nMedian 36.7 36.5 36.7\nP5 ; P95 29.7 ; 51.0 29.8 ; 50.6 29.7 ; 50.8\nMin; Max 26.5 ; 83.0 27.5 ; 67.0 26.5 ; 83.0\n\nMean (SD) 114.6 (14.8) 114.8 (14.4) 114.7 (14.6)\nMedian 113.0 113.2 113.0\nP5 ; P95 93.5 ; 140.0 94.0 ; 139.5 94.0 ; 139.7\nMin; Max 85.0 ; 180.0 83.8 ; 182.9 83.8 ; 182.9\n\nMean (SD) 5.7 (0.3) 5.7 (0.3) 5.7 (0.3)\nMedian 5.7 5.7 5.7\nP5 ; P95 5.2 ; 6.2 5.2 ; 6.3 5.2 ; 6.2\nMin; Max 4.1 ; 6.6 4.6 ; 6.6 4.1 ; 6.6\n\nMean (SD) 5.3 (0.6) 5.3 (0.6) 5.3 (0.6)\nMedian 5.2 5.2 5.2\nP5 ; P95 4.5 ; 6.3 4.5 ; 6.3 4.5 ; 6.3\nMin ; Max 3.8 ; 9.2 3.7 ; 8.4 3.7 ; 9.2\n\nMean (SD) 95.4 (10.7) 94.7 (10.5) 95.2 (10.6)\nMedian 94.4 93.7 94.2\nP5 ; P95 80.2 ; 114.2 80.5 ; 112.8 80.4 ; 113.5\nMin ; Max 68.1 ; 166.0 66.5 ; 150.5 66.5 ; 166.0", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 70, "section": "10.2 Demographics and other baseline characteristics"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1600177533", "title": "Patient exposure \u2014 total exposure \u2014 Study 2 treatment 2", "value": "The total exposure time (on-treatment) was 1480.8 vs 720.9 PYE and the total observation time (in-trial) was 1855.4 vs 918.1 PYO for semaglutide 2.4 mg vs placebo, respectively, and reflected the 2:1 randomisation (EOT Table 14.1.23).\n\nN: Number of subjects experiencing at least one event, %: Percentage of subjects experiencing at least one event, E: Number of events, R: Event rate per 100 years, PYE: The duration of the on-treatment period in years.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "The total exposure time (on-treatment) was 1480.8 vs 720.9 PYE and the total observation time (in-trial) was 1855.4 vs 918.1 PYO for semaglutide 2.4 mg vs placebo, respectively, and reflected the 2:1 randomisation (EOT Table 14.1.23).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 73, "section": "10.4.1 Exposure"}}, {"excerpt": "N: Number of subjects experiencing at least one event, %: Percentage of subjects experiencing at least one event, E: Number of events, R: Event rate per 100 years, PYE: The duration of the on-treatment period in years.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 175, "section": "173 of 6980"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1602259726", "title": "Key efficacy outcomes \u2014 Outcome 3 \u2014 difference in survival probability (95% CI) \u2014 Study 2 treatment 2", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": 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Thus, the potential of semaglutide 2.4 mg for weight management was confirmed. The pre-specified sensitivity analyses confirmed the robustness of the primary statistical analysis. The superiority of semaglutide 2.4 mg vs placebo on body weight was also supported by the weight-related secondary confirmatory endpoints. Thus, superiority of semaglutide 2.4 mg vs placebo was confirmed for body weight reduction \u226510% and \u226515% and change in waist circumference at week 68. A greater proportion of subjects achieved weight reduction \u226520% with semaglutide 2.4 mg vs placebo at week 68, and the decrease in mean BMI was greater with semaglutide 2.4 mg vs placebo. Consistent with the change in body weight, the biomarkers for body weight regulation, leptin and soluble leptin receptor, changed as expected for semaglutide 2.4 mg vs placebo. Finally, in a planned sub-population of subjects undergoing DEXA whole body scans, semaglutide 2.4 mg-induced weight loss was accompanied by greater reduction in fat mass than in lean body mass, leading to an improvement in body composition supporting a healthy weight loss. With respect to cardiovascular risk factors, superiority of semaglutide 2.4 mg vs placebo was confirmed for change in systolic blood pressure. In addition, the decrease in mean diastolic blood pressure was greater with semaglutide 2.4 mg vs placebo, and beneficial effects in favour of semaglutide 2.4 mg vs placebo were seen in all fasting blood lipids (total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, free fatty acids and triglycerides) and for the cardiovascular risk-related biomarkers (CRP and PAI-1 activity).\n\nTable 9-4 Protocol-required efficacy laboratory assessments (up to visit 25) Laboratory assessments Parameters Glucose metabolism \uf0b7 Fasting plasma glucosea \uf0b7 HbA1c \uf0b7 Fasting serum insulin Lipids \uf0b7 Cholesterol \uf0b7 HDL cholesterol \uf0b7 LDL cholesterol \uf0b7 Triglycerides \uf0b7 VLDL cholesterol \uf0b7 Free fatty acids Biomarkers \uf0b7 PAI-1 activity \uf0b7 CRP \uf0b7 Leptin \uf0b7 Soluble leptin receptor a An FPG result \u22643.9 mmol/L (70 mg/dL) in relation to planned fasting visits was not considered a hypoglycaemic episode but could be reported as an AE at the discretion of the investigator (Appendix 16.1.1 [Protocol, Appendix 4]).", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "The two estimands in this trial address the same population of interest (i.e. adults with overweight or obesity), cover the same endpoints (i.e. all efficacy-related endpoints) and are based on the same population level summary (the estimated mean treatment contrast between semaglutide and placebo), although the statistical methods applied to estimate the treatment effects differ.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 34, "section": "68 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in all"}}, {"excerpt": "Table 9-9 Major changes made in the statistical analysis plan to the planned statistical analysis in the protocol Change to planned statistical analysis Rationale for change and possible implications It has been added that the secondary estimand will cover all efficacy-related objectives Results from analysis of the secondary estimand are relevant for all objectives.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 62, "section": "9.7.2 Changes in planned analyses prior to trial unblinding"}}, {"excerpt": "From baseline to week 68, superiority of semaglutide 2.4 mg vs placebo was confirmed in the pre-defined fixed-sequence statistical testing hierarchy for the primary endpoints (change in body weight [%] and body weight loss \u22655%) and all confirmatory secondary endpoints (body weight loss \u226510%, body weight loss \u226515%, change in waist circumference, systolic blood pressure, SF-36 physical functioning score and IWQOL-Lite-CT physical function score).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 125, "section": "11.7 Efficacy conclusions"}}, {"excerpt": "Efficacy findings Superiority of semaglutide 2.4 mg vs placebo was confirmed for the two primary endpoints, body weight change (%) from baseline to week 68 and body weight reduction \u22655% at week 68. Thus, the potential of semaglutide 2.4 mg for weight management was confirmed. The pre-specified sensitivity analyses confirmed the robustness of the primary statistical analysis. The superiority of semaglutide 2.4 mg vs placebo on body weight was also supported by the weight-related secondary confirmatory endpoints. Thus, superiority of semaglutide 2.4 mg vs placebo was confirmed for body weight reduction \u226510% and \u226515% and change in waist circumference at week 68. A greater proportion of subjects achieved weight reduction \u226520% with semaglutide 2.4 mg vs placebo at week 68, and the decrease in mean BMI was greater with semaglutide 2.4 mg vs placebo. Consistent with the change in body weight, the biomarkers for body weight regulation, leptin and soluble leptin receptor, changed as expected for semaglutide 2.4 mg vs placebo. Finally, in a planned sub-population of subjects undergoing DEXA whole body scans, semaglutide 2.4 mg-induced weight loss was accompanied by greater reduction in fat mass than in lean body mass, leading to an improvement in body composition supporting a healthy weight loss. With respect to cardiovascular risk factors, superiority of semaglutide 2.4 mg vs placebo was confirmed for change in systolic blood pressure. In addition, the decrease in mean diastolic blood pressure was greater with semaglutide 2.4 mg vs placebo, and beneficial effects in favour of semaglutide 2.4 mg vs placebo were seen in all fasting blood lipids (total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, free fatty acids and triglycerides) and for the cardiovascular risk-related biomarkers (CRP and PAI-1 activity).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 188, "section": "13.1 Discussion"}}, {"excerpt": "Table 9-4 Protocol-required efficacy laboratory assessments (up to visit 25) Laboratory assessments Parameters Glucose metabolism \uf0b7 Fasting plasma glucosea \uf0b7 HbA1c \uf0b7 Fasting serum insulin Lipids \uf0b7 Cholesterol \uf0b7 HDL cholesterol \uf0b7 LDL cholesterol \uf0b7 Triglycerides \uf0b7 VLDL cholesterol \uf0b7 Free fatty acids Biomarkers \uf0b7 PAI-1 activity \uf0b7 CRP \uf0b7 Leptin \uf0b7 Soluble leptin receptor a An FPG result \u22643.9 mmol/L (70 mg/dL) in relation to planned fasting visits was not considered a hypoglycaemic episode but could be reported as an AE at the discretion of the investigator (Appendix 16.1.1 [Protocol, Appendix 4]).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 46, "section": "9.5.2.3 Laboratory assessments for efficacy"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1612865958", "title": "Other-design study \u2014 efficacy endpoint 3 heading", "value": "Odds of achieving baseline body weight loss >=10% at week 68", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Odds of achieving baseline body weight loss >=10% at week 68", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 319, "section": "14.2.1 Overview of confirmatory analyses (test hierarchy) - treatment policy estimand - full analysis"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1615120398", "title": "Efficacy outcome sample \u2014 P value (dichotomous) \u2014 treatment 1", "value": "Sema 2.4 mg / Placebo 2.11 [ 1.53; 2.91] <0.0001", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg / Placebo 2.11 [ 1.53; 2.91] <0.0001", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 465, "section": "14.2.113 SF-36 Physical Functioning change from baseline to week 68 - sensitivity analysis - treatment"}}], "reviewIssues": [{"code": "missing_recommended_evidence", "severity": "warning", "blocksApply": false, "message": "Efficacy outcome sample \u2014 P value (dichotomous) \u2014 treatment 1."}], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1616047389", "title": "Included studies \u2014 Study 2 intervention regimen", "value": "", "outputType": "free_text", "reviewKind": "text", "noEvidence": true, "withheldReason": "related_passages_not_grounded", "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [], "reviewIssues": [{"code": "low_confidence", "severity": "warning", "blocksApply": false, "message": "Autofill marked this suggestion as low confidence. 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28.76] <.0001 0.05 Superiority Confirmed Waist circumference (cm) change from baseline to week 68 Sema 2.4 mg - Placebo -9.42 [-10.30; -8.53] <.0001 0.05 Superiority Confirmed Systolic blood pressure (mmHg) change from baseline to week 68 Sema 2.4 mg - Placebo -5.10 [ -6.34; -3.87] <.0001 0.05 Superiority Confirmed SF-36 Physical Functioning score change from baseline to week 68 Sema 2.4 mg - Placebo 1.80 [ 1.18; 2.42] <.0001 0.05 Superiority Confirmed IWQOL-Lite-CT Physical Function score change from baseline to week 68 Sema 2.4 mg - Placebo 9.43 [ 7.50; 11.35] <.0001 0.05 Superiority Confirmed \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 Est.: Estimate, alpha: Local significance level, CI: Confidence interval, p-value: Unadjusted two-sided p-value for test of no difference. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:16 - tstathier.sas/thier.txt Cross-reference: EOT Table 14.2.1", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Sema 2.4 mg / Placebo 19.26 [ 12.89; 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To mitigate the risk of GI side effects, the trial included an initial 16-week dose-escalation period during which the dose was gradually increased to the maintenance dose of 2.4 mg once weekly. Treatment was continued on the maintenance dose of 2.4 mg once weekly for an additional 52 weeks until week 68 (end of treatment).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 35, "section": "9.1 Description of trial design"}}, {"excerpt": "Concomitant medications included \u2013 candesartan (candesartan), (Con. Med) (amlodipine), (Con. Med ) calcium acetate, magnesium acetate, potassium acetate, sodium acetate, sodium chloride). Treatment medications included \u2013 ibuprofen (ibuprofen), (Con. Med)(piritramide), (Con. Med) (pantoprazole), (Con. Med) (methocarbamol), (Con. Med) (metamizole sodium).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 840, "section": "837 of 6980"}}, {"excerpt": "Concomitant medications included - (Con. Med) (enoxaparin sodium). From 14-Nov-2018 until 20-Nov-2018 . Treatment medications included \u2013 (Con. Med) (enoxaparin sodium) (From 21-Nov-2018 until 27-Nov-2018 ), (Con. Med) (dabigatran etexilate mesilate),(Con. Med) (ferrous sulfate).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 884, "section": "882 of 6980"}}, {"excerpt": "Concomitant medications included - (Con. Med) (ascorbic acid, colecalciferol, cyanocobalamin, docusate sodium, folic acid, magnesium, nicotinamide, pyridoxine hydrochloride, retinol, riboflavin, selenium, thiamine hydrochloride, tocopherol, zinc).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 970, "section": "NOS, VITAMIN E NOS, ZINC), ZINC, VITAMIN B12 (CYANOCOBALAMIN), IRON, IBUPROFEN,"}}, {"excerpt": "Concomitant medications included - (Con. Med) (Con. Med) (DESOGESTREL), (Con. Med) (LEVETIRACETAM), FLUOXETINE, (Con. Med) (Insulin Detemir), SIMVASTATIN.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1159, "section": "1157 of 6980"}}, {"excerpt": "Concomitant medications included - tramadol (tramadol). Treatment medications included - bupivacain (bupivacaine hydrochloride).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1176, "section": "1173 of 6980"}}, {"excerpt": "Concomitant medications included - lisinopril(lisinopril), calcium(calcium), (Con. Med) [ascorbic acid;betacarotene;copper;tocofersolan;zinc](ascorbic acid, betacarotene, copper, tocofersolan, zinc), alpha lipoic acid(thioctic acid), (Con. Med) (ubidecarenone), glucosamine chondroitin [chondroitin sulfate sodium;glucosamine](chondroitin sulfate sodium, glucosamine), (Con. Med)(ascorbic acid, cupric oxide, dl-alpha tocopheryl acetate, xantofyl, zeaxanthin, zinc oxide), cod liver oil(cod-liver oil), rosuvastatin(rosuvastatin), metoprolol(metoprolol), (Con. Med) (macrogol 400, propylene glycol), multivitamins [vitamins nos](multivitamins [vitamins nos]), (Con. Med) (betamethasone dipropionate, clotrimazole), amiodarone(amiodarone), aspirin [acetylsalicylic acid](aspirin [acetylsalicylic acid]).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1117, "section": "1115 of 6980"}}, {"excerpt": "Concomitant medications included - naproxen(naproxen), diclofenac(diclofenac), metaxalone(metaxalone), (Con. Med) (sertraline hydrochloride).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 935, "section": "933 of 6980"}}, {"excerpt": "Concomitant medications included - (Con. Med) (metronidazole, miconazole nitrate), metronidazole (metronidazole). Treatment medications included - (Con. Med) (dydrogesterone), tranexamic acid (tranexamic acid), ceftriaxone (ceftriaxone).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 983, "section": "980 of 6980"}}, {"excerpt": "Concomitant medications included - (Con. Med) ((Con. Med)), (Con. Med) (Con. Med) (Con. Med) (Con.Med) , (Con. Med) (Con. Med) The patient had no history of gallbladder disease and no cholecystectomy had been performed.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1123, "section": "1121 of 6980"}}, {"excerpt": "Concomitant medications included - (Con. Med) (ethinylestradiol, levonorgestrel).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1184, "section": "1182 of 6980"}}, {"excerpt": "Concomitant medications included - (Con. Med) (ETHINYLESTRADIOL, ETONOGESTREL).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1210, "section": "1208 of 6980"}}, {"excerpt": "Concomitant medications included - IBUPROFEN, FOLIC ACID, (Con. Med) (COLECALCIFEROL), RAMIPRIL. Treatment medications included - (Con. Med) (ENOXAPARIN SODIUM), OMEPRAZOL E(OMEPRAZOLE).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1251, "section": "1249 of 6980"}}, {"excerpt": "Concomitant medications included - (Con. Med) (BUDESONIDE, FORMOTEROL FUMARATE). Treatment medications included - PREDNISOLONE, CHLORPHENAMINE, STEROIDS (NOT CODED), NEBS (NEBULIZERS) (NOT CODED), ANTIHISTAMINE (NOT CODED).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 844, "section": "842 of 6980"}}, {"excerpt": "The patient (Med. History) Concomitant medications included - ceftriaxone (ceftriaxone), (Con. Med) (cefalexin).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 847, "section": "845 of 6980"}}, {"excerpt": "Concomitant medications included \u2013 (Con. Med) (pantoprazole sodium sesquihydrate),(Con. Med) (drospirenone, ethinylestradiol). Treatment medications included - (Con. Med) (hydroxyzine), (Con. Med)(ceftriaxone sodium), (Con. Med) (dexamethasone sodium phosphate), (Con. Med) (enoxaparin sodium), (Con. Med) (carvedilol).", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 855, "section": "854 of 6980"}}, {"excerpt": "Concomitant medications included - cefazolin (cefazolin), (Con. Med)(cefalexin). Treatment medications included - (Con. Med) (cefalexin), (Con. 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high density lipoprotein HLGT high-level group term CRP C-reactive protein ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICIQ-UI-SF International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form IEC independent ethics committee IgE Immunoglobulin E IMP investigational medicinal product IND investigational new drug INR international normalized ratio IRB institutional review board ISO International Organization for Standardization IT in-trial IWQOL-Lite-CT Impact of Weight on Quality of Life-Lite for Clinical Trials IWRS interactive voice/web response system J2R-MI jump to reference multiple imputation KDIGO Kidney Disease: Improving Global Outcomes LAO-OT last available observation during the on-treatment period LDL low density lipoprotein MedDRA Medical Dictionary for Regulatory Activities MMRM mixed model for repeated measurements MRI magnetic resonance imaging NCS not clinically significant ND not 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analysis plan SAS safety analysis set s.c. subcutaneous(ly) SD standard deviation SF-36 Short Form 36 v2.0 acute SOC system organ class SPS-6 Stanford Presenteeism Scale STEP Semaglutide Treatment Effect in People with obesity SUSAR suspected unexpected serious adverse reaction T2D type 2 diabetes TEAE treatment emergent adverse event TEE total energy expenditure TP-MI tipping-point multiple imputation TSH thyroid stimulating hormone UK United Kingdom ULN upper limit of normal range US United States of America UTN universal trial number VLDL", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 25, "section": "4 List of abbreviations and definition of terms"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1793804968", "title": "Long-term extension \u2014 patient exposure \u2014 Study 1 treatment 2", "value": "Table 9-1 Trial products 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Across the primary analysis and the four sensitivity analyses, the ETDs for semaglutide 2.4 mg vs placebo and the associated 95% CIs were similar (Figure 11-5, EOT Table 14.2.11). The alignment across the four sensitivity analyses supported the robustness of the conclusions based on the primary analysis for the treatment policy estimand.\n\nFor the treatment policy estimand, four pre-specified sensitivity analyses using different imputation methods (SAP; Appendix 16.1.9) were performed to evaluate the robustness of the conclusions based on the primary analysis towards any impact of the assumptions regarding missing data. Across the primary analysis and the four sensitivity analyses, the ETDs for semaglutide 2.4 mg vs placebo and the associated 95% CIs were similar (Figure 11-7, EOT Table 14.2.27). The alignment across the four sensitivity analyses supported the robustness of the conclusions based on the primary analysis for the treatment policy estimand. Figure 11-7 Odds of achieving \u22655% weight loss at week 68 \u2212 primary and sensitivity statistical analyses \u2013 treatment policy estimand Cross-reference: EOT Figure 14.2.28 Furthermore, a 2-way tipping point analysis in which penalties are applied to both treatment groups (semaglutide 2.4 mg and placebo) was performed for the primary analysis for the treatment policy estimand. The purpose of the tipping point analysis was to identify the penalties required to tip the conclusion from superiority to not being able to confirm superiority based on the primary analysis. For both treatments, no penalty could be added to reverse the conclusion of the primary analysis in the range explored (from -30% to 30% by 1%). Hence, the tipping point sensitivity analysis supported the robustness of the conclusions based on the primary analysis for the treatment policy estimand (EOT Table 14.2.29).", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Figure 11-4 Body weight (%) change from baseline by week \u2013 missing data pattern plot Cross-reference: EOT Figure 14.2.7 Sensitivity analyses For the treatment policy estimand, four pre-specified sensitivity analyses using different imputation methods (SAP; Appendix 16.1.9) were performed to evaluate the robustness of the conclusions based on the primary analysis towards any impact of the assumptions regarding missing data. Across the primary analysis and the four sensitivity analyses, the ETDs for semaglutide 2.4 mg vs placebo and the associated 95% CIs were similar (Figure 11-5, EOT Table 14.2.11). The alignment across the four sensitivity analyses supported the robustness of the conclusions based on the primary analysis for the treatment policy estimand.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 91, "section": "11.3.1.3 Missing data patterns and sensitivity analyses"}}, {"excerpt": "For the treatment policy estimand, four pre-specified sensitivity analyses using different imputation methods (SAP; Appendix 16.1.9) were performed to evaluate the robustness of the conclusions based on the primary analysis towards any impact of the assumptions regarding missing data. Across the primary analysis and the four sensitivity analyses, the ETDs for semaglutide 2.4 mg vs placebo and the associated 95% CIs were similar (Figure 11-7, EOT Table 14.2.27). The alignment across the four sensitivity analyses supported the robustness of the conclusions based on the primary analysis for the treatment policy estimand. Figure 11-7 Odds of achieving \u22655% weight loss at week 68 \u2212 primary and sensitivity statistical analyses \u2013 treatment policy estimand Cross-reference: EOT Figure 14.2.28 Furthermore, a 2-way tipping point analysis in which penalties are applied to both treatment groups (semaglutide 2.4 mg and placebo) was performed for the primary analysis for the treatment policy estimand. The purpose of the tipping point analysis was to identify the penalties required to tip the conclusion from superiority to not being able to confirm superiority based on the primary analysis. For both treatments, no penalty could be added to reverse the conclusion of the primary analysis in the range explored (from -30% to 30% by 1%). 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"Patient disposition \u2014 Study 1 treatment 2", "value": "Subject ID 708893, Case Number (ID) Preferred term Weight increased Narrative category Death No SAE Yes SUSAR Yes Case unblinded during the trial Yes The case was: Broken by Sponsor AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Subject ID 708893, Case Number (ID) Preferred term Weight increased Narrative category Death No SAE Yes SUSAR Yes Case unblinded during the trial Yes The case was: Broken by Sponsor AE of special interest No Pregnancy No Case description Trial ID: NN9536-4373 Trial title: A 68-week, randomised, double-blinded, placebo-controlled, two-armed, parallel group, multicentre, multinational clinical trial comparing semaglutide subcutaneous 2.4 mg once-weekly with semaglutide placebo once-weekly, in subjects with overweight or obesity.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 1078, "section": "1077 of 6980"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1880334514", "title": "Adverse events of special interest", "value": "Adverse events of special interest\nGastrointestinal disorders (OT) 969 (74.2) 4309 252.6 314 (47.9) 739 89.1\nGallbladder-related disorders (OT) 34 ( 2.6) 42 2.5 8 ( 1.2) 8 1.0\nAcute pancreatitis (OT)# 3 ( 0.2) 3 0.2 0\nCardiovascular disorders (IT) 107 ( 8.2) 134 7.2 75 (11.5) 96 10.5\nAll neoplasms (IT) 93 ( 7.1) 112 6.0 49 ( 7.5) 56 6.1\nMalignant neoplasms (IT) 14 ( 1.1) 14 0.8 7 ( 1.1) 7 0.8\nHepatic events (OT) 31 ( 2.4) 37 2.2 20 ( 3.1) 24 2.9\nAcute renal failure (OT) 3 ( 0.2) 4 0.2 2 ( 0.3) 2 0.2\nHypoglycaemia (OT) 8 ( 0.6) 15 0.9 5 ( 0.8) 7 0.8\nInjection site reactions (OT) 65 ( 5.0) 99 5.8 44 ( 6.7) 82 9.9\nAllergic reactions (OT) 96 ( 7.4) 108 6.3 54 ( 8.2) 63 7.6\nPsychiatric disorders (OT) 124 ( 9.5) 160 9.4 83 (12.7) 113 13.6\nRare events (OT) 7 ( 0.5) 7 0.4 5 ( 0.8) 6 0.7\nMedication errors (OT) 15 ( 1.1) 15 0.9 5 ( 0.8) 6 0.7\nOverdose (OT) 11 ( 0.8) 11 0.6 5 ( 0.8) 6 0.7\nAbuse or misuse (OT) 0 1 ( 0.2) 1 0.1\nSuspected transmission of infectious agent (IT) 0 0\n\nFor most of the predefined safety focus areas there were no differences between semaglutide 2.4 mg and placebo (Table 12-2). 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Subjects with T2D and overweight or obesity are addressed in a dedicated trial (NN9536-4374 [STEP 2]). First-line treatment in weight management is lifestyle modification with reduced-calorie diet and increased physical activity, therefore only subjects who had tried but failed a dietary weight loss intervention were included.\n\nThe sample size and thereby the power for the trial was defined to support the safety evaluation, although no statistical inference was planned for safety assessments, and to fulfil regulatory requirements for number of exposed subjects across the programme. 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After that DBL, 2 country-level PDs, 16 site-level PDs and 15 subject-level PDs were identified and added with a cut-off date of 01 July 2020 (corresponding to the DBL covering anti-semaglutide antibody data and PK data).\n\nThe subjects affected were from the US, Canada, Mexico, UK, Denmark, Finland, India and Argentina.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 76, "section": "10.6.1 Summary of important protocol deviations"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1994652249", "title": "Included studies \u2014 Study 1 enrolment start date", "value": "Patient's BMI: (BMI) This Clinical Trial case from the (Country) was reported by an Investigator as \"Acute uncomplicated appendicitis\" and concerned a 47 Years old Female patient who was treated with Blinded Semaglutide (NN9536-4373) from 15-Aug-2018 to 29-Jan-2019 and restarted on 06-Feb-2019 at a reduced dose and ongoing due to \"Obesity\".", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Patient's BMI: (BMI) This Clinical Trial case from the (Country) was reported by an Investigator as \"Acute uncomplicated appendicitis\" and concerned a 47 Years old Female patient who was treated with Blinded Semaglutide (NN9536-4373) from 15-Aug-2018 to 29-Jan-2019 and restarted on 06-Feb-2019 at a reduced dose and ongoing due to \"Obesity\".", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 920, "section": "917 of 6980"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "1996243408", "title": "Statistical analysis \u2014 Study 1 additional endpoint missing data", "value": "It is clarified that RD-MI imputation was performed according to the timing of last available observation during the on-treatment period (LAO-OT) for all endpoints. Furthermore, it is clarified that the LAO-OT must be prior to the landmark visit (week 68). To clarify that the grouping of subjects according to timing is as in the publication by McEvoy.\n\nAnalysis of data from on-treatment period, A time-point is considered as on-treatment if any dose of trial product has been administered within the prior 14 days., MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline value of the endpoint as covariate, all nested within visit, The MMRM was performed on week 68 value of the endpoint and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for the response threshold of the endpoint and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline value of the endpoint as covariate. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:18 - tstatlogregx.sas/tmmrmxresp.txt\n\nMMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline waist circumference as covariate, all nested within visit. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:22 - tstatmmrm.sas/tmmrmwc.txt\n\nMMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit. The MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss >= 10% and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline body weight as covariate.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "It is clarified that RD-MI imputation was performed according to the timing of last available observation during the on-treatment period (LAO-OT) for all endpoints. Furthermore, it is clarified that the LAO-OT must be prior to the landmark visit (week 68). To clarify that the grouping of subjects according to timing is as in the publication by McEvoy.", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 62, "section": "9.7.2 Changes in planned analyses prior to trial unblinding"}}, {"excerpt": "Analysis of data from on-treatment period, A time-point is considered as on-treatment if any dose of trial product has been administered within the prior 14 days., MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline value of the endpoint as covariate, all nested within visit, The MMRM was performed on week 68 value of the endpoint and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for the response threshold of the endpoint and analysed using a binary logistic regression (LR) model with randomised treatment as factor and baseline value of the endpoint as covariate. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:18 - tstatlogregx.sas/tmmrmxresp.txt", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 515, "section": "14.2.152 Odds of achieving response in non-weight-related endpoints since baseline at week 68 -"}}, {"excerpt": "MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline waist circumference as covariate, all nested within visit. nn9536/nn9536-4373/ctr_20200811_er 07AUG2020:15:59:22 - tstatmmrm.sas/tmmrmwc.txt", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 376, "section": "14.2.60 Waist circumference change from baseline to week 68 - statistical analysis - hypothetical"}}, {"excerpt": "MMRM: All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit. 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2303\nScreening failures 305\nWithdrawn before randomisation 37\nRandomised 1306 ( 100) 655 ( 100) 1961 ( 100)\nRandomised in violation of incl., excl. and/or 17 ( 1.3) 9 ( 1.4) 26 ( 1.3)\nrandomisation criteria\nExposed 1306 ( 100) 655 ( 100) 1961 ( 100)\nAnalysis sets\nFull analysis set 1306 ( 100) 655 ( 100) 1961 ( 100)\nSafety analysis set 1306 ( 100) 655 ( 100) 1961 ( 100)\nTreatment completion\nOn-treatment at week 68 (treatment completers) 1083 (82.9) 508 (77.6) 1591 (81.1)\nAfter at least one temporary interruption 119 ( 9.1) 58 ( 8.9) 177 ( 9.0)\nAttended end-of-treatment visit without permanent 1080 (82.7) 506 (77.3) 1586 (80.9)\ndiscontinuation of trial product\nTrial product permanently discontinued 223 (17.1) 147 (22.4) 370 (18.9)\nPrimary reason for permanent discontinuation of\ntrial product\nAdverse event 91 ( 7.0) 21 ( 3.2) 112 ( 5.7)\nProtocol violation 3 ( 0.2) 5 ( 0.8) 8 ( 0.4)\nRandomised in violation of incl., excl. and/or 2 ( 0.2) 2 ( 0.3) 4 ( 0.2)\nrandomisation criteria\nIntention of becoming pregnant 0 1 ( 0.2) 1 (<0.1)\nOther 1 (<0.1) 2 ( 0.3) 3 ( 0.2)\nPregnancy 7 ( 0.5) 3 ( 0.5) 10 ( 0.5)\nLack of efficacy 1 (<0.1) 16 ( 2.4) 17 ( 0.9)\nAt the discretion of the investigator 4 ( 0.3) 1 ( 0.2) 5 ( 0.3)\nSafety concern as judged by the investigator 15 ( 1.1) 0 15 ( 0.8)\nWithdrawal of consent 9 ( 0.7) 10 ( 1.5) 19 ( 1.0)\nLost to follow-up 26 ( 2.0) 25 ( 3.8) 51 ( 2.6)\nOther 67 ( 5.1) 66 (10.1) 133 ( 6.8)\nAttended end-of-treatment visit after permanent 161 (12.3) 95 (14.5) 256 (13.1)\ndiscontinuation of trial product\n\nSubject disposition - summary - all subjects\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nTrial completion\nAttended end-of-trial visit (trial completers) 1240 (94.9) 609 (93.0) 1849 (94.3)\nAttended end-of-trial visit and end-of-treatment 1072 (82.1) 506 (77.3) 1578 (80.5)\nvisit without permanent discontinuation of trial\nproduct\nWithdrawn from trial 66 ( 5.1) 46 ( 7.0) 112 ( 5.7)\nPrimary reason for trial withdrawal\nWithdrawal by subject 26 ( 2.0) 17 ( 2.6) 43 ( 2.2)\nLost to follow-up 39 ( 3.0) 28 ( 4.3) 67 ( 3.4)\nDeath 1 (<0.1) 1 ( 0.2) 2 ( 0.1)\nWithdrawn from trial before week 68 43 ( 3.3) 35 ( 5.3) 78 ( 4.0)\nWithdrawn from trial without prior permanent 3 ( 0.2) 4 ( 0.6) 7 ( 0.4)\ndiscontinuation of trial product\n\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nIncluded in DEXA subpopulation 95 ( 100) 45 ( 100) 140 ( 100)\nIncluded in violation of inclusion criterion to have 2 ( 2.1) 1 ( 2.2) 3 ( 2.1)\nscreening BMI <= 40 kg/m^2\nExposed 95 ( 100) 45 ( 100) 140 ( 100)\nAnalysis sets\nFull analysis set 95 ( 100) 45 ( 100) 140 ( 100)\nSafety analysis set 95 ( 100) 45 ( 100) 140 ( 100)\nTreatment completion\nOn-treatment at week 68 (treatment completers) 77 (81.1) 31 (68.9) 108 (77.1)\nAfter at least one temporary interruption 9 ( 9.5) 0 9 ( 6.4)\nAttended end-of-treatment visit without permanent 77 (81.1) 31 (68.9) 108 (77.1)\ndiscontinuation of trial product\nTrial product permanently discontinued 18 (18.9) 14 (31.1) 32 (22.9)\nPrimary reason for permanent discontinuation of\ntrial product\nAdverse event 9 ( 9.5) 2 ( 4.4) 11 ( 7.9)\nWithdrawal of consent 2 ( 2.1) 1 ( 2.2) 3 ( 2.1)\nLost to follow-up 1 ( 1.1) 0 1 ( 0.7)\nOther 6 ( 6.3) 11 (24.4) 17 (12.1)\nAttended end-of-treatment visit after permanent 13 (13.7) 12 (26.7) 25 (17.9)\ndiscontinuation of trial product\nTrial completion\nAttended end-of-trial visit (trial completers) 91 (95.8) 44 (97.8) 135 (96.4)\nAttended end-of-trial visit and end-of-treatment 76 (80.0) 31 (68.9) 107 (76.4)\nvisit without permanent discontinuation of trial\nproduct\n\nSubject disposition - summary - DEXA subpopulation\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nWithdrawn from trial 4 ( 4.2) 1 ( 2.2) 5 ( 3.6)\nPrimary reason for trial withdrawal\nWithdrawal by subject 2 ( 2.1) 1 ( 2.2) 3 ( 2.1)\nLost to follow-up 2 ( 2.1) 0 2 ( 1.4)\nWithdrawn from trial before week 68 3 ( 3.2) 1 ( 2.2) 4 ( 2.9)\nWithdrawn from trial without prior permanent 0 0 0\ndiscontinuation of trial product\n\nScreened Randomised Treatment completers [a] Trial completers [b]\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSites Subjects Sites Subjects Subjects Subjects\nN N N N (%) [c] N (%) [d] N (%) [d]\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nTotal 129 2303 129 1961 (85.1) 1591 (81.1) 1849 (94.3)\nRegion\nEurope 55 857 55 748 (87.3) 617 (82.5) 701 (93.7)\nNorth America 47 999 47 826 (82.7) 647 (78.3) 767 (92.9)\nSouth America 8 151 8 135 (89.4) 116 (85.9) 133 (98.5)\nAsia (excluding East Asia) 13 150 13 117 (78.0) 84 (71.8) 115 (98.3)\nEast Asia 6 146 6 135 (92.5) 127 (94.1) 133 (98.5)\nCountry\nArgentina 5 69 5 65 (94.2) 58 (89.2) 64 (98.5)\nBelgium 5 66 5 60 (90.9) 47 (78.3) 59 (98.3)\nBulgaria 5 47 5 45 (95.7) 43 (95.6) 43 (95.6)\nCanada 7 74 7 63 (85.1) 47 (74.6) 60 (95.2)\nGermany 13 118 13 100 (84.7) 87 (87.0) 98 (98.0)\nDenmark 1 57 1 50 (87.7) 43 (86.0) 48 (96.0)\nFinland 2 63 2 60 (95.2) 54 (90.0) 58 (96.7)\nFrance 7 61 7 55 (90.2) 47 (85.5) 53 (96.4)\nUnited Kingdom 10 266 10 218 (82.0) 148 (67.9) 185 (84.9)\nIndia 13 150 13 117 (78.0) 84 (71.8) 115 (98.3)\nJapan 5 107 5 100 (93.5) 94 (94.0) 99 (99.0)\nMexico 3 82 3 70 (85.4) 58 (82.9) 69 (98.6)\nPoland 4 72 4 60 (83.3) 53 (88.3) 57 (95.0)\nRussian Federation 8 107 8 100 (93.5) 95 (95.0) 100 ( 100)\nTaiwan 1 39 1 35 (89.7) 33 (94.3) 34 (97.1)\nUnited States 40 925 40 763 (82.5) 600 (78.6) 707 (92.7)\nSite\nSite 1 15 1 14 (93.3) 11 (78.6) 14 ( 100)\nSite 1 13 1 11 (84.6) 7 (63.6) 10 (90.9)\nSite 1 17 1 14 (82.4) 10 (71.4) 14 ( 100)", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", "sourceEvidence": [{"excerpt": "Screened 2303\nScreening failures 305\nWithdrawn before randomisation 37\nRandomised 1306 ( 100) 655 ( 100) 1961 ( 100)\nRandomised in violation of incl., excl. and/or 17 ( 1.3) 9 ( 1.4) 26 ( 1.3)\nrandomisation criteria\nExposed 1306 ( 100) 655 ( 100) 1961 ( 100)\nAnalysis sets\nFull analysis set 1306 ( 100) 655 ( 100) 1961 ( 100)\nSafety analysis set 1306 ( 100) 655 ( 100) 1961 ( 100)\nTreatment completion\nOn-treatment at week 68 (treatment completers) 1083 (82.9) 508 (77.6) 1591 (81.1)\nAfter at least one temporary interruption 119 ( 9.1) 58 ( 8.9) 177 ( 9.0)\nAttended end-of-treatment visit without permanent 1080 (82.7) 506 (77.3) 1586 (80.9)\ndiscontinuation of trial product\nTrial product permanently discontinued 223 (17.1) 147 (22.4) 370 (18.9)\nPrimary reason for permanent discontinuation of\ntrial product\nAdverse event 91 ( 7.0) 21 ( 3.2) 112 ( 5.7)\nProtocol violation 3 ( 0.2) 5 ( 0.8) 8 ( 0.4)\nRandomised in violation of incl., excl. and/or 2 ( 0.2) 2 ( 0.3) 4 ( 0.2)\nrandomisation criteria\nIntention of becoming pregnant 0 1 ( 0.2) 1 (<0.1)\nOther 1 (<0.1) 2 ( 0.3) 3 ( 0.2)\nPregnancy 7 ( 0.5) 3 ( 0.5) 10 ( 0.5)\nLack of efficacy 1 (<0.1) 16 ( 2.4) 17 ( 0.9)\nAt the discretion of the investigator 4 ( 0.3) 1 ( 0.2) 5 ( 0.3)\nSafety concern as judged by the investigator 15 ( 1.1) 0 15 ( 0.8)\nWithdrawal of consent 9 ( 0.7) 10 ( 1.5) 19 ( 1.0)\nLost to follow-up 26 ( 2.0) 25 ( 3.8) 51 ( 2.6)\nOther 67 ( 5.1) 66 (10.1) 133 ( 6.8)\nAttended end-of-treatment visit after permanent 161 (12.3) 95 (14.5) 256 (13.1)\ndiscontinuation of trial product", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 191, "section": "14.1.1 Subject disposition - summary - all subjects"}}, {"excerpt": "Subject disposition - summary - all subjects\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nTrial completion\nAttended end-of-trial visit (trial completers) 1240 (94.9) 609 (93.0) 1849 (94.3)\nAttended end-of-trial visit and end-of-treatment 1072 (82.1) 506 (77.3) 1578 (80.5)\nvisit without permanent discontinuation of trial\nproduct\nWithdrawn from trial 66 ( 5.1) 46 ( 7.0) 112 ( 5.7)\nPrimary reason for trial withdrawal\nWithdrawal by subject 26 ( 2.0) 17 ( 2.6) 43 ( 2.2)\nLost to follow-up 39 ( 3.0) 28 ( 4.3) 67 ( 3.4)\nDeath 1 (<0.1) 1 ( 0.2) 2 ( 0.1)\nWithdrawn from trial before week 68 43 ( 3.3) 35 ( 5.3) 78 ( 4.0)\nWithdrawn from trial without prior permanent 3 ( 0.2) 4 ( 0.6) 7 ( 0.4)\ndiscontinuation of trial product", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 192, "section": "14.1.1 Subject disposition - summary - all subjects"}}, {"excerpt": "Sema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nIncluded in DEXA subpopulation 95 ( 100) 45 ( 100) 140 ( 100)\nIncluded in violation of inclusion criterion to have 2 ( 2.1) 1 ( 2.2) 3 ( 2.1)\nscreening BMI <= 40 kg/m^2\nExposed 95 ( 100) 45 ( 100) 140 ( 100)\nAnalysis sets\nFull analysis set 95 ( 100) 45 ( 100) 140 ( 100)\nSafety analysis set 95 ( 100) 45 ( 100) 140 ( 100)\nTreatment completion\nOn-treatment at week 68 (treatment completers) 77 (81.1) 31 (68.9) 108 (77.1)\nAfter at least one temporary interruption 9 ( 9.5) 0 9 ( 6.4)\nAttended end-of-treatment visit without permanent 77 (81.1) 31 (68.9) 108 (77.1)\ndiscontinuation of trial product\nTrial product permanently discontinued 18 (18.9) 14 (31.1) 32 (22.9)\nPrimary reason for permanent discontinuation of\ntrial product\nAdverse event 9 ( 9.5) 2 ( 4.4) 11 ( 7.9)\nWithdrawal of consent 2 ( 2.1) 1 ( 2.2) 3 ( 2.1)\nLost to follow-up 1 ( 1.1) 0 1 ( 0.7)\nOther 6 ( 6.3) 11 (24.4) 17 (12.1)\nAttended end-of-treatment visit after permanent 13 (13.7) 12 (26.7) 25 (17.9)\ndiscontinuation of trial product\nTrial completion\nAttended end-of-trial visit (trial completers) 91 (95.8) 44 (97.8) 135 (96.4)\nAttended end-of-trial visit and end-of-treatment 76 (80.0) 31 (68.9) 107 (76.4)\nvisit without permanent discontinuation of trial\nproduct", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 193, "section": "14.1.2 Subject disposition - summary - DEXA subpopulation"}}, {"excerpt": "Subject disposition - summary - DEXA subpopulation\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSema 2.4 mg Placebo Total\nN (%) N (%) N (%)\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nWithdrawn from trial 4 ( 4.2) 1 ( 2.2) 5 ( 3.6)\nPrimary reason for trial withdrawal\nWithdrawal by subject 2 ( 2.1) 1 ( 2.2) 3 ( 2.1)\nLost to follow-up 2 ( 2.1) 0 2 ( 1.4)\nWithdrawn from trial before week 68 3 ( 3.2) 1 ( 2.2) 4 ( 2.9)\nWithdrawn from trial without prior permanent 0 0 0\ndiscontinuation of trial product", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 194, "section": "14.1.2 Subject disposition - summary - DEXA subpopulation"}}, {"excerpt": "Screened Randomised Treatment completers [a] Trial completers [b]\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014 \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nSites Subjects Sites Subjects Subjects Subjects\nN N N N (%) [c] N (%) [d] N (%) [d]\n\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\nTotal 129 2303 129 1961 (85.1) 1591 (81.1) 1849 (94.3)\nRegion\nEurope 55 857 55 748 (87.3) 617 (82.5) 701 (93.7)\nNorth America 47 999 47 826 (82.7) 647 (78.3) 767 (92.9)\nSouth America 8 151 8 135 (89.4) 116 (85.9) 133 (98.5)\nAsia (excluding East Asia) 13 150 13 117 (78.0) 84 (71.8) 115 (98.3)\nEast Asia 6 146 6 135 (92.5) 127 (94.1) 133 (98.5)\nCountry\nArgentina 5 69 5 65 (94.2) 58 (89.2) 64 (98.5)\nBelgium 5 66 5 60 (90.9) 47 (78.3) 59 (98.3)\nBulgaria 5 47 5 45 (95.7) 43 (95.6) 43 (95.6)\nCanada 7 74 7 63 (85.1) 47 (74.6) 60 (95.2)\nGermany 13 118 13 100 (84.7) 87 (87.0) 98 (98.0)\nDenmark 1 57 1 50 (87.7) 43 (86.0) 48 (96.0)\nFinland 2 63 2 60 (95.2) 54 (90.0) 58 (96.7)\nFrance 7 61 7 55 (90.2) 47 (85.5) 53 (96.4)\nUnited Kingdom 10 266 10 218 (82.0) 148 (67.9) 185 (84.9)\nIndia 13 150 13 117 (78.0) 84 (71.8) 115 (98.3)\nJapan 5 107 5 100 (93.5) 94 (94.0) 99 (99.0)\nMexico 3 82 3 70 (85.4) 58 (82.9) 69 (98.6)\nPoland 4 72 4 60 (83.3) 53 (88.3) 57 (95.0)\nRussian Federation 8 107 8 100 (93.5) 95 (95.0) 100 ( 100)\nTaiwan 1 39 1 35 (89.7) 33 (94.3) 34 (97.1)\nUnited States 40 925 40 763 (82.5) 600 (78.6) 707 (92.7)\nSite\nSite 1 15 1 14 (93.3) 11 (78.6) 14 ( 100)\nSite 1 13 1 11 (84.6) 7 (63.6) 10 (90.9)\nSite 1 17 1 14 (82.4) 10 (71.4) 14 ( 100)", "location": {"documentName": "Phase3a-STEP1-report.pdf", "pageNumber": 195, "section": "14.1.3 Subject disposition by region, country and site - summary - all subjects"}}], "reviewIssues": [], "review": null, "version": "738a1560-50a6-4132-9091-f1efd02babac", "picoId": "pico_5865b6db8b8b", "sourceMaterialId": "ast_e88a541a073f"}, {"fieldId": "2025125224", "title": "Economic evaluation \u2014 treatment", "value": "The present trial was the main efficacy and safety trial in the STEP programme and designed to show that s.c. semaglutide 2.4 mg once weekly, as an adjunct to a reduced-calorie diet and increased physical activity, is an effective and safe option for treatment of overweight or obesity.", "outputType": "free_text", "reviewKind": "text", "noEvidence": false, "currentValue": "", "currentAnswer": "", "currentContentKind": "empty", 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Thus, the potential of semaglutide 2.4 mg for weight management was confirmed.\n\nThe superiority of semaglutide 2.4 mg vs placebo on body weight was also supported by the weight-related secondary confirmatory endpoints. Thus, superiority of semaglutide 2.4 mg vs placebo was confirmed for body weight reduction \u226510% and \u226515% and change in waist circumference at week 68. A greater proportion of subjects achieved weight reduction \u226520% with semaglutide 2.4 mg vs placebo at week 68, and the decrease in mean BMI was greater with semaglutide 2.4 mg vs placebo.\n\nWith respect to cardiovascular risk factors, superiority of semaglutide 2.4 mg vs placebo was confirmed for change in systolic blood pressure. 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