STEP 1: Research Study Investigating How Well Semaglutide Works in People Suffering From Overweight or Obesity

Study Overview
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Brief Summary
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This study will look at the change in participants' body weight from the start to the end of the study. The weight loss in participants taking semaglutide (a new medicine) will be compared to the weight loss of participants taking dummy medicine. In addition to taking the medicine, participants will have talks with study staff about healthy food choices, how to be more physically active and what you can do to lose weight. Participants will either get semaglutide or dummy medicine - which treatment participants get, is decided by chance. Participants will need to take 1 injection once a week. The study medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm. The study has two phases: A main phase and an extension phase.The main phase will last for about 1.5 years. Participants will have 15 clinic visits and 10 phone calls with the study doctor. Extension phase: Approximately 300 participants will continue in the extension phase in the following countries only: Canada, Germany, the UK and selected sites in the US and Japan. These participants will be in the study for about 2.5 years.They will not receive treatment, but will attend another 5 follow-up visits with the study doctor.

Official Title
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Effect and Safety of Semaglutide 2.4 mg Once-weekly in Subjects With Overweight or Obesity

Conditions
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Metabolism and Nutrition Disorder, Overweight or Obesity

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Placebo (semaglutide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Main phase: Male or female, age greater than or equal to 18 years at the time of signing informed consent Body mass index (BMI) greater than or equal to 30.0 kg/sqm or greater than or equal to 27.0 kg/sqm with the presence of at least one of the following weight-related comorbidities (treated or untreated): hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease History of at least one self-reported unsuccessful dietary effort to lose body weight Extension phase: Informed consent for the extension phase obtained before any trial related activities for the extension phase On randomised treatment on the target dose at week 68, i.e. treated with 2.4 mg semaglutide once-weekly or semaglutide placebo Exclusion Criteria: Main phase: Glycated haemoglobin (HbA1C) greater than or equal to 48 mmol/mol (6.5%) as measured by the central laboratory at screening A self-reported change in body weight greater than 5 kg (11 lbs) within 90 days before screening irrespective of medical records Extension phase: Female who is pregnant or intends to become pregnant during the extension phase Any disorder, unwillingness or inability, not covered by any of the other exclusion criteria, which in the investigator's opinion, might jeopardise the subject's compliance with the extension of the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide s.c. 2.4 mg once weekly<br>Participants will receive semaglutide for 68 weeks. | Drug: Semaglutide<br>* Participants will receive semaglutide subcutaneous (s.c.; under the skin) injection(s) once-weekly as well as diet and physical activity counselling for 68 weeks. Dose escalation of semaglutide will take place as follows: 0.25 mg from week 1 to 4, 0.5 mg from week 5 to 8, 1.0 mg from week 9 to 12, 1.7 mg from week 13 to 16 and 2.4 mg from week 17 to week 68.<br>|
| Placebo Comparator: Semaglutide placebo<br>Participants will receive semaglutide matching placebo for 68 weeks. | Drug: Placebo (semaglutide)<br>* Participants will receive semaglutide matching placebo s.c. injection(s) once-weekly as well as diet and physical activity counselling for 68 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight (%) | Change in body weight from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from both in-trial and on-treatment observation periods. In-trial observation period: the uninterrupted time interval from date of randomization (week 0) to date of last contact with trial site (week 75). On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68), including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period). | Baseline (week 0) to week 68 | 
| Participants Who Achieve 5 or More Percent Body Weight Reduction (Yes/no) | Number of participants who achieved weight loss more than or equal to 5% (yes/no) at week 68 are presented. The endpoint was evaluated based on the data from both in-trial and on-treatment observation periods. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68), including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. | After week 68 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects Who Achieve 10 or More Percent Body Weight Reduction (Yes/no) | Number of participants who achieved weight loss more than or equal to (≥) 10% at week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from date of randomization (week 0) to date of last contact with trial site (week 75). | Week 68 | 
| Participants Who Achieve 15 or More Percent Body Weight Reduction (Yes/no) | Number of participants who achieved more than or equal to (≥) 15% weight loss at week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Week 68 | 
| Participants Who Achieve 20 or More Percent Body Weight Reduction (Yes/no) | Number of participants who achieved more than or equal to (≥) 20% weight loss at week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Week 68 | 
| Change in Waist Circumference (cm) | Change in waist circumference from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to date of last contact with trial site (week 75). | Baseline (week 0) to week 68 | 
| Change in Systolic Blood Pressure (mmHg) | Change in systolic blood pressure from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to date of last contact with trial site (week 75). | Baseline (week 0) to week 68 | 
| Change in Short Form 36 (SF-36) | SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary and mental component summary). In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation, respectively, for the 2009 US general population. Change from week 0 in the domain scores and component summary scores were evaluated at week 68. A positive change score indicates an improvement since baseline. These endpoints were evaluated based on the data from in-trial observation period which is the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Impact of Weight on Quality of Life-Lite for Clinical Trial (IWQoL-Lite for CT) Score | IWQoL-Lite for CT is a modified version of an instrument designed to assess weight-related quality of life. It is used to assess the impact of body weight changes on patients' physical and psychosocial functioning in three composite scores (physical function, physical and psychosocial) and a total score. The scores range between 0-100 where higher scores indicate a better quality of life. A positive change score indicates an improvement since baseline. These endpoints were evaluated based on the data from in-trial observation period which is the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Weight (kg) | Change in body weight from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Mass Index (BMI) (kg/m2) | Change in body mass index from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in HbA1C (%) | Change in glycosylated haemoglobin (HbA1c) from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in HbA1C (mmol/Mol) | Change in HbA1c from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Fasting Plasma Glucose (FPG) (mg/dL) | Change in fasting plasma glucose from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Fasting Serum Insulin (mIU/L) - Ratio to Baseline | Change in fasting serum insulin from week 0 to week 68 is presented as ratio to baseline. Fasting serum insulin was measured in milli-international units per milliliter (mIU/mL). The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Diastolic Blood Pressure (mmHg) | Change in diastolic blood pressure from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Total Cholesterol (mg/dL) - Ratio to Baseline | Change in fasting total cholesterol from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in High-density Lipoproteins (HDL) (mg/dL) - Ratio to Baseline | Change in fasting HDL from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Low-density Lipoproteins (LDL) (mg/dL) - Ratio to Baseline | Change in fasting LDL from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Very Low-density Lipoproteins (VLDL) (mg/dL) - Ratio to Baseline | Change in fasting VLDL from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Free Fatty Acids (mg/dL) - Ratio to Baseline | Change in fasting free fatty acids from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Triglycerides (mg/dL) - Ratio to Baseline | Change in fasting triglycerides from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in High Sensitivity C-Reactive Protein (hsCRP) - (mg/L) - Ratio to Baseline | Change in high sensitivity C-reactive protein from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Plasminogen Activator Inhibitor-1 (PAI-1) Activity (AU/ml) - Ratio to Baseline | Change in plasminogen activator inhibitor-1 activity from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Soluble Leptin Receptor (ng/mL) - Ratio to Baseline | Change in soluble leptin receptor from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Leptin (ng/mL) - Ratio to Baseline | Change in leptin from baseline (week 0) to week 68 is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Composition (Total Fat Mass) (%) | Change in body composition (total fat mass) from baseline (week 0) to week 68 is presented. Body composition was assessed using Dual Energy X-ray Absorpmetry (DEXA). The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Composition (Total Fat Mass) (kg) | Change in body composition (total fat mass) from baseline (week 0) to week 68 is presented. Body composition was assessed using Dual Energy X-ray Absorpmetry (DEXA). The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Composition (Lean Body Mass) (%) | Change in body composition (lean body mass) from baseline (week 0) to week 68 is presented. Body composition was assessed using DEXA. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Composition (Lean Body Mass) (kg) | Change in body composition (lean body mass) from baseline (week 0) to week 68 is presented. Body composition was assessed using DEXA. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Composition (Visceral Fat Mass) (%) | Change in body composition (visceral fat mass) from baseline (week 0) to week 68 is presented. Body composition was assessed using DEXA. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Composition (Visceral Fat Mass) (kg) | Change in body composition (visceral fat mass) from baseline (week 0) to week 68 is presented. Body composition was assessed using DEXA. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Weight (%) - DEXA Subpopulation | Change in body weight from baseline (week 0) to week 68 is presented in DEXA subpopulation. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Change in Body Weight (kg) - DEXA Subpopulation | Change in body weight from baseline (week 0) to week 68 is presented in DEXA subpopulation. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). | Baseline (week 0) to week 68 | 
| Participants Who Achieve Responder Definition Value (Yes/no) for SF-36 Physical Functioning Score | The observed number of participants experiencing a meaningful within participant improvement in SF-36 Physical function after 68 weeks was determined based on two different thresholds. The threshold of 4.3 is the default generic responder threshold defined in SF-36 manual for a general population. The threshold of 3.7 is specific for the population with overweight or obesity included in the study and calculated using patient global rating anchor questionnaires to reflect participants' own perspective based on FDA recommendations. In the reported data, Yes infers the number of participants who have achieved an improvement in score greater than or equal to the threshold and No infers number of participants who have not achieved an improvement in score greater than or equal to the threshold. The endpoint was evaluated based on the in-trial observation period which is the uninterrupted time interval from randomization (week 0) to last trial related subject-site contact (week 75). | After week 68 | 
| Participants Who Achieve Responder Definition Value (Yes/no) for IWQoL-Lite for CT Physical Function Domain (5-items) Score | The observed number of participants experiencing a meaningful within participant improvement in IWQOL-Lite-CT physical function after 68 weeks was determined based on two different thresholds. The threshold of 20 was a preliminary responder threshold based on earlier studies. The threshold of 14.6 is specific for the population with overweight or obesity included in the study and calculated using patient global rating anchor questionnaires to reflect participants' own perspective based on FDA recommendations. In the reported data, Yes infers the number of participants who have achieved an improvement in score greater than or equal to the threshold and No infers the number of participants who have not achieved an improvement in score greater than or equal to the threshold. The endpoint was evaluated based on the in-trial observation period. In trial observation period: the uninterrupted time interval from randomization (week 0) to last trial related subject-site contact (week 75). | After week 68 | 
| Number of Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. All AEs mentioned here are treatment emergent adverse events (TEAE) defined as an event for which the onset of the event occurs in the on-treatment period. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68), including 7 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 7 consecutive missed doses (off-treatment period). | Baseline (week 0) to week 75 | 
| Number of Serious Adverse Events (SAEs) | A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, or is life-threatening, or requires inpatient hospitalization or causes prolongation of existing hospitalization results in persistent or significant disability/incapacity, or may have caused a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. The SAEs occurred from week 0 to week 75 is presented. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68), including 7 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 7 consecutive missed doses (off-treatment period). | Baseline (week 0) to week 75 | 
| Change in Pulse | Change in pulse from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68) including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period). | Baseline (week 0) to week 68 | 
| Change in Amylase - Ratio to Baseline | Change in amylase (measured as units per litre [U/L]) is presented as ratio to baseline. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68) including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period). | Baseline (week 0) to week 68 | 
| Change in Lipase - Ratio to Baseline | Change in lipase (measured as units per litre [U/L]) is presented as ratio to baseline. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68) including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period). | Baseline (week 0) to week 68 | 
| Change in Calcitonin - Ratio to Baseline | Change in calcitonin (measured as ng/L) is presented as ratio to baseline. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68) including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period). | Baseline (week 0) to week 68 |