Research Study Investigating How Well Semaglutide Works in People With Type 2 Diabetes 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 the participant's body weight from the start to the end of the study. This is to compare the effect on body weight in people taking semaglutide (a new medicine) and people taking dummy medicine. In addition to taking the study medicine, the participant will have talks with study staff about healthy food choices, how to be more physically active and what else the participant can do to lose weight. Overweight and obesity is associated with an increased risk of type 2 diabetes. Therefore, weight loss has shown to have a beneficial impact on the blood sugar levels. The participant will either get semaglutide or dummy medicine - which treatment the participant get is decided by chance. The participant will need to take 2 injections at the same time 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 will last for about 1.5 years

Official Title
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Effect and Safety of Semaglutide 2.4 mg Once-weekly in Subjects With Overweight or Obesity and Type 2 Diabetes

Conditions
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Obesity, Overweight

Intervention / Treatment
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* Drug: Semaglutide 1.0 mg
* Drug: Semaglutide 2.4 mg
* Drug: Placebo I (Semaglutide)
* Drug: Placebo II (Semaglutide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 27 kg/m^2 ' History of at least one self-reported unsuccessful dietary effort to lose body weight Diagnosed with type 2 diabetes (haemoglobin A1c 7-10% (53-86 mmol/mol) (both inclusive)) 180 days or longer prior to the day of screening Exclusion Criteria: A self-reported change in body weight greater than 5 kg (11 lbs) within 90 days before screening irrespective of medical records Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of less than 30 mL/min/1.73 m^2 (less than 60 ml/min/1.73 m^2 in subjects treated with Sodium-glucose Cotransporter 2 Inhibitors) according to chronic kidney disease (CKD)-Epidemiology Collaboration (EPI) creatinine equation as defined by Kidney Disease: Improving Global Outcomes (KDIGO) 2012 by the central laboratory at screening Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a pharmacologically pupil-dilated fundus examination performed by an ophthalmologist or an equally qualified health care provider (e.g. optometrist) within the past 90 days prior to screening or in the period between screening and randomisation

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 1.0 mg<br>Participants will receive semaglutide 1.0 mg and semaglutide placebo I during 68-week treatment period in addition to a reduced-calorie diet and increased physical activity. | Drug: Semaglutide 1.0 mg<br>* Subcutaneous (s.c.) injections of semaglutide once weekly at an escalating doses (0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week). The dose will be escalated to next level every 4 weeks.<br>Drug: Placebo I (Semaglutide)<br>* S.c. injections of placebo once weekly at a similar dose escalation manner as semaglutide 2.4 mg (placebo matched to semaglutide 0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week, 1.7 mg/week and 2.4 mg/week). The dose will be escalated to next level every 4 weeks.<br>|
| Experimental: Semaglutide 2.4 mg<br>Participants will receive semaglutide 2.4 mg and semaglutide placebo II during 68-week treatment period in addition to a reduced-calorie diet and increased physical activity. | Drug: Semaglutide 2.4 mg<br>* Subcutaneous injections of semaglutide once weekly at an escalating doses (0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week, 1.7 mg/week and 2.4 mg/week). The dose will be escalated to next level every 4 weeks.<br>Drug: Placebo II (Semaglutide)<br>* S.c. injections of placebo once weekly at a similar dose escalation manner as semaglutide 1.0 mg (placebo matched to semaglutide 0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week). The dose will be escalated to next level every 4 weeks.<br>|
| Placebo Comparator: Semaglutide placebo I/II<br>Participants will receive semaglutide placebo I and II during 68-week treatment period in addition to a reduced-calorie diet and increased physical activity. | Drug: Placebo I (Semaglutide)<br>* S.c. injections of placebo once weekly at a similar dose escalation manner as semaglutide 2.4 mg (placebo matched to semaglutide 0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week, 1.7 mg/week and 2.4 mg/week). The dose will be escalated to next level every 4 weeks.<br>Drug: Placebo II (Semaglutide)<br>* S.c. injections of placebo once weekly at a similar dose escalation manner as semaglutide 1.0 mg (placebo matched to semaglutide 0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week). The dose will be escalated to next level every 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight (%) - Semaglutide 2.4 mg Versus Placebo | Change in body weight (%) from baseline (week 0) to week 68 is presented. Results are based on the data from both in-trial and on-treatment observation periods. In-trial observation period: the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact (week 75). On-treatment observation period: the interval from the date of first trial product administration (week 0) to the date of last trial product administration (week 68) plus a 2-week follow-up period and excluding any off-treatment time intervals. Off-treatment time interval: time period with at least two consecutive missed doses. | Baseline (week 0) to week 68 | 
| Participants Who Achieve (Yes/no): Body Weight Reduction ≥5% - Semaglutide 2.4 mg Versus Placebo | Number of participants who achieved weight reduction ≥5% of their baseline body weight (yes/no) at week 68 is presented. Results are based on the data from both in-trial and on-treatment observation periods. In-trial observation period: the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. On-treatment observation period: the interval from the date of first trial product administration (week 0) to the date of last trial product administration (week 68) plus a 2 week follow-up period and excluding any off-treatment time intervals. Off-treatment time interval: time period with at least two consecutive missed doses. | At week 68 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight (%) - Semaglutide 2.4 mg Versus Semaglutide 1.0 mg | Change in body weight (%) from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Participants Who Achieve (Yes/no): Body Weight Reduction ≥5% - Semaglutide 2.4 mg Versus Semaglutide 1.0 mg | Number of participants who achieved weight reduction ≥5% of their baseline body weight (yes/no) at week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | At week 68 | 
| Change in Waist Circumference | Change in waist circumference from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in Body Weight (Kg) | Change in body weight (kg) from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in BMI | Change in body mass index (BMI) from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Participants Who Achieve (Yes/no): Body Weight Reduction ≥10% | Number of participants who achieved weight reduction ≥10% of their baseline body weight (yes/no) at week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | At week 68 | 
| Participants Who Achieve (Yes/no): Body Weight Reduction ≥15% | Number of participants who achieved weight reduction ≥15% of their baseline body weight (yes/no) at week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | At week 68 | 
| Participants Who Achieve (Yes/no): Body Weight Reduction ≥20% | Number of participants who achieved weight reduction ≥20% of their baseline body weight (yes/no) at week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | At week 68 | 
| Change in HbA1c (%) | Change in glycated haemoglobin (HbA1c (%)) from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in HbA1c (mmol/Mol) | Change in HbA1c (mmol/mol) from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in FPG (mg/dL) | Change in fasting plasma glucose (FPG) from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in Fasting Serum Insulin | Change in fasting serum insulin from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Participants Who Achieve (Yes/no): HbA1c <7.0% (53 mmol/Mol) | Number of participants who achieved HbA1c <7% (yes/no) at week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | At week 68 | 
| Participants Who Achieve (Yes/no): HbA1c ≤6.5% (48 mmol/Mol) | Number of participants who achieved HbA1c ≤6.5% (yes/no) at week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | At week 68 | 
| Participants Who Achieve (Yes/no): Body Weight Reduction ≥10% and HbA1c <7.0% | Number of participants who achieved weight reduction ≥10% of their baseline body weight and HbA1c <7.0% (yes/no) at week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | At week 68 | 
| Participants Who Achieve (Yes/no): Body Weight Reduction ≥15% and HbA1c <7.0% | Number of participants who achieved weight reduction ≥15% of their baseline body weight and HbA1c <7.0% (yes/no) at week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | At week 68 | 
| Change in Systolic Blood Pressure | Change in systolic blood pressure from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in Diastolic Blood Pressure | Change in diastolic blood pressure from baseline (week 0) to week 68 is presented. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in Total Cholesterol | Change in total cholesterol (measured in milligram per decilitre (mg/dL)) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in HDL Cholesterol | Change in high density lipoprotein (HDL; measured in mg/dL) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in LDL Cholesterol | Change in low density lipoprotein (LDL; measured in mg/dL) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in VLDL Cholesterol | Change in very low density lipoprotein (VLDL; measured in mg/dL) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in Free Fatty Acids | Change in free fatty acids (measured in mg/dL) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in Triglycerides | Change in triglycerides (measured in mg/dL) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in hsCRP | Change in high sensitivity C-reactive protein (hsCRP; measured in milligram per ilitre (mg/L)) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in PAI-1 Activity | Change in Plasminogen Activator Inhibitor-1 (PAI-1; measured in arbritary units per millilitre (AU/mL)) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in Short Form 36 v2.0 Acute (SF-36) (Physical Functioning Score) | 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 8 domains of functional health and well-being as well as 2 component summary scores (physical component summary and mental component summary). This endpoint shows results for 'physical functioning domain'. The 0-100 scale scores from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively. Change from week 0 in the domain scores were evaluated at week 68. A positive change score indicates an improvement since baseline. Results are based on the data from in-trial observation period. | Baseline (week 0) to week 68 | 
| Change in SF-36 (All Scores Except Physical Functioning) | 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 8 domains of functional health and well-being as well as 2 component summary scores (physical component summary and mental component summary). This endpoint shows results for all the domains, except physical functioning. The 0-100 scale scores from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively. 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. Results are based on the data from in-trial observation period. | Baseline (week 0) to week 68 | 
| Change in IWQOL-Lite for CT (Physical Function Domain (5-items) Score) | The Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT) is designed to assess the impact of changes in weight on patients' quality of life within the context of clinical trials. IWQOL-Lite-CT is a 20-item questionnaire-based instrument used to assess the impact of body weight changes on participant's overall health-related quality of life (HRQoL). All IWQOL-Lite-CT composite scores range from 0 to 100, with higher scores reflecting better levels of functioning. This endpoint shows results for 'physical function domain'. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Change in IWQOL-Lite for CT (All Scores Except Physical Function) | The Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT) is designed to assess the impact of changes in weight on patients' quality of life within the context of clinical trials. IWQOL-Lite-CT is a 20-item questionnaire-based instrument used to assess the impact of body weight changes on participant's overall health-related quality of life (HRQoL). All IWQOL-Lite-CT composite scores range from 0 to 100, with higher scores reflecting better levels of functioning. This endpoint shows results for 'physical and psychosocial domains, and for total'. Results are based on the data from in-trial observation period which was defined as the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact. | Baseline (week 0) to week 68 | 
| Participants Who Achieve (Yes/no): Responder Definition Value 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 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 overweight or obese population included in the study and calculated using patient global rating anchor questionnaires to reflect participants' own perspective based on Food and Drug Administration (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. Endpoint was evaluated based on in-trial observation period which is the uninterrupted time interval from randomization (week 0) to last trial related subject-site contact (week 75). | At week 68 | 
| Participants Who Achieve (Yes/no): Responder Definition Value 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 which was defined as the uninterrupted time interval from randomization (week 0) to last trial related subject-site contact (week 75). | At week 68 | 
| Number of TEAEs - Semaglutide 2.4 mg Versus Placebo | Adverse events (AEs) with onset during the on-treatment observation period were defined as treatment-emergent AEs (TEAEs). On-treatment observation period: the interval from the date of first trial product administration (week 0) to the date of last trial product administration (week 68) plus a 7 week follow-up period and excluding any off-treatment time intervals. Off-treatment time interval: time period with at least seven consecutive missed doses. | Week 0 to week 75 | 
| Number of SAEs - Semaglutide 2.4 mg Versus Placebo | Serious adverse event (SAE) results are based on the on-treatment observation period, which was defined as the interval from the date of first trial product administration (week 0) to the date of last trial product administration (week 68) plus a 7 week follow-up period and excluding any off-treatment time intervals. Off-treatment time interval: time period with at least seven consecutive missed doses. | Week 0 to week 75 | 
| Number of Treatment Emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemia Episodes - Semaglutide 2.4 mg Versus Placebo | Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the interval from the date of first trial product administration (week 0) to the date of last trial product administration (week 68) plus a 7 week follow-up period and excluding any off-treatment time intervals. Off-treatment time interval: time period with at least 7 consecutive missed doses. Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions. plasma glucose (PG) concentrations may not be available during an event, but neurological recovery following the return of PG to normal is considered sufficient evidence that the event was induced by a low PG concentration. Blood glucose (BG) confirmed symptomatic hypoglycaemia: An episode that is BG confirmed by PG value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. | Week 0 to week 75 | 
| Change in Pulse - Semaglutide 2.4 mg Versus Placebo | Change in pulse from baseline (week 0) to week 68 is presented. Results are based on the data from on-treatment observation period, which was defined as the interval from the date of first trial product administration (week 0) to the date of last trial product administration (week 68) plus a 2 week follow-up period and excluding any off-treatment time intervals. Off-treatment time interval: time period with at least two consecutive missed doses. | Baseline (week 0) to week 68 | 
| Change in Amylase - Semaglutide 2.4 mg Versus Placebo | Change in amylase (units/litre) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from on-treatment observation period, which was defined as the interval from the date of first trial product administration (week 0) to the date of last trial product administration (week 68) plus a 2 week follow-up period and excluding any off-treatment time intervals. Off-treatment time interval: time period with at least two consecutive missed doses. | Baseline (week 0) to week 68 | 
| Change in Lipase - Semaglutide 2.4 mg Versus Placebo | Change in lipase (units/litre) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from on-treatment observation period, which was defined as the interval from the date of first trial product administration (week 0) to the date of last trial product administration (week 68) plus a 2 week follow-up period and excluding any off-treatment time intervals. Off-treatment time interval: time period with at least two consecutive missed doses. | Baseline (week 0) to week 68 | 
| Change in Calcitonin - Semaglutide 2.4 mg Versus Placebo | Change in calcitonin (nanogram/litre) from baseline (week 0) to week 68 is presented as ratio to baseline. Results are based on the data from on-treatment observation period, which was defined as the interval from the date of first trial product administration (week 0) to the date of last trial product administration (week 68) plus a 2 week follow-up period and excluding any off-treatment time intervals. Off-treatment time interval: time period with at least two consecutive missed doses. | Baseline (week 0) to week 68 |