Investigation of Safety and Efficacy of Once-daily Semaglutide in Obese Subjects Without Diabetes Mellitus

Study Overview
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Brief Summary
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This trial is conducted globally. The aim of this trial is to investigate safety and efficacy of once-daily semaglutide in obese subjects without diabetes mellitus.

Official Title
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Investigation of Safety and Efficacy of Once-daily Semaglutide in Obese Subjects Without Diabetes Mellitus

Conditions
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Obesity, Metabolism and Nutrition Disorder

Intervention / Treatment
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* Drug: semaglutide
* Drug: liraglutide
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial - Male or female, age 18 years or older at the time of signing inform consent - Body mass index (BMI) equal or above 30.0 kg/m^2 at the screening visit - At least one unsuccessful weight loss attempt per investigator judgement Exclusion Criteria: - A HbA1c (glycosylated haemoglobin) equal to or above 6.5% at screening or diagnosed with type 1 or type 2 diabetes mellitus - Treatment with glucose lowering agent(s) within 90 days before screening - Screening calcitonin equal to or above 50 ng/L (pg/mL) - Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 - History of pancreatitis (acute or chronic) - Obesity induced by endocrine disorders (e.g. Cushing Syndrome) - Treatment with any medication within 90 days before screening that based on investigator's judgement may cause significant weight change - Previous surgical treatment for obesity (liposuction and/or abdominoplasty performed 1 year before screening is allowed) - History of major depressive disorder within 2 years before randomisation - Any lifetime history of a suicidal attempt - Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice)

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sema 0.05 mg<br>Dose 0.05 mg | Drug: semaglutide<br>* Once-daily subcutaneous (s.c., under the skin) administration with dose escalation.<br>|
| Experimental: Sema 0.1 mg<br>Dose 0.05 or 0.1 mg with dose escalation every fourth week | Drug: semaglutide<br>* Once-daily subcutaneous (s.c., under the skin) administration with dose escalation.<br>|
| Experimental: Sema 0.2 mg<br>Dose 0.05, 0.1 or 0.2 mg with dose escalation every fourth week | Drug: semaglutide<br>* Once-daily subcutaneous (s.c., under the skin) administration with dose escalation.<br>|
| Experimental: Sema 0.3 mg<br>Dose 0.05, 0.1, 0.2 or 0.3 mg with dose escalation every fourth week | Drug: semaglutide<br>* Once-daily subcutaneous (s.c., under the skin) administration with dose escalation.<br>|
| Experimental: Sema 0.4 mg<br>Dose 0.05, 0.1, 0.2, 0.3, or 0.4 mg with dose escalation every fourth week | Drug: semaglutide<br>* Once-daily subcutaneous (s.c., under the skin) administration with dose escalation.<br>|
| Experimental: Sema 0.3 mg (fast dose escalation)<br>Dose 0.05, 0.1, 0.2 or 0.3 mg with dose escalation every second week | Drug: semaglutide<br>* Once-daily subcutaneous (s.c., under the skin) administration with dose escalation.<br>|
| Experimental: Sema 0.4 mg (fast dose escalation)<br>Dose 0.05, 0.1, 0.2, 0.3, or 0.4 mg with dose escalation every second week | Drug: semaglutide<br>* Once-daily subcutaneous (s.c., under the skin) administration with dose escalation.<br>|
| Active Comparator: Lira 3.0 mg<br>Dose 0.6, 1.2, 1.8, 2.4, 3.0 mg with dose escalation every week | Drug: liraglutide<br>* Once-daily subcutaneous (s.c., under the skin) administration with dose escalation.<br>|
| Placebo Comparator: Placebo Sema 0.05 mg<br>Placebo arm matching active arm Sema 0.05 mg | Drug: placebo<br>* Once-daily subcutaneous (s.c., under the skin) administration.<br>|
| Placebo Comparator: Placebo Sema 0.1 mg<br>Placebo arm matching active arm Sema 0.1 mg | Drug: placebo<br>* Once-daily subcutaneous (s.c., under the skin) administration.<br>|
| Placebo Comparator: Placebo Sema 0.2 mg<br>Placebo arm matching active arm Sema 0.2 mg | Drug: placebo<br>* Once-daily subcutaneous (s.c., under the skin) administration.<br>|
| Placebo Comparator: Placebo Sema 0.3 mg<br>Placebo arm matching active arm Sema 0.3 mg | Drug: placebo<br>* Once-daily subcutaneous (s.c., under the skin) administration.<br>|
| Placebo Comparator: Placebo Sema 0.4 mg<br>Placebo arm matching active arm Sema 0.4 mg | Drug: placebo<br>* Once-daily subcutaneous (s.c., under the skin) administration.<br>|
| Placebo Comparator: Placebo Sema 0.3 mg (fast dose escalation)<br>Placebo arm matching active arm Sema 0.3 mg (fast dose escalation) | Drug: placebo<br>* Once-daily subcutaneous (s.c., under the skin) administration.<br>|
| Placebo Comparator: Placebo Sema 0.4 mg (fast dose escalation)<br>Placebo arm matching active arm Sema 0.4 mg (fast dose escalation) | Drug: placebo<br>* Once-daily subcutaneous (s.c., under the skin) administration.<br>|
| Placebo Comparator: Placebo Lira 3.0 mg<br>Placebo arm matching active arm Lira 3.0 mg | Drug: placebo<br>* Once-daily subcutaneous (s.c., under the skin) administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change in Body Weight (%) | Relative change from baseline (week 0) in body weight was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline body weight as covariate. In-trial observation period was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Weight Loss of ≥5% of Baseline Body Weight | Presented results are percentage of participants who lost more than or equal to 5% of their baseline (week 0) body weight at week 52. Analysis of observed in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using a binary logistic regression model with treatment, region and sex as factors and baseline body weight as covariate. In-trial observation period was defined as the period from randomisation to last contact with trial site. | Week 52 | 
| Participants With Weight Loss of ≥10% of Baseline Body Weight | Presented results are percentage of participants who lost more than or equal to 10% of their baseline (week 0) body weight at week 52. Analysis of observed in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using a binary logistic regression model with treatment, region and sex as factors and baseline body weight as covariate. In-trial observation period was defined as the period from randomisation to last contact with trial site. | Week 52 | 
| Change in Body Weight (kg) | Change from baseline (week 0) in body weight was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline body weight as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 
| Change in Waist Circumference | Change from baseline (week 0) in waist circumference was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline waist circumference as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 
| Change in Waist to Hip Circumference Ratio | Change from baseline (week 0) in waist to hip circumference ratio was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline waist to hip circumference ratio as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 
| Change in BMI | Change from baseline (week 0) in body mass index (BMI) was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline BMI as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 
| Change in HbA1c | Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline HbA1c as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 
| Change in FPG | Change from baseline (week 0) in fasting plasma glucose (FPG) was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline FPG as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 
| Change in Glycaemic Category (Normoglycaemia, Pre-diabetes, T2D) | The categorisation of glycaemic status as described in the protocol was not aligned with the usual diagnosis criteria which require repeated testing of blood glucose to confirm the diagnosis and allows for the diagnosis to be made based on random glucose assessments and/or 2-hour glucose assessments during an oral glucose tolerance test. Therefore, data were not collected for this outcome measure. | Week 0, Week 52 | 
| Change in SBP | Change from baseline (week 0) in systolic blood pressure (SBP) was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline SBP as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 
| Change in DBP | Change from baseline (week 0) in diastolic blood pressure (DBP) was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline DBP as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 
| Change in Lipids (Total Cholesterol, LDL Cholesterol, HDL Cholesterol, VLDL Cholesterol, Triglycerides and FFA) | Change from baseline (week 0) in lipids (total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, very low density lipoprotein (VLDL) cholesterol and triglycerides) was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and respective baseline lipid value as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. Free fatty acid (FFA) results are not presented as the values were considered invalid. The shipment of the samples to be tested for FFA was not as per the requirement. | Week 0, Week 52 | 
| Change in hsCRP | Change from baseline (week 0) in high-sensitivity C-reactive protein (hsCRP) was evaluated at week 52. Analysis of in-trial data with missing observations imputed from the pooled placebo arms based on a jump to reference multiple (x1000) imputation (J2R-MI) approach. Week 52 responses were analysed using an analysis of covariance model with treatment, region and sex as factors and baseline hsCRP as covariate. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0, Week 52 | 
| Change in IWQoL Lite | The planned analyses of the Impact of Weight on Quality of Life Lite (IWQoL-Lite) for Clinical Trials scores were not performed. The measure was still under development, and Novo Nordisk had not obtained a validated scoring of the instrument by the time of analysis of the trial results. Therefore, the total and subdomain scores on the IWQoL-Lite could not be provided. | Week 0, Week 52 | 
| Change in SF-36 | Short Form-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™ (acute version) questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary (PCS) and mental component summary (MCS)). The 0-100 scale scores (where higher scores indicated a better HRQoL) 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 of the 2009 U.S. general population. Change from baseline (week 0) in the domain scores and component summary (PCS and MCS) scores were evaluated at week 52. A positive change score indicates an improvement since baseline. Results are based on the in-trial observation period. | Week 0, Week 52 | 
| Participants With Change in Concomitant Medications (Antihypertensive and Lipid-lowering Medications) | Participants' status on receiving concomitant medication (antihypertensive and lipid-lowering medications) at week 0 (yes/no) and week 52 (decreased, no change, increased or missing) are presented. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, Week 52 | 
| Compliance With Nutritional Counselling | This outcome measure presents nutritional compliance results recorded at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52. Nutritional compliance was recorded on a 0 to 10 numeric rating scale (NRS), with higher scores representing better compliance. | Week 4-52 | 
| Number of AEs During the Trial | Adverse events (AEs) were recorded from week 0 to week 59. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0-59 | 
| Number of Hypoglycaemic Episodes During the Trial | Hypoglycaemic episodes were identified by either: 1) Subject reporting of symptoms of hypoglycaemia (low blood sugar) or 2) fasting plasma glucose (FPG) values ≤3.9 mmol/L (70 mg/dL) from blood sampling at site visits. Hypoglycaemic episodes were recorded from week 0 to week 59. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0-59 | 
| Number of New and Ongoing Nausea, Vomiting, Diarrhoea, and Constipation Events by Week | Presented results are the number of nausea, vomiting, diarrhoea, and constipation events recorded from week 0 to week 59. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 0-59 | 
| Nausea: Individual Scores of Nausea Questionnaire and Severity by NRS Score | This outcome measure presents results recorded at week 52. If a participant experienced an event of nausea within 24 hours prior to a site visit, a nausea questionnaire had to be completed. Participants experiencing such events were to answer 5 different categories in the questionnaire ('duration of nausea', 'time from the latest injection of trial product to the onset of nausea', 'time from last food intake to the onset of nausea', 'nausea accompanied by vomiting (yes/no)' and 'severity of nausea (worst during episode)'). Severity of nausea was recorded on a 0 to 10 numeric rating scale (NRS), where 0 = 'No nausea' and 10 = 'Nausea as bad as it could be'. Results are based on the in-trial observation period which was defined as the period from randomisation to last contact with trial site. | Week 52 | 
| Change in ECG | Number of participants with electrocardiogram (ECG) results, normal; abnormal, not clinically significant (NCS) or abnormal, clinically significant (CS) was recorded at baseline (week 0) and week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Pulse | Change from baseline (week 0) in pulse rate was evaluated at week 52. Analysis of observed data using a mixed model for repeated measurements (MMRM) with treatment, region and sex as factors and baseline pulse as covariate, all nested within visit. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Haematology: Haemoglobin | Change from baseline (week 0) in haemoglobin was evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Haematology: Haematocrit | Change from baseline (week 0) in haematocrit was evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Haematology: Thrombocytes, Leucocytes and Differential Count | Change from baseline (week 0) in haematological parameters, thrombocytes, leucocytes and differential cell count (eosinophils, neutrophils, basophils, monocytes and lymphocytes) were evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Haematology: Erythrocytes | Change from baseline (week 0) in erythrocytes was evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Biochemistry: Creatinine and Bilirubin (Total) | Change from baseline (week 0) in biochemistry parameters, creatinine and bilirubin (total) were evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Biochemistry: Creatinine Kinase, Amylase, Lipase, ALT, AST and ALP | Change from baseline (week 0) in biochemistry parameters, creatinine kinase, amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Biochemistry: Urea, Sodium, Potassium and Calcium (Total) | Change from baseline (week 0) in biochemistry parameters, urea, sodium, potassium and calcium (total) were evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Biochemistry: Albumin | Change from baseline (week 0) in albumin was evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Biochemistry: Calcitonin | Change from baseline (week 0) in calcitonin was evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Biochemistry: TSH | Change from baseline (week 0) in thyroid stimulating hormone (TSH) was evaluated at week 52. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Change in Mental Health Assessed by C-SSRS | Presented results are the number of participants with Columbia Suicidality Severity Rating Scale (C-SSRS) results recorded during baseline (week 0) and post baseline (week 4-52) visits. For classification of the events reported on the C-SSRS, the following categories were used: 1) Suicidal ideation, 2) Suicidal behaviour and 3) Non-suicidal self-injurious behaviour. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0 and Week 4-59 | 
| Change in Mental Health Assessed by PHQ-9 | Patient health questionnaire-9 (PHQ-9) was recorded at baseline (week 0) and week 52. The PHQ-9 questionnaire is a 9-item depression module included in the patient health questionnaire, a self-administered diagnostic tool used for assessment of mental disorders. On the PHQ-9, the participant rates the frequency of 9 items on a scale from 0 (not at all) to 3 (nearly every day). The PHQ-9 total score ranges from 0-27; total scores of 1-4 represent no depression, total scores of 5-9 represent mild depression, total scores of 10-14 represent moderate depression, total scores of 15-19 represent moderately severe depression and total scores of 20-27 represent severe depression. Results are based on the on-treatment observation period which was defined as the period from first trial product administration to last trial product administration. | Week 0, week 52 | 
| Anti-semaglutide Antibodies During and After Treatment | Participants were tested for anti-semaglutide antibodies from week 0 (post treatment) to week 52 (at weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52). This outcome measure is applicable only for the semaglutide treatment arms. | Week 0-52 |