Effect and Safety of Liraglutide 3.0 mg as an Adjunct to Intensive Behaviour Therapy for Obesity in a Non-specialist Setting

Study Overview
=================
Brief Summary
-----------------
This trial is conducted in the United States of America (USA). The purpose of the trial is to investigate the effect and safety of liraglutide 3.0 mg as an adjunct to intensive behaviour therapy for obesity in a non-specialist setting (IBT-CMS: Intensive Behaviour Therapy for obesity in a primary care setting according to Centers for Medicare & Medicaid Services (CMS) visit schedule).

Official Title
-----------------
Effect and Safety of Liraglutide 3.0 mg as an Adjunct to Intensive Behaviour Therapy for Obesity in a Non-specialist Setting

Conditions
-----------------
Metabolism and Nutrition Disorder, Obesity

Intervention / Treatment
-----------------
* Drug: liraglutide
* Drug: placebo
* Behavioral: CMS Intensive Behavior Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
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 BMI above or equal to 30 kg/m^2 Male or female, age 18 years or older at the time of signing informed consent Exclusion Criteria: HbA1c (glycosylated haemoglobin) above or equal to 6.5% (at screening visit), or diagnosis of type 1 or type 2 diabetes mellitus Recent history of cardiovascular disease (myocardial infarction or stroke within the past 6 months), severe congestive heart failure (NYHA class III, IV), or second degree or greater heart block Personal or family history of Medullary Thyroid Carcinoma (MTC), or Multiple Endocrine Neoplasia type 2 (MEN2) Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measure as required by local regulation or practice) Use in past 90 days of medications known to induce significant weight loss (e.g., prescription weight loss medications) or weight gain (e.g., chronic use of oral steroids, second generation antipsychotics) History of pancreatitis (acute or chronic) History of major depressive disorder within the past 2 years Any lifetime history of a suicide attempt Inadequately treated blood pressure defined as Grade 3 hypertension or higher (Systolic above or equal to 180 mmHg or diastolic above or equal to 110 mmHg) History of malignancy (except for non-melanoma skin cancer) within the past 5 years

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liraglutide<br> | Drug: liraglutide<br>* Administered subcutaneously (s.c., under the skin) once daily for 56 weeks. Dose gradually increased to 3.0 mg<br>Behavioral: CMS Intensive Behavior Therapy<br>* Intensive Behaviour Therapy for obesity<br>|
| Placebo Comparator: Placebo<br> | Drug: placebo<br>* Administered subcutaneously (s.c., under the skin) once daily for 56 weeks. Dose gradually increased to 3.0 mg<br>Behavioral: CMS Intensive Behavior Therapy<br>* Intensive Behaviour Therapy for obesity<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight (%) | Observed mean change in body weight from baseline (week 0) to week 56 was evaluated for two different observation periods. In-trial observation period: the uninterrupted time interval from the date of randomisation until and including the date of the follow-up visit or date of last contact. On-drug observation period: includes all time intervals in which subjects are considered to be on treatment from the date of first trial product administration to 7 days (or 14 days for AEs) after the final trial product administration, excluding potential off-treatment time intervals triggered by at least 7 consecutive missed doses (or 14 consecutive missed doses for AEs). The test of superiority of liraglutide to placebo for the treatment policy estimand was tested in a hierarchical manner for the two primary and the consequent 7 confirmatory secondary endpoints presented. | Week 0, week 56 | 
| Proportion of Subjects Losing at Least 5% of Baseline Body Weight at Week 56 | The estimated mean percentage of subjects losing at least 5% of baseline body weight at week 56 is presented. The endpoint was evaluated based on in-trial data and on-drug data. | Week 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Losing More Than 10% of Baseline Body Weight at Week 56 | The estimated mean percentage of subjects losing more than 10% of baseline body weight at week 56 is presented. The endpoint was evaluated based on in-trial data and on-drug data. | Week 56 | 
| Proportion of Subjects Losing More Than 15% of Baseline Body Weight at Week 56 | The estimated mean percentage of subjects losing more than 15% of baseline body weight at week 56 is presented. The endpoint was evaluated based on in-trial data and on-drug data. | Week 56 | 
| Proportion of Subjects Losing 4% or More of Baseline Body Weight | The estimated mean percentage of subjects losing 4% or more of baseline body weight at week 16 is presented. The endpoint was evaluated for treatment policy estimand (in-trial data). | Week 16 | 
| Change in Waist Circumference (cm) | Observed mean change from baseline in waist circumference. The endpoint was evaluated based on in-trial data and on-drug data. | Week 0, week 56 | 
| Change in Short Form-36 (SF-36) v2.0 Acute, Physical Functioning Score | SF-36 is a 36-item patient-reported survey of patient health that measures the subject's overall health-related quality of life (HRQoL). SF-36v2™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. The scores 0-100 (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. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. Change from baseline in SF-36 physical functioning score is presented. A positive change score indicates an improvement since baseline. The endpoint was evaluated based on in-trial data and on-drug data. | Week 0, week 56 | 
| Change in IWQoL-Lite for CT, Physical Function Domain (5-items) Score | Observed mean change in Impact of Weight on Quality of Life-Lite for Clinical Trials Version (IWQoL-Lite for CT ) score. IWQoL-Lite for CT (Weight on Quality of Life-Lite for Clinical Trial Version) is a modified version of an instrument designed to assess weight-related quality of life. The scores ranged between 0-100 where higher scores indicated a better quality of life. The endpoint was evaluated based on in-trial data and on-drug data. | Week 0, week 56 | 
| Change in Six Minutes Walking Distance Test (6MWT) | Observed mean change from baseline in 6 minutes walking distance test. The 6MWT is a common test of functional exercise capacity that assesses the distance a subject can walk in 6 minutes. The endpoint was evaluated based on in-trial data and on-drug data. | Week 0, week 56 | 
| Change From Baseline in HbA1c (%) | Observed mean change from baseline to week 56 in glycosylated haemoglobin (HbA1c). Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change From Baseline in FPG (mg/dL) | Observed mean change from baseline (week 0) in fasting plasma glucose (FPG). Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change From Baseline sBP (mmHg) | Observed mean change in systolic blood pressure from baseline to week 56. | Week 0, week 56 | 
| Change From Baseline dBP (mmHg) | Observed mean change from baseline (week 0) to week 56 in diastolic blood pressure (dBP). Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change From Baseline in Lipids -Total Cholesterol | Observed mean change from baseline (week 0) to week 56 in total cholesterol (TC). Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change From Baseline in Lipids - LDL Cholesterol | Observed mean change from baseline in low density cholesterol (LDL) from baseline (week 0) to week 56. Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change From Baseline in Lipids - HDL Cholesterol | Observed mean change from baseline in high density (HDL) cholesterol from baseline (week 0) to week 56. Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change From Baseline in Lipids - VLDL Cholesterol | Observed mean change from baseline in very low density cholesterol (VLDL) from baseline (week 0) to week 56. Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change From Baseline in Lipids - TG | Observed mean change from baseline in triglyceride (TG) from baseline (week 0) to week 56. Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change From Baseline in Lipids - FFA | Observed mean change from baseline in free fatty acids (FFA) from baseline (week 0) to week 56. Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change in Short Form-36 v2.0 Acute (SF-36) (Subdomains) | SF-36 is a 36-item patient-reported survey of patient health that measures the subject's overall health-related quality of life (HRQoL). SF-36v2™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. The scores 0-100 (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. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. Change from baseline in in the sub-domain scores is presented. A positive change score indicates an improvement since baseline. Results are evaluated based on in-trial data. | Week 0, week 56 | 
| Change in Short Form-36 v2.0 Acute (SF-36) (Physical Component Summary (PCS)) | Observed mean change from baseline (week 0) to week 56 in short form 36 v2.0 acute domain physical component summary (PCS). SF-36v2™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. The scores 0-100 (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. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. Change from baseline in SF-36 physical component summary (PCS) score is presented. A positive change score indicates an improvement since baseline. The endpoint was evaluated based on in-trial data and on-drug data. | Week 0, week 56 | 
| Change in Short Form-36 v2.0 Acute (SF-36) (Mental Component Summary (MCS) | Observed mean change from baseline (week 0) to week 56 in short form 36 v2.0 acute domain mental component summary (MCS). SF-36v2™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. The scores 0-100 (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. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. Change from baseline in SF-36 mental component summary is presented. A positive change score indicates an improvement since baseline. The endpoint was evaluated based on in-trial data and on-drug data. | Week 0, week 56 | 
| Change in Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT): Pain/Discomfort Domain Score | Observed mean change in Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT) domain pain and discomfort. IWQoL-Lite for CT (Weight on Quality of Life-Lite for Clinical Trial Version) is a modified version of an instrument designed to assess weight-related quality of life. The scores ranged between 0-100 where higher scores indicated a better quality of life. A positive change score indicates an improvement since baseline. Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change in Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT): Psychosocial Domain Score | Observed mean change in Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT) psychosocial domain. IWQoL-Lite for CT (Weight on Quality of Life-Lite for Clinical Trial Version) is a modified version of an instrument designed to assess weight-related quality of life. The scores ranged between 0-100 where higher scores indicated a better quality of life. A positive change score indicates an improvement since baseline. Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change in Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT): Total Score | Observed mean change from baseline (week 0) to week 56 in IWQoL-Lite for CT total score. IWQoL-Lite for CT (Weight on Quality of Life-Lite for Clinical Trial Version) is a modified version of an instrument designed to assess weight-related quality of life. The scores ranged between 0-100 where higher scores indicated a better quality of life. A positive change score indicates an improvement since baseline. Results based on FAS in-trial data is presented. | Week 0, week 56 | 
| Change in Weight Related Sign and Symptom (WRSS) Measure, Total Score | Observed mean change from baseline (week 0) to week 56 in WRSS measure, total score. The WRSS measures the presence and bothersome associated with weight-related symptoms. The WRSS questionnaire was not validated until after database lock. Therefore the total score couldn't be calculated and the supportive secondary endpoint Weight related sign and symptom (WRSS) measure, total score couldn't be analysed. | Week 0, week 56 | 
| Subjects Who After 56 Weeks Achieve (Yes/no): ≥ 4.3 T-score Points Increase From Baseline in SF-36 Physical Functioning Score | Percentage of subjects who achieved ≥ 4.3 T-score points increase from baseline in SF-36 physical functioning score at week 56 is presented. Results based on FAS in-trial data is presented. | Week 56 | 
| Subjects Who After 56 Weeks Achieve (Yes/no): ≥ 3.8 T-score Points Increase From Baseline in SF-36 Physical Component Score | Percentage of subjects who achieved ≥ 3.8 T-score points increase from baseline in SF-36 physical component score at week 56 is presented. Results based on FAS in-trial data is presented. | Week 56 | 
| Subjects Who After 56 Weeks Achieve (Yes/no): ≥ 4.6 T-score Points Increase From Baseline in SF-36 Mental Component Score | Percentage of subjects who achieved ≥ 4.6 T-score points increase from baseline in SF-36 mental component score at week 56 is presented. Results based on FAS in-trial data is presented. | Week 56 | 
| Responder Definition Value for IWQoL-Lite for CT Physical Function Domain (5-items) Score | Responder definition value for IWQoL-Lite for CT physical function domain (5-items) score' was defined as '≥ 20 responder definition value for IWQoL-Lite for CT physical function domain (5-items) score. Percentage of subjects considered IWQoL-Lite for CT physical function domain score responders (increase of ≥20 points) at week 56 is presented. Results based on FAS in-trial data is presented. | Week 56 | 
| Number of Weeks (Completed Calendar Weeks) From Randomisation to Week 56 Adherent to Trial Product | Adherence to trial product is assessed regularly at CMS-IBT visits. The number of weeks from randomisation to week 56, adherent to trial product is presented. | Week 0, week 56 | 
| Number of Weeks (Completed Calendar Weeks) From Randomisation to Week 56 Adherent to Caloric Diet | Adherence to caloric diet is assessed regularly at CMS-IBT visits. The number of weeks from randomisation to week 56, adherent to caloric diet is presented. | Week 0, week 56 | 
| Number of Weeks (Completed Calendar Weeks) From Randomisation to Week 56 Adherent to Physical Activity | Adherence to physical activity is assessed regularly at CMS-IBT visits. The number of weeks from randomisation to week 56, adherent to physical activity is presented. | Week 0, week 56 | 
| Number of Weeks (Completed Calendar Weeks) From Randomisation to Week 56 Adherent to Caloric Diet and Physical Activity | Adherence to caloric diet and physical activity is assessed regularly at CMS-IBT visits. The number of weeks from randomisation to week 56, adherent to caloric diet and physical activity is presented. | Week 0, week 56 | 
| Number of Weeks (Completed Calendar Weeks) From Randomisation to Week 56 Adherent to Caloric Diet, Physical Activity and Trial Product | Adherence to caloric diet, physical activity and trial product is assessed regularly at CMS-IBT visits. The number of weeks from randomisation to week 56, adherent to caloric diet, physical activity and trial product is presented. | Week 0, week 56 | 
| AEs From Randomisation Until and Including the Follow-up Period | Number of adverse events from randomisation to until the end of the post-treatment follow-up period (30 days). Results based on SAS on-drug data is presented. | Week 0 to week 56+30 days | 
| Change in Physical Examination | Observed change from baseline to week 56 in physical examination are categorised under parameters namely abdomen, gastrointestinal system, cardiovascular system, central and peripheral nervous system, general appearence, head, ears, eyes, nose, throat and neck, lymph node palpation, musculoskeletal system, respiratory system, skin and thyroid gland. The percentage of subjects assessed as normal, abnormal not clinically significant and abnormal clinically significant at baseline and week 56 is presented. | Week 1, week 56 | 
| Change in Resting Pulse | Observed mean change in pulse rate measured at resting position is presented. | Week 0, week 56 | 
| Change in ECG | The ECGs were interpreted by the investigator at baseline (week -1) and week 56 and categorised as normal, abnormal NCS or abnormal CS. Number of subjects in each ECG category at baseline and week 56 are presented. | Week -1, week 56 | 
| Change in Laboratory Measurements: Haematology (Haemoglobin Blood) | Observed mean change from baseline in haematological parameter blood haemoglobin. | Week 0, week 56 | 
| Change in Laboratory Measurements: Haematology (Haematocrit Blood) | Observed mean change from baseline in haematological parameter blood haematocrit. Haematocrit is presented as the percentage of red blood cells in total blood. Results based on SAS on-drug data is presented. | Week 0, week 56 | 
| Change in Laboratory Measurements: Haematology (Erythrocytes) | Observed mean change from baseline in haematological parameter - erythrocytes. | Week 0, week 56 | 
| Change in Laboratory Measurements: Haematology (Thrombocytes and Leukocytes) | Observed mean change from baseline in haematological parameters - thrombocytss and leukocytes. | Week 0, week 56 | 
| Change in Laboratory Measurements: Biochemistry (Albumin) | Observed mean change from baseline in biochemical parameter - albumin. Results based on SAS on-drug data is presented. | Week 0, week 56 | 
| Change in Laboratory Measurements: Biochemistry (Alkaline Phosphatase, Alanine Aminotransferase, Amylase, Aspartate Aminotransferase and Lipase) | Observed mean change from baseline in biochemical parameters - alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase and lipase. Results based on SAS on-drug data is presented. | Week 0, week 56 | 
| Change in Laboratory Measurements: Biochemistry (Bilirubin and Creatinine) | Observed mean change from baseline in biochemical parameters - bilirubin and creatinine. Results based on SAS on-drug data is presented. | Week 0, week 56 | 
| Change in Laboratory Measurements: Biochemistry (Total Calcium, Pottassium, Sodium and Urea) | Observed mean change from baseline in biochemical parameters - total calcium, pottassium, sodium and urea. Results based on SAS on-drug data is presented. | Week 0, week 56 | 
| Change in Laboratory Measurements: Biochemistry (C-reactive Protein and Uric Acid) | Observed mean change from baseline in biochemical parameters - high sensitive c-reactive protein and uric acid. Results based on SAS on-drug data is presented. | Week 0, week 56 | 
| Change in Laboratory Measurements: Biochemistry (Glomerular Filtration Rate, Serum) | Observed mean change from baseline in biochemical parameters - estimated glomerular filtration rate. Serum GFR is estimated using MDRD formula . Results based on SAS on-drug data is presented. | Week 0, week 56 | 
| Change in Laboratory Measurements: Biochemistry (Calcitonin) | Observed mean change from baseline in biochemical parameter - calcitonin. Results based on SAS on-drug data is presented. | Week 0, week 56 | 
| Change in Laboratory Measurements: Biochemistry (Thyroid Stimulating Hormone) | Observed mean change from baseline in biochemical parameters - thyroid stimulating hormone. Results based on SAS on-drug data is presented. | Week 0, week 56 |