A Safety and Efficacy Study of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects Participating in an Intensive Behavior Modification Program

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a combination of naltrexone SR and bupropion SR is safe and effective in treating obesity and leads to greater weight loss when given with a group lifestyle modification program than with group lifestyle modification alone.

Detailed Description
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The combination of group lifestyle modification counseling and pharmacotherapy has recently been shown to result in nearly twice the average weight loss at one year (12.1 kg) as pharmacotherapy alone (sibutramine, 5.0 kg) or lifestyle modification counseling alone (6.7 kg). Combining pharmacotherapy with a comprehensive program of diet, exercise and group lifestyle modification counseling may provide the best weight loss regimen. This study evaluated weight loss in subjects participating in such a comprehensive program who received a combination of naltrexone SR and bupropion SR, or placebo.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Comparing the Safety and Efficacy of Naltrexone Sustained Release (SR)/Bupropion SR and Placebo in Subjects With Obesity Participating in a Behavior Modification Program

Conditions
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Obesity, Overweight

Intervention / Treatment
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* Drug: Naltrexone SR 32 mg/ bupropion SR 360 mg/ day
* Drug: Placebo
* Behavioral: Intensive group lifestyle modification counseling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male subjects aged 18 to 65 years (inclusive) Body mass index (weight [kg]/height [m²]) ≥30 and ≤45 kg/m² for subjects with uncomplicated obesity, and BMI of ≥27 and ≤45 kg/m² for subjects with controlled hypertension and/or dyslipidemia Non-smoker and had not used tobacco or nicotine products for at least 6 months before screening Normotensive (systolic ≤140 mm Hg and diastolic ≤90 mm Hg). Anti-hypertensive medications were allowed with the exception of alpha-adrenergic blockers, beta-blockers, and clonidine. Medical regimen was to be stable for at least 8 weeks. Low-density lipoprotein level <190 mg/dL and triglycerides level <400 mg/dL. Medications for the treatment of dyslipidemia were allowed as long as the medical regimen had been stable for at least 8 weeks. No clinically significant abnormality of serum albumin, blood urea nitrogen (BUN), creatinine, bilirubin, calcium and phosphorus Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 2.5 times upper limit of normal (ULN) No clinically significant abnormality of hematocrit, white blood cell (WBC) count, WBC differential, or platelets Fasting glucose ≤126 mg/dL and not receiving hypoglycemic agents No clinically significant abnormality on urinalysis Thyroid stimulating hormone (TSH) within 1.5 times ULN or normal triiodothyronine (T3), if TSH was below normal limits Female subjects of childbearing potential had a negative serum pregnancy test An IDS-SR score <2 on individual items: 5 (sadness), 6 (irritability), 7 (anxiety/tension), and 18 (suicidality) and an IDS-SR total score <30 Female subjects of childbearing potential were non-lactating and agreed to continue to use effective contraception throughout the study and 30 days after discontinuation of study drug Completed a food diary for 6 of 7 consecutive days during screening Able to comply with all required study procedures and schedule Able to speak and read English Provided written informed consent Exclusion Criteria: Obesity of known endocrine origin (e.g., untreated hypothyroidism, Cushing's syndrome, established polycystic ovary syndrome) Serious medical condition (including but not limited to renal or hepatic insufficiency; congestive heart failure, angina pectoris, myocardial infarction, stroke, claudication, or acute limb ischemia; history of malignancy with exception of non-melanoma skin cancer or surgically cured cervical cancer) Serious psychiatric illness (e.g., lifetime history of bipolar disorder, schizophrenia or other psychosis, bulimia, and anorexia nervosa; current serious personality disorder, e.g., borderline; severe major depressive disorder, recent [previous 6 months] suicide attempt or current active suicidal ideation, recent hospitalization due to psychiatric illness) Response to the bipolar disorder questions that indicated the presence of bipolar disorder. Required medications for the treatment of a psychiatric disorder (with the exception of short-term insomnia) within the previous 6 months History of drug or alcohol abuse or dependence within 1 year Type I or Type II diabetes mellitus Baseline ECG with a corrected QT (QTc) interval (using Bazett's formula >450 millisecond (msec) [males] and >470 msec [females]) or the presence of any clinically significant cardiac abnormalities, including but not limited to patterns consistent with myocardial ischemia, electrolyte abnormalities, or atrial or ventricular dysrhythmia or significant conduction abnormalities Received excluded concomitant medications: any psychotropic agents (including antipsychotic, antidepressant, anxiolytic, mood stabilizer or anticonvulsant agents) with the exception of low-dose benzodiazepine or hypnotic agents for the treatment of insomnia; any anorectic or weight loss agents; any over-the-counter dietary supplements with psychoactive, appetite or weight effects; alpha-adrenergic blockers; beta-blockers; clonidine; coumadin; theophylline; cimetidine; oral corticosteroids; topiramate, Depo-Provera®; smoking cessation agents; regular use of opioid or opioid-like analgesics History of surgical or device (e.g., lap band) intervention for obesity History of seizures of any etiology, or of predisposition to seizures (e.g., history of cerebrovascular accident, head trauma with >5 minutes loss of consciousness, concussion symptoms lasting >15 minutes, brain surgery, skull fracture, subdural hematoma, or febrile seizures) History of treatment with bupropion or naltrexone within the preceding 12 months History of hypersensitivity or intolerance to bupropion or naltrexone Used drugs, herbs, or dietary supplements believed to significantly affect body weight or participated in a weight loss management program within one month prior to baseline Loss or gained >4.0 kilograms within the previous 3 months Females who were pregnant or breast-feeding or planning to become pregnant during the study period or within 30 days of discontinuing study drug Planned surgical procedure that could impact the conduct of the study Received any investigational drug or used an experimental device or procedure within the previous 30 days Participated in any previous clinical trial conducted by Orexigen Had any condition that in the opinion of the investigator made the subject unsuitable for inclusion into the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NB32<br>Naltrexone SR 32 mg/ bupropion SR 360 mg/ day with intensive group lifestyle modification counseling | Drug: Naltrexone SR 32 mg/ bupropion SR 360 mg/ day<br> <br> * Other names: NB32;Behavioral: Intensive group lifestyle modification counseling<br> <br> |
| Placebo Comparator: Placebo<br>Placebo with intensive group lifestyle modification counseling | Drug: Placebo<br> <br> Behavioral: Intensive group lifestyle modification counseling<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Co-primary: Body Weight- Mean Percent Change |  | Baseline, 56 weeks | 
| Co-primary: Body Weight- Proportion of Subjects With ≥5% Decrease |  | Baseline, 56 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight- Proportion of Subjects With ≥10% Decrease |  | Baseline, 56 weeks | 
| Change in Waist Circumference |  | Baseline, 56 weeks | 
| Change in Fasting Triglycerides Levels, Using Log-transformed Data |  | Baseline, 56 weeks | 
| Change in Fasting Insulin Levels, Using Log-transformed Data |  | Baseline, 56 weeks | 
| Change in Fasting HDL Cholesterol Levels |  | Baseline, 56 weeks | 
| Change in IWQOL-Lite Total Scores | IWQOL-Lite= Impact of Weight on Quality of Life-Lite Questionnaire Total score is based on a scale from 0 to 100, with 0 representing the poorest and 100 the best quality of life and where a score of 71-79 indicates moderate impairment | Baseline, 56 weeks | 
| Change in HOMA-IR Levels, Using Log-transformed Data | HOMA-IR= Homeostasis Model Assessment-Insulin Resistance | Baseline, 56 weeks | 
| Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data |  | Baseline, 56 weeks | 
| Change in Fasting Blood Glucose Levels |  | Baseline, 56 weeks | 
| Change in Fasting LDL Cholesterol |  | Baseline, 56 weeks | 
| Change in Systolic Blood Pressure |  | Baseline, 56 weeks | 
| Change in Diastolic Blood Pressure |  | Baseline, 56 weeks | 
| Change in IDS-SR Total Scores | IDS-SR= Inventory of Depressive Symptoms-Subject Rated IDS-SR total score is based on 30 items. The total score can range from 0-84, with 0 being no depressive symptoms and 84 being very severe depressive symptoms. A total score ≤ 13 indicates no depression. | Baseline, 56 weeks | 
| Change in Food Craving Inventory Sweets Subscale Scores | The Food Craving Inventory is a 33-item self-report measure designed to assess specific food cravings and is organized into 4 subscales (high fats, sweets, carbohydrates/starches, and fast-food fats). A craving was defined as an intense desire to consume a particular food (or food type) that was difficult to resist over the past month. Subjects rated their frequency of cravings for each of the 33 items using a 5-point scale, where 1=never, 2=rarely, 3=sometimes, 4=often, and 5=always. The sweets subscale consisted of 8 items and the score ranges from 8 (better outcome) to 40 (worse outcome). | Baseline, 56 weeks | 
| Change in Food Craving Inventory Carbohydrates Subscale Scores | The Food Craving Inventory is a 33-item self-report measure designed to assess specific food cravings and is organized into 4 subscales (high fats, sweets, carbohydrates/starches, and fast-food fats). A craving was defined as an intense desire to consume a particular food (or food type) that was difficult to resist over the past month. Subjects rated their frequency of cravings for each of the 33 items using a 5-point scale, where 1=never, 2=rarely, 3=sometimes, 4=often, and 5=always. The carbohydrates subscale consisted of 8 items and the score ranges from 8 (better outcome) to 40 (worse outcome). | Baseline, 56 weeks | 
| Change in Question 19 From 21-Item COE (Control of Eating) Questionnaire | Question 19: Generally, how difficult has it been to control your eating? Scoring: 0=not at all difficult; 100=extremely difficult | Baseline, 56 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Behavior Modification