A Safety and Efficacy Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the combination of naltrexone SR and bupropion SR is safe and effective in the treatment of obesity.

Detailed Description
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Two Phase II clinical trials demonstrated that a combination of bupropion SR and naltrexone is associated with greater weight loss than naltrexone alone, bupropion SR alone or placebo in subjects with uncomplicated obesity. The current study investigated the safety and efficacy of the combination of naltrexone SR and bupropion SR compared to placebo in obese subjects with uncomplicated obesity and in those with overweight/obesity and hypertension and/or dyslipidemia.

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 Sustained Release (SR) and Placebo in Obese Subjects

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: Ancillary therapy


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 obesity with controlled hypertension and/or dyslipidemia Normotensive (systolic ≤140 mm Hg and diastolic ≤90 mm Hg). Anti-hypertensive medications were allowed with the exception of alpha-adrenergic blockers and clonidine. Medical regimen was to be stable for at least 6 weeks prior to randomization. Medications for the treatment of dyslipidemia were allowed as long as the medical regimen had been stable for at least 6 weeks prior to randomization. Free of opioid medication for 7 days prior to randomization No clinically significant abnormality of serum albumin, blood urea nitrogen (BUN), creatinine, bilirubin, sodium, potassium, chloride, calcium or 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 and fasting triglycerides level <400 mg/dL No clinically significant abnormality on urinalysis Thyroid stimulating hormone (TSH) within normal limits or normal triiodothyronine (T3), if TSH was below normal limits Female subjects of childbearing potential had a negative serum pregnancy test Negative urine drug screen (UDS) 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 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) Serious medical condition (including but not limited to renal or hepatic insufficiency; Class III or IV congestive heart failure, history of angina pectoris, myocardial infarction, claudication, or acute limb ischemia within the previous 6 months; lifetime history of stroke) History of malignancy within the previous 5 years, with exception of non-melanoma skin cancer or surgically cured cervical cancer Lifetime history of serious psychiatric illness, including lifetime history of bipolar disorder, schizophrenia or other psychosis, bulimia, or anorexia nervosa Current serious psychiatric illness including severe personality disorder (e.g., borderline or antisocial), current severe major depressive disorder, recent (previous 6 months) suicide attempt, current active suicidal ideation or 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 prior to randomization History of drug or alcohol abuse or dependence (with the exception of nicotine dependence) within 1 year prior to study initiation Type I or Type II diabetes mellitus Screening 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 or agents for the treatment of attention deficit disorder) with the exception of low-dose benzodiazepine or hypnotic agents for the treatment of insomnia (up to 2 mg lorazepam/day or equivalent dose of a benzodiazepine or hypnotic agent); any anorectic or weight loss agents; any over the-counter dietary supplements or herbs with psychoactive, appetite or weight effects; alpha-adrenergic blockers; dopamine agonists; clonidine; coumadin; theophylline; cimetidine; oral corticosteroids; cholestyramine; cholestypol; Depo-Provera®; smoking cessation agents; use of opioid or opioid-like analgesics, including analgesics and antitussives History of surgical or device (e.g., gastric banding) 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 Initiation or discontinuation of tobacco products including inhaled tobacco (e.g., cigarettes, cigars, pipes, etc), chewing tobacco or snuff within 3 months prior to randomization or planned during study participation. Use of nicotine replacement products (e.g., nicotine gum, patch, etc) during study participation was not allowed 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 randomization Loss or gained >4.0 kilograms within the previous 3 months prior to randomization 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 Investigators, study personnel, sponsor representatives and their immediate families

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 ancillary therapy | Drug: Naltrexone SR 32 mg/bupropion SR 360 mg/day<br> <br> * Other names: NB32;Behavioral: Ancillary therapy<br>* Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling<br>|
| Placebo Comparator: Placebo<br>Placebo with ancillary therapy | Drug: Placebo<br> <br> Behavioral: Ancillary therapy<br>* Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling<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 From Baseline to Week 28 |  | Baseline, 28 weeks | 
| Co-primary: Body Weight- Proportion of Subjects With ≥5% Decrease From Baseline to Week 28 |  | Baseline, 28 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight- Mean Percent Change From Baseline to Week 56 | Beginning at Week 28 through Week 44, NB32-treated subjects who failed to achieve or maintain at least 5% body weight loss from baseline were re-randomized (1:1 ratio) to continue NB32 or begin treatment with a higher dose of naltrexone SR - naltrexone SR 48 mg/bupropion SR 360 mg (referred to as NB48) (daily dose of bupropion SR was 360 mg for NB32 and NB48).The analysis of NB32 vs. placebo at Week 56 was completed using a weighted analysis. This analysis was referred to as the weighted LOCF analysis. Subjects treated with NB32 who were re-randomized to NB48 were not included. Subjects re-randomized to NB32 were double-weighted and subjects who were not re-randomized were single-weighted. Subjects in the placebo group were single-weighted. The double weighting analysis restored the influence of poor performers at Weeks 28 to 44 in the NB32 group without including any data from the higher dose group (NB48). | Baseline, 56 weeks | 
| Body Weight- Proportion of Subjects With ≥5% Decrease From Baseline to Week 56 | Beginning at Week 28 through Week 44, NB32-treated subjects who failed to achieve or maintain at least 5% body weight loss from baseline were re-randomized (1:1 ratio) to continue NB32 or begin treatment with a higher dose of naltrexone SR - naltrexone SR 48 mg/bupropion SR 360 mg (referred to as NB48) (daily dose of bupropion SR was 360 mg for NB32 and NB48).The analysis of NB32 vs. placebo at Week 56 was completed using a weighted analysis. This analysis was referred to as the weighted LOCF analysis. Subjects treated with NB32 who were re-randomized to NB48 were not included. Subjects re-randomized to NB32 were double-weighted and subjects who were not re-randomized were single-weighted. Subjects in the placebo group were single-weighted. The double weighting analysis restored the influence of poor performers at Weeks 28 to 44 in the NB32 group without including any data from the higher dose group (NB48). | Baseline, 56 weeks | 
| Body Weight- Proportion of Subjects With ≥10% Decrease From Baseline to Week 28 |  | Baseline, 28 weeks | 
| Change in Waist Circumference |  | Baseline, 28 weeks | 
| Change in Fasting HDL Cholesterol Levels |  | Baseline, 28 weeks | 
| Change in Fasting Triglycerides Levels, Using Log-transformed Data |  | Baseline, 28 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, 28 weeks | 
| Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data |  | Baseline, 28 weeks | 
| Change in Fasting Insulin Levels, Using Log-transformed Data |  | Baseline, 28 weeks | 
| Change in Fasting Blood Glucose Levels |  | Baseline, 28 weeks | 
| Change in HOMA-IR Levels, Using Log-transformed Data | HOMA-IR= Homeostasis Model Assessment-Insulin Resistance | Baseline, 28 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, 28 weeks | 
| Change in Fasting LDL Cholesterol Levels |  | Baseline, 28 weeks | 
| Change in Systolic Blood Pressure |  | Baseline, 28 weeks | 
| Change in Diastolic Blood Pressure |  | Baseline, 28 weeks | 
| Change in IDS-SR Total Score | 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, 28 weeks | 
| Change in Food Craving Inventory Sweets Subscale Score | 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, 28 weeks | 
| Change in Food Craving Inventory Carbohydrates Subscale Score | 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, 28 weeks | 

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