A Study of the Safety and Efficacy of Two Doses of Naltrexone SR/Bupropion SR and Placebo 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 2 doses of the combination of naltrexone SR and bupropion SR are 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 bupropion SR alone, naltrexone alone, or placebo in subjects with uncomplicated obesity. The current study investigated the safety and efficacy of 2 doses 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 Two Doses 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 16 mg/Bupropion SR 360 mg /day
* 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 and male subjects, 18 to 65 years of age; Have BMI ≥30 and ≤45kg/m² for subjects with uncomplicated obesity, and BMI of ≥27 and ≤45kg/m² for subjects with obesity and controlled hypertension and/or dyslipidemia; Normotensive (systolic ≤140 mm Hg; diastolic ≤90 mm Hg). Anti-hypertensive medications are allowed with the exception of alpha-adrenergic blockers and clonidine; medical regimen must be stable for at least 6 weeks prior to randomization; Medications for treatment of dyslipidemia are allowed as long as medical regimen has 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, creatinine, bilirubin, sodium, potassium, chloride, calcium or phosphorus; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 2.5 x upper limit of normal range (ULN); No clinically significant abnormality of hematocrit, white blood cell (WBC) count, white cell differential, or platelets; Fasting glucose < 126 mg/dL on no hypoglycemic agents, fasting triglycerides <400 mg/dL; No clinically significant abnormality on urinalysis; TSH within normal limits or normal T3, if TSH is below normal limits; Negative serum pregnancy test in women of child-bearing potential; Negative urine drug screen; IDS-SR scores < 2 on items 5 (sadness), 6 (irritability), 7 (anxiety/tension) and 18 (suicidality), and IDS-SR total score < 30; Women of child bearing potential had to be non-lactating and agree to use effective contraception throughout the study period and 30 days after discontinuation of study drug; Able to comply with all required study procedures and schedule; Able to speak and read English; Willing and able to give written informed consent. Exclusion Criteria: Obesity of known endocrine origin (e.g., untreated hypothyroidism, Cushing's syndrome, established Polycystic Ovary Syndrome); Serious medical conditions (including but not limited to ongoing renal or hepatic insufficiency, Class III or IV congestive heart failure; myocardial infarction, history of angina pectoris, 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; A 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; A response to bipolar disorder questions indicating the presence of bipolar disorder; In need of 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 1 or Type 2 diabetes mellitus; Screening ECG with a corrected QT interval by the method of Bazett (QTcB) >450 msec (men) and > 470 millisecond (msec) (women) 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; Excluded concomitant medications: any psychotropic agents (including antipsychotic, antidepressant, anxiolytic, mood stabilizer, 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 medications, 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 (such as cigarettes, cigars, pipes, etc), chewing tobacco or snuff in the 3 months prior to randomization or planned during study participation. Use of nicotine replacement products (nicotine gum, patch) during study participation was not allowed; Use of drugs, herbs, or dietary supplements believed to significantly affect body weight or participation in a weight loss management program within one month prior to randomization; Loss or gain of more than 4.0 kilograms within 3 months prior to randomization; Pregnant or breast-feeding women or planning to become pregnant during the study period or within 30 days of discontinuing study drug; Planned surgical procedure that can impact the conduct of the study; Use of investigational drug, device or procedure within the previous 30 days; Participation in any previous clinical trial sponsored by Orexigen Therapeutics; Any condition which in the opinion of the investigator makes the subject unsuitable for inclusion in 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: NB16<br>Naltrexone SR 16 mg/Bupropion SR 360 mg /day with ancillary therapy | Drug: Naltrexone SR 16 mg/Bupropion SR 360 mg /day<br> <br> * Other names: NB16;Behavioral: Ancillary therapy<br>* Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling<br>|
| 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 |  | 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 HDL Cholesterol Levels |  | Baseline, 56 weeks | 
| Change in Fasting Triglycerides Levels, Using Log-transformed Data |  | 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 High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data |  | Baseline, 56 weeks | 
| Change in Fasting Insulin Levels, Using Log-transformed Data |  | Baseline, 56 weeks | 
| Change in Fasting Blood Glucose Levels |  | Baseline, 56 weeks | 
| Change in HOMA-IR Levels, Using Log-transformed Data | HOMA-IR= Homeostasis Model Assessment-Insulin Resistance | 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 | 
| Change in Fasting LDL Cholesterol Levels |  | 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 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, 56 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, 56 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Antiobesity agents, Antiobesity drugs, Overweight drug therapy, Obese drug therapy, Weight loss drug effects, Bupropion administration and dosage, Naltrexone administration and dosage, Double blind method, Combination drug therapy, Delayed action preparations