Clinical trial NCT00532779: A Study of the Safety and Efficacy of Two Doses of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Obesity
Overweight
Keywords: 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
Lead sponsor: Orexigen Therapeutics, Inc
Sponsor class: INDUSTRY
First posted: 2007-09-20
Enrollment: 1742
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Co-primary: Body Weight- Mean Percent Change
timeFrame: Baseline, 56 weeks
measure: Co-primary: Body Weight- Proportion of Subjects With ≥5% Decrease
timeFrame: Baseline, 56 weeks
Secondary outcomes:
measure: Body Weight- Proportion of Subjects With ≥10% Decrease
timeFrame: Baseline, 56 weeks
measure: Change in Waist Circumference
timeFrame: Baseline, 56 weeks
measure: Change in Fasting HDL Cholesterol Levels
timeFrame: Baseline, 56 weeks
measure: Change in Fasting Triglycerides Levels, Using Log-transformed Data
timeFrame: Baseline, 56 weeks
measure: Change in IWQOL-Lite Total Scores
timeFrame: Baseline, 56 weeks
measure: Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data
timeFrame: Baseline, 56 weeks
measure: Change in Fasting Insulin Levels, Using Log-transformed Data
timeFrame: Baseline, 56 weeks
measure: Change in Fasting Blood Glucose Levels
timeFrame: Baseline, 56 weeks
measure: Change in HOMA-IR Levels, Using Log-transformed Data
timeFrame: Baseline, 56 weeks
measure: Change in Question 19 From 21-Item COE (Control of Eating) Questionnaire
timeFrame: Baseline, 56 weeks
measure: Change in Fasting LDL Cholesterol Levels
timeFrame: Baseline, 56 weeks
measure: Change in Systolic Blood Pressure
timeFrame: Baseline, 56 weeks
measure: Change in Diastolic Blood Pressure
timeFrame: Baseline, 56 weeks
measure: Change in IDS-SR Total Scores
timeFrame: Baseline, 56 weeks
measure: Change in Food Craving Inventory Sweets Subscale Score
timeFrame: Baseline, 56 weeks
measure: Change in Food Craving Inventory Carbohydrates Subscale Score
timeFrame: Baseline, 56 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Radiant Research
state: Alabama
city: Fairhope
country: United States
facility: SelfCenter, PC
state: Alabama
city: Chandler
country: United States
facility: Radiant Research, Phoenix Southeast
state: Arizona
city: Anaheim
country: United States
facility: Advanced Clinical Research Institute
state: California
city: Orange
country: United States
facility: Advance Clinical Research Institute
state: California
city: San Diego
country: United States
facility: Scripps Clinic Del Mar
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System
state: California
city: Miami
country: United States
facility: Miami Research Associates
state: Florida
city: Pembroke Pines
country: United States
facility: University Clinical Research
state: Florida
city: Atlanta
country: United States
facility: Georgia Clinical Research
state: Georgia
city: Augusta
country: United States
facility: CSRA Partners in Health, Inc
state: Georgia
city: Honolulu
country: United States
facility: East-West Medical Research Institute
state: Hawaii
city: Chicago
country: United States
facility: Radiant Research
state: Illinois
city: Evansville
country: United States
facility: Welborn Clinic
state: Indiana
city: Overland Park
country: United States
facility: Radiant Research Kansas City
state: Kansas
city: Lexington
country: United States
facility: Central Kentucky Research Associates, Inc.
state: Kentucky
city: Baton Rouge
country: United States
facility: Pennington Biomedical Research Center
state: Louisiana
city: Slidell
country: United States
facility: Medical Research Institute
state: Louisiana
city: Baltimore
country: United States
facility: Health Trends Research, LLC
state: Maryland
city: Springfield
country: United States
facility: FutureCare Studies
state: Massachusetts
city: Reno
country: United States
facility: Center for Nutrition and Metabolic Disorders
state: Nevada
city: Charlotte
country: United States
facility: Center for Nutrition and Preventive Medicine
state: North Carolina
city: Raleigh
country: United States
facility: Wake Research Associates, LLC
state: North Carolina
city: Cleveland
country: United States
facility: Rapid Medical Research, Inc.
state: Ohio
city: Columbus
country: United States
facility: Central Ohio Nutrition Center, Inc.
state: Ohio
city: Oklahoma City
country: United States
facility: Lynn Health Science Institute
state: Oklahoma
city: Portland
country: United States
facility: Summit Research Network (Oregon), Inc.
state: Oregon
city: Cordova
country: United States
facility: Internal Medicine Associates of Cordova
state: Tennessee
city: Jackson
country: United States
facility: Jackson Clinic, PA
state: Tennessee
city: Austin
country: United States
facility: Covance Clinical Research Unit Austin
state: Texas
city: Dallas
country: United States
facility: Radiant Research
state: Texas
city: Dallas
country: United States
facility: Baylor Endocrine Center
state: Texas
city: San Antonio
country: United States
facility: Radiant Research
state: Texas
city: San Antonio
country: United States
facility: Oakwell Clinical Research
state: Texas
Study officials:
References:
citation: Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, Kim DD, Dunayevich E; COR-I Study Group. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010 Aug 21;376(9741):595-605. doi: 10.1016/S0140-6736(10)60888-4. Epub 2010 Jul 29.