Clinical trial NCT00456521: A Safety and Efficacy Study of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects Participating in an Intensive Behavior Modification Program
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Obesity
Overweight
Keywords: Obesity
Behavior Modification
Lead sponsor: Orexigen Therapeutics, Inc
Sponsor class: INDUSTRY
First posted: 2007-04-05
Enrollment: 793
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 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: 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.

Eligibility criteria: 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

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 Triglycerides 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 HDL Cholesterol Levels
timeFrame: Baseline, 56 weeks
measure: Change in IWQOL-Lite Total Scores
timeFrame: Baseline, 56 weeks
measure: Change in HOMA-IR Levels, Using Log-transformed Data
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 Blood Glucose Levels
timeFrame: Baseline, 56 weeks
measure: Change in Fasting LDL Cholesterol
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 Scores
timeFrame: Baseline, 56 weeks
measure: Change in Food Craving Inventory Carbohydrates Subscale Scores
timeFrame: Baseline, 56 weeks
measure: Change in Question 19 From 21-Item COE (Control of Eating) Questionnaire
timeFrame: Baseline, 56 weeks
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego: Dept of Family & Preventive Medicine
state: California
city: Denver
country: United States
facility: Center for Human Nutrition, University of Colorado Health Services Center
state: Colorado
city: Gainesville
country: United States
facility: Univ. of Florida, College of Public Health, and Health Professions
state: Florida
city: St. Louis
country: United States
facility: Washington Univ. Center for Human Nutrition
state: Missouri
city: New York
country: United States
facility: New York Obesity Research Center, St. Luke's-Roosevelt Hospital Center
state: New York
city: Philadelphia
country: United States
facility: Center for Weight and Eating Disorders, School of Med., University of Penn.
state: Pennsylvania
city: Philadelphia
country: United States
facility: Center for Obesity Research and Education, Temple University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of S. Carolina Weight Management Center
state: South Carolina
city: Houston
country: United States
facility: Behavioral Medicine Research Center
state: Texas
Study officials:
References:
citation: Wadden TA, Foreyt JP, Foster GD, Hill JO, Klein S, O'Neil PM, Perri MG, Pi-Sunyer FX, Rock CL, Erickson JS, Maier HN, Kim DD, Dunayevich E. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity (Silver Spring). 2011 Jan;19(1):110-20. doi: 10.1038/oby.2010.147. Epub 2010 Jun 17.