Clinical trial NCT00567255: A Safety and Efficacy Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Obesity
Overweight
Keywords: Obesity
Lead sponsor: Orexigen Therapeutics, Inc
Sponsor class: INDUSTRY
First posted: 2007-12-04
Enrollment: 1496
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 the combination of naltrexone SR and bupropion SR is 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 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.

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 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

Primary outcomes:
measure: Co-primary: Body Weight- Mean Percent Change From Baseline to Week 28
timeFrame: Baseline, 28 weeks
measure: Co-primary: Body Weight- Proportion of Subjects With ≥5% Decrease From Baseline to Week 28
timeFrame: Baseline, 28 weeks
Secondary outcomes:
measure: Body Weight- Mean Percent Change From Baseline to Week 56
timeFrame: Baseline, 56 weeks
measure: Body Weight- Proportion of Subjects With ≥5% Decrease From Baseline to Week 56
timeFrame: Baseline, 56 weeks
measure: Body Weight- Proportion of Subjects With ≥10% Decrease From Baseline to Week 28
timeFrame: Baseline, 28 weeks
measure: Change in Waist Circumference
timeFrame: Baseline, 28 weeks
measure: Change in Fasting HDL Cholesterol Levels
timeFrame: Baseline, 28 weeks
measure: Change in Fasting Triglycerides Levels, Using Log-transformed Data
timeFrame: Baseline, 28 weeks
measure: Change in IWQOL-Lite Total Scores
timeFrame: Baseline, 28 weeks
measure: Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data
timeFrame: Baseline, 28 weeks
measure: Change in Fasting Insulin Levels, Using Log-transformed Data
timeFrame: Baseline, 28 weeks
measure: Change in Fasting Blood Glucose Levels
timeFrame: Baseline, 28 weeks
measure: Change in HOMA-IR Levels, Using Log-transformed Data
timeFrame: Baseline, 28 weeks
measure: Change in Question 19 From 21-Item COE (Control of Eating) Questionnaire
timeFrame: Baseline, 28 weeks
measure: Change in Fasting LDL Cholesterol Levels
timeFrame: Baseline, 28 weeks
measure: Change in Systolic Blood Pressure
timeFrame: Baseline, 28 weeks
measure: Change in Diastolic Blood Pressure
timeFrame: Baseline, 28 weeks
measure: Change in IDS-SR Total Score
timeFrame: Baseline, 28 weeks
measure: Change in Food Craving Inventory Sweets Subscale Score
timeFrame: Baseline, 28 weeks
measure: Change in Food Craving Inventory Carbohydrates Subscale Score
timeFrame: Baseline, 28 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Lovelace Scientific Resources
state: Arizona
city: Phoenix
country: United States
facility: HOPE Research Institute
state: Arizona
city: Hot Springs
country: United States
facility: HealthStar Research
state: Arkansas
city: Carmichael
country: United States
facility: Northern California Research
state: California
city: Fresno
country: United States
facility: Sierra Medical Research
state: California
city: Newport Beach
country: United States
facility: Pharmacology Research Institute
state: California
city: Denver
country: United States
facility: Center for Human Nutrition University of Colorado Health Sciences Center
state: Colorado
city: Waterbury
country: United States
facility: Chase Medical Research, LLC
state: Connecticut
city: Washington
country: United States
facility: George Washington University
state: District of Columbia
city: Palm Harbor
country: United States
facility: Suncoast Clinical Research
state: Florida
city: Atlanta
country: United States
facility: Comprehensive NeuroScience, Inc
state: Georgia
city: Stockbridge
country: United States
facility: Clinical Research Atlanta
state: Georgia
city: Valparaiso
country: United States
facility: Northwest Indiana Center for Clinical Research
state: Indiana
city: Madisonville
country: United States
facility: Trover Center for Clinical Studies
state: Kentucky
city: Boston
country: United States
facility: Nutrition and Weight Mangement Center Boston Medical Center
state: Massachusetts
city: Milford
country: United States
facility: Milford Emergency Associates, Inc
state: Massachusetts
city: Okemos
country: United States
facility: Summit Research Network, Inc.
state: Michigan
city: Brooklyn Center
country: United States
facility: Twin Cities Clinical Research
state: Minnesota
city: St. Louis
country: United States
facility: Mercy Health Research
state: Missouri
city: St. Louis
country: United States
facility: Radiant Research, Inc.
state: Missouri
city: Las Vegas
country: United States
facility: Clinical Research Center of Nevada
state: Nevada
city: Dover
country: United States
facility: Endocrinology & Diabetes Consultants
state: New Hampshire
city: Albuquerque
country: United States
facility: Lovelace Scientific Resources
state: New Mexico
city: Manlius
country: United States
facility: Central New York Clinical Research
state: New York
city: New York
country: United States
facility: Comprehensive Weight Control Program
state: New York
city: Staten Island
country: United States
facility: Behavioral Medical Research
state: New York
city: Charlotte
country: United States
facility: Metrolina Medical Research
state: North Carolina
city: Cincinnati
country: United States
facility: Patient Priority
state: Ohio
city: Kettering
country: United States
facility: Wells Institute For Health Awareness
state: Ohio
city: Portland
country: United States
facility: The Portland Clinic
state: Oregon
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Greer
country: United States
facility: Mountain View Clinical Research
state: South Carolina
city: Mt. Pleasant
country: United States
facility: Palmetto Medical Research
state: South Carolina
city: Nashville
country: United States
facility: Clinical Research Associates, Inc.
state: Tennessee
city: Dallas
country: United States
facility: The Cooper Institute
state: Texas
city: Seattle
country: United States
facility: Summit Research Network, Inc.
state: Washington
Study officials:
References:
citation: Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, Kim D, Dunayevich E; COR-II Study Group. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring). 2013 May;21(5):935-43. doi: 10.1002/oby.20309.