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

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

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Overweight
• Intervention / Treatment: Drug: Placebo; Behavioral: Ancillary therapy; Drug: Naltrexone SR 32 mg/bupropion SR 360 mg/day

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.

• Study Type: Interventional
• Enrollment (Actual): 1496
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85050
      • Hope Research Institute
    • Phoenix, Arizona, United States, 85016
      • Lovelace Scientific Resources
  • Arkansas
    • Hot Springs, Arkansas, United States, 71913
      • Healthstar Research
  • California
    • Carmichael, California, United States, 98608
      • Northern California Research
    • Fresno, California, United States, 93710
      • Sierra Medical Research
    • Newport Beach, California, United States, 92660
      • Pharmacology Research Institute
  • Colorado
    • Denver, Colorado, United States, 80220
      • Center for Human Nutrition University of Colorado Health Sciences Center
  • Connecticut
    • Waterbury, Connecticut, United States, 06708
      • Chase Medical Research, LLC
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University
  • Florida
    • Palm Harbor, Florida, United States, 34684
      • Suncoast Clinical Research
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Comprehensive NeuroScience, Inc
    • Stockbridge, Georgia, United States, 30281
      • Clinical Research Atlanta
  • Indiana
    • Valparaiso, Indiana, United States, 46383
      • Northwest Indiana Center for Clinical Research
  • Kentucky
    • Madisonville, Kentucky, United States, 42431
      • Trover Center for Clinical Studies
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Nutrition and Weight Mangement Center Boston Medical Center
    • Milford, Massachusetts, United States, 01757
      • Milford Emergency Associates, Inc
  • Michigan
    • Okemos, Michigan, United States, 48864
      • Summit Research Network, Inc.
  • Minnesota
    • Brooklyn Center, Minnesota, United States, 55430
      • Twin Cities Clinical Research
  • Missouri
    • St. Louis, Missouri, United States, 63141
      • Mercy Health Research
    • St. Louis, Missouri, United States, 63141
      • Radiant Research, Inc.
  • Nevada
    • Las Vegas, Nevada, United States, 89104
      • Clinical Research Center Of Nevada
  • New Hampshire
    • Dover, New Hampshire, United States, 03820
      • Endocrinology & Diabetes Consultants
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108
      • Lovelace Scientific Resources
  • New York
    • Manlius, New York, United States, 13104
      • Central New York Clinical Research
    • New York, New York, United States, 10021
      • Comprehensive Weight Control Program
    • Staten Island, New York, United States, 10305
      • Behavioral Medical Research
  • North Carolina
    • Charlotte, North Carolina, United States, 28209
      • Metrolina Medical Research
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Patient Priority
    • Kettering, Ohio, United States, 45429
      • Wells Institute for Health Awareness
  • Oregon
    • Portland, Oregon, United States, 97205
      • The Portland Clinic
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
  • South Carolina
    • Greer, South Carolina, United States, 29349
      • Mountain View Clinical Research
    • Mt. Pleasant, South Carolina, United States, 29464
      • Palmetto Medical Research
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Clinical Research Associates, Inc.
  • Texas
    • Dallas, Texas, United States, 75230
      • The Cooper Institute
  • Washington
    • Seattle, Washington, United States, 98104
      • Summit Research Network, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: NB32; Naltrexone SR 32 mg/bupropion SR 360 mg/day with ancillary therapy	Behavioral: Ancillary therapy; Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling; Drug: Naltrexone SR 32 mg/bupropion SR 360 mg/day; Other Names: NB32
PLACEBO_COMPARATOR: Placebo; Placebo with ancillary therapy	Drug: Placebo; Behavioral: Ancillary therapy; Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Orexigen Therapeutics, Inc

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (ACTUAL): June 1, 2009
• Study Completion (ACTUAL): June 1, 2009

Study Registration Dates

• First Submitted: November 30, 2007
• First Submitted That Met QC Criteria: November 30, 2007
• First Posted (ESTIMATE): December 4, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): November 21, 2014
• Last Update Submitted That Met QC Criteria: November 18, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: Obesity
• Additional Relevant MeSH Terms: Body Weight; Overweight; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Narcotic Antagonists; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Alcohol Deterrents; Dopamine Uptake Inhibitors; Naltrexone; Bupropion
• Other Study ID Numbers: NB-303; COR-II (OTHER: Orexigen Therapeutics, Inc.)