A Study of the Safety and Efficacy of Two Doses of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects

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

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Overweight
• Intervention / Treatment: Drug: Placebo; Drug: Naltrexone SR 16 mg/Bupropion SR 360 mg /day; 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 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.

• Study Type: Interventional
• Enrollment (Actual): 1742
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Radiant Research
    • Fairhope, Alabama, United States, 36532
      • SelfCenter, PC
  • Arizona
    • Chandler, Arizona, United States, 85225
      • Radiant Research, Phoenix Southeast
  • California
    • Anaheim, California, United States, 92801
      • Advanced Clinical Research Institute
    • Orange, California, United States, 92869
      • Advance Clinical Research Institute
    • San Diego, California, United States, 92130
      • Scripps Clinic Del Mar
    • San Diego, California, United States, 92161
      • VA San Diego Healthcare System
  • Florida
    • Miami, Florida, United States, 33143
      • Miami Research Associates
    • Pembroke Pines, Florida, United States, 33024
      • University Clinical Research
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Georgia Clinical Research
    • Augusta, Georgia, United States, 30909
      • CSRA Partners in Health, Inc
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • East-West Medical Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60610
      • Radiant Research
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Welborn Clinic
  • Kansas
    • Overland Park, Kansas, United States, 66202
      • Radiant Research Kansas City
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Central Kentucky Research Associates, Inc.
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Pennington Biomedical Research Center
    • Slidell, Louisiana, United States, 70458
      • Medical Research Institute
  • Maryland
    • Baltimore, Maryland, United States, 21209
      • Health Trends Research, LLC
  • Massachusetts
    • Springfield, Massachusetts, United States, 01103
      • FutureCare Studies
  • Nevada
    • Reno, Nevada, United States, 89557
      • Center for Nutrition and Metabolic Disorders
  • North Carolina
    • Charlotte, North Carolina, United States, 28211
      • Center for Nutrition and Preventive Medicine
    • Raleigh, North Carolina, United States, 27612
      • Wake Research Associates, LLC
  • Ohio
    • Cleveland, Ohio, United States, 44122
      • Rapid Medical Research, Inc.
    • Columbus, Ohio, United States, 43213
      • Central Ohio Nutrition Center, Inc.
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Lynn Health Science Institute
  • Oregon
    • Portland, Oregon, United States, 97210
      • Summit Research Network (Oregon), Inc.
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Internal Medicine Associates of Cordova
    • Jackson, Tennessee, United States, 38305
      • Jackson Clinic, PA
  • Texas
    • Austin, Texas, United States, 78752
      • Covance Clinical Research Unit Austin
    • Dallas, Texas, United States, 75231
      • Radiant Research
    • Dallas, Texas, United States, 75246
      • Baylor Endocrine Center
    • San Antonio, Texas, United States, 78217
      • Radiant Research
    • San Antonio, Texas, United States, 78218
      • Oakwell Clinical Research

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 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NB16; Naltrexone SR 16 mg/Bupropion SR 360 mg /day with ancillary therapy	Drug: Naltrexone SR 16 mg/Bupropion SR 360 mg /day; Other Names: NB16; Behavioral: Ancillary therapy; Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling
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	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

Collaborators and Investigators

• Sponsor: Orexigen Therapeutics, Inc

Publications and helpful links

General Publications

• 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. Erratum In: Lancet. 2010 Aug 21;376(9741):594. Lancet. 2010 Oct 23;376(9750):1392.

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): May 1, 2009
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: September 19, 2007
• First Submitted That Met QC Criteria: September 19, 2007
• First Posted (Estimate): September 20, 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; 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
• 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-301; COR-I (Other Identifier: Orexigen Therapeutics, Inc.)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No