A Safety and Efficacy Study of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects Participating in an Intensive Behavior Modification Program

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00456521

Enrollment

793

Registered

2007-04-05

Start date

2007-03-31

Completion date

2008-12-31

Last updated

2014-12-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Obesity, Overweight

Keywords

Obesity, Behavior Modification

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.

Interventions

DRUGNaltrexone SR 32 mg/ bupropion SR 360 mg/ day

DRUGPlacebo

BEHAVIORALIntensive group lifestyle modification counseling

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

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

Design outcomes

Primary

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

Measure	Time frame	Description
Change in Fasting HDL Cholesterol Levels	Baseline, 56 weeks	—
Change in IWQOL-Lite Total Scores	Baseline, 56 weeks	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
Change in HOMA-IR Levels, Using Log-transformed Data	Baseline, 56 weeks	HOMA-IR= Homeostasis Model Assessment-Insulin Resistance
Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data	Baseline, 56 weeks	—
Change in Fasting Blood Glucose Levels	Baseline, 56 weeks	—
Change in Fasting LDL Cholesterol	Baseline, 56 weeks	—
Change in Systolic Blood Pressure	Baseline, 56 weeks	—
Change in Fasting Triglycerides Levels, Using Log-transformed Data	Baseline, 56 weeks	—
Body Weight- Proportion of Subjects With ≥10% Decrease	Baseline, 56 weeks	—
Change in Waist Circumference	Baseline, 56 weeks	—
Change in IDS-SR Total Scores	Baseline, 56 weeks	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.
Change in Food Craving Inventory Sweets Subscale Scores	Baseline, 56 weeks	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).
Change in Food Craving Inventory Carbohydrates Subscale Scores	Baseline, 56 weeks	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).
Change in Question 19 From 21-Item COE (Control of Eating) Questionnaire	Baseline, 56 weeks	Question 19: Generally, how difficult has it been to control your eating? Scoring: 0=not at all difficult; 100=extremely difficult
Change in Diastolic Blood Pressure	Baseline, 56 weeks	—
Change in Fasting Insulin Levels, Using Log-transformed Data	Baseline, 56 weeks	—

Countries

United States

Participant flow

Participants by arm

Arm	Count
NB32 Naltrexone SR 32 mg/ bupropion SR 360 mg/ day	591
Placebo Placebo	202
Total	793

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	150	25
Overall Study	Drug non-compliance, moved, other	26	11
Overall Study	Lack of Efficacy	3	6
Overall Study	Lost to Follow-up	22	17
Overall Study	Pregnancy	1	1
Overall Study	Protocol Violation	4	0
Overall Study	Withdrawal by Subject	43	24

Baseline characteristics

Characteristic	NB32	Placebo	Total
Age, Continuous	45.89 years STANDARD_DEVIATION 10.42	45.59 years STANDARD_DEVIATION 11.35	45.82 years STANDARD_DEVIATION 10.66
BMI	36.34 kg/m^2 STANDARD_DEVIATION 4.16	36.96 kg/m^2 STANDARD_DEVIATION 4.18	36.50 kg/m^2 STANDARD_DEVIATION 4.17
Race/Ethnicity, Customized American Indian or Alaska Native	7 participants	1 participants	8 participants
Race/Ethnicity, Customized Asian	6 participants	2 participants	8 participants
Race/Ethnicity, Customized Black or African American	145 participants	44 participants	189 participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 participants	0 participants	1 participants
Race/Ethnicity, Customized Other	27 participants	6 participants	33 participants
Race/Ethnicity, Customized White	405 participants	149 participants	554 participants
Sex: Female, Male Female	528 Participants	185 Participants	713 Participants
Sex: Female, Male Male	63 Participants	17 Participants	80 Participants
Weight	100.16 kg STANDARD_DEVIATION 15.42	101.88 kg STANDARD_DEVIATION 14.96	100.60 kg STANDARD_DEVIATION 15.31

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	465 / 584	132 / 200
serious Total, serious adverse events	22 / 584	1 / 200