A Safety and Efficacy Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects
Condition: Obesity; Overweight
MeSH terms: Overweight
Intervention: Naltrexone SR 32 mg/bupropion SR 360 mg/day; Placebo; Ancillary therapy
Intervention description: Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling
Intervention MeSH terms: Naltrexone; Bupropion
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 1496.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Obesity

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.
    

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