A Safety and Efficacy Study Comparing Naltrexone SR/Bupropion SR and Placebo in Obese Subjects With Type 2 Diabetes
Condition: Obesity; Overweight; Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Overweight; Diabetes Mellitus, Type 2
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: 505.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Obesity; Overweight; Diabetes Mellitus, Type 2

Summary:

      The purpose of this study is determine whether the combination of naltrexone SR and bupropion
      SR is safe and effective in treating obesity in subjects with type 2 diabetes.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Female or male subjects aged 18 to 70 years of age (inclusive)

          -  Body mass index (BMI) ≥27 and ≤45 kg/m²

          -  Diagnosed with type 2 diabetes mellitus and on no injectable antidiabetes medication
             or inhaled insulin for more than 3 months prior to randomization

          -  Took stable doses of oral single or combination hypoglycemic medications (biguanides,
             thiazolidinediones, meglitinides, α-glucosidase inhibitors, sulfonylureas, DPP4
             inhibitors) for at least 3 months prior to randomization or did not take medications
             for the treatment of type 2 diabetes mellitus

          -  Normotensive (systolic ≤145 mm Hg and diastolic ≤95 mm Hg). Antihypertensive
             medications were allowed with the exception of alpha-adrenergic blockers, and
             clonidine. Antihypertensive treatment was stable for at least 4 weeks prior to
             randomization.

          -  Medications for the treatment of dyslipidemia were allowed with the exception of
             cholestyramine and cholestypol as long as the medical regimen had been stable for at
             least 4 weeks prior to randomization.

          -  Free of opioid medication for 7 days prior to randomization

          -  HbA1c between 7% and 10%, fasting blood glucose <270 mg/dL, and fasting triglycerides
             <400 mg/dL

          -  No clinically significant abnormality of serum albumin, blood urea nitrogen (BUN),
             bilirubin, calcium, and phosphorus

          -  Creatinine levels were ≤1.4 mg/dL for female subjects and ≤1.5 mg/dL for male subjects

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were within
             2.5 × upper limit of laboratory normal range (ULN)

          -  No clinically significant abnormality of hematocrit, white blood cell (WBC) count, WBC
             differential, or platelets

          -  No clinically significant abnormality on urinalysis

          -  TSH within normal limits or normal T3, if TSH is below normal limits

          -  Female subjects of childbearing potential had a negative serum pregnancy test

          -  Negative urine drug screen

          -  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:

          -  Type I diabetes mellitus

          -  "Brittle-diabetes" or any hospitalization or emergency room visit due to poor diabetic
             control within 6 months prior to screening, history of diabetes-related dehydration
             leading to hospitalization, or history or evidence of ketoacidosis

          -  Obesity of known endocrine origin other than diabetes mellitus (e.g., untreated
             hypothyroidism, Cushing's syndrome, established polycystic ovary syndrome)

          -  Diabetes mellitus secondary to pancreatitis or pancreatectomy

          -  Serious medical condition including but not limited to renal or hepatic insufficiency
             and Class III or IV congestive heart failure; history of myocardial infarction, angina
             pectoris, claudication, or acute limb ischemia within 6 months prior to screening;
             lifetime history of stroke

          -  History of malignancy with exception of non-melanoma skin cancer or surgically cured
             cervical cancer within 5 years prior to screening

          -  Loss or gain of more than 5.0 kg within the 3 months prior to screening

          -  Severe microvascular or macrovascular complications of diabetes, including but not
             limited to proliferative retinopathy, active limb ulcerations, amputation of
             metatarsals or above

          -  Serious psychiatric illness, including lifetime history of bipolar disorder,
             schizophrenia or other psychosis, bulimia, and anorexia nervosa; current serious
             personality disorder (e.g., borderline or antisocial); current severe major depressive
             disorder; recent (6 months prior to screening) suicide attempt or 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 6 months prior to screening

          -  History of drug or alcohol abuse or dependence within 1 year prior to screening

          -  Baseline ECG with a QTc interval (Bazett's formula) >450 msec (men) and >470 msec
             (women) or the presence of any clinically significant cardiac abnormalities, including
             but not limited to patterns consistent with recent myocardial ischemia, electrolyte
             abnormalities, or atrial or ventricular dysrhythmia or significant conduction
             abnormalities

          -  Received the following excluded concomitant medications: any psychotropic agents
             (including antipsychotic, antidepressant, anxiolytic, mood stabilizer, anticonvulsant
             agents, and 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 intervention for obesity (e.g., gastric banding)

          -  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)

          -  Treatment with bupropion or naltrexone within 12 months prior to screening

          -  History of hypersensitivity or intolerance to bupropion or naltrexone

          -  Changes in smoking status or in tobacco or nicotine use within 3 months prior to
             screening or planned during study participation

          -  Participated in a weight loss management program within one month prior to
             randomization

          -  Females who were pregnant or breast-feeding or planned 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