Clinical trial NCT00474630: A Safety and Efficacy Study Comparing Naltrexone SR/Bupropion SR and Placebo in Obese Subjects With Type 2 Diabetes
Official title: A Multicenter, Randomized, Double Blind, Placebo Controlled Study Comparing the Safety and Efficacy of Naltrexone 32 mg Sustained Release (SR)/Bupropion 360 mg Sustained Release (SR) and Placebo in Obese Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Obesity
Overweight
Diabetes Mellitus, Type 2
Keywords: Obesity
Overweight
Diabetes Mellitus, Type 2
Lead sponsor: Orexigen Therapeutics, Inc
Sponsor class: INDUSTRY
First posted: 2007-05-17
Enrollment: 505
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: Optimal care of patients with diabetes mellitus includes vigorous and persistent efforts to achieve physiologic control of blood glucose as well as other often associated conditions including hypertension, dyslipidemia and excess weight. Pharmacologic interventions for the treatment of obesity in type 2 diabetes have shown significant reductions in HbA1c. 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 the combination of naltrexone SR and bupropion SR compared to placebo in obese subjects with type 2 diabetes mellitus.

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

Primary outcomes:
measure: Co-primary: Body Weight- Mean Percent Change
timeFrame: Baseline, 56 weeks
measure: Co-primary: Body Weight- Proportion of Subjects With ≥5% Decrease
timeFrame: Baseline, 56 weeks
Secondary outcomes:
measure: Change in HbA1c Levels
timeFrame: Baseline, 56 weeks
measure: Change in Fasting Triglycerides Levels, Using Log-transformed Data
timeFrame: Baseline, 56 weeks
measure: Change in Fasting HDL Cholesterol Levels
timeFrame: Baseline, 56 weeks
measure: Change in Fasting Blood Glucose Levels
timeFrame: Baseline, 56 weeks
measure: Change in Waist Circumference
timeFrame: Baseline, 56 weeks
measure: Body Weight- Proportion of Subjects With ≥10% Decrease
timeFrame: Baseline, 56 weeks
measure: HbA1c- Proportion of Subjects With HbA1c <7% at Endpoint
timeFrame: Baseline, 56 weeks
measure: Percent of Subjects Requiring Rescue Medications for Diabetes
timeFrame: Baseline, 56 weeks
measure: Percent of Subjects With Dose Reduction in Oral Antidiabetes Medications
timeFrame: Baseline, 56 weeks
measure: Percent of Subjects With Dose Increase in Oral Antidiabetes Medications
timeFrame: Baseline, 56 weeks
measure: Change in HOMA-IR Levels, Using Log-transformed Data
timeFrame: Baseline, 56 weeks
measure: Change in Fasting Insulin Levels, Using Log-transformed Data
timeFrame: Baseline, 56 weeks
measure: HbA1c- Proportion of Subjects With HbA1c <6.5% at Endpoint
timeFrame: Baseline, 56 weeks
measure: Change in IWQOL-Lite Total Scores
timeFrame: Baseline, 56 weeks
measure: Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data
timeFrame: Baseline, 56 weeks
measure: Percent of Subjects Discontinuing Due to Poor Glycemic Control
timeFrame: Baseline, 56 weeks
measure: Change in Question 19 From 21-Item COE (Control of Eating) Questionnaire
timeFrame: Baseline, 56 weeks
measure: Change in Fasting LDL Cholesterol Levels
timeFrame: Baseline, 56 weeks
measure: Change in Systolic Blood Pressure
timeFrame: Baseline, 56 weeks
measure: Change in Diastolic Blood Pressure
timeFrame: Baseline, 56 weeks
measure: Change in IDS-SR Total Scores
timeFrame: Baseline, 56 weeks
measure: Change in Food Craving Inventory Sweets Subscale Score
timeFrame: Baseline, 56 weeks
measure: Change in Food Craving Inventory Carbohydrates Subscale Score
timeFrame: Baseline, 56 weeks
Other outcomes:
Locations:
city: Fairhope
country: United States
facility: SelfCenter, PC
state: Alabama
city: Peoria
country: United States
facility: Pivotal Research Centers
state: Arizona
city: Phoenix
country: United States
facility: HOPE Research Institute
state: Arizona
city: Hot Springs
country: United States
facility: HealthStar Research
state: Arkansas
city: Beverly Hills
country: United States
facility: Impact Clinical Trials
state: California
city: Carmichael
country: United States
facility: Northern California Research
state: California
city: Fresno
country: United States
facility: Sierra Medical Research
state: California
city: Orange
country: United States
facility: Advance Clinical Research Institute
state: California
city: San Diego
country: United States
facility: Affiliated Research Institute
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System
state: California
city: Santa Ana
country: United States
facility: Apex Research Institue
state: California
city: Waterbury
country: United States
facility: Chase Medical Research, LLC
state: Connecticut
city: Fort Myers
country: United States
facility: LCFP Inc.
state: Florida
city: Miami
country: United States
facility: Miami Research Associates
state: Florida
city: Palm Harbor
country: United States
facility: Suncoast Clinical Research
state: Florida
city: Pembroke Pines
country: United States
facility: University Clinical Research
state: Florida
city: Augusta
country: United States
facility: CSRA Partners in Health, Inc
state: Georgia
city: Honolulu
country: United States
facility: East-West Medical Research Institute
state: Hawaii
city: Evansville
country: United States
facility: Deaconess Clinic
state: Indiana
city: Valparaiso
country: United States
facility: Northwest Indiana Center for Clinical Research
state: Indiana
city: Lexington
country: United States
facility: Central Kentucky Research Associates, Inc.
state: Kentucky
city: Louisville
country: United States
facility: L-Marc
state: Kentucky
city: Madisonville
country: United States
facility: Trover Center for Clinical Studies
state: Kentucky
city: Baton Rouge
country: United States
facility: Pennington Biomedical Research Center
state: Louisiana
city: Slidell
country: United States
facility: Medical Research Institute
state: Louisiana
city: Baltimore
country: United States
facility: Health Trends Research, LLC
state: Maryland
city: Springfield
country: United States
facility: FutureCare Studies
state: Massachusetts
city: Brooklyn Center
country: United States
facility: Twin Cities Clinical Research
state: Minnesota
city: Kansas City
country: United States
facility: The Center for Pharmaceutical Research
state: Missouri
city: St. Louis
country: United States
facility: Mercy Health Research
state: Missouri
city: St. Louis
country: United States
facility: Radiant Research, Inc.
state: Missouri
city: Reno
country: United States
facility: Center for Nutrition and Metabolic Diseases, Univ. of Nevada
state: Nevada
city: Dover
country: United States
facility: Endocrinology & Diabetes Consultants
state: New Hampshire
city: Albuquerque
country: United States
facility: Lovelace Scientific Resources
state: New Mexico
city: Flushing
country: United States
facility: Diabetes care and Information Center
state: New York
city: Manlius
country: United States
facility: Central New York Clinical Research
state: New York
city: Rochester
country: United States
facility: Rochester Clinical Research, Inc
state: New York
city: Charlotte
country: United States
facility: Metrolina Medical Research
state: North Carolina
city: Cleveland
country: United States
facility: Rapid Medical Research, Inc.
state: Ohio
city: Columbus
country: United States
facility: Central Ohio Nutrition Center, Inc.
state: Ohio
city: Kettering
country: United States
facility: Wells Institute for Health Awareness
state: Ohio
city: Mentor
country: United States
facility: Your Diabetes Endocrine and Nutrition Group
state: Ohio
city: Greer
country: United States
facility: Mountain View Clinical Research
state: South Carolina
city: Mt. Pleasant
country: United States
facility: Palmetto Medical Research
state: South Carolina
city: Chattanooga
country: United States
facility: ClinSearch
state: Tennessee
city: Nashville
country: United States
facility: Clinical Research Associates, Inc.
state: Tennessee
city: Dallas
country: United States
facility: The Cooper Institute
state: Texas
city: Dallas
country: United States
facility: Baylor Endocrine Center
state: Texas
city: Midland
country: United States
facility: Diabetes Center of the Southwest
state: Texas
city: San Antonio
country: United States
facility: InVisions Consultants, LLC
state: Texas
city: San Antonio
country: United States
facility: Diabetes & Glandular Disease Research Associates, Inc.
state: Texas
city: Seattle
country: United States
facility: Summit Research Network, Inc.
state: Washington
city: Spokane
country: United States
facility: Northside Internal Medicine
state: Washington
Study officials:
References:
citation: Hollander P, Gupta AK, Plodkowski R, Greenway F, Bays H, Burns C, Klassen P, Fujioka K; COR-Diabetes Study Group. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013 Dec;36(12):4022-9. doi: 10.2337/dc13-0234. Epub 2013 Oct 21.