A Safety and Efficacy Study Comparing Naltrexone SR/Bupropion SR and Placebo in Obese Subjects With Type 2 Diabetes

Study Overview
=================
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.

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

Conditions
-----------------
Obesity, Overweight, Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: Naltrexone SR 32 mg/bupropion SR 360 mg/ day
* Drug: Placebo
* Behavioral: Ancillary therapy


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NB32<br>Naltrexone SR 32 mg/bupropion SR 360 mg/ day with ancillary therapy | Drug: Naltrexone SR 32 mg/bupropion SR 360 mg/ day<br> <br> * Other names: NB32;Behavioral: Ancillary therapy<br>* Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling<br>|
| Placebo Comparator: Placebo<br>Placebo with ancillary therapy | Drug: Placebo<br> <br> Behavioral: Ancillary therapy<br>* Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |
| --- | --- | --- |
| Change in HbA1c Levels |  | Baseline, 56 weeks | 
| Change in Fasting Triglycerides Levels, Using Log-transformed Data |  | Baseline, 56 weeks | 
| Change in Fasting HDL Cholesterol Levels |  | Baseline, 56 weeks | 
| Change in Fasting Blood Glucose Levels |  | Baseline, 56 weeks | 
| Change in Waist Circumference |  | Baseline, 56 weeks | 
| Body Weight- Proportion of Subjects With ≥10% Decrease |  | Baseline, 56 weeks | 
| HbA1c- Proportion of Subjects With HbA1c <7% at Endpoint |  | Baseline, 56 weeks | 
| Percent of Subjects Requiring Rescue Medications for Diabetes |  | Baseline, 56 weeks | 
| Percent of Subjects With Dose Reduction in Oral Antidiabetes Medications |  | Baseline, 56 weeks | 
| Percent of Subjects With Dose Increase in Oral Antidiabetes Medications |  | Baseline, 56 weeks | 
| Change in HOMA-IR Levels, Using Log-transformed Data | HOMA-IR= Homeostasis Model Assessment-Insulin Resistance | Baseline, 56 weeks | 
| Change in Fasting Insulin Levels, Using Log-transformed Data |  | Baseline, 56 weeks | 
| HbA1c- Proportion of Subjects With HbA1c <6.5% at Endpoint |  | 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 | 
| Percent of Subjects Discontinuing Due to Poor Glycemic Control | Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed. Odds ratio not calculated as there were no subjects in the NB32 group that discontinued due to poor glycemic control. | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Obesity, Overweight, Diabetes Mellitus, Type 2