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

Obesity Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00474630
• Other study ID #: NB-304
• Secondary ID: COR-Diabetes
• Status: Completed
• Phase: Phase 3
• First received: May 15, 2007
• Last updated: November 18, 2014
• Start date: May 2007
• Est. completion date: June 2009

Study information

• Verified date: November 2014
• Source: Orexigen Therapeutics, Inc
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 505
• Est. completion date: June 2009
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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, a-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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Obesity
• Overweight

Intervention

Drug:
• Naltrexone SR 32 mg/bupropion SR 360 mg/ day

• Placebo

Behavioral:
• Ancillary therapy
Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling

Locations

Country	Name	City	State
United States	Lovelace Scientific Resources	Albuquerque	New Mexico
United States	CSRA Partners in Health, Inc	Augusta	Georgia
United States	Health Trends Research, LLC	Baltimore	Maryland
United States	Pennington Biomedical Research Center	Baton Rouge	Louisiana
United States	Impact Clinical Trials	Beverly Hills	California
United States	Twin Cities Clinical Research	Brooklyn Center	Minnesota
United States	Northern California Research	Carmichael	California
United States	Metrolina Medical Research	Charlotte	North Carolina
United States	ClinSearch	Chattanooga	Tennessee
United States	Rapid Medical Research, Inc.	Cleveland	Ohio
United States	Central Ohio Nutrition Center, Inc.	Columbus	Ohio
United States	Baylor Endocrine Center	Dallas	Texas
United States	The Cooper Institute	Dallas	Texas
United States	Endocrinology & Diabetes Consultants	Dover	New Hampshire
United States	Deaconess Clinic	Evansville	Indiana
United States	SelfCenter, PC	Fairhope	Alabama
United States	Diabetes care and Information Center	Flushing	New York
United States	LCFP Inc.	Fort Myers	Florida
United States	Sierra Medical Research	Fresno	California
United States	Mountain View Clinical Research	Greer	South Carolina
United States	East-West Medical Research Institute	Honolulu	Hawaii
United States	HealthStar Research	Hot Springs	Arkansas
United States	The Center for Pharmaceutical Research	Kansas City	Missouri
United States	Wells Institute for Health Awareness	Kettering	Ohio
United States	Central Kentucky Research Associates, Inc.	Lexington	Kentucky
United States	L-Marc	Louisville	Kentucky
United States	Trover Center for Clinical Studies	Madisonville	Kentucky
United States	Central New York Clinical Research	Manlius	New York
United States	Your Diabetes Endocrine and Nutrition Group	Mentor	Ohio
United States	Miami Research Associates	Miami	Florida
United States	Diabetes Center of the Southwest	Midland	Texas
United States	Palmetto Medical Research	Mt. Pleasant	South Carolina
United States	Clinical Research Associates, Inc.	Nashville	Tennessee
United States	Advance Clinical Research Institute	Orange	California
United States	Suncoast Clinical Research	Palm Harbor	Florida
United States	University Clinical Research	Pembroke Pines	Florida
United States	Pivotal Research Centers	Peoria	Arizona
United States	HOPE Research Institute	Phoenix	Arizona
United States	Center for Nutrition and Metabolic Diseases, Univ. of Nevada	Reno	Nevada
United States	Rochester Clinical Research, Inc	Rochester	New York
United States	Diabetes & Glandular Disease Research Associates, Inc.	San Antonio	Texas
United States	InVisions Consultants, LLC	San Antonio	Texas
United States	Affiliated Research Institute	San Diego	California
United States	VA San Diego Healthcare System	San Diego	California
United States	Apex Research Institue	Santa Ana	California
United States	Summit Research Network, Inc.	Seattle	Washington
United States	Medical Research Institute	Slidell	Louisiana
United States	Northside Internal Medicine	Spokane	Washington
United States	FutureCare Studies	Springfield	Massachusetts
United States	Mercy Health Research	St. Louis	Missouri
United States	Radiant Research, Inc.	St. Louis	Missouri
United States	Northwest Indiana Center for Clinical Research	Valparaiso	Indiana
United States	Chase Medical Research, LLC	Waterbury	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Orexigen Therapeutics, Inc

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Co-primary: Body Weight- Mean Percent Change		Baseline, 56 weeks	No
Primary	Co-primary: Body Weight- Proportion of Subjects With =5% Decrease		Baseline, 56 weeks	No
Secondary	Change in HbA1c Levels		Baseline, 56 weeks	No
Secondary	Change in Fasting Triglycerides Levels, Using Log-transformed Data		Baseline, 56 weeks	No
Secondary	Change in Fasting HDL Cholesterol Levels		Baseline, 56 weeks	No
Secondary	Change in Fasting Blood Glucose Levels		Baseline, 56 weeks	No
Secondary	Change in Waist Circumference		Baseline, 56 weeks	No
Secondary	Body Weight- Proportion of Subjects With =10% Decrease		Baseline, 56 weeks	No
Secondary	HbA1c- Proportion of Subjects With HbA1c <7% at Endpoint		Baseline, 56 weeks	No
Secondary	Percent of Subjects Requiring Rescue Medications for Diabetes		Baseline, 56 weeks	No
Secondary	Percent of Subjects With Dose Reduction in Oral Antidiabetes Medications		Baseline, 56 weeks	No
Secondary	Percent of Subjects With Dose Increase in Oral Antidiabetes Medications		Baseline, 56 weeks	No
Secondary	Change in HOMA-IR Levels, Using Log-transformed Data	HOMA-IR= Homeostasis Model Assessment-Insulin Resistance	Baseline, 56 weeks	No
Secondary	Change in Fasting Insulin Levels, Using Log-transformed Data		Baseline, 56 weeks	No
Secondary	HbA1c- Proportion of Subjects With HbA1c <6.5% at Endpoint		Baseline, 56 weeks	No
Secondary	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	No
Secondary	Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data		Baseline, 56 weeks	No
Secondary	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	No
Secondary	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	No
Secondary	Change in Fasting LDL Cholesterol Levels		Baseline, 56 weeks	No
Secondary	Change in Systolic Blood Pressure		Baseline, 56 weeks	No
Secondary	Change in Diastolic Blood Pressure		Baseline, 56 weeks	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	No