Naltrexone-Bupropion Versus Placebo-Bupropion for Weight Loss in Schizophrenia (NBC)

A Pilot Trial of Naltrexone-Bupropion Combination Versus Placebo Combined With Bupropion for Weight Loss in Comorbid Schizophrenia

The purpose of this study is to determine the efficacy of combining open-label extended release bupropion (flexible dosing up to 450mg target) and naltrexone (37.5mg) versus Bupropion and placebo along with a daily 500 calorie reduction diet recommendation for weight and health risk reduction in 40 overweight/obese individuals with schizophrenia.

Study Overview

• Status: Terminated
• Conditions: Obesity; Diabetes Mellitus, Type 2; Schizophrenia
• Intervention / Treatment: Drug: Naltrexone; Drug: Bupropion; Other: Placebo

Detailed Description

The combination of naltrexone with noradrenaline/dopamine reuptake blocker bupropion has been developed and FDA-approved for the treatment of obesity in the general population. Naltrexone does not normally produce weight loss in humans and bupropion produces modest weight loss, however the combination produces clinically significant weight loss, which appears to be more than the sum of its components would otherwise produce separately. Of interest to us, the combination has been shown to be effective for clinically significant weight loss in obese subjects with type 2 diabetes as well. Registration studies by the manufacturer of the combination pill excluded antipsychotic medication users, thus we have no information on the potential effectiveness of the combination in this population. Both naltrexone and bupropion are commonly used in psychiatry, naltrexone for co-morbid alcohol addiction, and bupropion for co-morbid depression and/or cigarette addiction. This is a 16-week pilot trial of 37.5mg naltrexone/placebo added to extended release bupropion in flexible dosing (150mg to 450mg) and a daily 500 calorie reduction diet recommendation for subjects with schizophrenia and obesity. A dose of 37.5mg is similar to the FDA-approved combination dose for naltrexone. However, based on our experience with bupropion, we have chosen to use bupropion in an un-blinded manner and reach the target dose of 450mg based on tolerance of the individual subject over the initial 3-week period.

Changes to the study since registration:

The study was initially registered with 3 arms (Naltrexone vs Bupropion vs Placebo)- whereas the original intent was always supposed to be a 2 armed study (Naltrexone vs Placebo- each with Bupropion included)- this was corrected when the results of the terminated study were entered. In addition, there was an initial intent to include diabetics in the study, but this was later removed as well.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Connecticut Mental Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Age 18 to 75
2. Meet DSM-IV criteria for schizophrenia or schizoaffective disorder based on SCID interview (If bipolar-schizoaffective: need to be adequately stabilized on a mood stabilizer and show no mania history for the past one year, as confirmed by study psychiatrist and patient's clinician)
3. Body Mass Index (BMI) of 28 and over
4. On a stable dose of antipsychotic medication; i.e. at least one month with no dose change, and three months from an antipsychotic switch
5. Deemed to be symptomatically stable by the clinical staff in the last two months
6. Over 7% total body weight increase on antipsychotics for subjects within first year of illness

Exclusion Criteria

1. Meet criteria for current opiate abuse or dependence (confirmed by positive urine drug screen for opiates or, if suspected by study doctor via patient history and or suspicion of occult opiate use.) Note: All subjects will be screened for drugs, not only those suspected of opiate use.
2. A history of seizures in the past five years (confirmed through chart review and discussion with patient's clinician)
3. Meet DSM criteria for Bipolar Disorder
4. History of mania in the past one year (confirmed through chart review and discussion with patient's clinician)
5. Uncontrolled hypertension
6. Insulin dependent diabetes mellitus
7. Current history of dementia, mental retardation
8. Not capable of giving informed consent for participation in the study
9. Women who are pregnant or breast-feeding
10. Physical conditions affecting body weight (e.g. Cushing's disease, polycystic ovary syndrome)
11. Severe liver dysfunction, (serum aminotransferases greater than three times normal), acute infectious hepatitis, liver failure.
12. History of glaucoma.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Naltrexone with Bupropion; Oral Naltrexone taken once a day and Oral Bupropion taken once a day for 16 weeks.	Drug: Naltrexone; 37.mg oral capsule taken once daily for over the course of the study (16 weeks); Other Names: Revia; Drug: Bupropion; Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.; Other Names: Wellbutrin; Zyban
Placebo Comparator: Placebo with Bupropion; Oral placebo capsule and Oral Bupropion taken once a day for 16 weeks.	Drug: Bupropion; Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.; Other Names: Wellbutrin; Zyban; Other: Placebo; Oral placebo taken once daily for the course of the study (16 week)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BMI	BMI will be calculated using weekly height and weight measurements (kg/m^2) at each assessment.	Baseline and Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight (kg)	Weight in kilograms will be measured at each assessment and change will be determined at study endpoint.	Baseline and Week 16
Health Risk Markers	Serum lipid profiles, fasting glucose, and glycosylated hemoglobin (hbA1c) will be measured at baseline and week 16 and change in these markers will be determined at endpoint	Baseline to Week 16
Waist Circumference (Inches)	Waist circumference will be measured in inches at each assessment.	Baseline and Week 16

Collaborators and Investigators

• Sponsor: Yale University
• Investigators: Principal Investigator: Cenk Tek, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): July 31, 2018
• Study Completion (Actual): July 31, 2018

Study Registration Dates

• First Submitted: April 17, 2017
• First Submitted That Met QC Criteria: April 24, 2017
• First Posted (Actual): April 28, 2017

Study Record Updates

• Last Update Posted (Actual): August 7, 2019
• Last Update Submitted That Met QC Criteria: August 5, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Diabetes; Schizophrenia; Obesity
• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Body Weight; Schizophrenia Spectrum and Other Psychotic Disorders; Body Weight Changes; Diabetes Mellitus, Type 2; Schizophrenia; Weight Loss; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Narcotic Antagonists; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Alcohol Deterrents; Dopamine Uptake Inhibitors; Naltrexone; Bupropion
• Other Study ID Numbers: 1606017928

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All de-identified data resulting from this award involving human subjects will be submitted to the NIMH Data Archive (NDA) - National Database for Clinical Trials Related to Mental Illness (NDCT) The Principal Investigator will work with NDA support staff to plan an appropriate data submission schedule and provide information on the steps for submission and sharing of data. Communication of this data sharing plan to appropriate research staff to ensure the timely submission of data. All human subject data provided will include an NDA Global Unique Identifier (GUID) and will not include personally identifiable information (PII). Analyzed data will be submitted no later than the time of publication. Even if a publication focuses on only part of an analyzed dataset, the entire analyzed dataset will be submitted when the first paper is published. All data made available for public use via NDA will be de-identified data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No