NBC: Naltrexone-Bupropion Versus Placebo-Bupropion for Weight Loss in Schizophrenia

• Sponsor: Yale University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03132571
• Collaborator: (none)
• Enrollment: 5
• Location: 1
• Arms: 2
• Actual Duration (Months): 14
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Diabetes Mellitus, Type 2; Obesity	Drug: Naltrexone; Drug: Bupropion; Other: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Naltrexone versus Placebo assignment will remain double-blinded for the duration of the study; Bupropion dosing will be open-label and not masked to either participant or investigator.
• Primary Purpose: Treatment
• Official Title: A Pilot Trial of Naltrexone-Bupropion Combination Versus Placebo Combined With Bupropion for Weight Loss in Comorbid Schizophrenia
• Actual Study Start Date: Jun 1, 2017
• Actual Primary Completion Date: Jul 31, 2018
• Actual Study Completion Date: Jul 31, 2018

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures

1. BMI [Baseline and Week 16]

   BMI will be calculated using weekly height and weight measurements (kg/m^2) at each assessment.

Secondary Outcome Measures

1. Weight (kg) [Baseline and Week 16]

   Weight in kilograms will be measured at each assessment and change will be determined at study endpoint.

2. Health Risk Markers [Baseline to Week 16]

   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

3. Waist Circumference (Inches) [Baseline and Week 16]

   Waist circumference will be measured in inches at each assessment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Connecticut Mental Health Center	New Haven	Connecticut	United States	06519

Sponsors and Collaborators

• Yale University

Investigators

• Principal Investigator: Cenk Tek, MD, Yale University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 13, 2018

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT03132571
• Other Study ID Numbers: 1606017928
• First Posted: Apr 28, 2017
• Last Update Posted: Aug 7, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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
• Keywords provided by Yale University: Schizophrenia; Diabetes; Obesity
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Weight Loss; Schizophrenia; Naltrexone; Bupropion

Study Results

Participant Flow

Pre-assignment Detail	30 people were screened by telephone. 18/30 people screened were deemed ineligible. The reasons for ineligibility were: antidepressant medication use (11/18), a history of seizures (4/18) and already taking Naltrexone (3/18). 12/30 people were eligible, 6/12 were initially interested in the study and ultimately, only 5/6 were consented.

Arm/Group Title	Naltrexone With Bupropion	Placebo With Bupropion
Arm/Group Description	Oral Naltrexone taken once a day and Oral Bupropion taken once a day for 16 weeks. Naltrexone: 37.mg oral capsule taken once daily for over the course of the study (16 weeks) Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.	Oral placebo capsule and Oral Bupropion taken once a day for 16 weeks. Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target. Placebo: Oral placebo taken once daily for the course of the study (16 week)
Period Title: Overall Study
STARTED	3	2
COMPLETED	3	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Naltrexone With Bupropion	Placebo With Bupropion	Total
Arm/Group Description	Oral Naltrexone taken once a day and Oral Bupropion taken once a day for 16 weeks. Naltrexone: 37.mg oral capsule taken once daily for over the course of the study (16 weeks) Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.	Oral placebo capsule and Oral Bupropion taken once a day for 16 weeks. Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target. Placebo: Oral placebo taken once daily for the course of the study (16 week)	Total of all reporting groups
Overall Participants	3	2	5
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.33 (8.14)	58.00 (1.41)	51.00 (8.63)
Sex: Female, Male (Count of Participants)
Female	0 0%	1 50%	1 20%
Male	3 100%	1 50%	4 80%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 66.7%	1 50%	3 60%
White	1 33.3%	1 50%	2 40%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	2 100%	5 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Presented are the baseline and 16 weeks summary data on the 5 patients enrolled.

Arm/Group Title	Naltrexone With Bupropion	Placebo With Bupropion
Arm/Group Description	Oral Naltrexone taken once a day and Oral Bupropion taken once a day for 16 weeks. Naltrexone: 37.mg oral capsule taken once daily for over the course of the study (16 weeks) Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.	Oral placebo capsule and Oral Bupropion taken once a day for 16 weeks. Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target. Placebo: Oral placebo taken once daily for the course of the study (16 week)
Measure Participants	3	2
Baseline	39.06 (6.03)	29.55 (0.07)
16 Weeks	37.33 (5.81)	30.65 (3.88)

2. Secondary Outcome

Title	Weight (kg)
Description	Weight in kilograms will be measured at each assessment and change will be determined at study endpoint.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Presented are the baseline and 16 weeks summary data on the 5 patients enrolled.

Arm/Group Title	Naltrexone With Bupropion	Placebo With Bupropion
Arm/Group Description	Oral Naltrexone taken once a day and Oral Bupropion taken once a day for 16 weeks. Naltrexone: 37.mg oral capsule taken once daily for over the course of the study (16 weeks) Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.	Oral placebo capsule and Oral Bupropion taken once a day for 16 weeks. Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target. Placebo: Oral placebo taken once daily for the course of the study (16 week)
Measure Participants	3	2
Baseline	118.78 (11.17)	87.25 (15.48)
16 Weeks	113.60 (11.24)	91.25 (27.64)

3. Secondary Outcome

Title	Health Risk Markers
Description	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
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

These labratory data were not collected and summarized due to the removal of diabetes from the study criteria and the early termination of the study.

Arm/Group Title	Naltrexone With Bupropion	Placebo With Bupropion
Arm/Group Description	Oral Naltrexone taken once a day and Oral Bupropion taken once a day for 16 weeks. Naltrexone: 37.mg oral capsule taken once daily for over the course of the study (16 weeks) Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.	Oral placebo capsule and Oral Bupropion taken once a day for 16 weeks. Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target. Placebo: Oral placebo taken once daily for the course of the study (16 week)
Measure Participants	0	0

4. Secondary Outcome

Title	Waist Circumference (Inches)
Description	Waist circumference will be measured in inches at each assessment.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Presented are the baseline and 16 weeks summary data on the 5 patients enrolled.

Arm/Group Title	Naltrexone With Bupropion	Placebo With Bupropion
Arm/Group Description	Oral Naltrexone taken once a day and Oral Bupropion taken once a day for 16 weeks. Naltrexone: 37.mg oral capsule taken once daily for over the course of the study (16 weeks) Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.	Oral placebo capsule and Oral Bupropion taken once a day for 16 weeks. Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target. Placebo: Oral placebo taken once daily for the course of the study (16 week)
Measure Participants	3	2
Baseline	50.08 (5.26)	41.87 (1.23)
16 Weeks	48.50 (5.76)	43.37 (2.29)

Adverse Events

Time Frame	Adverse events were monitored in patients up to 16 weeks post randomization.
Arm/Group Title	Naltrexone With Bupropion		Placebo With Bupropion
Arm/Group Description	Oral Naltrexone taken once a day and Oral Bupropion taken once a day for 16 weeks. Naltrexone: 37.mg oral capsule taken once daily for over the course of the study (16 weeks) Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.		Oral placebo capsule and Oral Bupropion taken once a day for 16 weeks. Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target. Placebo: Oral placebo taken once daily for the course of the study (16 week)
All Cause Mortality
	Naltrexone With Bupropion		Placebo With Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/2 (0%)
Serious Adverse Events
	Naltrexone With Bupropion		Placebo With Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Naltrexone With Bupropion		Placebo With Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		0/2 (0%)
General disorders
Nausea	2/3 (66.7%)		0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.