Naltrexone and Varenicline: Weight Gain and Tolerability in Cigarette Smokers

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00502216
• Collaborator: National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH), National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 23
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether the combination of naltrexone (Depade) and varenicline (Chantix) minimizes post-smoking cessation weight gain and how well the combination is tolerated.

Condition or Disease	Intervention/Treatment	Phase
Smoking; Nicotine Dependence	Drug: Naltrexone; Drug: Varenicline	Phase 1/Phase 2

Detailed Description

Varenicline, a medication recently approved by the FDA, results in smoking cessation rates as high as 50%, significantly better than bupropion or placebo. However, varenicline does not reduce post-cessation weight gain, so weight concerns may keep some smokers from taking advantage of this effective therapy.

A potential solution would be to combine varenicline with an agent that reduces weight gain. In this regard, several studies have shown that naltrexone reduces weight gain (O'Malley et al., 2006; Toll et al., 2007).

This effect appears to be dose dependent, favoring lower doses (i.e., 25 mg daily). Thus, the proposed study seeks to conduct a pilot clinical trial of low dose naltrexone (25 mg daily) compared to placebo for minimizing weight gain in combination with varenicline for smoking cessation. Forty individuals who smoke at least 10 cigarettes per day will receive open-label varenicline for 12 weeks according to the recommended titration schedule up to 1 mg varenicline twice daily. Subjects will be randomized to receive either placebo or 25 mg naltrexone daily, with treatment starting at the quit date (after 1 week on varenicline to minimize nausea, a side effect of both varenicline and naltrexone) and continuing for 11 weeks. Subjects will take 12.5 mg naltrexone daily for the first week and 25 mg naltrexone daily for the next 10 weeks of treatment. In an effort to uncover mechanisms for naltrexone's weight suppressant effects, an experiment will be conducted using food odors and food consumption to examine naltrexone's effects on palatability, incentive value, and alliesthesia.

This experiment will be conducted pretreatment and after 2 weeks on naltrexone. The primary aim of this pilot study is to examine weight gain in participants who complete the clinical trial treatment. Weight gain for those who are continuously abstinent for the last 4 weeks of treatment and rates of adverse events will be secondary outcomes. The effects of naltrexone on odor/food palatability, incentive value, and alliesthesia will be exploratory outcomes. Effect size estimates for weight gain will be generated for a NIH grant application.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Naltrexone and Varenicline: Weight Gain and Tolerability in Smokers
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day	Drug: Naltrexone; Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day; Drug: Varenicline; Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day; Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day; Other Names: Chantix
Placebo Comparator: 2 Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day	Drug: Varenicline; Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day; Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day; Other Names: Chantix

Outcome Measures

Primary Outcome Measures

1. Weight Gain in Treatment Completers [baseline and 12 weeks]

Secondary Outcome Measures

1. Weight Gain in Participants Who Are Continuously Abstinent for the Last 4 Weeks of Treatment [4 weeks]

2. Tolerability of the Combination of 25 mg Naltrexone and 2 mg Varenicline [11 weeks]

   Tolerability was measured by tracking adverse events. These data are reported in detail in the adverse events section. Presented are an unduplicated count of participants that experienced at least 1 adverse event.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Between the ages of 18 and 75

2. Smoking 10 or more cigarettes per day

3. Fewer than 3 months of smoking abstinence in the past year

4. Motivated to stop smoking

Exclusion Criteria:

1. Current use of opiates, and/or a urine toxicology screen positive for opiates

2. Chronic pain conditions necessitating opioid treatment (naltrexone, an opioid antagonist will make these medications ineffective)

3. Evidence of significant hepatocellular injury as evidence by AST or ALT >3 x normal or elevated bilirubin

4. History of cirrhosis

5. Any serious or unstable disease within 6 months

6. Seizure risk

7. Diabetes mellitus requiring insulin or oral hypoglycemic medications

8. Hepatic or renal impairment

9. Use of a monoamine oxidase inhibitor in the prior 14 days

10. Clinically significant cardiovascular disease within 6 months

11. Uncontrolled hypertension

12. Baseline systolic blood pressure higher than 150 mm Hg or diastolic blood pressure higher than 95 mm Hg

13. Severe chronic obstructive pulmonary disease

14. History of cancer (except treated basal cell or squamous cell carcinoma of the skin)

15. History of clinically significant allergic reactions

16. Major depressive disorder within the past year requiring treatment

17. History of or current panic disorder, psychosis, bipolar disorder, or eating disorders

18. Alcohol or drug abuse/dependency within the past year

19. Use of another investigational drug within 30 days

20. Intention to donate blood or blood products during the treatment phase of the study

21. Use of tobacco products other than cigarettes or use of marijuana

22. Use of nicotine replacement therapy, clonidine, varenicline, bupropion, or nortriptyline within the month prior to enrollment or intention to use medication that might interfere with study medication

23. Body Mass Index (calculated as weight in kilograms divided by the square of height in meters) less than 15 or greater than 38 or weight less than 45 kg.

24. Females of childbearing potential who are pregnant, nursing, or not practicing effective contraception (oral injectable, or implantable contraceptives, intrauterine device, or barrier method with spermacide)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University School of Medicine Substance Abuse Treatment Unit	New Haven	Connecticut	United States	06511

Sponsors and Collaborators

• Yale University
• National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Benjamin A. Toll, PhD, Yale University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT00502216
• Other Study ID Numbers: 0704002538; P50AA015632; NIH Grant P50-AA15632; NIH Grant K12-DA00167
• First Posted: Jul 17, 2007
• Last Update Posted: Jan 17, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Yale University: Tobacco; Smoking; Weight; Naltrexone; Varenicline
• Additional relevant MeSH terms: Weight Gain; Tobacco Use Disorder; Naltrexone; Varenicline

Study Results

Participant Flow

Arm/Group Title	Varenicline + Naltrexone	Varenicline + Placebo
Arm/Group Description	Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day	Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day
Period Title: Overall Study
STARTED	21	19
COMPLETED	21	19
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Varenicline + Naltrexone	Varenicline + Placebo	Total
Arm/Group Description	Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day	Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day	Total of all reporting groups
Overall Participants	21	19	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.29 (11.08)	42.42 (9.57)	46.55 (11.00)
Sex: Female, Male (Count of Participants)
Female	15 71.4%	12 63.2%	27 67.5%
Male	6 28.6%	7 36.8%	13 32.5%
Region of Enrollment (participants) [Number]
United States	21 100%	19 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Weight Gain in Treatment Completers
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Subpopulation of participants who reported quitting smoking

Arm/Group Title	Varenicline + Naltrexone	Varenicline + Placebo
Arm/Group Description	Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day	Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day
Measure Participants	17	11
Mean (Standard Deviation) [Pounds]	3.35 (6.61)	4.14 (5.15)

2. Secondary Outcome

Title	Weight Gain in Participants Who Are Continuously Abstinent for the Last 4 Weeks of Treatment
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Analyzed are those that remained abstinent for last 4 weeks of treatment

Arm/Group Title	Varenicline + Naltrexone	Varenicline + Placebo
Arm/Group Description	Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day	Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day
Measure Participants	3	3
Mean (Standard Deviation) [pounds]	0 (4.36)	7.67 (2.31)

3. Secondary Outcome

Title	Tolerability of the Combination of 25 mg Naltrexone and 2 mg Varenicline
Description	Tolerability was measured by tracking adverse events. These data are reported in detail in the adverse events section. Presented are an unduplicated count of participants that experienced at least 1 adverse event.
Time Frame	11 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline + Naltrexone	Varenicline + Placebo
Arm/Group Description	Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day	Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day
Measure Participants	21	19
Count of Participants [Participants]	10 47.6%	4 21.1%

Adverse Events

Arm/Group Title	Varenicline + Naltrexone		Varenicline + Placebo
Arm/Group Description	Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day		Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day
All Cause Mortality
	Varenicline + Naltrexone		Varenicline + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Varenicline + Naltrexone		Varenicline + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Varenicline + Naltrexone		Varenicline + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/21 (47.6%)		4/19 (21.1%)
Gastrointestinal disorders
Constipation	3/21 (14.3%)		1/19 (5.3%)
Flatulence	2/21 (9.5%)		1/19 (5.3%)
Acid reflux	0/21 (0%)		1/19 (5.3%)
Vomiting	1/21 (4.8%)		0/19 (0%)
General disorders
Nausea	6/21 (28.6%)		0/0 (NaN)
Fatigue	4/21 (19%)		0/19 (0%)
Joint pain	2/21 (9.5%)		1/19 (5.3%)
Other	2/21 (9.5%)		1/19 (5.3%)
Drowsiness	1/21 (4.8%)		0/19 (0%)
Dry Mouth	1/21 (4.8%)		0/19 (0%)
Headache	1/21 (4.8%)		0/19 (0%)
Nightmares	1/21 (4.8%)		0/19 (0%)
Sweating	1/21 (4.8%)		0/19 (0%)
Metabolism and nutrition disorders
Decreased Appetite	1/21 (4.8%)		0/19 (0%)
Increased Appetite	1/21 (4.8%)		0/19 (0%)
Nervous system disorders
Dizzyness	1/21 (4.8%)		0/19 (0%)
Psychiatric disorders
Anxiety	3/21 (14.3%)		1/19 (5.3%)
Depression	3/21 (14.3%)		0/19 (0%)
Insomnia	3/21 (14.3%)		0/19 (0%)
Sleepiness	2/21 (9.5%)		0/19 (0%)
Vivid dreams	2/21 (9.5%)		0/19 (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.