Naltrexone and Varenicline: Weight Gain and Tolerability in Cigarette Smokers

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Naltrexone and Varenicline: Weight Gain and Tolerability in Smokers

Conditions
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Smoking, Nicotine Dependence

Intervention / Treatment
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* Drug: Naltrexone
* Drug: Varenicline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between the ages of 18 and 75 Smoking 10 or more cigarettes per day Fewer than 3 months of smoking abstinence in the past year Motivated to stop smoking Exclusion Criteria: Current use of opiates, and/or a urine toxicology screen positive for opiates Chronic pain conditions necessitating opioid treatment (naltrexone, an opioid antagonist will make these medications ineffective) Evidence of significant hepatocellular injury as evidence by AST or ALT >3 x normal or elevated bilirubin History of cirrhosis Any serious or unstable disease within 6 months Seizure risk Diabetes mellitus requiring insulin or oral hypoglycemic medications Hepatic or renal impairment Use of a monoamine oxidase inhibitor in the prior 14 days Clinically significant cardiovascular disease within 6 months Uncontrolled hypertension Baseline systolic blood pressure higher than 150 mm Hg or diastolic blood pressure higher than 95 mm Hg Severe chronic obstructive pulmonary disease History of cancer (except treated basal cell or squamous cell carcinoma of the skin) History of clinically significant allergic reactions Major depressive disorder within the past year requiring treatment History of or current panic disorder, psychosis, bipolar disorder, or eating disorders Alcohol or drug abuse/dependency within the past year Use of another investigational drug within 30 days Intention to donate blood or blood products during the treatment phase of the study Use of tobacco products other than cigarettes or use of marijuana 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 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. 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day | Drug: Naltrexone<br>* Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day<br>Drug: Varenicline<br>* 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<br>* Other names: Chantix;|
| Placebo Comparator: 2<br>Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day | Drug: Varenicline<br>* 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<br>* Other names: Chantix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight Gain in Treatment Completers |  | baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight Gain in Participants Who Are Continuously Abstinent for the Last 4 Weeks of Treatment |  | 4 weeks | 
| Tolerability of the Combination of 25 mg Naltrexone and 2 mg Varenicline | 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. | 11 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tobacco, Smoking, Weight, Naltrexone, Varenicline