Nicotine Dependence, Smoking
Conditions
Keywords
Tobacco, Smoking, Weight, Naltrexone, Varenicline
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.
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.
Interventions
DRUGNaltrexone
Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day
DRUGVarenicline
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
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute on Drug Abuse (NIDA)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Weight Gain in Treatment Completers | baseline and 12 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Varenicline + Naltrexone Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day | 21 |
| Varenicline + Placebo Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day | 19 |
| Total | 40 |
Baseline characteristics
| Characteristic | Varenicline + Naltrexone | Varenicline + Placebo | Total |
|---|---|---|---|
| Age, Continuous | 50.29 years STANDARD_DEVIATION 11.08 | 42.42 years STANDARD_DEVIATION 9.57 | 46.55 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 21 participants | 19 participants | 40 participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 21 | 4 / 19 |
| serious Total, serious adverse events | 0 / 21 | 0 / 19 |
Outcome results
Primary
Weight Gain in Treatment Completers
Time frame: baseline and 12 weeks
Population: Subpopulation of participants who reported quitting smoking
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Varenicline + Naltrexone | Weight Gain in Treatment Completers | 3.35 Pounds | Standard Deviation 6.61 |
| Varenicline + Placebo | Weight Gain in Treatment Completers | 4.14 Pounds | Standard Deviation 5.15 |
Secondary
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.
Time frame: 11 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Varenicline + Naltrexone | Tolerability of the Combination of 25 mg Naltrexone and 2 mg Varenicline | 10 Participants |
| Varenicline + Placebo | Tolerability of the Combination of 25 mg Naltrexone and 2 mg Varenicline | 4 Participants |
Secondary
Weight Gain in Participants Who Are Continuously Abstinent for the Last 4 Weeks of Treatment
Time frame: 4 weeks
Population: Analyzed are those that remained abstinent for last 4 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Varenicline + Naltrexone | Weight Gain in Participants Who Are Continuously Abstinent for the Last 4 Weeks of Treatment | 0 pounds | Standard Deviation 4.36 |
| Varenicline + Placebo | Weight Gain in Participants Who Are Continuously Abstinent for the Last 4 Weeks of Treatment | 7.67 pounds | Standard Deviation 2.31 |