Heavy Drinking, Nicotine Dependence, Smoking
Conditions
Keywords
Smoking cessation, Smoking, Tobacco, Varenicline, Alcohol
Brief summary
The purpose of this study is to determine whether extended pretreatment with varenicline (Chantix) is more efficacious for smoking cessation than standard pretreatment, how well varenicline is tolerated in heavy drinking smokers, and whether varenicline reduces alcohol consumption.
Detailed description
Smoking rates are elevated among drinkers compared to non-drinkers (Marks et al., 1997). Moreover, there is some evidence that both smokers who drink alcohol are less successful quitting smoking (Leeman, Huffman, & O'Malley, 2007). Thus, identifying interventions that are effective in reducing both smoking and heavy drinking in this population is warranted. Varenicline, a medication recently approved by the FDA, results in smoking cessation rates as high as 50%, significantly better than bupropion or placebo. There is preliminary experimental evidence from both animal and human laboratory research that varenicline reduces alcohol seeking and consumption (McKee, 2008; Steensland et al., 2007). The typical dose schedule for varenicline involves a 1 week pretreatment phase prior to quitting smoking (Gonzales et al., 2006; Jorenby et al., 2006; Nides et al., 2006). However, greater quit rates have been observed 1 month after using varenicline compared to 1 week. Therefore, it is possible that extended pretreatment with varenicline may also yield better cessation outcomes than the standard 1 week lead in period. This may be particularly true if pretreatment also reduces alcohol consumption prior to the quit attempt. Thirty regular smokers who drink alcohol heavily will receive open-label varenicline for 5 weeks according to the recommended titration schedule up to 1mg varenicline twice daily. Prior to the smoking quit date, subjects will be randomized to receive either extended pretreatment with varenicline (titration up to 1mg) for 4 weeks or short-term varenicline pretreatment (3 weeks placebo followed by 1 week of varenicline). The primary aims of the study are to examine: (a) the efficacy of extended varenicline pretreatment for smoking cessation, (b) the safety and tolerability of varenicline in heavy drinking smokers, and (c) the efficacy of varenicline for reducing alcohol consumption in human participants. Effect size estimates for prolonged smoking abstinence and heavy drinking will be generated for a NIH grant application.
Interventions
DRUGExtended Varenicline Pretreatment
4 weeks varenicline (Chantix) titrated to 1 mg oral tablet twice per day before the smoking quit date followed by 4 weeks varenicline (Chantix) 1 mg oral tablet twice per day treatment.
DRUGShort-term Varenicline Pretreatment
3 weeks placebo + 1 week varenicline (Chantix)pretreatment + 4 weeks varenicline 1 mg oral tablet twice per day treatment following the smoking quit date.
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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 5 or more cigarettes per occasion at least 3 times per week. 3. Fewer than 3 months of smoking abstinence in the past year. 4. Motivated to stop smoking. 5. Report exceeding maximum weekly drinking limits every week in the past 4 weeks and exceeding maximum daily drinking limits on at least 1 occasion in the past 4 weeks. Weekly heavy drinking is defined as 8 or more drinks for women and 15 or more drinks for men. Daily heavy drinking is defined as 4 or more drinks for women and 5 or more drinks for men on an occasion.
Exclusion criteria
1. Exhibit current, clinically significant physical disease or abnormality on the basis of medical history, physical examination, or routine laboratory evaluation 2. Any unexplained elevations in liver enzymes (i.e., transaminases, bilirubin) 3. Clinically significant cardiovascular disease 4. Uncontrolled hypertension 5. Hepatic or renal impairment 6. Severe chronic obstructive pulmonary disease 7. Diabetes mellitus requiring insulin or oral hypoglycemic medications. 8. Baseline systolic blood pressure higher than 150 mm Hg or diastolic blood pressure higher than 95 mm Hg 9. History of cancer (except treated basal cell or squamous cell carcinoma of the skin). 10. History of clinically significant allergic reactions. 11. Exhibit serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe major depression, panic disorder, borderline personality disorder, organic mood or mental disorders, or substantial suicide or violence risk) by history or psychological examination) 12. Have a current diagnosis of DSM-IV drug dependence other than nicotine or alcohol. 13. Have a current Diagnostic and Statistical Manual Diploma in Social Medicine IV (DSM-IV) diagnosis of alcohol dependence that is clinically severe defined by a) a history of seizures, delirium, or hallucinations during alcohol withdrawal, b) a Clinical Institute Withdrawal Assessment scale (Sullivan et al., 1989) score of \> 8, c) report drinking to avoid withdrawal symptoms, or d) have had prior treatment of withdrawal. 14. Use of another investigational drug within 30 days. 15. Intention to donate blood or blood products during the treatment phase of the study. 16. Use of tobacco products other than cigarettes or use of marijuana. 17. 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. 18. 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. 19. Females of childbearing potential who are pregnant, nursing, or not practicing effective contraception (oral, injectable, or implantable contraceptives, intrauterine device, or barrier method with spermicide).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Continuous Smoking Abstinence in the Extended Varenicline Pretreatment Versus Short-term Varenicline Pretreatment Conditions. | Last 4 weeks of treatment | Compares the number of participants who reported no smoking, not even a puff, from the quit date through until the end of treatment (i.e., last 4 weeks of treatment) in the varenicline versus placebo pretreatment conditions. |
| Mean Percentage of Heavy Drinking Days Comparing Participants in the Extended Varenicline Pretreatment Versus Short-term Varenicline Pretreatment Conditions | First 3 weeks (pretreatment) | Compares the mean percentage of heavy drinking days over the 3-week placebo-controlled pretreatment phase comparing participants in the extended varenicline pretreatment versus the short-term varenicline pretreatment conditions. Heavy drinking defined as consuming 4 or more drinks per occasion for women and 5 or more drinks per occasion for men. Drinking in the final week of pretreatment prior to the quit-date is not included because both groups were receiving active varenicline during this period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Reported an Adverse Event in the Varenicline Pretreatment Versus Placebo Pretreatment Conditions | First 3 weeks (pretreatment) | Compares the number of participants who reported an adverse event in the extended varenicline pretreatment versus short-term varenicline pretreatment conditions during the 3-week placebo controlled pretreatment phase |
Participant flow
Recruitment details
Outpatient research clinic
Pre-assignment details
Prior to randomization, inclusion and exclusion criteria were assessed. Reasons for exclusion included health problems, not meeting drinking/smoking criteria, other drug use, and depression requiring treatment.
Participants by arm
| Arm | Count |
|---|---|
| Extended Varenicline Pretreatment Arm 1 (Experimental) = 3 weeks varenicline (Chantix) 1 mg oral tablet twice per day pretreatment + 5 weeks varenicline (Chantix) 1 mg oral tablet twice per day treatment | 15 |
| Short Varenicline Pretreatment (Placebo) Arm 2 (Experimental) = 3 weeks placebo pretreatment + 5 weeks varenicline (Chantix) 1 mg oral tablet twice per day treatment | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Placebo Controlled Pretreatment Period | No longer interested in treatment | 2 | 1 |
Baseline characteristics
| Characteristic | Short Varenicline Pretreatment (Placebo) | Extended Varenicline Pretreatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 15 Participants | 30 Participants |
| Age, Continuous | 43.47 years STANDARD_DEVIATION 7.99 | 42.87 years STANDARD_DEVIATION 8.52 | 43.17 years STANDARD_DEVIATION 8.12 |
| Region of Enrollment United States | 15 participants | 15 participants | 30 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 15 | 14 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
Mean Percentage of Heavy Drinking Days Comparing Participants in the Extended Varenicline Pretreatment Versus Short-term Varenicline Pretreatment Conditions
Compares the mean percentage of heavy drinking days over the 3-week placebo-controlled pretreatment phase comparing participants in the extended varenicline pretreatment versus the short-term varenicline pretreatment conditions. Heavy drinking defined as consuming 4 or more drinks per occasion for women and 5 or more drinks per occasion for men. Drinking in the final week of pretreatment prior to the quit-date is not included because both groups were receiving active varenicline during this period.
Time frame: First 3 weeks (pretreatment)
Population: All participants were included in the analysis, assuming an intention to treat method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Extended Varenicline Pretreatment | Mean Percentage of Heavy Drinking Days Comparing Participants in the Extended Varenicline Pretreatment Versus Short-term Varenicline Pretreatment Conditions | 22.7 percentage of heavy drinking days | Standard Deviation 17.5 |
| Short-term Varenicline Pretreatment | Mean Percentage of Heavy Drinking Days Comparing Participants in the Extended Varenicline Pretreatment Versus Short-term Varenicline Pretreatment Conditions | 38.0 percentage of heavy drinking days | Standard Deviation 31.2 |
p-value: 0.06General Linear Model
Primary
Number of Participants Reporting Continuous Smoking Abstinence in the Extended Varenicline Pretreatment Versus Short-term Varenicline Pretreatment Conditions.
Compares the number of participants who reported no smoking, not even a puff, from the quit date through until the end of treatment (i.e., last 4 weeks of treatment) in the varenicline versus placebo pretreatment conditions.
Time frame: Last 4 weeks of treatment
Population: All participants were included in the analysis, assuming an intention to treat method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Extended Varenicline Pretreatment | Number of Participants Reporting Continuous Smoking Abstinence in the Extended Varenicline Pretreatment Versus Short-term Varenicline Pretreatment Conditions. | 4 Participants |
| Short-term Varenicline Pretreatment | Number of Participants Reporting Continuous Smoking Abstinence in the Extended Varenicline Pretreatment Versus Short-term Varenicline Pretreatment Conditions. | 2 Participants |
p-value: 0.36Chi-squared
Secondary
Number of Participants Who Reported an Adverse Event in the Varenicline Pretreatment Versus Placebo Pretreatment Conditions
Compares the number of participants who reported an adverse event in the extended varenicline pretreatment versus short-term varenicline pretreatment conditions during the 3-week placebo controlled pretreatment phase
Time frame: First 3 weeks (pretreatment)
Population: All participants were included in the analysis, assuming an intention to treat method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Extended Varenicline Pretreatment | Number of Participants Who Reported an Adverse Event in the Varenicline Pretreatment Versus Placebo Pretreatment Conditions | 10 Number of participants |
| Short-term Varenicline Pretreatment | Number of Participants Who Reported an Adverse Event in the Varenicline Pretreatment Versus Placebo Pretreatment Conditions | 3 Number of participants |
p-value: 0.03Fisher Exact