Nicotine Dependence
Conditions
Keywords
Gemfibrozil, Nicotine Dependence, Smoking, Cigarettes
Brief summary
The purpose of this study is to investigate the effect of gemfibrozil on nicotine reinforcement and cue-elicited craving. Other objectives of this study include screening for the ability of gemfibrozil to aid smoking abstinence during a brief quit attempt and examining the validity of using laboratory measures of tobacco dependence to predict smoking abstinence. It is hypothesized that gemfibrozil will result in diminished nicotine reinforcement, an attenuated response to smoking cues, and an increase in smoking abstinence compared with placebo. It is also hypothesized that the laboratory measures will prove valid in predicting abstinence.
Detailed description
Animal studies have shown that drugs acting as agonists at alpha-type peroxisome proliferator-activated receptors (PPARα) suppress nicotine self-administration, attenuate relapse to nicotine-seeking behavior in the reinstatement model, and block nicotine-induced neuronal firing and dopamine release in reward pathways of the brain. These results have been demonstrated with synthetic PPARα agonists and with fibrate drugs (clofibrate, fenofibrate), which are used clinically to treat elevated cholesterol and triglycerides levels. Thus, PPARα is a potential target for the treatment of tobacco addiction. This is the first human study to investigate whether a fibrate drug (gemfibrozil, Lopid®) can reduce nicotine reward and aid smokers in becoming tobacco abstinent. The objectives of this study are: 1. to investigate the effect of gemfibrozil on laboratory measures of nicotine reinforcement and cue-elicited craving 2. to screen for the ability of gemfibrozil to aid smoking abstinence during a brief quit attempt 3. to examine the validity of using laboratory measures of tobacco dependence to predict smoking abstinence and possible gemfibrozil-related increases in smoking abstinence This outpatient study will be conducted at the Center for Addiction and Mental Health (CAMH) in Toronto, Canada. This site will enroll 40 adult smokers who intend to quit smoking in the next 3 months. The study is a double-blind, placebo-controlled, crossover design comparing the effects of gemfibrozil and placebo. The study will comprise two 2-week medication phases with a washout period of at least one week. At the end of the first medication week laboratory measures will be taken and during the second medication week participants will make a quit attempt and abstinence will be assessed. Outcome measures include laboratory assessments of nicotine reinforcement and smoking cue reactivity. The measure of nicotine reinforcement is the percentage of nicotine cigarette puffs chosen during a forced-choice task. Measures of cue reactivity include tobacco craving, mood, and autonomic responsivity. Other measures are days of smoking abstinence during the quit-attempt weeks. Abstinence is assessed by self-reports of no smoking and by breath carbon monoxide \< 5 ppm on clinic visits. Other assessments of abstinence include self-reported tobacco craving and withdrawal.
Interventions
DRUGGemfibrozil
600 mg of gemfibrozil (one capsule) twice daily for two weeks.
DRUGPlacebo
One lactose pill twice a day for two weeks.
Sponsors
Centre for Addiction and Mental Health
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
19 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 19-65 year old males and females * smoking at least 10 cigarettes per day for at least 2 years * intend to quit smoking within the next 3 months * medically and psychologically healthy as determined by screening criteria
Exclusion criteria
* currently attempting to quit smoking * treatment for tobacco addiction in the past 3 months * use of nicotine replacement products, bupropion, or varenicline in the past 3 months as an aid to quit or reduce smoking * use of any oral tobacco product in the past 3 months * history of drug or alcohol dependence within last 5 years * consumption of more than 15 alcoholic drinks per week on average during the past month * use of any illicit drug more than once per week on average during the past month * current use of gemfibrozil or other fibrate medication * current use of any medication that is contraindicated for gemfibrozil or that would interfere with the protocol in the opinion of MAI/QI. This includes, but is not limited to, anticoagulants, statins, other fibrates, other lipid-lowering agents such as niacin or herbal remedies, and any oral or injected medications for diabetes. * any pre-existing gall-bladder disease or operation in the past 12 months * any history of or current cardiovascular, liver, hepatic or renal disease * diabetes * pregnant, nursing, or become pregnant during the study * use of psychoactive drugs or medications as revealed by urine toxicology
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Days With Self-report of No Smoking and Breath Carbon Monoxide of <5 PPM During Quit-attempt Weeks | 1 week in each phase | the number of days of no smoking was calculated for each participant. Abstinence was verified by daily Self-reports of no smoking and breath carbon monoxide \< 5 ppm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Choice of Nicotinized Cigarettes After 1 Week of Treatment | during the lab forced choice paradigm after 1 week of treatment | Percentage of choice of Nicotinized cigarettes was calculated for each participant during the lab session which took place after 1 week of treatment. Each session started with participants taking four puffs of their preferred-brand cigarette to standardize the time from last nicotine exposure. Participants were asked to complete some questionnaires at baseline. Then, they were asked to relax for 30 min listening to music or reading. Four exposure trials followed that were separated by 30 min of relaxation. In each exposure trial, participants took four puffs of a Nicotinized (A) or Denicotinized (less than 0.05 mg nicotine.) (B) cigarette in the order of ABAB or BABA. Cigarettes were color-coded. Participants then began four choice trials separated by 30 min of relaxation. In each trial, participants chose any combination of 4 puffs from the two cigarettes. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cue- Reactivity Visual Analogue Scale for Craving After 1 Week of Treatment | during the lab Cue- reactivity paradigm after 1 week of treatment | In this study, each session started with participants taking four puffs of their preferred-brand cigarette to standardize the time from last nicotine exposure. Participants were then seated in a comfortable chair and completed the baseline Visual Analogue Scale for craving 0-100 mm (The higher the number the more is the craving). The smoking cue was a pack of cigarettes and a lighter. Participants were instructed to light the cigarette without puffing and hold it for 30 sec while the physiological recordings were measured. Then the participant was asked to extinguish the cigarette. The neutral cue was an unsharpened pencil, a notepad, and a sharpener. Participants were instructed to sharpen the pencil and hold it as if writing for 30 sec. Participants completed the Visual Analogue Scale for craving during the cue, and 15 and 30 min after cue presentation. |
Countries
Canada
Participant flow
Pre-assignment details
1 participant was excluded after enrollment after disclosure of a mental illness which is an exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants 600 mg of gemfibrozil (one capsule) twice daily for two weeks.
Gemfibrozil: 600 mg of gemfibrozil (one capsule) twice daily for two weeks. or One lactose pill twice a day for two weeks. | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 13 |
| other Total, other adverse events | 8 / 14 | 6 / 13 |
| serious Total, serious adverse events | 0 / 14 | 0 / 13 |
Outcome results
Primary
Number of Days With Self-report of No Smoking and Breath Carbon Monoxide of <5 PPM During Quit-attempt Weeks
the number of days of no smoking was calculated for each participant. Abstinence was verified by daily Self-reports of no smoking and breath carbon monoxide \< 5 ppm
Time frame: 1 week in each phase
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gemfibrozil | Number of Days With Self-report of No Smoking and Breath Carbon Monoxide of <5 PPM During Quit-attempt Weeks | 0.2 days | Standard Error 0.1 |
| Placebo | Number of Days With Self-report of No Smoking and Breath Carbon Monoxide of <5 PPM During Quit-attempt Weeks | 0 days | Standard Error 0 |
p-value: 0.1t-test, 2 sided
p-value: 0.1t-test, 2 sided
Secondary
The Percentage of Choice of Nicotinized Cigarettes After 1 Week of Treatment
Percentage of choice of Nicotinized cigarettes was calculated for each participant during the lab session which took place after 1 week of treatment. Each session started with participants taking four puffs of their preferred-brand cigarette to standardize the time from last nicotine exposure. Participants were asked to complete some questionnaires at baseline. Then, they were asked to relax for 30 min listening to music or reading. Four exposure trials followed that were separated by 30 min of relaxation. In each exposure trial, participants took four puffs of a Nicotinized (A) or Denicotinized (less than 0.05 mg nicotine.) (B) cigarette in the order of ABAB or BABA. Cigarettes were color-coded. Participants then began four choice trials separated by 30 min of relaxation. In each trial, participants chose any combination of 4 puffs from the two cigarettes.
Time frame: during the lab forced choice paradigm after 1 week of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gemfibrozil | The Percentage of Choice of Nicotinized Cigarettes After 1 Week of Treatment | 0.775 percentage of choice of nicotinized ciga | Standard Error 0.034 |
| Placebo | The Percentage of Choice of Nicotinized Cigarettes After 1 Week of Treatment | 0.77 percentage of choice of nicotinized ciga | Standard Error 0.05 |
p-value: 0.9t-test, 2 sided
p-value: 0.9t-test, 2 sided
Other Pre-specified
Cue- Reactivity Visual Analogue Scale for Craving After 1 Week of Treatment
In this study, each session started with participants taking four puffs of their preferred-brand cigarette to standardize the time from last nicotine exposure. Participants were then seated in a comfortable chair and completed the baseline Visual Analogue Scale for craving 0-100 mm (The higher the number the more is the craving). The smoking cue was a pack of cigarettes and a lighter. Participants were instructed to light the cigarette without puffing and hold it for 30 sec while the physiological recordings were measured. Then the participant was asked to extinguish the cigarette. The neutral cue was an unsharpened pencil, a notepad, and a sharpener. Participants were instructed to sharpen the pencil and hold it as if writing for 30 sec. Participants completed the Visual Analogue Scale for craving during the cue, and 15 and 30 min after cue presentation.
Time frame: during the lab Cue- reactivity paradigm after 1 week of treatment
Population: participants self-reportd Visual analogue scale (0-100 mm) for craving at the time of presenting the smoking cue. The higher the number on the scale, the more is the craving
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gemfibrozil | Cue- Reactivity Visual Analogue Scale for Craving After 1 Week of Treatment | 51 units on a scale: from 0-100 mm | Standard Error 32.7 |
| Placebo | Cue- Reactivity Visual Analogue Scale for Craving After 1 Week of Treatment | 44 units on a scale: from 0-100 mm | Standard Error 27.4 |
p-value: 0.4ANOVA
p-value: 0.4ANOVA