Initial Screening of Gemfibrozil as a Novel Treatment for Tobacco Addiction

• Sponsor: Centre for Addiction and Mental Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT01876810
• Collaborator: (none)
• Enrollment: 28
• Locations: 2
• Arms: 2
• Duration (Months): 24
• Patients Per Site: 14
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Nicotine Dependence	Drug: Gemfibrozil; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Testing the PPAR Hypothesis of Nicotine Dependence in Humans: Gemfibrozil as a Novel Treatment for Tobacco Addiction
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gemfibrozil 600 mg of gemfibrozil (one capsule) twice daily for two weeks.	Drug: Gemfibrozil; 600 mg of gemfibrozil (one capsule) twice daily for two weeks.; Other Names: Lopid
Placebo Comparator: Placebo pill One lactose pill twice a day for two weeks.	Drug: Placebo; One lactose pill twice a day for two weeks.; Other Names: Lactose

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centre for Addiction and Mental Health	Toronto	Ontario	Canada	M5S 1S8
2	Centre of Addiction and Mental Health	Toronto	Ontario	Canada	M5S 2S1

Sponsors and Collaborators

• Centre for Addiction and Mental Health

Investigators

• Principal Investigator: Bernard Le Foll, MD, PhD, Centre for Addiction and Mental Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Information about research at the Centre for Addiction and Mental Health, Canada's largest mental health and addiction teaching

Publications

None provided.

• Responsible Party: Bernard Le Foll, Scientist, Centre for Addiction and Mental Health
• ClinicalTrials.gov Identifier: NCT01876810
• Other Study ID Numbers: 082/2012; NCT01900145
• First Posted: Jun 13, 2013
• Last Update Posted: Apr 20, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Bernard Le Foll, Scientist, Centre for Addiction and Mental Health: Gemfibrozil; Nicotine Dependence; Smoking; Cigarettes
• Additional relevant MeSH terms: Tobacco Use Disorder; Gemfibrozil

Study Results

Participant Flow

Pre-assignment Detail	1 participant was excluded after enrollment after disclosure of a mental illness which is an exclusion criteria.

Arm/Group Title	Gemfibrozil/Placebo	Placebo/Gemfibrozil
Arm/Group Description	Participants received 600 mg of gemfibrozil (one capsule) twice daily for two weeks. Then a washout period of 1 week of no medication. Then they received 1 capsule of placebo twice daily for 2 weeks	Participants received 1 capsule of placebo for 2 weeks. Then a washout period of 1 week of no medication. Then they received 600 mg of gemfibrozil (one capsule) twice daily for two weeks.
Period Title: Overall Study
STARTED	14	14
COMPLETED	14	13
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	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.
Overall Participants	27
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	27 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	10 37%
Male	17 63%

Outcome Measures

1. Primary Outcome

Title	Number of Days With Self-report of No Smoking and Breath Carbon Monoxide of <5 PPM During Quit-attempt Weeks
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemfibrozil	Placebo
Arm/Group Description	Participants taking Gemfibrozil: 600 mg of gemfibrozil (one capsule) twice daily for two weeks during the 1st phase of the study or during the second phase after a washout period .	Participants taking Placebo (one capsule) twice daily for two weeks during the 1st phase of the study or during the second phase after a washout period.
Measure Participants	27	27
Mean (Standard Error) [days]	0.2 (0.1)	0 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gemfibrozil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1
	Comments	For all analyses, results are considered significant at p<.05.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1
	Comments	For all analyses, results were considered significant at p< 0.05
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0
	Estimation Comments

2. Secondary Outcome

Title	The Percentage of Choice of Nicotinized Cigarettes After 1 Week of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemfibrozil	Placebo Group
Arm/Group Description	Participants taking Gemfibrozil: 600 mg of gemfibrozil (one capsule) twice daily for two weeks during the 1st phase of the study or during the second phase after the washout period.	Participants taking Placebo (one capsule) twice daily for two weeks during the 1st phase of the study or during the second phase after the washout period.
Measure Participants	27	27
Mean (Standard Error) [percentage of choice of nicotinized ciga]	0.775 (0.034)	0.77 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gemfibrozil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9
	Comments	For all analyses, results were considered significant at p< 0.05
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.034
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9
	Comments	For all analyses, results were considered significant at p< 0.05
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.05
	Estimation Comments

3. Other Pre-specified Outcome

Title	Cue- Reactivity Visual Analogue Scale for Craving After 1 Week of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Gemfibrozil	Placebo Group
Arm/Group Description	Participants taking Gemfibrozil 600 mg (one capsule twice daily) for two weeks during the 1st phase of the study or during the second phase after the washout period.	Participants taking Placebo (one capsule) twice daily for two weeks during the 1st phase of the study or during the second phase after the washout period.
Measure Participants	27	27
Mean (Standard Error) [units on a scale: from 0-100 mm]	51 (32.7)	44 (27.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gemfibrozil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4
	Comments
	Method	ANOVA
	Comments	Repeated-measures ANOVA on Drug X Cue X Time were used
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	51.3
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 31.7
	Estimation Comments	participants self-reportd VAS craving at the time of neutral cue presentation

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4
	Comments	For all analyses, results were considered significant at p< 0.05
	Method	ANOVA
	Comments	Repeated-measures ANOVA on Drug X Cue X Time were used
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	43.7
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 26.5
	Estimation Comments

Adverse Events

Time Frame	The side effects were collected for each participant over six weeks from the start of treatment (2 weeks gemfibrozil/or placebo), 1 week washout period, (2 weeks gemfibrozil/or placebo), and 1 week after completion of the study.
Arm/Group Title	Gemfibrozil/Placebo		Placebo/Gemfibrozil
Arm/Group Description	600 mg of gemfibrozil (one capsule) twice daily for two weeks. Participants taking Gemfibrozil: 600 mg of gemfibrozil (one capsule) twice daily for two weeks during the 1st phase of the study followed by a the washout period. Then they received 1 capsule of placebo twice daily for 2 weeks		One lactose pill twice a day for two weeks. Participants taking Placebo (one capsule) twice daily for two weeks during the 1st phase of the study followed by a the washout period. Then they received 1 capsule of gemfibrozil twice daily for 2 weeks
All Cause Mortality
	Gemfibrozil/Placebo		Placebo/Gemfibrozil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Serious Adverse Events
	Gemfibrozil/Placebo		Placebo/Gemfibrozil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Gemfibrozil/Placebo		Placebo/Gemfibrozil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/14 (57.1%)		6/13 (46.2%)
Gastrointestinal disorders
Change in appetite	2/14 (14.3%)	2	4/13 (30.8%)	4
stomach upset	3/14 (21.4%)	3	2/13 (15.4%)	2
Nervous system disorders
Headache	3/14 (21.4%)	3	0/13 (0%)	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.