Nicotine Dependence
Conditions
Keywords
Smoking, Abstinence
Brief summary
The goals of this within-subject pilot study are: (1) assess the feasibility and safety of administering the Catechol-O-Methyl-Transferase (COMT) inhibitor, tolcapone, to smokers, and (2) explore whether tolcapone may reduce abstinence-induced cognitive and affective symptoms that promote relapse. A secondary exploratory goal is to assess whether these effects may be more pronounced in smokers who carry a high risk COMT genotype for smoking relapse: COMT val/val.
Detailed description
Despite decades of research to develop pharmacotherapies for nicotine dependence (ND), with current FDA approved medications (bupropion, varenicline and NRTs) the majority (\>60%) of smokers relapse in the first year following treatment (Lerman, Patterson et al. 2005; Tonstad, Tonnesen et al. 2006). Testing novel medications that may reduce abstinence symptoms that prompt smoking relapse is a plausible route to identifying new treatments for nicotine dependence. The goals of this within-subject pilot study are: (1) assess the feasibility and safety of administering the Catechol-O-Methyl-Transferase (COMT) inhibitor, tolcapone, to smokers, and (2) explore whether tolcapone may reduce abstinence-induced cognitive and affective symptoms that promote relapse. A secondary exploratory goal is to assess whether these effects may be more pronounced in smokers who carry a high risk COMT genotype for smoking relapse: COMT val/val. Sixteen smokers (8 met/met genotype and 8 val/val genotype) who meet study eligibility criteria will complete two 10-day medication periods: one while taking tolcapone and one while taking placebo (order counterbalanced). The testing session will occur on day 7 of each medication phase and include three computerized tasks. Participants will be asked to refrain from smoking for at least 14 hours (overnight) prior to the testing day in each medication phase. There will be a 3-day medication taper on days 8-10 of each medication period, followed by a washout period of at least 7 days between medication periods. The main outcomes to be evaluated are participant enrollment and retention, side effects, and performance on computerized tasks. Positive results from this pilot study would provide a basis for a larger scale investigation to assess the efficacy of tolcapone as a medication that ameliorates abstinence induced neurocognitive symptoms in smokers.
Interventions
DRUGTolcapone
Day 1 100mg three times per day Day 2 - Day 7 200mg three times per day Day 8 200mg twice a day Day 9 200mg once a day Day 10 100mg once a day
DRUGPlacebo
Day 1 100mg three times per day Day 2 - Day 7 200mg three times per day Day 8 200mg twice a day Day 9 200mg once a day Day 10 100mg once a day
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Healthy as determined by a responsible physician, based on a medical evaluation including history, physical and psychiatric examination, laboratory tests, liver function monitoring. 2. Smokers who are between 18 and 55 years of age and have an IQ greater than 90. 3. Capable of giving written informed consent, which includes compliance with the requirements and restrictions, listed in the consent form. 4. Based upon self-report, subjects must smoke \>10 cigarettes/day and be interested in quitting smoking in the next 6 months (i.e., treatment-seekers). 5. Women of childbearing potential must consent to using a medically accepted method of birth control (e.g., condoms and spermicide, oral contraceptive, Depo-provera injection, contraceptive patch, tubal ligation).
Exclusion criteria
Smoking Behavior 1. Use of chewing tobacco or snuff 2. Current enrollment or plans to enroll in another smoking cessation program in the next month 3. Plan to use other nicotine substitutes or smoking cessation treatments in the next month 4. Provide a baseline carbon monoxide (CO) reading \< 10ppm Alcohol/Drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Eligible Participants Enrolled Who Completed the Study. | 30 days | Number of enrolled participants who complete the final study visit |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| N-back (Working Memory) Correct Reaction Time After Overnight Abstinence. | 30 days | To obtain preliminary data on the effects of Tolcapone on abstinence-induced neurocognitive deficits in abstinent smokers with differing COMT genotypes. We examined reaction time differences on the n-back task between tolcapone and placebo treatment. |
| Correct Reaction Time During Attention Task Performance After Overnight Abstinence. | 30 days | We wanted to examine the effects of Tolcapone on the Continuous Performance Task (attention task) after overnight abstinence as compared to placebo. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited using mass media advertising from July 2008 to April 2009.
Pre-assignment details
Each participant's catechol-o-methyl transferase (COMT) genotype was determined prior to medication assignment.
Participants by arm
| Arm | Count |
|---|---|
| Tolcapone First, Then Placebo Day 1: 100mg three times per day orally Day 2 - Day 7: 200mg three times per day orally Day 8: 200mg twice a day orally Day 9: 200mg once a day orally Day 10: 100mg once a day orally | 9 |
| Placebo First, Then Tolcapone Day 1: 100mg three times per day orally Day 2 - Day 7: 200mg three times per day orally Day 8: 200mg twice a day orally Day 9: 200mg once a day orally Day 10: 100mg once a day orally | 10 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1: 10 Days | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo First, Then Tolcapone | Tolcapone First, Then Placebo | 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 | 10 Participants | 9 Participants | 19 Participants |
| Age, Continuous | 40.5 years STANDARD_DEVIATION 11.77 | 36.55 years STANDARD_DEVIATION 11.41 | 38.63 years STANDARD_DEVIATION 11.45 |
| Region of Enrollment United States | 10 participants | 9 participants | 19 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 6 Participants | 3 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 10 |
| serious Total, serious adverse events | 0 / 9 | 0 / 10 |
Outcome results
Primary
Number of Eligible Participants Enrolled Who Completed the Study.
Number of enrolled participants who complete the final study visit
Time frame: 30 days
Population: Number of Participants who completed the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolcapone First, Then Placebo | Number of Eligible Participants Enrolled Who Completed the Study. | 9 Participants |
| Placebo First, Then Tolcapone | Number of Eligible Participants Enrolled Who Completed the Study. | 8 Participants |
Secondary
Correct Reaction Time During Attention Task Performance After Overnight Abstinence.
We wanted to examine the effects of Tolcapone on the Continuous Performance Task (attention task) after overnight abstinence as compared to placebo.
Time frame: 30 days
Population: Only participants who completed both study phases were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolcapone First, Then Placebo | Correct Reaction Time During Attention Task Performance After Overnight Abstinence. | 460.14 Milliseconds | Standard Deviation 34.53 |
| Placebo First, Then Tolcapone | Correct Reaction Time During Attention Task Performance After Overnight Abstinence. | 457.64 Milliseconds | Standard Deviation 39.28 |
Secondary
N-back (Working Memory) Correct Reaction Time After Overnight Abstinence.
To obtain preliminary data on the effects of Tolcapone on abstinence-induced neurocognitive deficits in abstinent smokers with differing COMT genotypes. We examined reaction time differences on the n-back task between tolcapone and placebo treatment.
Time frame: 30 days
Population: Only participants who completed both sessions were analysed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolcapone First, Then Placebo | N-back (Working Memory) Correct Reaction Time After Overnight Abstinence. | 597.09 Milliseconds | Standard Deviation 136.85 |
| Placebo First, Then Tolcapone | N-back (Working Memory) Correct Reaction Time After Overnight Abstinence. | 608.21 Milliseconds | Standard Deviation 151.8 |