Pilot Study of Tolcapone in Smokers

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT01202955
• Collaborator: (none)
• Enrollment: 19
• Location: 1
• Arms: 2
• Duration (Months): 11
• Patients Per Site Per Month: 1.7

Study Details

Study Description

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.

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

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Pilot Study of Tolcapone Effects on Abstinence-Induced Cognitive Symptoms in Smokers
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tolcapone Tolcapone	Drug: Tolcapone; 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; Other Names: Tasmar
Placebo Comparator: Placebo Placebo	Drug: Placebo; 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

Outcome Measures

Primary Outcome Measures

1. Number of Eligible Participants Enrolled Who Completed the Study. [30 days]

   Number of enrolled participants who complete the final study visit

Secondary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts 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 Exclusion Criteria

1. History of substance abuse and/or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana, MDMA/ecstasy, or stimulants)

2. Current alcohol consumption that exceeds >14 standard drinks/week for men and >7 standard drinks/week for women over the last 6 months

Medication Exclusion Criteria

1. Current use or recent discontinuation (within last 4-weeks) of any medication including the following:

• Any form of psychotropic medications including:

• antipsychotics,

• atypical antipsychotics,

• mood-stabilizers,

• anti-depressants (tricyclics, SSRI's, MAOI's, nonselective MAOIs, Wellbutrin/Zyban),

• anti-panic agents,

• anti-obsessive agents,

• anti-anxiety agents, and

• stimulants (e.g., Provigil, Ritalin)

• Varenicline

• Medication for chronic pain

• Anti-coagulants (e.g., Warfarin)

• Any heart medications

• Daily medication for asthma

• Apomorphine, dobutamine, isoproterenol, levodopa, methyldopa, or sympathomimetic (e.g., albuterol, pseudoephedrine)

1. Current use of any smoking cessation medication.

Medical Exclusion Criteria

1. Women who are pregnant, planning a pregnancy, or lactating.

2. History or current diagnosis of psychosis, major depression or bipolar disorder, schizophrenia, or any Axis 1 disorder as identified by the MINI.

3. Serious or unstable disease within the past 6 months (e.g., cancer [except squamous cell carcinoma], heart disease, HIV, liver disease, Parkinson's disease).

4. History of epilepsy or a seizure disorder.

5. History or current diagnosis (last 6-months) of abnormal rhythms and/or tachycardia (>100 beats/minute); history or current diagnosis of chronic obstructive pulmonary disease (COPD), cardiovascular disease (stroke, angina, coronary heart disease), heart attack in the last 6 months, uncontrolled hypertension (SBP>150 or DBP>90)

6. History of Kidney and/or liver failure (including transplant) or problems (e.g., cirrhosis); current liver disease or impairment.

7. History or current diagnosis of hepatitis.

8. Liver function tests more than 20% outside of the normal range.

9. Allergies to the study medication, tolcapone (Tasmar).

10. History of severe, uncontrolled muscle movements (e.g., uncontrolled jerking, twitching) or a certain severe muscle problem (rhabdomyolysis).

11. Experience of dizziness or lightheadedness upon standing on a regular basis (i.e., daily).

Genetic Profile

1. Individuals with the heterozygous genotype (val/met) on the catechol-methyl transferase (COMT) gene. (Note: this is a small pilot study comparing effects of Tolcapone on cognitive performance between val/val (n=8) individuals.) Future research done at our center will plan to include those carrying the val/met genotype.

2. Individuals with the homozygous genotype, met/met, on the COMT gene. As of December 2008, the study has accrued 8 met/met participants. To balance the genotype groups, the study will recruit an equal number of participants with the val/val genotype on the COMT gene and not include any further participants with the homozygous, met/met genotype. Future research done at our center will plan to include those carrying the met/met genotype.

3. Non-European ancestry as determined by self report at initial telephone screening; we expect there to be ethnic differences in allele frequencies for COMT; therefore, as of December 2008, to reduce ethnic admixture that could bias the genetic analysis of this small sample, the study will be restricted to individuals of European ancestry. All participants of non-European ancestry will be referred to other studies at our center.

General Exclusion

1. Any medical condition or concomitant medication that could compromise participant safety or treatment, as determined by the Principal Investigator and/or Study Physician.

2. Inability to provide informed consent or complete any of the study tasks as determined by the Principal Investigator and/or Study Physician.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania

Investigators

• Principal Investigator: Caryn Lerman, PhD, University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT01202955
• Other Study ID Numbers: 808250
• First Posted: Sep 16, 2010
• Last Update Posted: Sep 12, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by University of Pennsylvania: Smoking, Abstinence
• Additional relevant MeSH terms: Tobacco Use Disorder; Tolcapone

Study Results

Participant Flow

Recruitment Details	Participants were recruited using mass media advertising from July 2008 to April 2009.
Pre-assignment Detail	Each participant's catechol-o-methyl transferase (COMT) genotype was determined prior to medication assignment.

Arm/Group Title	Tolcapone First, Then Placebo	Placebo First, Then Tolcapone
Arm/Group Description	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	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
Period Title: Period 1: 10 Days
STARTED	9	10
COMPLETED	9	8
NOT COMPLETED	0	2
Period Title: Period 1: 10 Days
STARTED	9	8
COMPLETED	9	8
NOT COMPLETED	0	0
Period Title: Period 1: 10 Days
STARTED	9	8
COMPLETED	9	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Tolcapone First, Then Placebo	Placebo First, Then Tolcapone	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	9	10	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	9 100%	10 100%	19 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.55 (11.41)	40.5 (11.77)	38.63 (11.45)
Sex: Female, Male (Count of Participants)
Female	6 66.7%	4 40%	10 52.6%
Male	3 33.3%	6 60%	9 47.4%
Region of Enrollment (participants) [Number]
United States	9 100%	10 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Number of Eligible Participants Enrolled Who Completed the Study.
Description	Number of enrolled participants who complete the final study visit
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Number of Participants who completed the study.

Arm/Group Title	Tolcapone First, Then Placebo	Placebo First, Then Tolcapone
Arm/Group Description	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	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
Measure Participants	9	10
Number [Participants]	9 100%	8 80%

2. Secondary Outcome

Title	N-back (Working Memory) Correct Reaction Time After Overnight Abstinence.
Description	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

Outcome Measure Data

Analysis Population Description

Only participants who completed both sessions were analysed

Arm/Group Title	Tolcapone First, Then Placebo	Placebo First, Then Tolcapone
Arm/Group Description	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	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
Measure Participants	17	17
Mean (Standard Deviation) [Milliseconds]	597.09 (136.85)	608.21 (151.8)

3. Secondary Outcome

Title	Correct Reaction Time During Attention Task Performance After Overnight Abstinence.
Description	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

Outcome Measure Data

Analysis Population Description

Only participants who completed both study phases were analyzed.

Arm/Group Title	Tolcapone First, Then Placebo	Placebo First, Then Tolcapone
Arm/Group Description	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	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
Measure Participants	17	17
Mean (Standard Deviation) [Milliseconds]	460.14 (34.53)	457.64 (39.28)

Adverse Events

Time Frame	30 days
Adverse Event Reporting Description	No adverse events, serious or other, were reported during by any participants during this pilot study.
Arm/Group Title	Tolcapone First, Then Placebo		Placebo First, Then Tolcapone
Arm/Group Description	To maintain the study blind, both the active Tolcapone and placebo medication periods used an increased-titration dose. Below is the breakdown of the increase in dosing of the active 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 During the placebo period, all participants followed the above dosing schedule; however, the capsules contained no tolcapone.		To maintain the study blind, both the active Tolcapone and placebo medication periods used an increased-titration dose. Below is the breakdown of the increase in dosing of the active 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 During the placebo period, all participants followed the above dosing schedule; however, the capsules contained no tolcapone.
All Cause Mortality
	Tolcapone First, Then Placebo		Placebo First, Then Tolcapone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tolcapone First, Then Placebo		Placebo First, Then Tolcapone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Tolcapone First, Then Placebo		Placebo First, Then Tolcapone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/10 (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.