Neural Substrates in Nicotine Withdrawal

Tobacco Use Disorder Clinical Trial

Official title:

Neural Substrates of Cognitive Deficits in Nicotine Withdrawal

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01001520
• Other study ID #: 809858
• Secondary ID: R01DA026849
• Status: Completed
• Phase: Phase 2
• First received: October 22, 2009
• Last updated: May 29, 2014
• Start date: January 2010
• Est. completion date: October 2012

Study information

• Verified date: May 2014
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study will test the hypothesis that a medication called tolcapone (Brand Name: Tasmar) will help reduce cognitive problems that smokers experience when they quit. This study will also determine whether the benefits of this medication differ depending on a smokers' genetic background.

Description:

Tolcapone, an FDA-approved treatment for Parkinson's disease, improves cognitive performance in healthy controls with COMT val/val genotypes, putatively by increasing prefrontal dopamine levels. We propose a within-subject double-blind cross-over neuroimaging study of short-term (11 days) treatment with tolcapone (vs. placebo).

Thirty chronic smokers (15 with val/val genotypes and 15 with val/met or met/met genotypes) will undergo blood oxygenation level dependent (BOLD) fMRI during the two medication periods:

1. after 24 hours of monitored abstinence while on tolcapone, and

2. after 24 hours of monitored abstinence while on placebo (medication order counterbalanced with at least a 10-day washout).

The BOLD fMRI data will be acquired while subjects perform a working memory task (Fractal N-back), a sustained attention task (Continuous Performance Task; CPT), and a response inhibition task (Go/No-Go). The primary outcome is medication effects (within subject) on task-related BOLD activation after 24 hours of abstinence. Changes in behavioral performance and subjective symptoms will be examined in relation to brain activity changes.

The proposed study will provide a critical mechanistic understanding of the role of COMT in abstinence-induced cognitive symptoms that promote smoking relapse. Information obtained in this study may further establish cognitive performance measures as endophenotypes for nicotine dependence.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 218
• Est. completion date: October 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Smokers who are between 18 and 65 years of age who self-report smoking at least 10 cigarettes (menthol and non-menthol) per day for at least the last 6 months.

• Healthy as determined by the Study Physician, based on a medical evaluation including medical history and physical examination, psychiatric evaluation, and liver function tests (LFTs and GGT enzyme levels).

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and HIPAA form.

• Women of childbearing potential must consent to use a medically accepted method of birth control while participating in the study (e.g., condoms and spermicide, oral contraceptive, Depo-provera injection, contraceptive patch, tubal ligation) and have 3 months of regular menstrual cycles.

• Capable of providing a Carbon Monoxide (CO) breath test reading greater than 10 parts per million (ppm) at the medical screening visit.

Exclusion Criteria:

Smoking behavior

• Current enrollment or plans to enroll in another research or smoking cessation program in the next 3 months.

• Provide a CO reading less than or equal to 10ppm at the medical screening visit.

• Plans to use nicotine substitutes (gum, patch, lozenge, e-cigarette) while enrolled in the study.

Alcohol/Drug Exclusion:

• History (past 2 years) or current diagnosis of substance abuse and/or currently receiving treatment for substance abuse (alcohol, THC, cocaine, PCP, amphetamines, methamphetamines, MDMA/ecstasy, opiates, methadone, benzodiazepines, tricyclic antidepressants, and barbiturates).

• Current alcohol consumption that exceeds 21 standard drinks/week over the last 6 months.

• Positive urine drug screen (for substances listed previously) at the medical screening visit or either testing day.

• Breath Alcohol Concentration (BrAC) assessment greater than or equal to 0.01 at medical screening visit or either testing day.

Medication Exclusion Criteria:

Current use or recent discontinuation (within last 28 days) of any medication including the following:

• Any form of psychotropic medications including: Antipsychotics; Mood-stabilizers (e.g., lithium, valproic acid, carbamazepine/tegretol); Anti-depressants (tricyclics, SSRI's, MAOI's, non-selective MAOIs, Wellbutrin, St. John's Wort); Anti-anxiety/Anti-panic agents; Anti-obsessive agents; Prescription stimulants (e.g., Provigil, Ritalin); Diet Pills/Anorectics; Systemic Steroids; Daily medication for chronic pain (e.g., opiates) or muscle spasms; Daily use of over the counter stimulants in pill form (e.g., ephedrine)

• Anti-coagulants (e.g., Warfarin)

• Any heart medications (e.g., dobutamine, isoproterenol)

• Daily medication for asthma

• Parkinson's disease medications (e.g., levodopa, methyldopa, apomorphine)

• Sympathomimetic (e.g., albuterol, pseudoephedrine)

• Other smoking cessation medications (Wellbutrin/Zyban, Chantix/varenicline)

Medical Exclusion Criteria:

• Women who are pregnant, planning a pregnancy within the next 3 months, or lactating.

• History or current diagnosis of any Axis 1 disorder as identified by the MINI (Mini International Neuropsychiatric Interview) or self-report. For major depression, only a current diagnosis will be exclusionary.

• History or current diagnosis of Attention-Deficit Hyperactivity Disorder (ADHD).

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

• History of epilepsy or a seizure disorder.

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

• History or current kidney and/or liver failure (including transplant), disease, or impairment (e.g., cirrhosis); history or current diagnosis of hepatitis (excluding hepatitis A); liver function tests more than 20% outside of the normal range; Gamma-glutamyl Transpepsidase (GGT) values greater than 20% outside the normal range.

• Allergy to the study medication, tolcapone (Tasmar).

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

• Low or borderline intellectual functioning - determined by receiving a score of less than 90 on the Shipley Institute of Living Scale (SILS) which correlates with the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Estimated IQ Test (administered at the medical screening visit).

• Experience of dizziness or lightheadedness upon standing on a daily basis.

• Lifetime history of stroke.

fMRI Exclusion Criteria:

• Self-reported history of claustrophobia.

• Left-handedness.

• Color blindness.

• Any impairment preventing subjects from using response pad necessary for cognitive testing.

• Circumstances or conditions that may interfere with magnetic resonance imaging (MRI).

• Having a cochlear implant or wearing bilateral hearing aids.

• Self-reported history of head trauma (including being knocked unconscious for 3 minutes or greater and diagnosis of a concussion) or CNS tumor.

• Self-reported use of pacemakers, certain metallic implants, or presence of metal in the eye as contraindicated for MRI.

• History of gunshot wound.

• Weight greater than 300lbs. at medical screening or either testing day.

• Completion of cognitive testing in study #810493 or #811325 within the last 6 months.

Genetic Profile Exclusion Criteria:

• In order to balance the distribution of males and females, some participants who meet genotype and other eligibility criteria may not be enrolled in the study.

General Exclusion Criteria:

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

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Tobacco Use Disorder

Intervention

Drug:
• Tolcapone
Participants will be asked to take study medication each day for both 11-day study medication periods. The study medication assignments for each participant in this project is randomized and counterbalanced. This means that approximately 50% of participants will take tolcapone during the first medication period, followed by the placebo in the second medication period. Alternatively, approximately 50% of participants will take the placebo during the first medication period, followed by tolcapone during the second medication period.
• Placebo
Participants will be asked to take study medication each day for both 11-day study medication periods. The study medication assignments for each participant in this project is randomized and counterbalanced. This means that approximately 50% of participants will take tolcapone during the first medication period, followed by the placebo in the second medication period. Alternatively, approximately 50% of participants will take the placebo during the first medication period, followed by tolcapone during the second medication period.

Locations

Country	Name	City	State
United States	University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pennsylvania	National Institute on Drug Abuse (NIDA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Right Dorsolateral Prefrontal Cortex; Right DLPFC)	Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.; To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.	At fMRI scan sessions - Days 8 and 29	No
Primary	Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Left Dorsolateral Prefrontal Cortex; Left DLPFC)	Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.; To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.	At fMRI scan sessions - Days 8 and 29	No
Primary	Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Dorsal Cingulate/Medial Prefrontal Cortex; MF/CG)	Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.; To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.	At fMRI scan sessions - Days 8 and 29	No
Primary	Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Posterior Cingulate Cortex; PCC)	Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.; To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.	At fMRI scan sessions - Days 8 and 29	No
Primary	Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Ventromedial Prefrontal Cortex; vmPFC)	Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.; To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.	At fMRI scan sessions - Days 8 and 29	No
Secondary	Cognitive Performance: Accuracy	Subjects underwent two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each study medication period, after at least 24 hours of smoking abstinence, subjects completed an fMRI brain scan. During these fMRI scan sessions, participants completed computer tasks that were designed to test working memory and attention. These tasks were similar to computer games, in that participants would push a button in response to the pictures they see.; Specifically, we tested whether subjects, while taking tolcapone, would display increased accuracy during the N-back working memory task compared to their performance while they took the placebo. We measured accuracy by counting the absolute number of true positives scored (the number each subject got correct during the task). This was a within-subject analysis.	At fMRI scan sessions - Days 8 and 29	No
Secondary	Cognitive Performance: Reaction Time	Subjects underwent two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each study medication period, after at least 24 hours of smoking abstinence, subjects completed an fMRI brain scan. During these fMRI scan sessions, participants completed computer tasks that were designed to test working memory and attention. These tasks were similar to computer games, in that participants would push a button in response to the pictures they see.; Specifically, we tested whether subjects, while taking tolcapone, would display increased average reaction time (in milliseconds) during the N-back working memory task compared to their performance while they took the placebo. This was a within-subject analysis.	At fMRI scan sessions - Days 8 and 29	No
Secondary	Subjective Symptoms: Smoking Behavior	In order to determine if tolcapone (vs. placebo) would affect subject smoking behavior, we collected the daily number of cigarettes each subject smoked from Days 1 through 7 during each study medication period. This allowed us to calculate the average number of daily cigarettes smoked, across all subjects, during each study medication period (i.e., the average number of cigarettes/day smoked while all subjects took tolcapone and the average number of cigarettes/day smoked while all subjects took placebo). Then, we statistically assessed if there was a significant difference between these averages.	Days 1 through 7 of each study period	No
Secondary	Subjective Symptoms: Cigarette Craving	Subjective symptoms were assessed during each in-person session throughout each study medication period. During each visit, we asked subjects to complete the Questionnaire for Smoking Urges-Brief (QSU-B). Specifically, subjects completed the QSU-B at day 5, day 8 (fMRI scanning session 1), day 26 (day 5 of study medication period 2), and day 29 (day 8 of study medication period 2; fMRI scanning session 2).; The range of possible scores on the QSU-B is 10-70, with higher values indicating an increased craving for cigarettes. This range of scores represent a "total" score; there are no subscales.; While the QSU-B was collected at all in-person sessions, we only analyzed the scores collected from the fMRI scanning sessions of each period (day 8 and day 29). To analyze, we averaged the total scores across all 20 subjects from each fMRI scanning session and statistically analyzed for significant differences between these two averages. This was a within-subject analysis.	Day 8 (fMRI scanning session) of each study period	No
Secondary	Subjective Symptoms: Withdrawal Symptoms	Subjective symptoms were assessed during each in-person session throughout each study medication period. During each visit, we asked subjects to complete the Minnesota Nicotine Withdrawal Scale - Revised version (MNWS). The scale assesses eight DSM-IV items of nicotine withdrawal. The range of possible total scores on the MNWS is 0-60, with higher values indicating an increased nicotine withdrawal. This range of scores represent a "total" score; there are no subscales. The MNWS-N (right now/at the moment) was assessed during each fMRI scanning session visit (Day 8).; To assess if tolcapone (vs. placebo) affect withdrawal symptoms, we statistically analyzed the average of the total MNWS scores across, all 20 subjects, for each study medication period. Specifically, we analyzed for significant differences between reported withdrawal symptoms while taking tolcapone vs. taking placebo.	Day 8 of each study period	No