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Neural Substrates in Nicotine Withdrawal

Information source: University of Pennsylvania
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Tobacco Use Disorder

Intervention: Tolcapone (Drug); Placebo (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: University of Pennsylvania

Official(s) and/or principal investigator(s):
Caryn Lerman, Ph.D., Principal Investigator, Affiliation: University of Pennsylvania
James Loughead, Ph.D., Principal Investigator, Affiliation: University of Pennsylvania

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.

Clinical Details

Official title: Neural Substrates of Cognitive Deficits in Nicotine Withdrawal

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

Primary outcome:

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)

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)

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)

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)

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)

Secondary outcome:

Cognitive Performance: Accuracy

Cognitive Performance: Reaction Time

Subjective Symptoms: Smoking Behavior

Subjective Symptoms: Cigarette Craving

Subjective Symptoms: Withdrawal Symptoms

Detailed 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.

Eligibility

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

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.

Locations and Contacts

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
Additional Information

Starting date: January 2010
Last updated: May 29, 2014

Page last updated: August 23, 2015

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