Neural Substrates in Nicotine Withdrawal

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT01001520
First received: October 22, 2009
Last updated: July 11, 2013
Last verified: July 2013

October 22, 2009
July 11, 2013
January 2010
October 2012   (final data collection date for primary outcome measure)
Blood Oxygenation Level Dependent (BOLD) fMRI Signal [ Time Frame: At fMRI scan sessions - Days 8 and 29 ] [ Designated as safety issue: No ]
Participants will undergo two, 11-day study medication periods (one on tolcapone and one on placebo). On Day 8 of each study medication period (which fall on study days 8 and 29), participants will complete an fMRI brain scan, measuring BOLD fMRI signal.
Blood Oxygenation Level Dependent (BOLD) fMRI Signal [ Time Frame: At fMRI scan sessions - Days 0 (Baseline), 13 and 43 ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01001520 on ClinicalTrials.gov Archive Site
  • Cognitive performance [ Time Frame: At fMRI scan sessions - Days 8 and 29 ] [ Designated as safety issue: No ]
    At each fMRI scan session, participants will complete neurocognitive testing while in the fMRI scanner. These tasks are designed to test working memory and attention and are similar to computer games, in that participants will push a button in response to the pictures they see.
  • Subjective symptoms - smoking behavior, urges, mood, nicotine withdrawal [ Time Frame: Days 5 & 8 of each study period; Baseline session ] [ Designated as safety issue: No ]
    The subjective symptoms listed above will be assessed at the following in-person sessions: Baseline session, day 5, day 8 (fMRI scanning session 1), day 26 (day 5 of study medication period 2), and day 29 (fMRI scanning session 2).
  • Side effects of tolcapone [ Time Frame: Days 5 & 8 of each study period; Baseline session ] [ Designated as safety issue: Yes ]
    Side effects of tolcapone will be assessed at the following in-person sessions: Baseline session, day 5, day 8 (fMRI scanning session 1), day 26 (day 5 of study medication period 2), and day 29 (fMRI scanning session 2).
  • Cognitive performance [ Time Frame: At fMRI scan sessions - Days 0 (Baseline), 13 and 43 ] [ Designated as safety issue: No ]
  • Subjective symptoms - smoking behavior, urges, mood, nicotine withdrawal [ Time Frame: All in-person sessions - Medical Screening visit, Days 0, 5, 9, 10, 11, 12, 13, 35, 39, 40, 41, 42, 43 ] [ Designated as safety issue: No ]
  • Side effects of tolcapone [ Time Frame: All in-person sessions - Medical Screening visit, Days 0, 5, 9, 10, 11, 12, 13, 35, 39, 40, 41, 42, 43 ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Neural Substrates in Nicotine Withdrawal
Neural Substrates of Cognitive Deficits in Nicotine Withdrawal

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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Tobacco Use Disorder
  • 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.

    Other Name: Tasmar
  • Drug: 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.

  • Placebo Comparator: Placebo (Sugar Pill)
    11-day placebo-controlled medication period
    Intervention: Drug: Placebo
  • Active Comparator: Tolcapone
    11-day phase, tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily); oral dosing; medication is encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
    Intervention: Drug: Tolcapone
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
28
October 2012
October 2012   (final data collection date for primary outcome measure)

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.
Both
18 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01001520
809858, R01DA026849
Yes
University of Pennsylvania
University of Pennsylvania
National Institute on Drug Abuse (NIDA)
Principal Investigator: Caryn Lerman, Ph.D. University of Pennsylvania
Principal Investigator: James Loughead, Ph.D. University of Pennsylvania
University of Pennsylvania
July 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP