Neural Substrates in Nicotine Withdrawal

NCT01001520 | Completed Phase 2 Results DMC

• 2 other identifiers: 809858R01DA026849
• Study Type: interventional
• Target: 218
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Tobacco Use Disorder

Keywords

Genetics; Nicotine; Cognition; fMRI

Outcome Measures

Primary Outcomes (5)

• 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

• 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

• 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

• 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

• 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

Secondary Outcomes (5)

• Cognitive Performance: Accuracy

  At fMRI scan sessions - Days 8 and 29

• Cognitive Performance: Reaction Time

  At fMRI scan sessions - Days 8 and 29

• Subjective Symptoms: Smoking Behavior

  Days 1 through 7 of each study period

• Subjective Symptoms: Cigarette Craving

  Day 8 (fMRI scanning session) of each study period

• Subjective Symptoms: Withdrawal Symptoms

  Day 8 of each study period

Study Arms (2)

Placebo (Sugar Pill)

PLACEBO COMPARATOR

11-day placebo-controlled medication period

Drug: Placebo

Tolcapone

ACTIVE COMPARATOR

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)

Drug: Tolcapone

Interventions

Tolcapone DRUG

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.

Also known as: Tasmar

Tolcapone

Placebo DRUG

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 (Sugar Pill)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.
• 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)

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Tobacco Use Disorder

Interventions

Tolcapone

Condition Hierarchy (Ancestors)

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Benzophenones; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Nitrophenols; Phenols; Ketones; Nitro Compounds

Limitations and Caveats

Genetic studies, particularly imaging studies, have drawbacks such as small sample size and focus on single candidate genes; both can be said of this study.

Results Point of Contact

• Title: Caryn Lerman, PhD
• Organization: University of Pennsylvania

clerman@mail.med.upenn.edu

215-746-7141

Study Officials

• Caryn Lerman, Ph.D.

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

• James Loughead, Ph.D.

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2009
• First Posted: October 26, 2009
• Study Start: January 1, 2010
• Primary Completion: October 1, 2012
• Study Completion: October 1, 2012
• Last Updated: July 2, 2014
• Results First Posted: July 2, 2014

Record last verified: 2014-05

Locations

US (1)