Neural Substrates in Nicotine Withdrawal

University of Pennsylvania

Status and phase: Completed; Phase 2

Conditions: Tobacco Use Disorder

Treatments: Drug: Tolcapone; Drug: Placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01001520

R01DA026849 (U.S. NIH Grant/Contract)

809858

Details and patient eligibility

About

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.

Full 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.

Enrollment: 218 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

---

218 participants in 2 patient groups, including a placebo group

Placebo (Sugar Pill)

Placebo Comparator group

Description:

11-day placebo-controlled medication period

Treatment:

Drug: Placebo

Tolcapone

Active Comparator group

Description:

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)

Treatment:

Drug: Tolcapone