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Pharmacogenetics of Nicotine Addiction Treatment (PNAT)

Phase 3
18 Years
65 Years
Open (Enrolling)
Nicotine Addiction

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Trial Information

Pharmacogenetics of Nicotine Addiction Treatment (PNAT)

Smoking is an enormous public health problem with a great need for research to improve
treatment outcomes. Our prior data indicates that the CYP2A6 enzyme is critical in the
metabolic inactivation of nicotine, and also influences smoking behavior and response to
therapies. With a vision toward translation of our research to practice, we have
characterized a genetically-informed biomarker of CYP2A6 activity, specifically the nicotine
metabolite ratio (NMR; 3'hydroxycotinine/cotinine), which reflects both CYP2A6 genetic
variation and environmental influences on CYP2A6 activity. The NMR is measured
non-invasively in smokers with established reliability, stability, analytic validity, and
efficacy as a predictor of the ability to quit smoking and treatment response in multiple
retrospective trials. Translation of these findings to clinical practice requires validation
in a prospective clinical trial comparing alternative therapies for smoking cessation. Thus,
the proposed trial is a prospective, stratified, placebo-controlled, multi-center clinical
trial of alternative therapies for smoking cessation treatment in 1,350 smokers.
Randomization to placebo (PLA), transdermal nicotine (TN), or varenicline (VAR) will be
stratified prospectively based on the nicotine metabolite ratio (NMR). Abstinence from
smoking at the end of treatment will be the primary outcome. To facilitate translation to
practice, analysis of the cost-effectiveness of our proposed approach will also be
completed. The proposed research provides the next critical step to validate a
genetically-informed diagnostic tool, the NMR, which clinicians can use in the future to
optimize treatment decisions for their patients who wish to quit smoking.

Inclusion Criteria:

Eligible participants will be males and females

1. Between the ages of 18-65.

2. Smoke at least 10 cigarettes/day for the past 6 months.

3. Provide a baseline CO reading greater than 10ppm at the Intake Session.

4. Are seeking smoking cessation treatment.

5. Plan to live in the area for the next 12 months.

6. Fluent English speaker.

7. Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the combined consent and HIPAA form. All
subjects must consent to use a medically accepted method of birth control (e.g.,
condoms and spermicide, oral contraceptive, Depo-Provera injection, contraceptive
patch, tubal ligation) or abstain from sexual intercourse during the time they are
taking study medication (pills and patches) and for at least one month after the
medication period ends. All female subjects of child-bearing potential should not be
pregnant for the duration of the study.

Exclusion Criteria:

Smoking Behavior

1. Regular (daily) use of chewing tobacco, snuff or snus.

2. Current enrollment or plans to enroll in another smoking cessation or research
program in the next 12 months.

3. Plan to use other nicotine substitutes or smoking cessation treatments in the next 12

4. Provide a baseline CO reading less than or equal to 10ppm at the Intake Session.

Alcohol/Drug Exclusion Criteria

1. History (within the last year) or currently receiving treatment for substance abuse
(e.g., alcohol, opioids, cocaine, marijuana, or stimulants), excluding nicotine.

2. Current use of cocaine and/or methamphetamines (urine drug screen at the Intake

3. Current alcohol consumption that exceeds greater than 25 standard drinks/week.

4. Current alcohol abuse or dependence.

5. Current non-alcoholic psychoactive substance abuse or dependence.

Medical Exclusion Criteria

1. Women who are pregnant, planning a pregnancy, or lactating.

2. History of epilepsy or a seizure disorder.

3. Current medical problems for which transdermal nicotine is contraindicated including:

- Allergy to latex.

- History of kidney and/or liver disease, including transplant (self-report).

- Uncontrolled hypertension (SBP greater than 160 or DBP greater than 100).

4. Serious or unstable disease within the past 6 months.

5. History (last 6 months) of abnormal heart rhythms, tachycardia and cardiovascular
disease (stroke, angina, heart attack) may result in ineligibility. These conditions
will be evaluated on a case by case basis by the Study Physician.

6. Inability to provide a blood sample to be used to assess nicotine metabolite ratio.

Psychiatric Exclusion Criteria (as determined by self report & MINI)

1. Current diagnosis of major depression. Persons with a history of major depression, if
stable for 6 months or longer, are eligible, provided they are not excluded based on
medications (below).

2. Any suicide risk score on MINI or self-reported suicide attempt on telephone screen.

3. Current or past hypomanic/manic episode.

4. History or current diagnosis of Post Traumatic Stress Disorder (PTSD).

5. History or current diagnosis of psychotic disorder, bipolar disorder, schizophrenia.

Medication Exclusion Criteria

1. Current use or recent discontinuation (within the last 14-days) of:

- Smoking cessation medication (e.g. Zyban, Wellbutrin, Wellbutrin SR, Chantix);
NOTE: Once participants are found eligible for the study, they are instructed to
use the smoking cessation medication provided to them by the study staff. If a
subject reports an isolated (non-daily) instance of using a non-study smoking
cessation medication, the study physician and PI will evaluate the situation and
determine if it is safe for the subject to continue participation.

- Anti-psychotic medications.

- Certain medications used to treat depression, including Wellbutrin, MAOIs, and
tricyclic antidepressants.

- Prescription stimulants (e.g. Provigil, Ritalin, Adderall).

2. Current use of:

- Nicotine replacement therapy (NRT); NOTE: Once participants are found eligible
for the study, they are told they should only use the NRT provided to them by
the study staff. If a subject reports an isolated (non-daily) instance of NRT
use during the study, they may be permitted to continue.

- Tagamet (cimetidine).

- Heart medications such as digoxin, quinidine, nitroglycerin; use of these
medications may result in ineligibility and will therefore be evaluated on a
case-by-case basis by the Study Physician.

- Anti-coagulants (e.g., Coumadin, Warfarin).

3. Daily use of:

- Opiate-containing medications for chronic pain; if a participant reports taking
an opiate-containing medication every day for the 14 days prior to the telephone
screen and/or Intake Session, the participant will be ineligible.

- Rescue Inhalers (e.g. albuterol, proventil, ventolin, or maxair)

General Exclusion

1. Any medical condition, illness, disorder or concomitant medication that could
compromise participant safety or treatment, as determined by the Principal
Investigator and/or Study Physician.

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

Type of Study:


Study Design:

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

Outcome Measure:

7-day point prevalence quit rate

Outcome Description:

The definition of this measure requires: (a) no self-reported smoking (not even a puff of a cigarette) for at least the 7 days prior to the assessment, and (b) biochemical verification of abstinence.

Outcome Time Frame:

Week 12

Safety Issue:


Principal Investigator

Caryn Lerman, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pennsylvania


United States: Food and Drug Administration

Study ID:




Start Date:

January 2011

Completion Date:

August 2014

Related Keywords:

  • Nicotine Addiction
  • Tobacco, Smoking, Varenicline, Nicotine Patch
  • Tobacco Use Disorder
  • Behavior, Addictive



MD Anderson Cancer Center, University of Texas Houston, Texas  77030
University at Buffalo - State University of New York Buffalo, New York  14260
Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania Philadelphia, Pennsylvania  19104