Pharmacogenetics of Nicotine Addiction Treatment

Smoking is an enormous public health problem with a great need for research to improve
treatment outcomes. Our prior data indicates that the cytochrome P450 2A6 (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 approximately 1,200
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. Quit rate at 6-month
follow-up is a secondary 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 Carbon Monoxide (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 Health Insurance
Portability and Accountability Act (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
months.

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
Session).

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 (determined as a Systolic Blood pressure (SBP) reading
greater than 160 and/or a Diastolic Blood Pressure (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, Monoamine
Oxidase Inhibitors (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.