Varenicline and Nicotine Replacement Therapy for Initial Smoking Cessation and Treatment in Smokers

PRIMARY OBJECTIVES:

I. To estimate the main effects of varenicline 2mg (VAR) and nicotine patch + lozenge (NPL)
on smokers who remain on these medications throughout the trial.

II. To estimate the probability that abstinence at twelve weeks as a function of treatment
assignment at six weeks (augmentation) is moderated by initial treatment assignment (i.e. at
baseline).

III. To estimate the probability that abstinence at twelve weeks as a function of treatment
assignment at six weeks (switching) is moderated by initial treatment assignment (i.e. at
baseline).

IV. To estimate the probability that treatment continuation, switching, or augmentation
confers benefit conditional upon failing to quit after the initial treatment with nicotine
patch + lozenge (NPL) for six weeks.

V. To estimate the probability that treatment continuation, switching, or augmentation
confers benefit conditional upon failing to quit after initial treatment with VAR for six
weeks.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive varenicline orally (PO) once daily (QD) or twice daily (BID),
placebo patches QD, and placebo lozenges PO QD beginning on day 9 and continue for 6 weeks.
Patients that are abstinent at week 6 may continue treatment for an additional 6 weeks.
Patients also receive behavioral smoking cessation counseling consisting of 4 in-person
visits, 4 phone visits, and 4 brief supportive phone calls lasting 10-15 minutes each over
the 12 weeks of treatment.

GROUP II: Patients receive placebo tablets PO QD or BID, nicotine patches QD, and nicotine
lozenges PO QD beginning on day 9 and continue for 6 weeks. Patients that are abstinent at
week 6 may continue treatment for an additional 6 weeks. Patients also receive behavioral
smoking cessation counseling consisting of 4 in-person visits, 4 phone visits, and 4 brief
supportive phone calls lasting 10-15 minutes each over the 12 weeks of treatment.

Patients who fail to achieve abstinence at week 6 are re-randomized to receive 6 additional
weeks of therapy consisting of either a continuation of the same treatment; switching to the
untried intervention (either NPL or varenicline); or receive NPL treatment with an additional
patch (high-dose NPL) or high-dose varenicline.

After completion of study treatment, patients are followed up at 3 and 6 months.

Inclusion Criteria:

- Smoking 5 or more cigarettes, little cigars and/or cigarillos per day, on average,
within the 2 months preceding the screening visit and expired carbon monoxide (CO)
greater than or equal to 6 parts per million (ppm) (if less than or equal to 5, then
positive cotinine test)

- Interested in treatment that might change smoking behavior

- Able to follow verbal and written instructions in English and complete all aspects of
the study

- Provide informed consent and agree to all assessments and study procedures

- Have an address and telephone number where he/she may be reached

- Be the only participant in his/her household

Exclusion Criteria:

- Within the month immediately preceding the screening visit, use of any form of tobacco
products other than cigarettes, little cigars and/or cigarillos on 3 or more days
within a week if the individual refuses to refrain from such tobacco use during the
course of the study

- Current enrollment or plans to enroll in another smoking cessation program in the next
12 months

- Plan to use other nicotine substitutes (i.e., over-the-counter [OTC] or prescription
medication for smoking cessation) or smoking cessation treatments in the next 12
months

- Uncontrolled hypertension (systolic blood pressure; [SBP] greater than 180 or
diastolic blood pressure; [DBP] greater than 110)

- History of severe kidney disease (e.g chronic or acute kidney failure) with creatinine
clearance below 30 and/or severe liver disease with liver tests over 4 times the upper
normal level

- Laboratory evaluations (kidney and liver) outside normal limits and of potential
clinical significance in the opinion of the investigator

- Serious or unstable disease within the past 3 months

- History (last 3 months) of abnormal heart rhythms, 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

- Current use of certain medications: (1) smoking cessation meds (last 7 days), i.e.,
Wellbutrin, Bupropion, Zyban, nicotine replacement therapy (NRT), Chantix, (2) certain
medications to treat depression (last 14 days), i.e. monoamine oxidase inhibitors
(MAOIs) and Elavil (Amitriptyline), (3) a case by case determination will be made by
study physician for medication on precautionary list, i.e. nitroglycerin, or (4) daily
use of opioids for 30 days or more on phone screen or at screening is exclusionary
however pro re nata (PRN) use is allowed (i.e., 3:7 days per week or less or if more
frequent, use less than a month's duration)

- Meet criteria for the following psychiatric and/or substance use disorders as assessed
by the MINI International Neuropsychiatric Interview (MINI): items C (current manic or
hypomanic episode only), I (alcohol abuse - Alcohol Addendum - past 6 months only;
current alcohol dependence), J (substance abuse - Substance Abuse Addendum - past 6
months only; current substance dependence), K (current psychotic disorder or current
mood disorder with psychotic features); individuals who meet criteria for
non-exclusionary psychiatric disorders that are considered clinically unstable and/or
unsuitable to participate as determined by the principal investigator and/or study
physician

- Individuals rated as moderate (9-16) to high (17 or greater) on suicidality as
assessed by Module B of the MINI

- Psychiatric hospitalization within 1 year of screening date

- A positive urine pregnancy test during the screening period; women who are two years
post-menopausal, or who have had a tubal ligation or a partial or full hysterectomy
will not be subject to a urine pregnancy test

- Pregnant, breast-feeding or of childbearing potential and is not protected by a
medically acceptable, effective method of birth control while enrolled in the study;
medically acceptable contraceptives include: (1) approved hormonal contraceptives
(such as birth control pills, patches, implants or injections), (2) barrier methods
(such as a condom or diaphragm) used with a spermicide, or (3) an intrauterine device
(IUD); contraceptive measures sold for emergency use after unprotected sex are not
acceptable methods for routine use

- History of hypersensitivity or allergic reaction to varenicline, NRT, or any component
of these formulations

- Any medical or psychiatric condition, illness, disorder, or concomitant medication
that could compromise participant safety or treatment, as determined by the principal
investigator and/or study physician

- Subject considered by the investigator as unsuitable candidate for receipt of an
investigational drug, or unstable to be followed up throughout the entire duration of
the study

- Positive toxicology screen for any of the following drugs: cocaine, opiates,
methadone, benzodiazepines, barbiturates, amphetamines, methamphetamines,
phencyclidine (PCP), or tetrahydrocannabinol (THC); a. participants with valid
prescriptions for opiates, benzodiazepines, barbiturates, amphetamines or methadone
will not be excluded; b. participants failing the toxicology screen will be allowed to
re-screen once; if they test positive again, they will not be allowed to return