Reward Sensitivity and Pharmacotherapy for Smoking Cessation

Study Groups:

If you agree to take part in this study, you will be randomly assigned (as in the roll of a
dice) to 1 of 2 study groups. This is done because no one knows if one study group is better,
the same, or worse than the other group. You will have an equal chance of being assigned to
Group 1 or 2.

- If you are in Group 1, you will receive varenicline and a placebo patch. A placebo is
not a drug. It looks like the study drug but is not designed to treat any disease or
illness. It is designed to be compared with a study drug to learn if the study drug has
any real effect.

- If you are in Group 2, you will receive an active nicotine patch and a placebo tablet.

Neither you nor the study doctor will know which group you are assigned to. However, if
needed for your safety, the study staff will be able to find out what you are receiving
(called "unblinding").

Once the study has ended and the Data Safety Monitoring Board (DSMB) at MD Anderson has
granted approval, you may be unblinded at your request.

Study Drug Administration:

You will start taking your assigned study drug(s) the day after Visit 1.

You should take varenicline/placebo tablets by mouth with a cup (8 ounces) of water after
eating a full meal. On Days 1-3, you will take 1 dose of the study drug each morning.
Starting on Day 4, and then every day after that, you will take 1 dose in the morning and 1
dose in the evening (for a total of 2 doses of the study drug each day). You must return any
study drug bottles as well as any unused study drug to the study staff at each study visit.

You should apply the nicotine/placebo patch to the upper arm. You should put it in a slightly
different place each day to avoid skin irritation. You may take the patch off at night to
avoid sleeping problems.

You will be given a study diary to record how many cigarettes you smoke (if any) each day
while you are on study.

You must return your study diary and any unused study drugs, patches, and/or containers at
each study visit.

Study Visits (Visits 1-7):

At every study visit:

- You will complete questionnaires about several topics, including depression, suicide,
your smoking behavior, and any effects from the study drug. These questionnaires should
take about 30-45 minutes in total to complete.

- You will be giving the opportunity to complete the questionnaires verbally with a study
staff member (either on phone or in person depending on the visit number) or
electronically on your computer using a website administered by an online survey
development company called Qualtrics.

- You will receive counseling about quitting smoking, where you will talk about possible
"triggers" for smoking and strategies for dealing with quitting smoking. These sessions
will take about 15 minutes each.

At Visits 1, 4 and 6:

- Urine or saliva will be collected for a routine test to check your cotinine, nicotine,
and anabasine levels. Cotinine is a chemical released in your body when it breaks down
nicotine and will show whether and how much you have recently smoked. Anabasine is used
to show if nicotine is found in the blood due to a nicotine replacement therapy or from
tobacco use.

- Your CO level and weight. will be measured.

- If you did not have one during screening, you will have a physical exam.

- If you did not complete at one during screening or before Visit 1, you will complete the
EEG/lab session.

- If you can become pregnant, urine will be collected for a pregnancy test.

- At V1, if your CO machine tests results are unclear, and the study staff thinks it is
appropriate, a NicAlert test will be performed. Urine will be collected for the NicAlert
test, which is more sensitive at detecting levels of smoking than the CO machine.

During counseling on Day 8, you will set a "quit date" for stopping smoking for about 1 week
after you start taking the study drug/placebo. You should not quit smoking before the quit
date. You may also set goals to reduce smoking. You should try to stay smoke-free after the
quit date. You will also be given a drug instruction sheet, a card with emergency contact
information, and a participant manual to help you follow along with the topics discussed
during counseling.

Visits 2, 3, 5 and 7 will be conducted over the phone. You will complete questionnaires about
several topics (either on the phone or electronically), including depression, mood, your
smoking behavior, and any effects from the study drug. You will also be asked about any drugs
you may be taking. Each call should take about 25-45 minutes.

The study staff will call you 1 day before your quit date and 3 days after your quit date to
check on your progress in quitting smoking. Each call should take about 10-15 minutes.

Lab Session:

You will take part in a lab session at or before Visit 1 to test your brain activity. You
will be asked to watch slides. The slides will include pictures of people, nature, and
artwork. Slides showing nude people, medical procedures, and victims of car crashes will also
be shown. You will be shown examples of these slides before beginning the procedure and given
the opportunity to withdraw from the study.

During the lab session, your brain electrical activity will be checked with an
electroencephalogram (EEG). To do this, small sensors will be placed on your scalp and face.
You should not drink more than 2 cups of coffee or other caffeinated drinks for at least 2½
hours before the session. At the lab session, you may be asked to smoke a cigarette if the
doctor thinks it is needed for you to show your normal smoking behavior.

You will also complete computer tasks, including questionnaires that will measure your
emotions and attention level. These tasks should take about 90 minutes to complete.

The lab session may last up to 2 hours.

Ecological Momentary Assessments (EMA):

EMA are used to gather information about your mood and cravings as they happen in your
day-to-day life. At your randomization visit, you will be loaned a smart phone device, and
will be asked to complete questionnaires on the device at different times everyday throughout
the active treatment phase (12 weeks). In these questionnaires, you will be asked about
events from the previous day, such as cigarettes per day, alcohol intake, mood, sleep,
motivation, and whether you took your prescribed drugs on time. These questionnaires should
take up to about 20 minutes per day to complete.

Length of Treatment:

You will receive the study drug/placebo for up to 12 weeks. You will be taken off study early
if the doctor thinks it is in your best interest or if you are unable to follow study
directions.

Your participation on the study will be over after the follow-up visits.

End-of-Treatment Visit (Visit 8):

After you have finished taking the study drug/placebo, the following tests and procedures
will be performed:

- Your CO level will be measured.

- Blood (about 2 teaspoons) will be drawn to check your liver and kidney function.

- Urine or saliva will be collected to measure your nicotine, anabasine, and cotinine
level.

- You will complete the same questionnaires you completed at the regular study visits.

- You will receive counseling about quitting smoking.

- If you can become pregnant, urine will be collected for a pregnancy test.

Follow-Up Visits (Visits 9 and 10):

At about 3 and 6 months after you have stopped smoking, the following tests and procedures
will be performed:

- Your CO level will be measured.

- Urine or saliva will be collected to measure your nicotine, anabasine, and cotinine
level.

- You will complete the same questionnaires you completed at the regular study visits.

This is an investigational study. Varenicline and the nicotine patch are both FDA approved
and commercially available to help people stop smoking. The study doctor can explain how the
study drugs are designed to work.

Up to 160 participants will be enrolled in this portion of the study. All will take part at
MD Anderson.

Inclusion Criteria:

1. Age: 18-75 years old

2. Smoking 5 or more cigarettes, little cigars 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 2).

3. Interested in treatment that might change smoking behavior

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

5. Provide informed consent and agree to all assessments and study procedures

6. Have an address and telephone number where they may be reached

7. Be the only participant in their household

Exclusion Criteria:

1. Within the month immediately preceding the screening visit, use of any form of tobacco
products other than cigarettes, little cigars 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.

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

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

4. Uncontrolled hypertension (systolic blood pressure; SBP greater than 180 or diastolic
blood pressure; DBP greater than 110)

5. 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

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

7. Serious or unstable disease within the past 3 months

8. 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.

9. Current use of certain medications: (1) Smoking cessation meds (last 7 days), i.e.,
Wellbutrin, Bupropion, Zyban, NRT, Chantix, (2) Certain medications to treat
depression (last 14 days), i.e. 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 PRN use is allowed (i.e., 3:7 days per week or
less or if more frequent, use less than a month's duration.

10. 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/lifetime psychotic disorder or
current/lifetime 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.

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

12. Psychiatric hospitalization within 1 year of screening date.

13. 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.

14. 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.

15. History of hypersensitivity or allergic reaction to Varenicline, NRT, or any component
of these formulations.

16. 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.

17. 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.

18. Positive toxicology screen for any of the following drugs: cocaine, opiates,
methadone, benzodiazepines, barbiturates, amphetamines, methamphetamines, PCP, or 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.

19. Must not have visual problems that in the investigators opinion would interfere in the
completion of the study assessments

20. Unwilling to change hairstyle or remove a wig as necessary for the appointment to
accommodate the net that is required to be worn on the scalp during the study
procedure.

21. Reports diagnosis of seizure disorder or a history of neurological illness or closed
head injury that in the opinion of the PI feels that it would affect the results of
the EEG.