Pharmacogenetics, Emotional Reactivity and Smoking

Bupropion and Varenicline are smoking cessation aids that may help people to quit smoking.

During the orientation visit, the study will be explained to you and you will be given an
opportunity to ask, and have answered, any questions you may have. You will also be asked to
give a buccal (cheek cell) sample for genetic analysis. This session will last about 1.5
hours.

During the screening visit, you will be asked questions about your health, medication use,
smoking history, and tobacco use. You will be asked about any current or past feelings of
depression. Also, a small blood sample will be drawn (about 2 tablespoons) from your upper
arm for a liver and kidney function test and a saliva sample will be collected to measure
whether you are smoking. Women who are able to have children must have a negative urine
pregnancy test. This session will last about 2.5 hours.

If you are eligible to take part in the study, you will be randomly assigned (as in the toss
of a coin) to one of three treatment groups. Participants in the first group will receive
Bupropion. Participants in the second group will receive Varenicline. Participants in the
third group will receive a placebo. A placebo is a substance that looks like the study drug
but which has no active ingredients. You will have an equal chance of being assigned to the
Bupropion, Varenicline, or placebo treatment group. Neither you nor your counselor will know
to which group you were assigned.

All participants will take study pills (either Bupropion, Varenicline, or placebo) by mouth
for 12 weeks. The dose of study medication may or may not change during the study. You will
be responsible for returning any unused, used, or partly used study medication bottles to a
study staff member.

All participants will receive smoking cessation counseling to help them quit smoking, in the
form of both in-person and telephone counseling sessions. Some of the counseling sessions may
be videotaped or audio-taped. The videotapes will be used to help the investigators make sure
that the counselors are following the correct procedures and will be erased within one year
following your completion of the study. No one but the study investigators or those delegated
by the study investigators will be allowed to view the tapes and the identity of the
participants will be kept strictly confidential. Staff that may be given permission to view
the tapes include project staff, consultants that review and rate how well the study
counselors follow guidelines, and/or consultants that review how well the assessments are
given.

You will need to come to the Behavioral Science Research Clinic at M. D. Anderson for 9
clinic visits over an 8-month period. You will receive 5 telephone calls from the study staff
(while in treatment and during follow-up) to check on your progress in quitting smoking.

You will complete your first lab evaluation session (baseline) before any treatment begins
(while you are still smoking). Immediately after the baseline lab session (on the same day),
you will begin to receive counseling to quit smoking. You will begin taking one of the 3
study medications (Bupropion, Varenicline, or placebo) the next morning.

There will be 3 lab sessions, during which you will be asked to complete questionnaires about
your mood and feelings (about 30 minutes total). Also, you will give a breath sample by
blowing air into a small tube. This sample shows how much you have smoked. In each session
you will be asked to watch slides and listen to a series of tones through earphones. The
slides will include pictures of people, nature scenes, and artwork. Slides showing victims of
car crashes, medical procedures, and nude people 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 sessions, your heart rate, brain electrical activity (EEG),
skin sweating, and muscle tension will be monitored. To do this, small sensors will be placed
on the fingers, arms, scalp and face. You should not drink more than 2 cups of coffee or
other caffeine drinks at least 2.5 hours before each session.

During the first counseling visit, you will set a quit date for stopping smoking about 2
weeks after starting your study medication. You are asked not to quit smoking before the set
quit date. After your quit date, you are asked to stay smoke free. You are asked to attend
all your sessions whether you are smoking or not. All participants will receive smoking
cessation counseling in the form of both in-person and telephone counseling sessions. The
purpose of these visits will be to prepare you for quitting and to check the effects of the
study medication on your attempt to stop smoking.

At each of your clinic visits, your blood pressure will be taken and you will be asked to
blow air through a carbon monoxide (CO) measuring device. CO is a gas that is found in higher
levels among cigarette smokers. At several visits you will be asked to provide a saliva
sample to check for cotinine, a chemical produced by the breakdown of nicotine during
smoking. You will be asked to give a saliva sample in a collection tube. Like the CO test,
this test will help researchers measure how much you are smoking.

At your visits you will be asked questions about your smoking behavior. You will also be
asked questions about your health and medical condition, and about any medications you are
taking. You will be asked to complete a daily diary on cigarette smoking and drug dosing.

You will also be asked to mail saliva samples back to the clinic at least two times after
stopping the medication. This will allow researchers to check on your smoking status.

Your total participation in this study will last about 8 months. This will include a 3-month
and 6-month follow-up visit after your scheduled quit date. If the study staff is not able to
reach you by phone, mail, or the information provided by your contacts, they may try to
locate you through telephone directory assistance (411) or internet search sources (for
example, Google or Yahoo!), which use information from the public domain (meaning everyone
has access to it). If the study staff is still unable to find you, they may use a locator
service such as Transunion or the National Change of Address (NCOA) database maintained by
the United States Postal Service, as a last resort. Transunion uses magazine subscriptions
and credit applications to find new addresses, and the NCOA uses the Change of Address cards
filed with the post office when a person moves and requests their mail be forwarded to a new
address. If the study staff has to use either of these services, they would only disclose
your name and last known address.

At the end of the study, you will be able to ask additional questions about the results of
the study and about procedures you have experienced during the study. Additionally, you will
be able to sign up to receive a copy of the paper that will be written at the completion of
the study.

This is an investigational study. Up to 375 smokers will take part in this study. All will be
enrolled at MD Anderson.

Inclusion Criteria:

1. Age: 18-65 years old

2. Smoking: >/= 5 cigarettes per day within the 2 months preceding the screening visit
and expired CO greater than or equal to 6 ppm.

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

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

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

6. Be the only participant in their household

Exclusion Criteria:

1. Within the month immediately preceding the screening visit; use of any form of tobacco
product other than cigarettes on 3 or more days within a week only if the individual
refuses to refrain from non-cigarette tobacco use during the course of this study

2. Within the month immediately preceding the screening visit; use of marijuana in any
form on 3 or more days within a week

3. Within the two weeks immediately preceding the screening visit, involvement on more
than 3 days in any formal smoking cessation activities

4. Current visual or auditory problems that in the opinion of the investigator would
interfere with the completion of study assessments

5. Treatment on a continuous basis within 2 weeks before the screening visit: any
contraindicated medication for Varenicline or Bupropion.

6. Uncontrolled hypertension or other major contraindications for Bupropion or
Varenicline.

7. Severe renal impairment (CR Clearance <30 ml/min/1.73 m2).

8. Laboratory evaluations outside normal limits and of potential clinical significance in
the opinion of the investigator

9. Meet current criteria for psychiatric disorders or substance abuse as assessed by the
MINI for items A, B, D, I, J, K, L, M and N, including a past manic or hypomanic
episode as well as a lifetime psychotic disorder.

10. Subject rated as moderate to high on suicidality as assessed by the MINI.

11. Psychiatric hospitalization within 1 year of screening date.

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

13. Pregnant, breast-feeding, or of childbearing potential who is not protected by a
medically acceptable, effective method of birth control while enrolled in the study

14. Use of Varenicline or Bupropion within two weeks before the screening visit.

15. History of hypersensitivity or allergic reaction to Varenicline, tricyclic
antidepressant, Bupropion (Wellbutrin, Zyban) or similar chemical classes or any
component of these formulations.

16. 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.