Combining Varenicline and Bupropion for Smoking Cessation

The Study Drugs:

Bupropion and varenicline are designed to imitate the effects that nicotine has on the body.
This may reduce cigarette cravings and help patients quit smoking.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as
in the roll of a dice) to 1 of 3 treatment groups.

- If you are in Group 1, you will receive varenicline and bupropion.

- If you are in Group 2, you will receive varenicline and a placebo. A placebo is a
substance that looks like the study drug (in this case, bupropion) but that has no
active ingredients.

- If you are in Group 3, you will receive a placebo that looks like varenicline and a
placebo that looks like bupropion.

You will have a higher chance (5 out of 6) of receiving study drug than receiving just
placebo. Equal numbers of patients will be in Groups 1 and 2. Neither you nor the study
doctor will know to which group you are assigned. However, if needed for your safety, the
study staff will be able to find out which study drug you are receiving.

Study Drug Administration:

You will begin taking the study drugs/placebo 1 to 10 days after the first study visit. A
dose of the study drug/placebo combination will be made up of 1 tablet of varenicline or
placebo and 1 tablet of bupropion or placebo. You should take each dose of study
drugs/placebo with a cup (8 oz.) of water after eating a full meal.

On Days 1-3, you will take 1 dose of the study drug/placebo combination in the morning.

Beginning 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/placebo combination each day).
You must return any study drug bottles as well as any unused study drug to a study staff
member at each study visit.

You will be given a smoking diary to record how many cigarettes you smoke (if any) each day
while you are on study. You must turn in this diary at each study visit.

Study Visits:

About 1 time each week while you are taking the study drugs/placebo, the following tests and
procedures will be performed:

- Your weight and blood pressure will be measured.

- Your CO level will be measured.

- You will be asked about any other drugs you may be taking and about any side effects you
may be having.

- You will answer 8 questionnaires about several topics, including depression, suicide,
your smoking behavior, any effects from the study drugs, and any symptoms of
attention-deficit hyperactivity disorder (ADHD). These should take about 30-45 minutes
total to complete.

- You will do tasks that will measure your logic and attention. These will take about 15
-20 minutes to complete.

- You will receive counseling about quitting smoking in which you discuss possible
"triggers" for smoking and strategies for dealing with quitting smoking. These sessions
will take about 15 minutes each time.

During counseling at the first study visit, you will set a "quit date" for stopping smoking
for about 1 week after you start taking the study drug. You should not quit smoking before
the quit date. You should stay smoke-free after the quit date. Additionally, you will be
given a medication instruction sheet, a card with emergency contact information, and a
participant manual to help you follow along with the topics discussed during counseling.

At Week 2, saliva will be collected to check your cotinine level.

At Week 4, blood (about 2 teaspoons) will be drawn to assess liver and kidney function.

Lab Sessions:

You may be asked to take part in lab sessions during Visits 1, 2, and 6 to test your brain
activity and attention span. You will be asked to watch slides and listen to a series of
tones. 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 sessions, your brain electrical activity (EEG) will be monitored. 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 2.5 hours before each session. At the first
lab session, you may be asked to smoke a cigarette if the doctor thinks it is needed for you
to exhibit your normal smoking behavior.

Length of Study:

You will receive the study drug for up to 12 weeks. However, the entire length of the study
is about 13 months (55 weeks), which includes 3, 6, and 12-month post-quit follow up visits.
You will be taken off study if the doctor thinks it is in your best interest.

End-of-Study Visit:

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

- Your weight and blood pressure will be measured.

- Your CO level will be measured.

- You will be asked about any side effects you may be having and about any other drugs you
may be taking.

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

- You will answer the same questionnaires you completed at the regular study visits. These
should take about 30-45 minutes total to complete.

- Saliva will be collected to measure your cotinine level.

Follow-Up Visits:

About 3, 6, and 12 months after you have stopped smoking, the following tests and procedures
will be performed:

- Your weight, heart rate, and blood pressure will be measured.

- Your CO level will be measured.

- You will be asked about any side effects you may be having and about any other drugs you
may be taking.

- You will answer the same questionnaires you completed at the regular study visits. These
should take about 30-45 minutes total to complete.

- Saliva will be collected to measure your cotinine level.

You will be called by the study staff 1 day before your quit date, 3 days after your quit
date, and at Weeks 14, 20, 34, 42, and 48 weeks after your quit date to check on your
progress in quitting smoking. Each call should take about 10-15 minutes.

This is an investigational study. Varenicline and bupropion are both FDA approved and
commercially available to help people stop smoking. The use of the drugs in combination is
investigational.

Up to 385 participants will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Age: 25-70 years old

2. Smoking 5 or more cigarettes per day, on average, within the 2 months preceding the
screening visit and expired CO of greater than or equal to 6ppm.

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

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

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

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
products other than cigarettes 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. 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. Treatment on a continuous basis within 2 weeks before the screening visit: any
contraindicated medication for Varenicline or Bupropion. Classes of contraindicated
medications include, but are not limited to, antiasthmatics, antipsychotics, some
antidepressants, antihypertensives, antiarrhythmics, antineoplastics, some
antiseizures, and MAO inhibitors (See Appendix U for specific list of excluded and
precautionary medications).

5. Uncontrolled hypertension (average reading of systolic blood pressure greater than 150
or diastolic blood pressure greater than 95) or other major contraindications for
Bupropion or Varenicline (See section on Screening).

6. Severe renal impairment (Creatinine Clearance less than 30 ml/min/1.73 m2).

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

8. Meet current criteria for psychiatric disorders or substance abuse as assessed by the
MINI plus (major depressive episode) and the MINI for items B, D, I, J (Alcohol
Addendum-past 6 months only), K, L, M and N including a past manic or hypomanic
episode as well as a lifetime psychotic disorder.

9. Individuals rated as moderate (6 - 9) to high (10 or greater) on suicidality as
assessed by Module C of the MINI.

10. Psychiatric hospitalization within 1 year of screening date.

11. 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.

12. 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.

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

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

15. Current or previous history of a seizure disorder.

16. Current or previous history of anorexia.

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.