Official Title: “Pharmacogenetics, Emotional Reactivity and Smoking”

Recent advances in smoking cessation have focused on the use of Varenicline and antidepressants (e.g., Bupropion) for the treatment of nicotine dependence. While the efficacy of these treatments has been established in previous studies, we know little about how they work. The specific aims of this project are to assess the effects of these drugs on changes in emotional reactivity during cessation, to determine if these effects are moderated by genotype, and to determine whether emotional reactivity predicts time to relapse. A standardized laboratory assessment procedure, known as the acoustic startle probe, will be used to assess emotional reactivity. In this study, 375 smokers will be randomly assigned to receive Bupropion, Varenicline or placebo. Participants will complete three startle assessments consisting of the presentation of an acoustic stimulus (startle probe), immediately preceded by positive, negative or neutral emotional cues or smoking related stimuli. We hypothesize that the emotional reactivity of all smokers during cessation will be significantly less for those treated with either Varenicline or Bupropion in comparison to placebo. It is also hypothesized that emotional reactivity will be lower for those carrying the DRD2 A1 allele and using Varenicline vs. A1 smokers using either Bupropion or placebo.

Homozygous A2s are expected to respond similarly to both drugs with higher levels of emotional reactivity being observed for placebo. We will also characterize other potential markers for neurotransmitter function (DRD4, DAT, SERT, NET) in terms of differences in both baseline emotional reactivity, and response to pharmacotherapy vs. the control. We hope to understand more fully how pharmacotherapies for smoking cessation affect emotional reactivity during cessation (nicotine withdrawal) and what role genetics may play in conferring an advantage to one treatment vs. another, through this mechanism.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: December 2010

Pharmacogenetics - Pilot:

As part of the pilot phase of this study, you are being asked to participate in laboratory sessions that will be part of a larger study.

If you agree to take part in this study, you will be asked to come to the Behavioral Science Research Clinic at M. D. Anderson for up to 4 laboratory sessions, about once or twice a week. During each of the lab sessions, you will be asked to complete questionnaires about your mood and feelings. 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. You may also be asked to participate in a mental math exercise. 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. Most clinic visits will last about 2 hours.

Before some sessions, you may be required to not smoke. Before other sessions, you may smoke normally. Additionally, you may be asked to smoke during some of your laboratory sessions.

At each of your clinic visits, 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 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 .

So that the study researchers can stay in contact with you throughout the study, you will be asked at the screening visit to provide the name and address of 3 contacts (family member/friends) that you feel confident would have updated contact information on you. You will also be asked to sign a letter giving your contacts permission to provide your updated information to the study staff.

If the staff is not able to reach you by phone, mail, or the information provided by your contacts, they may attempt to find you through the 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).

You are being asked to participate for a period of about 4 weeks. 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.

This is an investigational study. You will not have to pay to take part in this study. Up to 50 smokers will take part in the pilot phase of this study.

Pharmacogenetics:

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 will 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. At the first lab session, you may also be asked to smoke a cigarette. This is done to make sure that all participants in this study are at the same level in terms of when they last smoked.

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 M. D. Anderson.

Intervention(s) in this Clinical Trial

• Drug: Bupropion
  • 150 mg PO Daily
• Drug: Varenicline
  • 0.5 mg PO Daily
• Drug: Placebo
  • Placebo by mouth for 12 weeks.
• Behavioral: Smoking Cessation Counseling
  • Counseling over 8 months and telephone support calls.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Bupropion
• Experimental: 2
  • Varenicline
• Placebo Comparator: 3
  • Placebo

Primary Measures

• The goal of this behavioral research study is to learn more about how the drugs Bupropion and Varenicline affect mood and physiological responses in different groups of people as they attempt to quit smoking.
  • Time Frame: 5 Years
    Safety Issue?: No

Secondary Measures

• To learn how these drugs affect responses related to changes in emotion and whether or not a person's genetic make-up makes a difference in how they respond to the medication.
  • Time Frame: 5 Years
    Safety Issue?: No

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 (<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.
• 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.
• 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: M.D. Anderson Cancer Center

Overall Clinical Trial Officials and Contacts

Paul Cinciripini, PhD Principal Investigator U.T.M.D. Anderson Cancer Center  

Overall Contact: Paul Cinciripini, PhD 713-792-0919 

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00507728

Study ID Number: 2003-1024

ClinicalTrials.gov Identifier: NCT00507728

Health Authority: United States: Institutional Review Board

UT MD Anderson Cancer Center Website