Pharmacogenetics, Emotional Reactivity and Smoking

Study Overview
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Brief Summary
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The goals of this placebo-controlled randomized clinical trial were to evaluate the differences in emotional reactivity (peak startle response to affective stimuli) during a cessation attempt among smokers treated with bupropion, varenicline, or placebo, and to determine if these differences were moderated by genotype.

Detailed Description
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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.

Official Title
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Pharmacogenetics, Emotional Reactivity and Smoking

Conditions
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Tobacco Use Disorder, Smoking Cessation

Intervention / Treatment
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* Drug: Bupropion
* Drug: Varenicline
* Drug: Placebo
* Behavioral: Smoking Cessation Counseling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18-65 years old Smoking: >/= 5 cigarettes per day within the 2 months preceding the screening visit and expired CO greater than or equal to 6 ppm. Able to follow verbal and written instructions in English and complete all aspects of the study Have an address and home telephone number where they may be reached Provide informed consent and agree to all assessments and study procedures Be the only participant in their household Exclusion Criteria: 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 Within the month immediately preceding the screening visit; use of marijuana in any form on 3 or more days within a week Within the two weeks immediately preceding the screening visit, involvement on more than 3 days in any formal smoking cessation activities Current visual or auditory problems that in the opinion of the investigator would interfere with the completion of study assessments Treatment on a continuous basis within 2 weeks before the screening visit: any contraindicated medication for Varenicline or Bupropion. Uncontrolled hypertension or other major contraindications for Bupropion or Varenicline. Severe renal impairment (CR Clearance <30 ml/min/1.73 m2). Laboratory evaluations outside normal limits and of potential clinical significance in the opinion of the investigator 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. Subject rated as moderate to high on suicidality as assessed by 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, one year post-tubal ligation, or who have had a partial or full hysterectomy will not be subject to a urine pregnancy test. 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 Use of Varenicline or Bupropion within two weeks before the screening visit. History of hypersensitivity or allergic reaction to Varenicline, tricyclic antidepressant, Bupropion (Wellbutrin, Zyban) or similar chemical classes or any component of these formulations. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bupropion<br>Bupropion starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter). | Drug: Bupropion<br>* Starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter)<br>* Other names: Zyban;Behavioral: Smoking Cessation Counseling<br>* Counseling over 8 months and telephone support calls.<br>|
| Experimental: Varenicline<br>Varenicline starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter). | Drug: Varenicline<br>* Starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter)<br>* Other names: Chantix;Behavioral: Smoking Cessation Counseling<br>* Counseling over 8 months and telephone support calls.<br>|
| Placebo Comparator: Placebo<br>Placebo by mouth for 12 weeks. | Drug: Placebo<br>* Placebo by mouth for 12 weeks.<br>Behavioral: Smoking Cessation Counseling<br>* Counseling over 8 months and telephone support calls.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Emotional Reactivity By Pharmacotherapy | Emotional reactivity measured by the peak eye blink electromyography (EMG) of the orbicularis oculi (ORB) muscle responses to acoustic startle probe delivered during the presentation of emotionally valent stimuli (pleasant, unpleasant, neutral, and smoking-related pictures). A single value was estimated by averaging within the specific time interval. | Baseline to 1 month | 
| Emotional Reactivity By Pharmacotherapy Moderated by DRD2 A1 Allele | The emotional reactivity (ORB EMG) of smokers during cessation will be moderated by genotype. A single value was estimated by averaging within the specific time interval. During a quit attempt, smokers were evaluated on how they react to smoking related cues. An interaction term was then formed by the reactivity to smoking stimulus and genotype. | Baseline to 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Smoking Abstinence at 3 Months | Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking. | Baseline to 3 months | 
| Smoking Abstinence at 3 Months by DRD2 A1 Allele | Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking. | Baseline to 3 Month | 
| Smoking Abstinence at 6 Months | Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking. | Abstinence at 6 Months ( the effects shown are the increase/decrease in probability of abstinence for 1 unit increase in the predictor) | 
| Abstinence at 6 Months by DRD2 A1 Allele | Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking. | Baseline to 6 Month ( the effects shown are the increase/decrease in probability of abstinence for 1 unit increase in the predictor) | 
| Symptoms of Nicotine Withdrawal Using the Wisconsin Smoking Withdrawal Scale (WSWS) | Symptoms of nicotine withdrawal measured using Wisconsin Smoking Withdrawal Scale (WSWS). The Wisconsin Withdrawal Scale (WSWS) contains 7 factors: Anger, Anxiety, Sadness, Concentration, Craving, Sleep, and Hunger. WSWS consists of 28 items that are scored on a 5-point Likert type scale (0 = strongly disagree, 4 = strongly agree). A single value was estimated by averaging within the specific time interval. Higher values represent worse outcome. The average value was estimated from Baseline to 8 months | Baseline to 8 months | 
| Symptoms of Nicotine Withdrawal and Negative Affect Using Positive and Negative Affect Scale (PANAS) | Symptoms of nicotine withdrawal and negative affect were measured using the Positive and Negative Affect Scale (PANAS). The Positive and Negative Affect Schedule (PANAS) is a self-report questionnaire to measure both positive and negative affect. Each item is rated on a 5-point scale of 1 (not at all) to 5 (very much). Scores can range from 10-50 for both the Positive and Negative Affect with the lower scores representing lower levels of Positive/Negative Affect and higher scores representing higher levels of Positive/Negative Affect. The average value was estimated from Baseline to 8 months | Baseline to 8 months | 
| Symptoms of Depression Using the Center for Epidemiologic Studies Depression Scale (CES-D) | Symptoms of nicotine withdrawal measured using Center for Epidemiologic Studies Depression Scale (CES-D). Center of Epidemiologic Studies Depression Scale (CESD) a 20-item measure that asks caregivers to rate how often over the past week they experienced symptoms associated with depression, such as restless sleep, poor appetite, and feeling lonely. Response options range from 0 to 3 for each item (0 = Rarely or None of the Time, 1 = Some or Little of the Time, 2 = Moderately or Much of the time, 3 = Most or Almost All the Time). Scores range from 0 to 60, with high scores indicating greater depressive symptoms. The average value was estimated from Baseline to 8 months | Baseline to 8 months | 
| Measures of Smoking Satisfaction and Psychological Reward Using the Modified Cigarette Evaluation Questionnaire (mCEQ) Subscales | Modified Cigarette Evaluation Questionnaire (mCEQ). mCEQ Smoking satisfaction: range (1-21); mCEQ Psychological Reward: range(1-35); mCEQ Aversion: range (1-14); mCEQ Enjoyment of Resp.Tract Sens: range (1-7); mCEQ Craving Reduction: range (1-7). For all scales of mCEQ higher scores indicate worse outcomes (greater intensity of smoking effect). Scores of mCEQ Smoking satisfaction, mCEQ psychological reward and mCEQ aversion were summed to create the subscales. mCEQ Enjoyment of Resp Tract Sens and mCEQ Craving Reduction were single items. | Baseline to 8 months | 
| Skin Conductance Response | Skin conductance response (SCR) amplitude measured by placing an electrodermal response transducer on the fore and ring fingers of the participants non-dominant hand, and heart rate (HR) was collected by placing a photoelectric pulse plethysmogram transducer on the middle finger of the participants non-dominant hand, during the presentation of emotionally valent stimuli (positive, negative, neutral, and smoking-related pictures). A single value was estimated by averaging within the specific time interval. | Baseline to 1 month | 
| Heart Rate Response | Heart Rate Response. A single value was estimated by averaging within the specific time interval. During a quit attempt, smokers were evaluated on how they react to smoking related cues. An interaction term was then formed by the reactivity to smoking stimulus and genotype. | Baseline to 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Smoking, Pharmacogenetics, Emotional Reactivity, Smoking Cessation Counseling, Bupropion, Wellbutrin, Wellbutrin SR, Zyban, Varenicline, Chantix, Placebo