Pharmacogenetics of Nicotine Addiction Treatment

Study Overview
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Brief Summary
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The purpose of this research program is to understand how a biomarker called the nicotine metabolite ratio (also referred to as NMR) may influence a smoker's ability to quit smoking.

Detailed Description
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Smoking is an enormous public health problem with a great need for research to improve treatment outcomes. Our prior data indicates that the cytochrome P450 2A6 (CYP2A6) enzyme is critical in the metabolic inactivation of nicotine, and also influences smoking behavior and response to therapies. With a vision toward translation of our research to practice, we have characterized a genetically-informed biomarker of CYP2A6 activity, specifically the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine), which reflects both CYP2A6 genetic variation and environmental influences on CYP2A6 activity. The NMR is measured non-invasively in smokers with established reliability, stability, analytic validity, and efficacy as a predictor of the ability to quit smoking and treatment response in multiple retrospective trials. Translation of these findings to clinical practice requires validation in a prospective clinical trial comparing alternative therapies for smoking cessation. Thus, the proposed trial is a prospective, stratified, placebo-controlled, multi-center clinical trial of alternative therapies for smoking cessation treatment in approximately 1,200 smokers. Randomization to placebo (PLA), transdermal nicotine (TN), or varenicline (VAR) will be stratified prospectively based on the nicotine metabolite ratio (NMR). Abstinence from smoking at the end of treatment will be the primary outcome. Quit rate at 6-month follow-up is a secondary outcome. To facilitate translation to practice, analysis of the cost-effectiveness of our proposed approach will also be completed. The proposed research provides the next critical step to validate a genetically-informed diagnostic tool, the NMR, which clinicians can use in the future to optimize treatment decisions for their patients who wish to quit smoking.

Official Title
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Pharmacogenetics of Nicotine Addiction Treatment (PNAT)

Conditions
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Nicotine Addiction

Intervention / Treatment
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* Drug: Varenicline
* Drug: Placebo
* Drug: Transdermal Nicotine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible participants will be males and females Between the ages of 18-65. Smoke at least 10 cigarettes/day for the past 6 months. Provide a baseline Carbon Monoxide (CO) reading greater than 10ppm at the Intake Session. Are seeking smoking cessation treatment. Plan to live in the area for the next 12 months. Fluent English speaker. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and Health Insurance Portability and Accountability Act (HIPAA) form. All subjects must consent to use a medically accepted method of birth control (e.g., condoms and spermicide, oral contraceptive, Depo-Provera injection, contraceptive patch, tubal ligation) or abstain from sexual intercourse during the time they are taking study medication (pills and patches) and for at least one month after the medication period ends. All female subjects of child-bearing potential should not be pregnant for the duration of the study. Exclusion Criteria: Smoking Behavior Regular (daily) use of chewing tobacco, snuff or snus. Current enrollment or plans to enroll in another smoking cessation or research program in the next 12 months. Plan to use other nicotine substitutes or smoking cessation treatments in the next 12 months. Provide a baseline CO reading less than or equal to 10ppm at the Intake Session. Alcohol/Drug Exclusion Criteria History (within the last year) or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana, or stimulants), excluding nicotine. Current use of cocaine and/or methamphetamines (urine drug screen at the Intake Session). Current alcohol consumption that exceeds greater than 25 standard drinks/week. Current alcohol abuse or dependence. Current non-alcoholic psychoactive substance abuse or dependence. Medical Exclusion Criteria Women who are pregnant, planning a pregnancy, or lactating. History of epilepsy or a seizure disorder. Current medical problems for which transdermal nicotine is contraindicated including: Allergy to latex. History of kidney and/or liver disease, including transplant (self-report). Uncontrolled hypertension (determined as a Systolic Blood pressure (SBP) reading greater than 160 and/or a Diastolic Blood Pressure (DBP) greater than 100). Serious or unstable disease within the past 6 months. History (last 6 months) of abnormal heart rhythms, tachycardia and 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. Inability to provide a blood sample to be used to assess nicotine metabolite ratio. Psychiatric Exclusion Criteria (as determined by self report & MINI) Current diagnosis of major depression. Persons with a history of major depression, if stable for 6 months or longer, are eligible, provided they are not excluded based on medications (below). Any suicide risk score on MINI or self-reported suicide attempt on telephone screen. Current or past hypomanic/manic episode. History or current diagnosis of Post Traumatic Stress Disorder (PTSD). History or current diagnosis of psychotic disorder, bipolar disorder, schizophrenia. Medication Exclusion Criteria Current use or recent discontinuation (within the last 14-days) of: Smoking cessation medication (e.g. Zyban, Wellbutrin, Wellbutrin SR, Chantix); NOTE: Once participants are found eligible for the study, they are instructed to use the smoking cessation medication provided to them by the study staff. If a subject reports an isolated (non-daily) instance of using a non-study smoking cessation medication, the study physician and PI will evaluate the situation and determine if it is safe for the subject to continue participation. Anti-psychotic medications. Certain medications used to treat depression, including Wellbutrin, Monoamine Oxidase Inhibitors (MAOIs), and tricyclic antidepressants. Prescription stimulants (e.g. Provigil, Ritalin, Adderall). Current use of: Nicotine replacement therapy (NRT); NOTE: Once participants are found eligible for the study, they are told they should only use the NRT provided to them by the study staff. If a subject reports an isolated (non-daily) instance of NRT use during the study, they may be permitted to continue. Tagamet (cimetidine). Heart medications such as digoxin, quinidine, nitroglycerin; use of these medications may result in ineligibility and will therefore be evaluated on a case-by-case basis by the Study Physician. Anti-coagulants (e.g., Coumadin, Warfarin). Daily use of: Opiate-containing medications for chronic pain; if a participant reports taking an opiate-containing medication every day for the 14 days prior to the telephone screen and/or Intake Session, the participant will be ineligible. Rescue Inhalers (e.g. albuterol, proventil, ventolin, or maxair) General Exclusion Any medical condition, illness, disorder or concomitant medication that could compromise participant safety or treatment, as determined by the Principal Investigator and/or Study Physician. Inability to provide informed consent or complete any of the study tasks as determined by the Principal Investigator and/or Study Physician.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (Slow Metabolizers)<br>Subjects in this arm are those identified as slow metabolizers of nicotine (based on their NMR) and will take placebo pills daily for twelve weeks & wear a placebo patch daily for eleven weeks. The placebo pill will look identical to the active varenicline tablets; however, they will not contain any active medication. Subjects will follow the same drug regimen as those in the active varenicline arm. The placebo patch will look identical to the active transdermal nicotine patches; however, they do not contain actual nicotine. Subjects will follow the same regimen as those in the active transdermal nicotine arm. All subjects in this arm will receive smoking cessation counseling during their sessions. | Drug: Placebo<br>* Day 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally Week 1 - 6: 21mg placebo patch Week 7 - 8: 14mg placebo patch Week 9 - 11: 7mg placebo patch<br>* Other names: Placebo patches;|
| Active Comparator: Varenicline (Slow Metabolizers)<br>Subjects in this arm are those identified as slow metabolizers of nicotine (based on their NMR) and will take active varenicline pills daily for twelve weeks & wear a placebo patch daily for eleven weeks. When taking the active varenicline, subjects will follow the same treatment regimen per the manufacturer. The placebo patch will look identical to the active transdermal nicotine patches; however, they do not contain actual nicotine. Subjects will follow the same regimen as those in the active transdermal nicotine arm. All subjects in this arm will receive smoking cessation counseling during their sessions. | Drug: Varenicline<br>* Day 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally<br>* Other names: Chantix;|
| Active Comparator: Transdermal Nicotine (Slow Metabolizers)<br>Subjects in this arm are those identified as slow metabolizers of nicotine (based on their NMR) and will take placebo pills daily for twelve weeks & will wear an active transdermal nicotine patch daily for eleven weeks. The placebo pill will look identical to the active varenicline tablets; however, they will not contain any active medication. Subjects will follow the same drug regimen as those in the active varenicline arm. When wearing the active transdermal nicotine, subjects will follow the same treatment regimen per the manufacturer. All subjects in this arm will receive smoking cessation counseling during their sessions. | Drug: Transdermal Nicotine<br>* Week 1-6: 21mg nicotine patch Week 7-8: 14mg nicotine patch Week 9-11: 7mg nicotine patch<br>* Other names: Nicotine Patch;|
| Placebo Comparator: Placebo (Normal Metabolizers)<br>Subjects in this arm are those identified as normal metabolizers of nicotine (based on their NMR) and will take placebo pills daily for twelve weeks & wear a placebo patch daily for eleven weeks. The placebo pill will look identical to the active varenicline tablets; however, they will not contain any active medication. Subjects will follow the same drug regimen as those in the active varenicline arm. The placebo patch will look identical to the active transdermal nicotine patches; however, they do not contain actual nicotine. Subjects will follow the same regimen as those in the active transdermal nicotine arm. All subjects in this arm will receive smoking cessation counseling during their sessions. | Drug: Placebo<br>* Day 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally Week 1 - 6: 21mg placebo patch Week 7 - 8: 14mg placebo patch Week 9 - 11: 7mg placebo patch<br>* Other names: Placebo patches;|
| Active Comparator: Varenicline (Normal Metabolizers)<br>Subjects in this arm are those identified as normal metabolizers of nicotine (based on their NMR) and will take active varenicline pills daily for twelve weeks & wear a placebo patch daily for eleven weeks. When taking the active varenicline, subjects will follow the same treatment regimen per the manufacturer. The placebo patch will look identical to the active transdermal nicotine patches; however, they do not contain actual nicotine. Subjects will follow the same regimen as those in the active transdermal nicotine arm. All subjects in this arm will receive smoking cessation counseling during their sessions. | Drug: Varenicline<br>* Day 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally<br>* Other names: Chantix;|
| Active Comparator: Transdermal Nicotine (Normal Metabolizers)<br>Subjects in this arm are those identified as normal metabolizers of nicotine (based on their NMR) and will take placebo pills daily for twelve weeks & will wear an active transdermal nicotine patch daily for eleven weeks. The placebo pill will look identical to the active varenicline tablets; however, they will not contain any active medication. Subjects will follow the same drug regimen as those in the active varenicline arm. When wearing the active transdermal nicotine, subjects will follow the same treatment regimen per the manufacturer. All subjects in this arm will receive smoking cessation counseling during their sessions. | Drug: Transdermal Nicotine<br>* Week 1-6: 21mg nicotine patch Week 7-8: 14mg nicotine patch Week 9-11: 7mg nicotine patch<br>* Other names: Nicotine Patch;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 7-day Point Prevalence Quit Rate at End-of-Treatment (EOT) | The percentage of ITT subjects who were verified as abstinent. Abstinence was defined as no self-reported smoking (not even a puff) for at least 7 days before the telephone assessment, with in-person verification for those self-reporting abstinence. In-person verification consisted of breath carbon monoxide analysis, with a reading of 8 parts-per-million or less confirming abstinence. Subjects who were lost to follow-up were considered smokers. | Week 11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 7-day Point Prevalence Quit Rate at 6-month Follow up Survey | The percentage of ITT subjects who were verified as abstinent at the 6-month follow up survey. Abstinence was defined as no self-reported smoking (not even a puff) for at least 7 days before the telephone assessment, with in-person verification for those self-reporting abstinence. In-person verification consisted of breath carbon monoxide analysis, with a reading of 8 parts-per-million or less confirming abstinence. Subjects who were lost to follow-up were considered smokers. | Week 24 | 
| Total Side-Effect Severity Index at Pre-Quit | The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers). Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects. | Pre-Quit (Week -1/Baseline) | 
| Total Side-Effect Severity Index at Target Quit Date | The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers). Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects. | Target Quit Date (Week 0) | 
| Total Side-Effect Severity Index at Week 1 | The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers). Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects. | Week 1 | 
| Total Side-Effect Severity Index at Week 4 | The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers). Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects. | Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tobacco, Smoking, Varenicline, Nicotine Patch