A Comparative Effectiveness & Long Term Health Study in Wisconsin Smokers

Study Overview
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Brief Summary
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The overall purpose of this research is two-fold. First, the two smoking cessation medication treatments with the strongest evidence of effectiveness have never been directly compared. This research will determine how these two treatments compare in effectiveness in a head-to-head trial, and which types of smokers benefit most from each. Second, much of the data on smoking and health come from studies from many years ago. Today's smokers differ from earlier smokers in many ways that could influence the impact of smoking on health (e.g., weight, sex, diet, socio-economic status); the proposed work will determine how smoking cessation affects cardiovascular and pulmonary health in today's smokers.

Detailed Description
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The proposed study will recruit and treat a large sample of contemporary smokers and former smokers at an age of increasing health risk, to achieve the following over-arching aims that are important to the NHLBI mission: Specific Aim 1: Produce important new data on how to treat smoking optimally by conducting an open label comparative effectiveness trial (CET) that for the first time directly contrasts the two smoking cessation pharmacotherapies with the strongest extant evidence of efficacy: combination NRT and varenicline. Specific Aim 2: Determine the impact of smoking cessation on biomarkers and health risk factors, especially those relevant to CVD, in today's smokers, which will elucidate the mechanisms via which cessation benefits health. Specific Aim 3: Identify which individuals are at greatest risk for exacerbation of biomarkers or risk factor status due to continued smoking, and who will benefit most from cessation. This will help identify individuals who are most in need of cessation intervention. While all smokers need to quit, this evidence could ultimately be used to help focus treatment and motivate smokers and clinicians to intervene more intensively with patients at greatest risk. Two secondary aims are to use the results of Primary Aim 1 to develop a treatment assignment algorithm for the optimal treatment of today's smokers and to use the results from Primary Aim 2 to determine the relation of health biomarkers to clinically meaningful disease outcomes such as CVD events. We will re-recruit as many smoking and non smoking participants from our past longitudinal cohort study(Wisconsin Smokers' Health study; NCT01122238) in 2004. We will then recruit additional smokers to participate in the comparative effectiveness trial and join the longitudinal cohort.. All participants who enroll will complete questionnaires about their demographics, smoking history, withdrawal symptoms, affect, alcohol use, stressors, medication usage and diet. They will also complete a structured clinical interview to assess mental health. They will provide blood samples for testing of various markers of cardiovascular disease and risk as well as for genetics testing. They will all have carotid ultrasounds, pulmonary function tests, arterial tonometry assessments, and 12-lead ECGs. Participants in Madison will also have a treadmill stress test. Participants will wear a pedometer for 1 week and record the daily number of steps. Participants will provide permission for staff to review their medical charts to assess smoking-relevant diagnoses and treatment. These assessments will occur at baseline and again 3 years later. A smaller subset of these assessments will also be conducted 1 year after enrollment. Participants will also complete brief phone assessments at 6-month intervals up to the 3-year visit. Interested and eligible smoking participants from the original cohort study and all newly recruited participants will enroll in a new smoking cessation intervention study. Participants in the cessation treatment study will be randomly assigned to receive the nicotine patch, nicotine patch + nicotine lozenge or varenicline. If the participant from the original cohort study is not eligible to use all study medications but is otherwise eligible for cessation treatment, s/he will be assigned to a non-randomized treatment arm and will receive nicotine patch (if appropriate). All cessation participants will receive 6 individual counseling sessions.

Official Title
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A Comparative Effectiveness & Long Term Health Study in Wisconsin Smokers

Conditions
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Smoking Cessation, Smoking, Nicotine Dependence

Intervention / Treatment
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* Drug: Varenicline
* Drug: Nicotine lozenge
* Drug: Nicotine Patch


Participation Criteria
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Eligibility Criteria
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We are only recruiting by invitation only (to members of our past cohort). We will open up enrollment to the public in the Madison, WI and Milwaukee WI areas at the end of 2012. Inclusion Criteria: a. To be eligible for the Comparative effectiveness trial, participants must: smoke 5 or more cigarettes per day, desire to quit smoking but not be currently engaged in cessation treatment, be medically eligible to use either combination NRT or varenicline, have reliable phone access, if female, must not be pregnant and must be willing to use an acceptable birth control method. Exclusion Criteria: There are no exclusion criteria for participating in the main health outcomes study, other than being unwilling to complete study assessments. All smoking participants from new and original cohorts will be excluded from the cessation trial for the following reasons: end-stage renal disease with hemodialysis; prior suicide attempts within the last 5 years or current suicidal ideation; diagnosis of and/or treatment for schizophrenia; other psychotic disorders or bipolar disorder within the last 10 years; current PHQ-9 score indicative of moderately severe depression; severe untreated hypertension >200/100 mmHg; currently taking Wellbutrin, Zyban or bupropion; hospitalized for a stroke, heart attack, congestive heart failure or diabetes within the last year; used pipe tobacco, cigars, snuff or chew more than twice in the past week. It should be noted that if any incidental findings appear in any of the cardiology tests (e.g., ultrasound, tonometry, ECG, or exercise stress test; see forms in Supplemental Information section of application), the study cardiologist (Dr. Stein or his designee) will be assign the participant to the non-randomized treatment arm and they will be given the nicotine patch and the same counseling intervention as CET participants. They will not be included in the CET analyses. This will be done to properly address the cardiovascular risk warning from the FDA regarding varenicline (Chantix).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Effectiveness of Nicotine patch only<br> | Drug: Nicotine Patch<br>* Participants will receive 12 weeks NRT. Patch dosing will be 8 weeks of 21 mg, then 2 weeks of 14 mg, then 2 weeks of 7 mg (those smoking 5-10 cigs/day will receive reduced patch dosing). Medication use will start on the morning of their assigned quit day. They will be urged to use 1 patch/day, unless it produces adverse effects.<br>|
| Experimental: Effectiveness of Combination NRT<br> | Drug: Nicotine lozenge<br>* Participants will receive 12 weeks NRT. Participants will be given 2 mg or 4 mg lozenges based on morning smoking latency, and will be given package insert use instructions. Medication use will start on the morning of their assigned quit day. They will be urged to use at least 5 pieces/day, unless this amount produces adverse effects.<br>Drug: Nicotine Patch<br>* Participants will receive 12 weeks NRT. Patch dosing will be 8 weeks of 21 mg, then 2 weeks of 14 mg, then 2 weeks of 7 mg (those smoking 5-10 cigs/day will receive reduced patch dosing). Medication use will start on the morning of their assigned quit day. They will be urged to use 1 patch/day, unless it produces adverse effects.<br>|
| Experimental: Effectiveness of Varenicline [Chantix]<br> | Drug: Varenicline<br>* Participants will receive 12 weeks of pharmacotherapy during the post-quit period plus an additional 7 day pre-quit run-in. Participants will be asked to take a 0.5 mg pill once a day for the first 3 days and then increase to a 0.5 mg pill twice a day (8 hours apart) for 4 days. On the 8th day, their target quit date, they will increase to their target maintenance dose of a 1 mg pill twice daily. If participants report significant adverse events such as nausea, a dose reduction to two 0.5 mg doses per day will be advised.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemically-confirmed 7-Day Point-Prevalence Abstinence at 26 Weeks | Self-reported total abstinence from any tobacco use (even a single puff) for the seven days preceding the target follow-up day, confirmed with an exhaled carbon monoxide reading of <10 ppm.. | Assessed 26 weeks after the target quit day. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Days to Relapse | The number of days to relapse is defined as the number of days from the target quit day until the first of seven consecutive days of smoking. | Assessed from the target quit day through 26 weeks. | 
| Number of Participants With Initial Cessation in the First 7 Days Post-quit | Defined as at least 1 day of abstinence during the first 7 days after the target quit day. | Assessed for the first seven days after the target quit date. | 
| The Effects of Quitting Smoking vs. Continued Smoking on Change in Carotid Intima-media Thickness (CIMT). | Change in carotid intima-media thickness (CIMT) from Baseline to Year 3 as a function of smoking status (abstinent versus smoking) at Year 3. Change is calculated as Baseline CIMT score minus Year 3 CIMT score. CIMT score is thickness of the carotid intima-media in millimeters (mm). Lower CIMT values indicate a better outcome. | Assessed at Baseline and Year 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Smoking, Smoking Cessation, Nicotine