A Study of Varenicline for Prevention of Relapse to Smoking in Patients With Schizophrenia or Bipolar Disorder

Study Overview
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Brief Summary
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Varenicline (Chantix) is a smoking cessation treatment that was approved in 2006 by the FDA for treatment of nicotine dependence and may be particularly beneficial in smokers with schizophrenia or bipolar disorder. Early experience with varenicline indicates that it will be effective for smoking cessation in schizophrenia and in addition, has the potential to be therapeutic for cognitive dysfunction in this population. In addition, more data is needed to evaluate the safety, tolerability and effectiveness of Varenicline in people with bipolar disorder. To assess this possibility, we will evaluate the safety and efficacy of 12 months of varenicline in schizophrenia or bipolar disorder patients who are able to quit smoking in the short term with this treatment. To do so, we will enroll 324 smokers with schizophrenia or bipolar disorder from 6 mental health clinics in Massachusetts, New Hampshire, Michigan and Minnesota into an open, 12-week smoking cessation program that includes varenicline added to weekly group cognitive behavioral therapy (CBT). Those who achieve at least 2 weeks of continuous abstinence during the last 2 weeks of the open intervention will be randomized to the relapse prevention phase: a 40-week, double blind, placebo-controlled trial of varenicline at the dose used to quit smoking added to a tapering CBT schedule. Participants will then discontinue study medications and behavioral treatment and enter a 3-month follow up phase.

Detailed Description
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Participants will be moderate to heavy smokers, aged 18-70, who have smoked an average of ≥10 cigarettes/day for the past year and who have not quit during the past year for a period >1 month. During a 12-week open phase smoking cessation program, eligible subjects will be given active varenicline in addition to a 13-session weekly cognitive behavioral therapy program for smoking cessation. Dr. Evins (Principal Investigator) or a co-investigator will meet with subjects individually at Baseline of the Smoking Cessation Program to assess their medical eligibility for varenicline. A chart review will also be conducted by a research physician or psychiatrist. Dr. Evins or another prescribing co-investigator will write a prescription for varenicline for each medically eligible subject. Subjects will receive their study medication at the end of each weekly group meeting. Any subject who experiences a serious side effect to the medication will meet with Dr. Evins or another medical co-investigator individually. Subjects will set quit dates between the fourth and fifth CBT session weeks. Self-reports and exhaled carbon monoxide (CO) levels will be used to assess smoking status. Those subjects who have been abstinent for ≥2 weeks at the end of the 12th session group will be eligible for a 40-week relapse prevention program. After enrolling in the Relapse Prevention Program, subjects will be randomized to receive varenicline or placebos in addition to CBT for relapse prevention. At Week 12 (the week before the end of the Smoking Cessation Program), Dr. Evins or another prescribing co-investigator will write prescriptions for subjects eligible for the randomized Relapse Prevention phase (i.e. successful quitters); these prescriptions will be sent to the Massachusetts General Hospital Research Pharmacy, where they will be filled according to the randomization code that the a research pharmacist will create. When subjects come for the CBT orientation group session of the Relapse Prevention Program (Week 13), they will receive a 1-month supply of varenicline or placebo pill. During this randomized Relapse Prevention phase, medication compliance will be assessed at every group meeting by pill-count. Subjects will be asked about medication compliance and side effects at each group by the CBT group leaders and staff. Any subject who experiences a serious side effect to the medication will meet with Dr. Evins or another medical co-investigator individually. In addition, Dr. Evins or a medical co-investigator will review the adverse events forms for each subject every week. Again, self-report and CO levels will be used to monitor smoking status. Before and during both the open and randomized relapse prevention phases, subjects will be periodically assessed for cognitive performance, clinical characteristics, and adverse events in order to evaluate effects of withdrawal, predictors of cessation and relapse, and medication side effects. Following the completion of the 40-week relapse prevention phase, 3 follow-up assessments will be performed over a 3-month period to evaluate smoking status, cognitive functioning, and clinical effects.

Official Title
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Extended Duration Pharmacotherapy for Prevention of Relapse to Smoking

Conditions
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Schizophrenia, Schizoaffective Disorder, Bipolar Disorder, Smoking

Intervention / Treatment
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* Drug: Varenicline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women and men aged 18-70 DSM-IV diagnosis of schizophrenia, schizoaffective disorder or bipolar disorder by diagnostic interview and chart review Smoke at least 10 cigarettes per day Clinically stable, on a stable dose of antipsychotic (schizophrenia) or mood stabilizer (bipolar) medication for at least 1 month No current active suicidal ideation Expired air carbon monoxide (CO) concentration >9 ppm Willing to take study medications and set a quit date within 2-3 weeks of beginning treatment and be willing to participate in the relapse prevention and follow-up portions of the study Women of childbearing potential must have a negative urine pregnancy test at baseline and agree to use an approved form of contraception during the study. Exclusion Criteria: DSM-IV diagnosis of dementia, neurodegenerative disease, or other organic mental disorder Substance use disorder other than nicotine or caffeine in the last 6 months Major depressive disorder within the last 6 months Serious unstable medical illness including, cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease such that hospitalization for treatment of that illness is likely within the next 2 months Life-threatening arrhythmia or cerebro-vascular event within 6 months, cardiovascular event within 2 months or uncontrolled hypertension History of multiple head injuries with neurological sequelae, a single severe head injury with lasting neurological sequelae, or current CNS tumor Liver function tests elevated over twice normal Renal insufficiency with estimated creatinine clearance <40 ml/min Plan to continue use of tobacco products othe than cigarettes (e.g., cigar, pipe) Use of an investigational medication or device in the past 30 days Current suicidal or homicidal ideation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Active Comparator: Randomized Phase: Varenicline<br>Varenicline is a partial agonist at alpha4beta2 nicotinic acetylcholine receptors (nAChRs) and a full agonist at alpha 7 nAChRs that has been shown to be effective for smoking cessation compared with placebo and bupropion, with effects on abstinence rates for up to one year. Varenicline has demonstrated safety when dosed at 1 mg twice per day for up to one year. Because varenicline, at a dose of 1 mg twice per day, may be a more effective treatment for sustained abstinence than bupropion, it was chosen as the medication intervention for this study. | Drug: Varenicline<br>* At each weekly study visit from the baseline visit to study week 11, ALL subjects will receive a one-week supply of varenicline with instructions on how to take the study medication. Titration is as follows: 0.5 mg varenicline per day for 3 days, then 0.5 mg twice per day for 4 days, and then 1 mg twice per day for 11 weeks. In addition, participants who enter the relapse prevention phase and are randomized to the varenicline condition will receive varenicline at the dose used to attain initial abstinence for 40 weeks.<br>* Other names: Chantix;|
| Placebo Comparator: Randomized Phase: Placebo<br> | Drug: Placebo<br>* At each weekly study visit from the baseline visit to study week 11,ALL subjects will receive a one-week supply of varenicline with instructions on how to take the study medication. Titration is as follows: 0.5 mg varenicline per day for 3 days, then 0.5 mg twice per day for 4 days, and then 1 mg twice per day for 11 weeks. In addition, participants who enter the relapse prevention phase and are randomized to the placebo condition will receive placebo pills for 40 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of 7-day Point Prevalence Abstinence at the End of the Relapse Prevention Phase (Study Week 53) in the Extended Duration Pharmacotherapy Group vs. the Placebo Group |  | 76 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Extended Duration Pharmacotherapy When Added to Antipsychotic Medications in Schizophrenia Patients Who Have Recently Quit Smoking as Assessed by the Brief Psychiatric Rating Scale | Brief Psychiatric Rating Scale is a 24 item scale that is designed to assess positive and negative symptoms, and general psychopathology in people with serious mental illness. Each item is rated on a 7-point scale from not present to extremely severe; higher scores in a range of 24 to 168, indicate more severe symptoms Ratings are based on observation and patient report. The validity of the BPRS is generally high when compared with other measures of general psychopathology. It was administered at baseline, study weeks 12, 18, 26, 38, 52 | at week 52 | 
| Effect of Treatment With Varenicline Versus Placebo on Health-related Quality of Life Indices in Recently Abstinent Smokers With Schizophrenia or Bipolar Disorder as Measured by the 12-Item Short Form Health Survey (SF-12) | The 12-Item Short Form Health Survey (SF-12) is a 12-item measure of perceived health status with good reliability, validity and correlation with other health measures. It is scored via a standard algorithm, with higher scores indicating better patient self perception of health, with a mean score of 50 and a standard deviation of 10 in a representative sample of the US population. The score is computed using the scores of the twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health and 100 indicates the highest level of health. This was administered at baseline and end of study. | at week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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schizophrenia, bipolar disorder, varenicline, smoking cessation, relapse prevention, cognitive behavioral therapy