Zonisamide Augmentation of Varenicline Treatment for Smoking Cessation

Study Overview
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Brief Summary
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Randomized trial to evaluate whether zonisamide can enhance varenicline-induced smoking cessation.

Detailed Description
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About 20.6 % of the US population smokes cigarettes. This group includes nicotine dependent smokers who are resistant to current smoking cessation treatments. Varenicline is a smoking cessation medication found in meta-analytic reviews to be superior to other smoking cessation treatments, but 56% of patients who take varenicline do not quit. One strategy to increase quit rates may be to administer a second medication to augment the efficacy of varenicline. The anti-epileptic medication zonisamide is a good candidate for adjunct treatment as it increases dopaminergic tone, normalizes glutamate homeostasis, potentiates Gamma-Aminobutyric Acid (GABA) release. Zonisamide improves sleep and promotes weight loss, two prominent issues not addressed by varenicline. Finally, the PI of this proposal has documented unpleasant changes in the taste of cigarettes and reductions in nicotine withdrawal among smokers receiving zonisamide as part of another clinical trial. The proposed study will explore the efficacy of varenicline + zonisamide for smoking cessation in a controlled, clinical trial. Eligible participants (n=60) will be smokers (>10 cig/day for >1 year) seeking treatment. They will be randomly assigned to receive varenicline + double-blind zonisamide or placebo for a 10-weeks. Participants will visit the clinic weekly to receive medications and smoking cessation counseling and to complete self-report questionnaires. Smoking status will be assessed via weekly urinalysis testing for cotinine (abstinence: <200ng/ml). Cotinine is a sensitive indicator of smoking status with a longer half-life then carbon monoxide (CO) and is more likely to detect low or intermittent smoking. The study hypothesis is that participants who receive the combination zonisamide + varenicline will achieve greater smoking abstinence compared to varenicline alone. The primary outcome measure will be the 4-week rate of biochemically-confirmed continuous smoking abstinence during weeks 7-10. Secondary outcomes will include self-reported rates of smoking, subjective effects of cigarettes, weight change from baseline to week 10, sleep quality, and nicotine withdrawal severity. This study will advance the science and clinical treatment of smoking cessation, and will provide the prerequisite data to develop a larger scale clinical trial evaluation of the combination zonisamide + varenicline for smoking cessation.

Official Title
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Zonisamide Augmentation of Varenicline Treatment for Smoking Cessation

Conditions
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Nicotine Dependence

Intervention / Treatment
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* Drug: zonisamide
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 18 - 65 years old; smoking > 10 cigarettes per day for > 1 year Desire to quit smoking Provide a cotinine positive urine sample Commitment to come to the clinic once a week for the 10-week study duration Exclusion Criteria: Allergy to varenicline or sulfonamide drugs (e.g., trimethoprim/sulfamethoxazole, zonisamide or topiramate); Renal insufficiency (eGFR < 60 mL) Renal tubular acidosis History of nephrolithiasis Unexplained hematuria Transaminase elevations > 3 times the Upper Limit of Normal (ULN) BMI < 19 Diabetes mellitus Respiratory insufficiency Asthma requiring medication Heart failure Chronic diarrhea predisposing to acidosis Glaucoma, family history of glaucoma, one-sided blindness History of seizures or use of anticonvulsant medications (not including sedatives) HIV infection on HAART medication (or CD4 T cell count < 200 /mL) History of serious psychiatric disorder: psychosis, dementia, depression requiring medication in last 6 months, suicidal or homicidal ideation, evidence of violent behavior in the last 6 months. Recent use (last 30 days) of bupropion, nortriptyline, or clonidine Recent use (last 30 days) of Nicotine Replacement Products that would interfere with urine cotinine testing Use of tobacco products other than cigarettes For female participants, pregnancy, lactation, or refusal to use an effective method of contraception.

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 |
| --- | --- |
| Experimental: zonisamide<br>participants will receive zonisamide capsules (up to 300 mg) to take once a day. | Drug: zonisamide<br>* In addition to zonisamide vs placebo treatment, varenicline tablets will be dispensed with specific instructions to take at the recommended doses for smoking cessation Participants will receive brief smoking cessation counseling and referral to a quitline<br>* Other names: zonegran®;|
| Placebo Comparator: Placebo<br>Participants will receive placebo capsules to take once a day | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Participants Abstinent From Smoking During Study Weeks 7-10 | Biochemically-verified continuous smoking abstinence during weeks 7-10 of the study. | weeks 7-10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nicotine Withdrawal Symptom Severity | Total Score from the Minnesota Nicotine Withdrawal Questionnaire (MNWQ), assessed at weekly visits. The MNWQ is a commonly-used 12-item Likert scale self-report measure of nicotine symptoms. Individual symptoms were rated from 0 (none) to 4 (severe) for each item and the Total score range was 0 - 48. Ratings were collected once weekly during study visits. | Past 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tobacco, smoking cessation, nicotine, cigarettes, nicotine withdrawal