Nicotine Dependence
Conditions
Keywords
tobacco, smoking cessation, nicotine, cigarettes, nicotine withdrawal
Brief summary
Randomized trial to evaluate whether zonisamide can enhance varenicline-induced smoking cessation.
Detailed description
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.
Interventions
DRUGzonisamide
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
DRUGplacebo
Sponsors
National Institute on Drug Abuse (NIDA)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Participants Abstinent From Smoking During Study Weeks 7-10 | weeks 7-10 | Biochemically-verified continuous smoking abstinence during weeks 7-10 of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nicotine Withdrawal Symptom Severity | Past 24 hours | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zonisamide Participants receive zonisamide + varenicline for smoking cessation | 34 |
| Placebo Participants receive placebo + varenicline for smoking cessation | 40 |
| Total | 74 |
Baseline characteristics
| Characteristic | Zonisamide | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 45.3 years STANDARD_DEVIATION 9.8 | 45.6 years STANDARD_DEVIATION 9.8 | 45.9 years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 73 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants | 50 Participants | 27 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 24 Participants | 13 Participants |
| Region of Enrollment United States | 34 participants | 74 participants | 40 participants |
| Sex: Female, Male Female | 8 Participants | 21 Participants | 13 Participants |
| Sex: Female, Male Male | 26 Participants | 53 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 40 |
| other Total, other adverse events | 28 / 34 | 28 / 40 |
| serious Total, serious adverse events | 0 / 34 | 0 / 40 |
Outcome results
Primary
Percent Participants Abstinent From Smoking During Study Weeks 7-10
Biochemically-verified continuous smoking abstinence during weeks 7-10 of the study.
Time frame: weeks 7-10
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zonisamide | Percent Participants Abstinent From Smoking During Study Weeks 7-10 | 5 Participants |
| Placebo | Percent Participants Abstinent From Smoking During Study Weeks 7-10 | 6 Participants |
Secondary
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.
Time frame: Past 24 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 1 (pre-quit day) | 5.3 units on a scale | — |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Screening Visit | 4.6 units on a scale | Standard Deviation 6 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Admission Visit | 5.1 units on a scale | Standard Deviation 5.3 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 2 (pre-quit day) | 4.8 units on a scale | Standard Deviation 6 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 3 (target quit day) | 4.7 units on a scale | Standard Deviation 5.4 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 4 | 3.8 units on a scale | Standard Deviation 5.1 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 5 | 3.8 units on a scale | Standard Deviation 3.7 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 6 | 3.4 units on a scale | Standard Deviation 4.3 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 7 | 3.8 units on a scale | Standard Deviation 4.7 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 8 | 2.7 units on a scale | Standard Deviation 3.3 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 9 | 3.1 units on a scale | Standard Deviation 3 |
| Zonisamide | Nicotine Withdrawal Symptom Severity | Week 10 | 2.6 units on a scale | Standard Deviation 4.9 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 9 | 4.1 units on a scale | Standard Deviation 4.4 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 5 | 4.7 units on a scale | Standard Deviation 5.3 |
| Placebo | Nicotine Withdrawal Symptom Severity | Screening Visit | 5.6 units on a scale | Standard Deviation 5.5 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 8 | 4.0 units on a scale | Standard Deviation 4.5 |
| Placebo | Nicotine Withdrawal Symptom Severity | Admission Visit | 7.0 units on a scale | Standard Deviation 6.3 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 1 (pre-quit day) | 6.2 units on a scale | Standard Deviation 7.3 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 6 | 4.0 units on a scale | Standard Deviation 5 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 2 (pre-quit day) | 5.7 units on a scale | Standard Deviation 6.3 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 10 | 4.8 units on a scale | Standard Deviation 5.8 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 3 (target quit day) | 6.6 units on a scale | Standard Deviation 7 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 7 | 4.4 units on a scale | Standard Deviation 4.7 |
| Placebo | Nicotine Withdrawal Symptom Severity | Week 4 | 5.9 units on a scale | Standard Deviation 7 |