Trial of Cytisine in Adult Smokers

Study Overview
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Brief Summary
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This placebo-controlled Phase 2b trial is being conducted at sites within the United States (US) to evaluate the effectiveness cytisine dosage (1.5 mg, 3.0 mg) and administration schedule (commercial titration versus simplified 3 times daily [TID] schedule) within a 25-day treatment period.

Official Title
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A Multicenter, Double-blind, Randomized, Placebo-controlled Phase 2b Trial of Cytisine in Adult Smokers

Conditions
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Smoking Cessation

Intervention / Treatment
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* Drug: Cytisine
* Drug: Placebo Comparator
* Behavioral: Behavioral support


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, age ≥ 18 years. Current daily cigarette smokers (averaging ≥ 10 cigarettes per day upon completing a 7-day screening diary) and who intend to quit smoking. Expired air carbon monoxide (CO) ≥ 10 parts per million (ppm). Failed at least one previous attempt to stop smoking with or without therapeutic support. Willing to initiate study treatment on the day after randomization and set a quit date that is 5-7 days after starting treatment. Willing to actively participate in the study's smoking cessation behavioral support provided throughout the study. Able to fully understand all study requirements, willing to participate, comply with dosing schedule, and sign the Informed Consent Form. Exclusion Criteria: Known hypersensitivity to cytisine or any of the excipients. Positive urinary drugs of abuse screen, determined within 28 days before the first dose of cytisine. Clinically significant abnormal serum chemistry or hematology values within 28 days of randomization (i.e. requiring treatment). Clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined after minimum of 5 minutes in supine position within 28 days of randomization (i.e. requiring treatment or further assessment). Body mass index (BMI) classification for being underweight (< 18.5 kg/m^2) or having ≥ Class 2 obesity (≥ 35 kg/m^2). Recent history (within 3 months) of acute myocardial infarction, unstable angina, stroke, cerebrovascular incident or hospitalization for congestive heart failure. Current uncontrolled hypertension (blood pressure ≥ 160/100 mmHg). Documented diagnosis of schizophrenia or bipolar psychiatric illness; currently psychotic; having suicidal ideation (Suicide Behaviors Questionnaire-Revised [SBQ-R] score ≥ 7); or current symptoms of moderate to severe depression (Hospital Anxiety and Depression Scale [HADS] score ≥ 11). Renal impairment defined as a creatinine clearance (CrCl) < 60 mL/min (estimated with the Cockroft-Gault equation) or hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 times the upper limit of normal (ULN). Women who are pregnant or breast-feeding. Male or Female subjects of child bearing potential who do not agree to use acceptable methods of birth control during the study treatment period. Participation in a clinical study with an investigational drug within 4 weeks of randomization. Treatment with other smoking cessation medications (bupropion, varenicline, nortriptyline, or any nicotine replacement therapy [NRT]) within 4 weeks of randomization or planned use of these other smoking cessation medications during the study. Use within 2 weeks of randomization or planned use during the study of non-cigarette nicotine products (e-cigarettes, pipe tobacco, cigars, snuff, chewing tobacco, hookah) or marijuana vaping or smoking. Any other reason that the investigator views the subject should not participate or would be unable to fulfill the requirements for the study.

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.5 mg Cytisine, Commercial Schedule<br>1.5 mg cytisine dose using the commercial 25-day titration schedule + behavioral support | Drug: Cytisine<br>* film coated tablet containing 1.5 mg cytisine in a single tablet<br>Behavioral: Behavioral support<br>* 12 behavioral support sessions by a qualified staff member plus supportive literature and online resources<br>|
| Experimental: 3.0 mg Cytisine, Commercial Schedule<br>3.0 mg cytisine dose using the commercial 25-day titration schedule + behavioral support | Drug: Cytisine<br>* film coated tablet containing 1.5 mg cytisine in a single tablet<br>Behavioral: Behavioral support<br>* 12 behavioral support sessions by a qualified staff member plus supportive literature and online resources<br>|
| Placebo Comparator: Placebo, Commercial Schedule<br>Placebo tablets using the commercial 25-day titration schedule + behavioral support | Drug: Placebo Comparator<br>* 1.5 mg cellulose powder to match final weight of the cytisine tablet<br>Behavioral: Behavioral support<br>* 12 behavioral support sessions by a qualified staff member plus supportive literature and online resources<br>|
| Experimental: 1.5 mg Cytisine, TID Schedule<br>1.5 mg cytisine dose for 25 days using a simplified 3 times daily (TID) schedule + behavioral support | Drug: Cytisine<br>* film coated tablet containing 1.5 mg cytisine in a single tablet<br>Behavioral: Behavioral support<br>* 12 behavioral support sessions by a qualified staff member plus supportive literature and online resources<br>|
| Experimental: 3.0 mg Cytisine, TID Schedule<br>3.0 mg cytisine dose for 25 days using a simplified TID schedule + behavioral support | Drug: Cytisine<br>* film coated tablet containing 1.5 mg cytisine in a single tablet<br>Behavioral: Behavioral support<br>* 12 behavioral support sessions by a qualified staff member plus supportive literature and online resources<br>|
| Placebo Comparator: Placebo, TID Schedule<br>Placebo tablets for 25 days using a simplified TID schedule + behavioral support | Drug: Placebo Comparator<br>* 1.5 mg cellulose powder to match final weight of the cytisine tablet<br>Behavioral: Behavioral support<br>* 12 behavioral support sessions by a qualified staff member plus supportive literature and online resources<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Efficacy Analysis of Primary Outcome Measure: Percentage of Expected Cigarettes Smoked Per Participant During Study Treatment | The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. The percentage of expected cigarettes smoked was computed as Y = (100 x N) / (T x R) where N represents total number of cigarettes smoked each day over the treatment period from Day 1 to Day 25; T represents number of post-randomization days where number of cigarettes smoked is recorded; and R represents the average number of cigarettes smoked daily over the 7-day screening period as baseline. T*R represents the total number of cigarettes that would have been smoked without intervention over the number of recorded days. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID). | Day 1 through Day 25 | 
| Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, Commercial Schedule | The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. (See Outcome Measure 1 description for details.) The sensitivity analysis of the primary outcome measure was only performed if results of Statistical Analysis 5 for Outcome Measure 1 demonstrated the placebo treatment arms (commercial and TID) were not significantly different, and so could be pooled. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID). | Day 1 through Day 25 | 
| Sensitivity Analysis of Primary Outcome Measure: Analysis for Percentage of Expected Cigarettes Smoked Versus Pooled Placebo Arms, TID Schedule | The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. (See Outcome Measure 1 description for details.) The sensitivity analysis of the primary outcome measure was only performed if results of Statistical Analysis 5 for Outcome Measure 1 demonstrated the placebo treatment arms (commercial and TID) were not significantly different, and so could be pooled. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID). | Day 1 through Day 25 |