A Single Dose-escalation Study of Cytisine in Adult Smokers

Study Overview
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Brief Summary
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The objectives of this study are: To assess the tolerability and safety of cytisine as a single oral dose. To define the Cmax levels associated to the occurrence of dose-limiting adverse events.

Official Title
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A Phase I, Double-blind, Randomized, Placebo-controlled, Single Dose-escalation Study to Evaluate the Tolerability and Safety of Cytisine in Adult Smokers

Conditions
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Smoking Cessation

Intervention / Treatment
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* Drug: cytisine
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet ALL of the following criteria to be eligible for inclusion into the study: Free written informed consent prior to any procedure required by the study. Male or female subjects, age ≥18 years, at the time of signing the informed consent. Current daily cigarette smokers (averaging at least 10 cigarettes per day in the past 30 days). Expired air carbon monoxide (CO) ≥10 ppm. Able to swallow multiple tablets at one time. Able to fully understand, comply with all study requirements. Exclusion Criteria: Subjects meeting ANY of the following exclusion criteria will NOT be eligible for inclusion into the study at screening. Known hypersensitivity to cytisine or any of the excipients. Known severe hypersensitivity to any other drug. Positive urinary drugs of abuse screen, determined within 28 days before cytisine/placebo dosing. Positive ethanol breath test. Clinically significant abnormal serum chemistry, hematology, coagulation or urinalysis values within 28 days of randomization (i.e. requiring treatment or monitoring). Clinically significant abnormalities in 12-lead echocardiogram (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/m2) or having ≥Class 2 obesity (≥35 kg/m2). History of acute myocardial infarction, unstable angina, stroke, cerebrovascular incident, cardiac arrhythmia, or hospitalization for congestive heart failure. Blood pressure ≥160/100 mmHg, measured on the dominant arm, after at least 3 minutes in supine position. Creatinine clearance (CrCl) <80 mL/min (estimated with the Cockroft-Gault equation). Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 x the upper limit of normal (ULN). Any inability to comply with study restrictions (See Section 9) Any inability or difficulty in fasting. Difficulty in donating blood on either arm. If woman of childbearing potential, positive result in serum beta-human chorionic gonadotropin (hCG) pregnancy test. Women who are breast-feeding. Subjects who do not agree to use acceptable methods of birth control during the study (See Section 9.4). Participation in a clinical study with an investigational drug within the previous 2 months. Participation in more than 2 clinical trials within the previous 12 months. Any other reason that the investigator views the subject should not participate or would be unable to fulfill the requirements for the study. Subjects meeting ANY of the following exclusion criteria will NOT be eligible for inclusion into the study at admission to each cohort. Any recent disease or condition or treatment that, according to the Investigator, would put the subject at undue risk due to study participation. Positive urinary drugs of abuse screen. Positive ethanol breath test. If female of childbearing potential, positive result in urine beta-hCG pregnancy test. 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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Accepts Healthy Volunteers

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 |
| --- | --- |
| Experimental: Cohort 1: Cytisine 6.0 mg<br>Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: cytisine<br>* cytisine film-coated oral tablet<br>* Other names: cytisinicline;|
| Placebo Comparator: Cohort 1: Placebo<br>Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: placebo<br>* matching placebo oral tablet<br>|
| Experimental: Cohort 2: Cytisine 9.0 mg<br>Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: cytisine<br>* cytisine film-coated oral tablet<br>* Other names: cytisinicline;|
| Placebo Comparator: Cohort 2: Placebo<br>Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: placebo<br>* matching placebo oral tablet<br>|
| Experimental: Cohort 3: Cytisine 12.0 mg<br>Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: cytisine<br>* cytisine film-coated oral tablet<br>* Other names: cytisinicline;|
| Placebo Comparator: Cohort 3: Placebo<br>Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: placebo<br>* matching placebo oral tablet<br>|
| Experimental: Cohort 4: Cytisine 15.0 mg<br>Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: cytisine<br>* cytisine film-coated oral tablet<br>* Other names: cytisinicline;|
| Placebo Comparator: Cohort 4: Placebo<br>Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: placebo<br>* matching placebo oral tablet<br>|
| Experimental: Cohort 5: Cytisine 18.0 mg<br>Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: cytisine<br>* cytisine film-coated oral tablet<br>* Other names: cytisinicline;|
| Placebo Comparator: Cohort 5: Placebo<br>Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: placebo<br>* matching placebo oral tablet<br>|
| Experimental: Cohort 6: Cytisine 21.0 mg<br>Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: cytisine<br>* cytisine film-coated oral tablet<br>* Other names: cytisinicline;|
| Placebo Comparator: Cohort 6: Placebo<br>Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: placebo<br>* matching placebo oral tablet<br>|
| Experimental: Cohort 7: Cytisine 24.0 mg<br>Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: cytisine<br>* cytisine film-coated oral tablet<br>* Other names: cytisinicline;|
| Placebo Comparator: Cohort 7: Placebo<br>Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: placebo<br>* matching placebo oral tablet<br>|
| Experimental: Cohort 8: Cytisine 27.0 mg<br>Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: cytisine<br>* cytisine film-coated oral tablet<br>* Other names: cytisinicline;|
| Placebo Comparator: Cohort 8: Placebo<br>Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: placebo<br>* matching placebo oral tablet<br>|
| Experimental: Cohort 9: Cytisine 30.0 mg<br>Cytisine will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: cytisine<br>* cytisine film-coated oral tablet<br>* Other names: cytisinicline;|
| Placebo Comparator: Cohort 9: Placebo<br>Placebo will be administered in the morning, orally, with 240 mL of water, after fasting overnight for at least 10 hours. | Drug: placebo<br>* matching placebo oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Study Discontinuation | An adverse event (AE) is defined as any untoward medical occurrence that does not necessarily have to have a causal relationship with the treatment. A serious AE is any untoward medical occurrence or effect, that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; or is an important medical event which requires medical intervention to prevent one of the above. Treatment emergent events are those that occurred after the first dose of study drug. | From first dose of study drug through Day 6 | 
| Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) |  | Day 1: Pre-dose (within 30 minutes prior to dosing), 15, 30, 40, 50 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, and 3 hours (+/-2 minutes) post-dose | 
| Pharmacokinetics: Time to Occurrence of Cmax (Tmax) |  | Day 1: Pre-dose (within 30 minutes prior to dosing), 15, 30, 40, 50 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, and 3 hours (+/-2 minutes) post-dose |