Study to Evaluate Effect of Food on Bioavailability of Single 3 mg Tablet and Pharmacokinetics (PK) of Multiple 3 mg Doses in Healthy Adult Smokers

Study Overview
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Brief Summary
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To assess the effect of food on the bioavailability of 3 mg cytisinicline following single-dose administration, and to evaluate the PK profile of 3 mg cytisinicline TID following multiple days of administration during Days 5-8.

Official Title
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A Phase 1 Study to Investigate the Effect of Food on the Bioavailability of a Single Cytisinicline 3 mg Tablet and Evaluation of the Pharmacokinetics of Multiple 3 mg Doses (Three Times Daily) in Healthy Adult Smokers

Conditions
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Smoking Cessation

Intervention / Treatment
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* Drug: Cytisinicline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Free written informed consent prior to any procedure required by the study. Willingness to accept and comply with all study procedures and restrictions. Male or female subject ≥ 18 years, at the date of signing the informed consent. Regular moderate combustible cigarette smokers (self-reported average of at least 10 cigarettes per day). Body mass index (BMI) of 18.0 to 30.0 kg/m^2, inclusive. Healthy subject, based on medical history, physical examination, vital signs, ECG and clinical laboratory tests. Negative test results for anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab), Hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus antibodies (anti-HCVAb). A female subject is eligible if she also meets one of the following criteria: is of non-childbearing potential (underwent a permanent sterilization method [eg, hysterectomy, bilateral salpingectomy or bilateral oophorectomy], is clinically diagnosed infertile, or is in a post-menopausal state); or is of childbearing potential and agrees to use an accepted contraceptive method from at least 4 weeks prior to admission and until at least 4 weeks after the last dose administration (Day 8). Exclusion Criteria: AT SCREENING Known hypersensitivity/allergic reaction to cytisinicline or any of the excipients. Known severe hypersensitivity reaction to any other drug. Any medical condition (eg, gastrointestinal, renal or hepatic, including peptic ulcer, inflammatory bowel disease or pancreatitis) or surgical condition (eg, cholecystectomy, gastrectomy) that may affect drug pharmacokinetics (absorption, distribution, metabolism or excretion) or subject safety. Stroke or acute myocardial infarction within the previous 3 months. History of hyperthyroidism. History of psychosis or of a psychotic event. Estimated renal creatinine clearance (CLCr) below the lower limit of the normal range (ie, 90-120 mL/min/1.73 m^2 for males and 80-110 mL/min/1.73 m^2 for females), based on creatinine clearance calculation by the Cockcroft-Gault formula and normalized to an average body surface area of 1.73 m^2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above the upper limit of the normal (ULN) range. Positive result in urine drugs-of-abuse or ethanol tests at Screening. Excessive caffeine consumption, defined as ≥ 800 mg per day. Veins unsuitable for intravenous puncture on either arm (eg, veins that are difficult to locate, access or puncture; veins with a tendency to rupture during or after puncture). Participation in any clinical trial within the previous 2 months. Use of any smoking cessation medications such as cytisinicline, bupropion, varenicline, nortriptyline, or any nicotine replacement therapy (NRT; eg, nicotine patch, nicotine chewing gum, or electronic cigarettes) in the previous 8 weeks. Participation in more than 2 clinical trials within the previous 12 months. Blood donation or significant blood loss (≥ 450 mL) due to any reason or had plasmapheresis within the previous 2 months. Female subjects who are lactating or pregnant by serum pregnancy test. Any other condition that the investigator considers the subject to be unsuitable for the study. AT ADMISSION Any recent disease or condition or treatment that, according to the investigator, would put the subject at undue risk due to study participation or occurred at a time frame in which may interfere with the pharmacokinetics of study drug. Use of any medicinal products, prescription and non-prescription (including vitamins, food supplements, herbal supplements [including St John's Wort]), in the previous 2 weeks, unless in the investigator's opinion the medication does not interfere with the pharmacokinetics of study drug or compromise subject safety. NOTE: The use of topical products without systemic absorption, acetaminophen (paracetamol) at doses of ≤ 2 grams/day, and hormonal contraceptives are acceptable. Use of any smoking cessation medications (eg, cytisinicline, bupropion, varenicline, nortriptyline, or any NRT eg, nicotine patch, nicotine chewing gum, or electronic cigarettes) since Screening. Positive result in drugs-of-abuse or ethanol tests. If female, positive pregnancy test in urine. Any other condition that the investigator considers to render the subject unsuitable 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Cytisinicline 3 mg Once Daily (QD), Fasting<br>3 mg cytisinicline tablet administered in the morning, between 7:00 and 9:00 AM, in fasting conditions on Day 1 (Period 1) or Day 3 (Period 2). Participants will fast overnight for at least 10 hours before cytisinicline administration and will continue to fast for 4 hours after dosing. | Drug: Cytisinicline<br>* film-coated oral tablets containing 3 mg cytisinicline<br>* Other names: Cytisine;|
| Experimental: Part 1: Cytisinicline 3 mg QD, Fed<br>3 mg cytisinicline tablet administered in the morning, between 7:00 and 9:00 AM, in fed conditions on Day 1 (Period 1) or Day 3 (Period 2). After an overnight fasting of at least 10 hours, participants will consume a standard high-fat-high-calorie meal within 30 minutes. Cytisinicline will be administered with 240 mL of water within 5 minutes after completion of the meal. | Drug: Cytisinicline<br>* film-coated oral tablets containing 3 mg cytisinicline<br>* Other names: Cytisine;|
| Experimental: Part 2: Cytisinicline 3 mg 3 Times Daily (TID)<br>3 mg cytisinicline tablet administered TID each day on Day 5 to 8 (Period 3) as follows: Dose 1 will be administered in the morning between 7:00 and 9:00 AM,; Dose 2 at 5 hours (±10 minutes) after Dose 1; Dose 3 at 5 hours (±10 minutes) after Dose 2. Cytisinicline will be administered on an empty stomach (cytisinicline given at least 2 hours before food or 1 hour after food). | Drug: Cytisinicline<br>* film-coated oral tablets containing 3 mg cytisinicline<br>* Other names: Cytisine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Time of Maximum Observed Plasma Concentration (Tmax) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Time Point Prior to the First Quantifiable Concentration (Tlag) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Time of Last Quantifiable Observed Concentration (Tlast) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Area Under Plasma Concentration-Time Curve (AUC) Over the Dosing Interval (AUC0-τ) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| AUC From Time of Dosing (t=0h) to the Time of the Last Quantifiable Concentration (AUC0-t) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Total AUC Extrapolated to Infinity (AUC0-∞) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Percentage of AUC0-∞ Due to Extrapolation From the Time of the Last Quantifiable Concentration (Tlast) to Infinity (%AUCextrap) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Apparent Terminal Elimination Rate Constant (λz) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Apparent Terminal Elimination Half-Life (t1/2) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Apparent Clearance (CL/F) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Apparent Volume of Distribution (V/F) |  | Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose | 
| Pre-dose Plasma Concentration (Ctrough) for Dose 1, Dose 2 and Dose 3 |  | Days 5 to 8 (Period 3): pre-dose | 
| Cmax for Dose 1, Dose 2 and Dose 3 |  | Days 5-7 (Period 3): predose, Day 8 (Period 3): pre-dose and up to 5 hours post-dose (Doses 1 and 2), predose and up to 24 hours post-dose (Dose 3) | 
| Tmax for Dose 1, Dose 2 and Dose 3 |  | Days 5-7 (Period 3): predose, Day 8 (Period 3): pre-dose and up to 5 hours post-dose (Doses 1 and 2), predose and up to 24 hours post-dose (Dose 3) | 
| AUC0-τ for Dose 1, Dose 2 and Dose 3 | τ=5 h for Dose 1 and Dose 2 and τ=24 h for Dose 3 | Days 5-7 (Period 3): predose, Day 8 (Period 3): pre-dose and up to 5 hours post-dose (Doses 1 and 2), predose and up to 24 hours post-dose (Dose 3) | 
| Concentration Over the Dosing Interval (Cτ) for Dose 1, Dose 2 and Dose 3 | τ=5 h for Dose 1 and Dose 2 and τ=24 h for Dose 3 | Days 5-7 (Period 3): predose, Day 8 (Period 3): pre-dose and up to 5 hours post-dose (Doses 1 and 2), predose and up to 24 hours post-dose (Dose 3) | 
| Apparent Terminal Elimination Half-Life Interval (t1/2) post Dose 3 |  | Day 8 (Period 3): up to 24 hours post-dose 3 | 
| Ratio of Cmax (R[Cmax]) | Accumulation of cytisinicline following TID administration will be assessed by estimating R(Cmax), where R is the ratio of the pharmacokinetic parameter following administration of Dose 1 on Day 8 vs. single-dose administration under fasting conditions during Period 1 or 2. | Day 1 (Period 1) or Day 3 (Period 2), Day 8 (Period 3): Dose 1 (up to 5 hours post-dose) | 
| Ratio of AUC0-τ (R[AUC0-τ]) | Accumulation of cytisinicline following TID administration will be assessed by estimating R(AUC0-τ), where R is the ratio of the pharmacokinetic parameter following administration of Dose 1 on Day 8 vs. single-dose administration under fasting conditions during Period 1 or 2. | Day 1 (Period 1) or Day 3 (Period 2), Day 8 (Period 3): Dose 1 (up to 5 hours post-dose) | 
| R(AUC0-τ/AUC0-∞) | Time invariance will be assessed as R(AUC0-τ/AUC0-∞), where AUC0-τ is estimated on Day 8 Dose 1 and AUC0-∞ is estimated for the single-dose under fasting conditions during Period 1 or 2. | Day 1 (Period 1) or Day 3 (Period 2), Day 8 (Period 3): Dose 1 (up to 5 hours post-dose) | 
| Time to Steady State | Time to steady state will be assessed by visual inspection of the Ctrough versus time plot. | Days 5 to 8 (Period 3): pre-dose | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) |  | From first dose of study drug through the End-of Study Visit (Day 28-31) | 
| Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECG) |  | Baseline through Day 9 | 
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs |  | Baseline through Day 9 | 
| Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Tests |  | Baseline through Day 9 |