Safety Study of Cytisinicline in Adult Combustible and/or E-cigarette Smokers

Inclusion criteria

• Prior participation in the ORCA-2, ORCA-3 or ORCA-V1 clinical studies.
• Former ORCA-2/ORCA-3 and ORCA-V1 subjects who are current daily cigarette smokers and/or daily nicotine-containing electronic cigarette users. Amount of daily combustible and/or nicotine containing electronic cigarette use at baseline is determined by subject self-report.
• At Screening, subjects must have expired carbon monoxide (CO) ≥10 ppm if self-reporting as smokers or ≥30 ng/mL cotinine using a point-of-care cotinine oral fluid screening device if self-reporting as users of nicotine containing electronic cigarettes.
• Willing to initiate cytisinicline treatment on the day after enrollment and set a quit date within 14 days of starting treatment.
• Willing to actively participate in the study's cessation behavioral support provided throughout the study.
• Able to fully understand study requirements, willing to participate, and comply with dosing schedule.
• Sign the Informed Consent Form.

Exclusion criteria

• Known hypersensitivity to cytisinicline or any of the excipients.
• Clinically significant abnormal screening serum chemistry or hematology values.
• Clinically significant abnormal screening 12-lead ECG determined after minimum of 5 minutes in supine position (ie, requiring treatment or further assessment).
• Recent history (within 3 months prior to screening) of acute myocardial infarction, unstable angina, stroke, cerebrovascular incident or hospitalization for congestive heart failure.
• Current uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg).
• Currently psychotic or having had a psychotic event within 3 months prior to screening; currently having suicidal ideation or risk for suicide (corresponding to question 4 or 5 on the screening C-SSRS OR "Yes" to any suicidal behavior question on the screening C-SSRS with clear suicidal intent or previous attempt); or current symptoms of moderate to severe depression (depression score ≥11 on the HADS) at screening. If any subject becomes psychotic during the study, they must be removed from cytisinicline treatment and/or additional study visits.
• Severe renal impairment defined as a creatinine clearance (CrCl) <60 mL/min on screening lab (estimated with the Cockroft-Gault equation).
• Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 x the upper limit of normal (ULN) on screening lab.
• Women who are pregnant or breast-feeding.
• Female subjects of childbearing potential who do not agree to use acceptable methods of birth control during the study. Acceptable methods of birth control include:

• True abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception].
• Barrier methods:

• diaphragm
• cervical cap
• contraceptive sponge
• Hormonal methods:

• Oral contraceptives
• Vaginal ring such as NuvaRing
• Skin patch such as Xulane
• Injection such as Depro-Provera
• Implantable rod such as Nexplanon
• Participation in a clinical study with an investigational drug in the 4 weeks prior to enrollment.
• Any other reason that the investigator views the subject should not participate or would be unable to fulfill the requirements for the study.