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

A Multicenter, Open-Label Study Assessing Long-Term Exposure With Cytisinicline 3 mg TID

Safety assessment of long-term 3 mg cytisinicline three times daily (TID) exposure for 52 weeks is the main purpose of this study, conducted in the United States.

Inclusion Criteria:

1. Prior participation in the ORCA-2, ORCA-3 or ORCA-V1 clinical studies.
2. 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.
3. 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.
4. Willing to initiate cytisinicline treatment on the day after enrollment and set a quit date within 14 days of starting treatment.
5. Willing to actively participate in the study's cessation behavioral support provided throughout the study.
6. Able to fully understand study requirements, willing to participate, and comply with dosing schedule.
7. Sign the Informed Consent Form.

Exclusion Criteria:

1. Known hypersensitivity to cytisinicline or any of the excipients.

2. Clinically significant abnormal screening serum chemistry or hematology values.

3. Clinically significant abnormal screening 12-lead ECG determined after minimum of 5 minutes in supine position (ie, requiring treatment or further assessment).

4. Recent history (within 3 months prior to screening) of acute myocardial infarction, unstable angina, stroke, cerebrovascular incident or hospitalization for congestive heart failure.

5. Current uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg).

6. 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.

7. Severe renal impairment defined as a creatinine clearance (CrCl) <60 mL/min on screening lab (estimated with the Cockroft-Gault equation).

8. Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 x the upper limit of normal (ULN) on screening lab.

9. Women who are pregnant or breast-feeding.

10. 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

11. Participation in a clinical study with an investigational drug in the 4 weeks prior to enrollment.

12. Any other reason that the investigator views the subject should not participate or would be unable to fulfill the requirements for the study.