This will be a multi-center, double-blind, randomized, placebo-controlled, Phase 3 study conducted in male or female adults who are daily nicotine e-cigarette users only.

A total of approximately 800 subjects will be randomly assigned (1:1) to one of two Arms:

• Arm B, 12 weeks cytisinicline + behavior support: N=400 or
• Arm A, 12 weeks of placebo+ behavior support: N=400) The primary objective is to assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 12 weeks plus behavioral support) have a higher probability of nicotine vaping cessation from Week 9 to Week 12 as compared to subjects randomized to Arm A (placebo TID for 12 weeks plus behavioral support).

Inclusion Criteria:

• Male or female subjects, age ≥18 years.
• Test positive for cotinine using a point-of-care Oral Fluid Screening Device (OFD) with positive detection at ≥30 ng/mL cotinine.
• Current daily nicotine-containing electronic cigarette usage as recorded in a screening diary for at least 7 consecutive days. Willing to bring the e-cigarette or nicotine device used to the clinical site so that the specific product type, flavor, and nicotine level can be documented.
• Failed at least one previous attempt to stop vaping with or without therapeutic support.
• Willing to initiate study treatment on the day after randomization and set a quit date within Day 7 and Day 14.
• Willing to actively participate in the study's vaping 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:

• Currently smoking or having smoked within 3 months prior to study randomization, any combustible cigarettes, other combustible tobacco products or non-combustible tobacco products such as heat not burn products or nicotine pouches (ie, dual users).
• Currently smoking/vaping cannabis or having smoked or vaped cannabis within 4 weeks (28 days) prior to study randomization or planned use while on study. Other methods of cannabis consumption, eg, edibles, tinctures, capsules, topicals, etc. are allowed.
• Expired Carbon Monoxide (CO) levels ≥6 ppm, indicating recent combustible tobacco or cannabis smoking.
• A score of 0-3 on the Penn State e-Cigarette Dependence Index indicating no dependence.
• More than 1 study subject in same household during the study treatment period.
• Known hypersensitivity to any of the excipients, previous cytisinicline treatment in a prior clinical study, or any previous use of cytisinicline.
• Positive urinary drugs of abuse screen determined within 28 days before the first dose of study drug. (Note: Although THC is part of the standard drug screen, it is not necessarily exclusionary. Refer to exclusion criteria #2).
• Clinically significant abnormal serum chemistry or hematology values, as determined by the investigator, within 28 days of randomization.
• Clinically significant abnormalities on screening visit 12-lead ECG, as determined by the investigator, after minimum of 5 minutes in supine position within 28 days of randomization.
• 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 in the 3 months prior to the screening visit. If any subject becomes psychotic during the study, they must be removed from treatment and/or additional study visits.
• Currently having suicidal ideation or risk for suicide (YES to either question 3, 4 or 5 OR YES to any suicidal behavior question on the C-SSRS with clear suicidal intent or suicide attempt within the last 10 years).
• Current symptoms of moderate to severe depression (depression score ≥11 using depression questions on the Hospital Anxiety and Depression Scale [HADS] at screening visit).
• Renal impairment defined as a creatinine clearance (CrCl) <60 mL/min at screening visit (estimated with the Cockroft-Gault equation and reported by the central laboratory).
• Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 x the upper limit of normal (ULN) at screening visit.
• Recent history or symptoms (within 4 weeks of randomization) of unstable respiratory disease (eg, pneumonia, product-use associated lung injury or EVALI, etc).
• 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
• intrauterine device (IUD)
• double barrier method (condom with spermicide)
• Hormonal methods:
• Oral contraceptives
• Vaginal ring such as NuvaRing
• Skin patch such as Xulane
• Injection such as Depro-Provera
• Implantable rod such as Nexplanon
• Intrauterine device (IUD)
• Participation in a clinical study with an investigational drug or biologic in the 4 weeks prior to study randomization.
• Use of any smoking cessation medications (bupropion, varenicline, nortriptyline, or any nicotine replacement therapy [NRT]) in the 4 weeks prior to study randomization or planned use of these or other nicotine replacement medications during the study.
• Any planned use during the study of combustible cigarettes or other nicotine-containing, non-vaping products (eg, pipe tobacco, cigars, snuff, smokeless tobacco, hookah, ZYN pouches, etc).
• Any other reason that the investigator views the subject should not participate or would be unable to fulfill the requirements for the study.