A Second Study of Cytisinicline for Smoking Cessation in Adult Smokers (ORCA-3)

A Second Multicenter, Double-blind, Randomized, Placebo-controlled Phase 3 Trial Evaluating the Efficacy and Safety of Cytisinicline in Adult Smokers

This placebo-controlled Phase 3 study is being conducted at sites within the United States to evaluate 3 mg cytisinicline TID for treatment duration of 42 days/6 weeks and evaluate 3 mg cytisinicline TID for treatment duration of 84 days/12 weeks.

Study Overview

• Status: Completed
• Conditions: Smoking Cessation
• Intervention / Treatment: Drug: Placebo; Behavioral: Behavioral support; Drug: Cytisinicline

• Study Type: Interventional
• Enrollment (Actual): 792
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Florida
    • DeLand, Florida, United States, 32720
      • Accel Research Sites - DeLand Clinical Research Unit
    • Fort Myers, Florida, United States, 33912
      • Alliance for Multispecialty Research, LLC
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research
  • Illinois
    • Oak Brook, Illinois, United States, 60523
      • Affinity Health Corp
  • Indiana
    • Evansville, Indiana, United States, 47714
      • MediSphere Medical Research Center, LLC
  • New Jersey
    • Princeton, New Jersey, United States, 08540
      • Global Medical Institutes LLC; Princeton Medical Institute
  • North Carolina
    • Wilmington, North Carolina, United States, 28403
      • Trial Management Associates, LLC
  • Ohio
    • Cleveland, Ohio, United States, 44122
      • Velocity Clinical Research, Inc.
    • Columbus, Ohio, United States, 43212
      • Aventiv Research Inc
  • Oklahoma
    • Norman, Oklahoma, United States, 73069
      • Intend Research
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Clinical Research Associates, Inc.
  • Virginia
    • Newport News, Virginia, United States, 23606
      • Health Research of Hampton Toads, Inc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female subjects, age ≥ 18 years.
2. Current daily cigarette smokers (averaging at least 10 cigarettes per day upon completing a 7-day screening smoking diary) and who intend to quit smoking.
3. Expired air carbon monoxide (CO) ≥ 10 ppm.
4. Failed at least one previous attempt to stop smoking with or without therapeutic support.
5. Willing to initiate study treatment on the day after randomization and set a quit date within 5-7 days of starting treatment.
6. Willing to actively participate in the study's smoking cessation behavioral support provided throughout the study.
7. Able to fully understand all study requirements, willing to participate, and comply with dosing schedule.
8. Sign the Informed Consent Form.

Exclusion Criteria:

1. More than 1 study participant in same household during the 12-week treatment period.
2. Previous cytisinicline treatment in a prior clinical study or any other cytisine usage.
3. Known hypersensitivity to cytisinicline or any of the excipients.
4. Positive urinary drugs of abuse screen, determined within 28 days before the first dose of cytisinicline.
5. Clinically significant abnormal serum chemistry or hematology values within 28 days of randomization (ie, requiring treatment or monitoring).
6. Clinically significant abnormalities in 12-lead ECG determined after minimum of 5 minutes in supine position within 28 days of randomization (ie, requiring treatment or further assessment).
7. Recent history (within 3 months) of acute myocardial infarction, unstable angina, stroke, cerebrovascular incident, or hospitalization for congestive heart failure.
8. Current uncontrolled hypertension (blood pressure ≥160/100 mmHg).
9. Currently psychotic or having had a psychotic event within 3 months. If any subject becomes psychotic during the study, they must be removed from treatment and/or additional study visits.
10. Currently having suicidal ideation or risk for suicide ("Yes" to either question 4 or question 5 OR "Yes" to any suicidal behavior question on the Columbia Suicide Severity Rating Scale [C-SSRS] with clear suicidal intent or previous attempt).
11. Current symptoms of moderate to severe depression (depression score ≥11on the HADS).
12. Renal impairment defined as a creatinine clearance (CrCl) <60 mL/min (estimated with the Cockroft-Gault equation).
13. Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 x the upper limit of normal (ULN).
14. Women who are pregnant or breast-feeding.
15. Male or female subjects of childbearing potential who do not agree to use acceptable methods of birth control during the study treatment period.
16. Participation in a clinical study with an investigational drug in the 4 weeks prior to randomization.
17. Treatment with other smoking cessation medications (bupropion, varenicline, nortriptyline, or any nicotine replacement therapy [NRT]) in the 4 weeks prior to randomization or planned use of these other smoking cessation medications during the study.
18. Use within the 2 weeks prior to randomization or planned use during the study of non-cigarette and/or noncombustible nicotine products (pipe tobacco, cigars, snuff, smokeless tobacco, hookah, e-cigarettes/vaping) or marijuana smoking or vaping.
19. Any other reason that the investigator views the subject should not participate or would be unable to fulfill the requirements for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo + Behavioral Support; One placebo tablet orally (PO) three times daily (TID) for 12 weeks plus behavioral support	Drug: Placebo; film-coated oral tablets containing matched placebo; Behavioral: Behavioral support; Behavioral support sessions by a qualified study site staff member will be participant-driven and will include direct engagement with the subject about their attempt to quit smoking. Each session will last approximately 10 minutes.
Experimental: 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support; One cytisinicline tablet PO TID for 6 weeks followed by one placebo tablet PO TID for 6 weeks plus behavioral support	Drug: Placebo; film-coated oral tablets containing matched placebo; Behavioral: Behavioral support; Behavioral support sessions by a qualified study site staff member will be participant-driven and will include direct engagement with the subject about their attempt to quit smoking. Each session will last approximately 10 minutes.; Drug: Cytisinicline; film-coated oral tablets containing 3 mg cytisinicline; Other Names: Cytisine
Experimental: 12-Week Cytisinicline + Behavioral Support; One cytisinicline tablet PO TID for 12 weeks plus behavioral support	Behavioral: Behavioral support; Behavioral support sessions by a qualified study site staff member will be participant-driven and will include direct engagement with the subject about their attempt to quit smoking. Each session will last approximately 10 minutes.; Drug: Cytisinicline; film-coated oral tablets containing 3 mg cytisinicline; Other Names: Cytisine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Smoking Abstinence From Weeks 3 to Week 6	Smoking abstinence as verified by weekly expired carbon monoxide (CO) measurements ≤ 10 parts per million (ppm).	Weeks 3 to 6
Percentage of Participants With Smoking Abstinence From Weeks 9 to Week 12	Smoking abstinence as verified by weekly expired CO measurements ≤ 10 ppm.	Weeks 9 to 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Continuous Smoking Abstinence From Week 3 to Week 24	Smoking abstinence as verified by expired CO measurements ≤ 10 ppm. Measurements were weekly from Week 3 to Week 12 and monthly from Week 12 to Week 24.	Week 3 to Week 24
Percentage of Participants With Continuous Smoking Abstinence From Week 9 to Week 24	Smoking abstinence as verified by expired CO measurements ≤ 10 ppm. Measurements were weekly from Week 9 to Week 12 and monthly from Week 12 to Week 24.	Week 9 to Week 24
Percentage of Participants Taking Cytisinicline Who Are Relapse-Free at Week 24	Relapse is defined as participant reported resuming smoking or an expired CO measure ≥ 10 ppm. Relapse is defined as a participant having met one of the following: not being abstinent from Weeks 3 to 6; not being abstinent at the Week 12 visit; not being abstinent or not self-reporting abstinence during the Week 16 to Week 24 follow-up period. (During the follow-up period [Weeks 16 to 24], up to a total of 5 cigarettes could have been smoked.)	Week 24

Collaborators and Investigators

• Sponsor: Achieve Life Sciences
• Investigators: Study Director: Daniel Cain, Vice-President Clinical Research, Achieve Life Sciences, Inc.

Publications and helpful links

General Publications

• Prochaska J, Rubinstein M, Perdok R, Blumenstein B, Jacobs C. Cytisinicline for smoking cessation in individuals with self-reported COPD: a post hoc analysis of the ORCA-2 and ORCA-3 trials. Thorax. 2025 Sep 17:thorax-2025-223880. doi: 10.1136/thorax-2025-223880. Online ahead of print.
• Rigotti NA, Benowitz NL, Prochaska JJ, Rubinstein M, Clarke A, Blumenstein B, Cain DF, Jacobs C. Cytisinicline for Smoking Cessation: The ORCA Phase 3 Replication Randomized Clinical Trial. JAMA Intern Med. 2025 Jun 1;185(6):648-655. doi: 10.1001/jamainternmed.2025.0628.

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2022
• Primary Completion (Actual): March 21, 2023
• Study Completion (Actual): March 21, 2023

Study Registration Dates

• First Submitted: January 12, 2022
• First Submitted That Met QC Criteria: January 12, 2022
• First Posted (Actual): January 25, 2022

Study Record Updates

• Last Update Posted (Estimated): January 14, 2026
• Last Update Submitted That Met QC Criteria: December 23, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavior; Health Behavior; Smoking Cessation; Psychotherapy; Behavioral Disciplines and Activities; Behavior Therapy; cytisine
• Other Study ID Numbers: ACH-CYT-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No