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CompletedNCT05206370ORCA-3Updated Jan 14, 2026Results posted

A Second Study of Cytisinicline for Smoking Cessation in Adult Smokers

A Phase 3 interventional study of Cytisinicline and Placebo in Smoking Cessation, sponsored by Achieve Life Sciences. Completed at 12 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-01-14.

Sponsored by Achieve Life Sciences · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
792
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

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.

02

Conditions studied

  • Smoking Cessation

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03

In context

Smoking Cessation

304 studies on the registry are indexed under Smoking Cessation; 139 are open to participants now.

This study's enrollment of 792 is above the median of 154 across 285 interventional studies indexed under Smoking Cessation.

Browse Smoking Cessation studies →

Lead sponsor

Achieve Life Sciences is the lead sponsor of 29 studies on the registry; 1 is open to participants now.

Of its 11 completed or terminated interventional studies of FDA-regulated products, 7 (64%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
792 participants (actual)

Study arms

  • Placebo comparator
    Placebo + Behavioral Support

    One placebo tablet orally (PO) three times daily (TID) for 12 weeks plus behavioral support

    Drug: Placebo · Behavioral: Behavioral support

  • 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: Cytisinicline · Drug: Placebo · Behavioral: Behavioral support

  • Experimental
    12-Week Cytisinicline + Behavioral Support

    One cytisinicline tablet PO TID for 12 weeks plus behavioral support

    Drug: Cytisinicline · Behavioral: Behavioral support

Interventions

  • DrugCytisinicline

    film-coated oral tablets containing 3 mg cytisinicline

    Also known as: Cytisine

  • DrugPlacebo

    film-coated oral tablets containing matched placebo

  • BehavioralBehavioral 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.

06

What researchers measure

Primary outcomes

  1. 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).

    Time frame: Weeks 3 to 6

  2. Percentage of Participants With Smoking Abstinence From Weeks 9 to Week 12

    Smoking abstinence as verified by weekly expired CO measurements ≤ 10 ppm.

    Time frame: Weeks 9 to 12

Secondary outcomes

  1. 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.

    Time frame: Week 3 to Week 24

  2. 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.

    Time frame: Week 9 to Week 24

  3. 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.)

    Time frame: Week 24

07

Results

Posted Jan 14, 2026

Participant flow

Participant flow — Overall Study
MilestonePlacebo + Behavioral Support6-Week Cytisinicline + 6-Week Placebo + Behavioral Support12-Week Cytisinicline + Behavioral Support
Started265263264
Completed209207212
Not completed565652
Withdrew: Adverse event345
Withdrew: Withdrawal by subject273024
Withdrew: Physician decision132
Withdrew: Death013
Withdrew: Lost to follow-up231614
Withdrew: Other, nor specified224

Outcome measures

PrimaryPercentage 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).

Time frame:
Weeks 3 to 6
Reported as:
Number · percentage of participants
Percentage of Participants With Smoking Abstinence From Weeks 3 to Week 6
percentage of participantsPlacebo + Behavioral Support6-Week Cytisinicline + 6-Week Placebo + Behavioral Support
Percentage of Participants With Smoking Abstinence From Weeks 3 to Week 66.014.8
Statistical analysis
  • Placebo + Behavioral Support vs 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support · Exact computations · p = 0.0008 (Two-sided, calculated by exact computations with clinical site as a stratifier.) · Odds ratio (or): 2.85 · 95% CI 1.475 to 5.617Common odds ratio (stratified by site)
  • Placebo + Behavioral Support vs 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support · Exact computations · p = 0.0010 (Two-sided, derived from marginal odds ratio) · Odds ratio (or): 2.71 · 95% CI 1.485 to 5.094Marginal (unadjusted) odds ratio
  • Placebo + Behavioral Support vs 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support · Cochran-Mantel-Haenszel · p = 0.0006 (p-value for difference in proportions) · Difference in proportions: 0.09 · 95% CI 0.033 to 0.134
PrimaryPercentage of Participants With Smoking Abstinence From Weeks 9 to Week 12

Smoking abstinence as verified by weekly expired CO measurements ≤ 10 ppm.

Time frame:
Weeks 9 to 12
Reported as:
Number · percentage of participants
Percentage of Participants With Smoking Abstinence From Weeks 9 to Week 12
percentage of participantsPlacebo + Behavioral Support12-Week Cytisinicline + Behavioral Support
Percentage of Participants With Smoking Abstinence From Weeks 9 to Week 129.430.3
Statistical analysis
  • Placebo + Behavioral Support vs 12-Week Cytisinicline + Behavioral Support · Exact computations · p = < 0.0001 (Two-sided, calculated by exact computations with clinical site as a stratifier.) · Odds ratio (or): 4.40 · 95% CI 2.566 to 7.343Common odds ratio (stratified by site)
  • Placebo + Behavioral Support vs 12-Week Cytisinicline + Behavioral Support · Exact computations · p = < 0.0001 (Two-sided, derived from marginal odds ratio.) · Odds ratio (or): 4.17 · 95% CI 2.575 to 6.885Marginal (unadjusted) odds ratio
  • Placebo + Behavioral Support vs 12-Week Cytisinicline + Behavioral Support · Cochran-Mantel-Haenszel · p = < 0.0001 (p-value for difference in proportions4) · Difference in proportions: 0.21 · 95% CI 0.141 to 0.267
SecondaryPercentage 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.

Time frame:
Week 3 to Week 24
Reported as:
Number · percentage of participants
Percentage of Participants With Continuous Smoking Abstinence From Week 3 to Week 24
percentage of participantsPlacebo + Behavioral Support6-Week Cytisinicline + 6-Week Placebo + Behavioral Support
Percentage of Participants With Continuous Smoking Abstinence From Week 3 to Week 241.16.8
Statistical analysis
  • Placebo + Behavioral Support vs 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support · Exact computations · p = 0.0006 (Two-sided, calculated by exact computations with clinical site as a stratifier.) · Odds ratio (or): 6.25 · 95% CI 1.851 to 34.619Common odds ratio (Stratified by site)
  • Placebo + Behavioral Support vs 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support · Exact computations · p = 0.0007 (Two-sided, derived from marginal odds ratio.) · Odds ratio (or): 6.42 · 95% CI 2.026 to 27.544Marginal (unadjusted) odds ratio
  • Placebo + Behavioral Support vs 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support · Cochran-Mantel-Haenszel · p = 0.0007 (p-value for difference in proportions) · Difference in proportions: 0.06 · 95% CI 0.023 to 0.075
SecondaryPercentage 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.

Time frame:
Week 9 to Week 24
Reported as:
Number · percentage of participants
Percentage of Participants With Continuous Smoking Abstinence From Week 9 to Week 24
percentage of participantsPlacebo + Behavioral SupportCytisinicline + Behavioral Support
Percentage of Participants With Continuous Smoking Abstinence From Week 9 to Week 244.220.5
Statistical analysis
  • Placebo + Behavioral Support vs Cytisinicline + Behavioral Support · Exact computations · p = < 0.0001 (Two-sided, calculated by exact computations with clinical site as a stratifier.) · Odds ratio (or): 5.79 · 95% CI 2.888 to 12.458Common odds ratio (stratified by site)
  • Placebo + Behavioral Support vs Cytisinicline + Behavioral Support · Exact computations · p = < 0.0001 (Two-sided, derived from marginal odds ratio.) · Odds ratio (or): 5.94 · 95% CI 3.091 to 12.130Marginal (unadjusted) odds ratio
  • Placebo + Behavioral Support vs Cytisinicline + Behavioral Support · Cochran-Mantel-Haenszel · p = < 0.0001 (p-value for difference in proportions) · Difference in proportions: 0.16 · 95% CI 0.110 to 0.202
SecondaryPercentage 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.)

Time frame:
Week 24
Reported as:
Number · percentage of participants
Percentage of Participants Taking Cytisinicline Who Are Relapse-Free at Week 24
percentage of participants6-Week Cytisinicline + 6-Week Placebo + Behavioral Support12-Week Cytisinicline + Behavioral Support
Percentage of Participants Taking Cytisinicline Who Are Relapse-Free at Week 248.710.6
Statistical analysis
  • 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support vs 12-Week Cytisinicline + Behavioral Support · Exact computations · p = 0.5538 (Two-sided, calculated by exact computations with clinical site as a stratifier.) · Odds ratio (or): 1.22 · 95% CI 0.652 to 2.297Common odds ratio (stratified by site)
  • 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support vs 12-Week Cytisinicline + Behavioral Support · Exact computations · p = 0.5560 (Two-sided, derived from marginal odds ratio.) · Odds ratio (or): 1.24 · 95% CI 0.691 to 2.231Marginal (unadjusted) odds ratio
  • 6-Week Cytisinicline + 6-Week Placebo + Behavioral Support vs 12-Week Cytisinicline + Behavioral Support · Zelen's exact test (Pr ≤ P) · p = 0.2822

Adverse events

Collected over From signing of informed consent through Week 24. Non-serious events are listed at a 2% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo + Behavioral Support0/262 (0%)8/262 (3.1%)110/262 (42%)
6-Week Cytisinicline + 6-Week Placebo + Behavioral Support1/263 (0.4%)8/263 (3%)132/263 (50.2%)
12-Week Cytisinicline + Behavioral Support3/260 (1.2%)8/260 (3.1%)137/260 (52.7%)
Most frequent serious events
Showing 10 of 23
Most frequent serious events
EventPlacebo + Behavioral Support6-Week Cytisinicline + 6-Week Placebo + Behavioral Support12-Week Cytisinicline + Behavioral Support
FatigueGeneral disorders0/2620/2631/260
Groin abscessInfections and infestations0/2620/2631/260
PneumoniaInfections and infestations1/2620/2631/260
OverdoseInjury, poisoning and procedural complications0/2620/2631/260
Stab woundInjury, poisoning and procedural complications0/2620/2631/260
Haemorrhagic strokeNervous system disorders0/2620/2631/260
ParanoiaPsychiatric disorders0/2620/2631/260
Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders1/2621/2631/260
Cholecystitis acuteHepatobiliary disorders1/2620/2630/260
PyelonephritisInfections and infestations1/2620/2630/260
Most frequent other events
Showing 10 of 27
Most frequent other events
EventPlacebo + Behavioral Support6-Week Cytisinicline + 6-Week Placebo + Behavioral Support12-Week Cytisinicline + Behavioral Support
InsomniaPsychiatric disorders20/26229/26332/260
COVID-19Infections and infestations27/26218/26327/260
NauseaGastrointestinal disorders19/26226/26319/260
Abnormal dreamsPsychiatric disorders16/26224/26320/260
HeadacheNervous system disorders18/26221/26322/260
HypertensionVascular disorders13/2627/2638/260
Upper respiratory tract infectionInfections and infestations9/26211/26312/260
DiarrhoeaGastrointestinal disorders12/26212/2638/260
Dry mouthGastrointestinal disorders6/26212/2636/260
FatigueGeneral disorders3/2627/26311/260

Baseline characteristics

Age, Continuous
Age, Continuous(years)Placebo + Behavioral Support6-Week Cytisinicline + 6-Week Placebo + Behavioral Support12-Week Cytisinicline + Behavioral SupportTotal
Mean51 ± 11.452 ± 11.752 ± 12.352 ± 11.8
Sex: Female, Male
Sex: Female, Male(Participants)Placebo + Behavioral Support6-Week Cytisinicline + 6-Week Placebo + Behavioral Support12-Week Cytisinicline + Behavioral SupportTotal
Female146142151439
Male119121113353
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Placebo + Behavioral Support6-Week Cytisinicline + 6-Week Placebo + Behavioral Support12-Week Cytisinicline + Behavioral SupportTotal
Hispanic or Latino17151345
Not Hispanic or Latino248248251747
Unknown or Not Reported0000
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Placebo + Behavioral Support6-Week Cytisinicline + 6-Week Placebo + Behavioral Support12-Week Cytisinicline + Behavioral SupportTotal
American Indian or Alaska Native1405
Asian0224
Black or African American513850139
Native Hawaiian or Other Pacific Islander0022
White210216205631
Other, Not Specified33511
08

Study locations

12 sites
  • Accel Research Sites - DeLand Clinical Research Unit
    DeLand, Florida 32720, United States
  • Alliance for Multispecialty Research, LLC
    Fort Myers, Florida 33912, United States
  • Jacksonville Center for Clinical Research
    Jacksonville, Florida 32216, United States
  • Affinity Health Corp
    Oak Brook, Illinois 60523, United States
  • MediSphere Medical Research Center, LLC
    Evansville, Indiana 47714, United States
  • Global Medical Institutes LLC; Princeton Medical Institute
    Princeton, New Jersey 08540, United States
  • Trial Management Associates, LLC
    Wilmington, North Carolina 28403, United States
  • Velocity Clinical Research, Inc.
    Cleveland, Ohio 44122, United States
  • Aventiv Research Inc
    Columbus, Ohio 43212, United States
  • Intend Research
    Norman, Oklahoma 73069, United States
  • Clinical Research Associates, Inc.
    Nashville, Tennessee 37203, United States
  • Health Research of Hampton Toads, Inc
    Newport News, Virginia 23606, United States
09

References and documents

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. 2026 Jan 15;81(2):164-169. doi: 10.1136/thorax-2025-223880. PubMed 40962497 ↗
  • 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. PubMed 40257755 ↗

Study documents

  • Study protocol · Nov 15, 2021
  • Statistical analysis plan · Apr 27, 2023

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jan 14, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT05206370
Lead sponsor
Achieve Life Sciences
Responsible party
Sponsor
First posted
Jan 25, 2022
Start date
Jan 20, 2022
Primary completion
Mar 21, 2023
Completion
Mar 21, 2023
Results posted
Jan 14, 2026
Last update
Jan 14, 2026

Study contacts

Daniel Cain, Vice-President Clinical Research
study director · Achieve Life Sciences, Inc.

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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