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Effect of Cytisine vs Varenicline on Smoking CessationA Randomized Clinical Trial

Educational Objective
To learn about a novel pharmacotherapy for smoking cessation.
1 Credit CME
Key Points

Question  Is cytisine noninferior to varenicline regarding smoking cessation?

Findings  In this noninferiority randomized clinical trial that included 1452 participants, verified 6-month continuous abstinence rates were 11.7% for the cytisine group vs 13.3% for the varenicline group, a difference that did not meet the noninferiority margin of 5%.

Meaning  The study findings failed to demonstrate noninferiority of cytisine compared with varenicline regarding smoking cessation.


Importance  Cytisine is more effective than placebo and nicotine replacement therapy for smoking cessation. However, cytisine has not been tested against the most effective smoking cessation medication, varenicline, which is associated with adverse events known to lead to discontinuation of therapy.

Objective  To examine whether standard cytisine treatment (25 days) was at least as effective as standard varenicline treatment (84 days) for smoking cessation.

Design, Setting, and Participants  This noninferiority, open-label randomized clinical trial with allocation concealment and blinded outcome assessment was undertaken in Australia from November 2017 through May 2019; follow-up was completed in January 2020. A total of 1452 Australian adult daily smokers willing to make a quit attempt were included. Data collection was conducted primarily by computer-assisted telephone interview, but there was an in-person visit to validate the primary outcome.

Interventions  Treatments were provided in accordance with the manufacturers’ recommended dosage: cytisine (n = 725), 1.5-mg capsules taken 6 times daily initially then gradually reduced over the 25-day course; varenicline (n = 727), 0.5-mg tablets titrated to 1 mg twice daily for 84 days (12 weeks). All participants were offered referral to standard telephone behavioral support.

Main Outcomes and Measures  The primary outcome was 6-month continuous abstinence verified using a carbon monoxide breath test at 7-month follow-up. The noninferiority margin was set at 5% and the 1-sided significance threshold was set at .025.

Results  Among 1452 participants who were randomized (mean [SD] age, 42.9 [12.7] years; 742 [51.1%] women), 1108 (76.3%) completed the trial. Verified 6-month continuous abstinence rates were 11.7% for the cytisine group and 13.3% for the varenicline group (risk difference, −1.62% [1-sided 97.5% CI, −5.02% to ∞]; P = .03 for noninferiority). Self-reported adverse events occurred less frequently in the cytisine group (997 events among 482 participants) compared with the varenicline group (1206 events among 510 participants) and the incident rate ratio was 0.88 (95% CI, 0.81 to 0.95; P = .002).

Conclusions and Relevance  Among daily smokers willing to quit, cytisine treatment for 25 days, compared with varenicline treatment for 84 days, failed to demonstrate noninferiority regarding smoking cessation.

Trial Registration  anzctr.org.au Identifier: ACTRN12616001654448

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Ryan J. Courtney, PhD, National Drug and Alcohol Research Centre, University of New South Wales, R1 Building, 22-32 King St, Randwick, NSW, Australia (r.courtney@unsw.edu.au).

Accepted for Publication: April 28, 2021.

Author Contributions: Drs Courtney and Farrell had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Courtney, McRobbie, Tutka, Petrie, Shakeshaft, Thomas, Walker, Gartner, Mattick, Paul, Ferguson, Zwar, Richmond, Doran, Boland, Hall, West, Farrell.

Acquisition, analysis, or interpretation of data: Courtney, McRobbie, Weaver, Petrie, Mendelsohn, Shakeshaft, Talukder, Macdonald, Thomas, Kwan, Walker, Paul, Ferguson, Doran, Farrell.

Drafting of the manuscript: Courtney, McRobbie, Tutka, Petrie, Kwan, Walker, Ferguson, Doran, Farrell.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Courtney, Weaver, Petrie.

Obtained funding: Courtney, McRobbie, Petrie, Shakeshaft, Walker, Gartner, Mattick, Paul, Ferguson, Richmond, Doran, Farrell.

Administrative, technical, or material support: Courtney, McRobbie, Shakeshaft, Talukder, Macdonald, Thomas, Kwan, Mattick, Ferguson, Richmond, Boland, Farrell.

Supervision: Courtney, McRobbie, Tutka, Thomas, Kwan, Mattick, Paul, Ferguson, Richmond, Boland, Farrell.

Conflict of Interest Disclosures: Dr McRobbie reported receiving honoraria from Pfizer for speaking at smoking cessation meetings and attending advisory board meetings. Drs McRobbie and Walker reported previously receiving cytisine from Sopharma for the conduct of a noninferiority trial of cytisine vs nicotine replacement therapy. Dr Tutka reported serving as consultant to Aflofarm, which is a manufacturer of cytisine. Dr Mendelsohn reported receiving funding from Pfizer Australia, GlaxoSmithKline, and Johnson & Johnson Pacific for teaching, consulting, serving on an advisory board, and conference expenses. Dr Kwan reported receiving speaking fees from Pfizer. Dr Walker reported receiving cytisine from Achieve Life Sciences for the conduct of a noninferiority trial of cytisine (Tabex) vs varenicline; receiving investigator-initiated grants and smoking cessation medication (varenicline) and matching placebo from Pfizer for the conduct of a relapse prevention trial in patients with chronic obstructive pulmonary disease who smoke; and serving as a consultant for and receiving honoraria and travel support for speaking at research meetings from Achieve Life Sciences and Pfizer (manufacturers of smoking cessation medications). Dr Gartner reported receiving grants from the Australian Research Council, Metro South Health Service, Central Queensland Hospital and Health Service, Arthritis Australia, and the HIV Foundation Queensland. Dr Ferguson reported previously serving as a consultant to Pfizer and GlaxoSmithKline Consumer Healthcare on matters relating to smoking cessation and harm minimization; having been a member of a scientific advisory board for Johnson & Johnson; receiving researcher-initiated project grant funding from Pfizer (through the Grand initiative); and having provided consulting services to JUUL Labs Inc while working as a consultant for Pinney Associates. Dr Zwar reported receiving honoraria from Pfizer and GlaxoSmithKline for advice on smoking cessation education programs and for conference expenses. Dr West reported serving as a consultant to Pfizer, which manufactures varenicline, and receiving grants from Pfizer. Dr Farrell reported receiving unrestricted research funding from Mundipharma, Seqirus, and Indivior. No other disclosures were reported.

Funding/Support: This research was funded by project grant 1108318 and career development fellowship grant 1148497 (awarded to Dr Courtney) from the Australian National Health and Medical Research Council. The University of New South Wales National Drug and Alcohol Research Centre is supported by grant funding from the Australian government under the Substance Misuse Prevention and Service Improvements Fund. All study medications were purchased by the research team.

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the study participants, the individuals at the social research center who conducted the baseline and follow-up interviews, the individuals at the Chemist Warehouse pharmacy for storing and dispensing medications (central pharmacy), Josephine Pang, MBBS (compensated study physician), staff at the University of New South Wales trial coordinating center, and the uncompensated data and safety monitoring board members (Julia Lappin, PhD, Jason Grebely, PhD, and Kathy Petoumenos, PhD [all 3 with the University of New South Wales], and Daniel Barker, PhD [University of Newcastle]). We also thank Mohammad Siahpush, PhD (University of Nebraska Medical Center), for uncompensated contributions to the overall trial and for input on the statistical analysis plan, and Alan Melrose, LLB (University of New South Wales), for uncompensated support with other trial-related inquiries.

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AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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