Is cytisinicline an effective and safe pharmacotherapy to promote smoking cessation?
In a randomized clinical trial that included 810 adults who smoked, both a 6-week and a 12-week course of a novel cytisinicline dosing regimen were more effective than placebo and were well tolerated, producing significantly higher continuous smoking abstinence rates compared with placebo during the last 4 weeks of drug treatment and from the end of treatment to 24 weeks.
Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering a new nicotine dependence treatment option.
Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4β2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal.
To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo.
Design, Setting, and Participants
A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021.
Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support.
Main Outcomes and Measures
Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary).
Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred.
Conclusions and Relevance
Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options.
ClinicalTrials.gov Identifier: NCT04576949
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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.
Accepted for Publication: May 23, 2023.
Corresponding Author: Nancy A. Rigotti, MD, Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, 100 Cambridge St, Ste 1600, Boston, MA 02114 (email@example.com).
Author Contributions: Drs Rigotti and Blumenstein 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: All authors.
Acquisition, analysis, or interpretation of data: Rigotti, Benowitz, Leischow, Clarke, Cain, Jacobs.
Drafting of the manuscript: Rigotti, Leischow, Nides, Blumenstein, Clarke, Cain, Jacobs.
Critical revision of the manuscript for important intellectual content: Rigotti, Benowitz, Prochaska, Leischow, Clarke, Cain, Jacobs.
Statistical analysis: Blumenstein, Jacobs.
Obtained funding: Cain, Jacobs.
Administrative, technical, or material support: Leischow, Cain.
Supervision: Rigotti, Prochaska, Leischow, Clarke, Jacobs.
Other–regulatory coordination with FDA for conducting this trial: Jacobs.
Conflict of Interest Disclosures: Dr Rigotti reported receiving grants and personal fees from Achieve Life Sciences during the conduct of the study; personal fees from UpToDate outside the submitted work; and funds from the National Cancer Institute, paid through contracts with Bizzell US and Strategix Management LLC, to co-chair the workshop, Current State of Tobacco Cessation Interventions and Tobacco Prevention Research. Dr Benowitz reported receiving personal fees for serving on a data monitoring board for Achieve Life Sciences during the conduct of the study and personal fees from being an expert witness against tobacco companies outside the submitted work. Dr Prochaska reported receiving personal fees for serving on a data monitoring board for Achieve Life Sciences during the conduct of the study and personal fees from plaintiff law firms in litigation against tobacco companies for expert witness work and from technology companies developing treatments for quitting smoking for consulting and advising outside the submitted work. Dr Leischow reported receiving grants from Achieve Life Sciences during the conduct of the study and nonfinancial support from Pfizer (medication for a National Institutes of Health–funded study on over-the-counter use of varenicline) outside the submitted work. Dr Nides reported receiving personal fees from Achieve Life Sciences during the conduct of the study and personal fees from Pfizer outside the submitted work. Dr Blumenstein reported being a self-employed biostatistical consultant to Achieve Life Sciences. Dr Clarke reported being an employee of Achieve Life Sciences; in addition, Dr Clarke had a patent for succinate salt of cytisine and use thereof issued and a patent for compositions comprising cytisine in the treatment and/or prevention of addiction in subjects in need thereof pending. Mr Cain reported being an employee of Achieve Life Sciences; in addition, Mr Cain had patents 11083715 and 11083716 issued to Achieve Life Sciences. Dr Jacobs reported being an employee of Achieve Life Sciences; in addition, Dr Jacobs had patents 11083715 and 11083716 issued to Achieve Life Sciences.
Funding/Support: This study was supported by Achieve Life Sciences.
Role of the Funder/Sponsor: This phase 3 trial was designed by Achieve Life Sciences with input from the authors and regulatory reviews at the Food and Drug Administration. Achieve Life Sciences had oversight of the conduct of the study; collection, management, and analysis of the data, and submitted trial results to the Food and Drug Administration under an Investigational New Drug application for cytisinicline. Achieve Life Sciences collaborated with all external coauthors on the interpretation of the data. The manuscript was drafted by Dr Rigotti and reviewed and approved by all coauthors. Several individuals employed by Achieve Life Sciences who fulfilled authorship criteria were coauthors of the manuscript. Achieve Life Sciences had the right to review the manuscript but not to veto publication or control the decision regarding manuscript submission. The decision to submit the manuscript for publication was made by the principal investigator, Dr Rigotti.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We thank the study participants and the cytisinicline investigators and support staff for their contributions.
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