Key Points
Question
Is cytisinicline an effective and safe pharmacotherapy to promote smoking cessation?
Findings
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.
Meaning
Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering a new nicotine dependence treatment option.
Abstract
Importance
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.
Objective
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.
Interventions
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).
Results
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.
Trial Registration
ClinicalTrials.gov Identifier: NCT04576949
This randomized trial compares the efficacy and tolerability of 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo for smoking cessation in adults who smoked cigarettes daily.
Introduction
Cigarette smoking is the leading preventable cause of premature mortality worldwide.1 Individuals who stop tobacco use reduce their health risks and increase life expectancy.2,3 Those who use a smoking cessation medication, such as nicotine replacement, bupropion, or varenicline, increase their odds of achieving sustained abstinence when attempting to quit.4,5,6,7 However, these US Food and Drug Administration (FDA)–approved pharmacotherapies have modest long-term abstinence rates and are associated with adverse events that may discourage their use.6 No smoking cessation pharmacotherapy has received FDA approval since 2006.8 New options are needed.
Cytisinicline, historically known as cytisine, is a naturally occurring plant-based alkaloid that has been used as an over-the-counter smoking cessation product in Central and Eastern Europe for decades but is not approved for marketing and labeling by regulatory agencies in countries outside this region.9,10 Cytisinicline, like varenicline, binds selectively to the α4β2 nicotinic acetylcholine receptor subtype that mediates nicotine dependence, acting as a partial agonist to reduce nicotine withdrawal symptoms while also blocking the reinforcement generated by nicotine when smoking cigarettes.9
The manufacturers’ recommended cytisine dosage is 1.5-mg tablets initially taken 6 times daily then gradually reduced over a 25-day course of treatment. With this regimen, cytisine demonstrated higher smoking cessation efficacy than placebo in a double-blind, randomized clinical trial in Poland11 and greater effectiveness than a nicotine patch in an open-label, randomized clinical trial in New Zealand.12 In a randomized, open-label, noninferiority trial in Australia among individuals who smoked daily and were willing to quit, a trial of cytisine treatment for 25 days, compared with varenicline treatment for 84 days, failed to demonstrate noninferiority regarding smoking cessation.13 No serious safety issues were identified in these trials or during the decades of commercial use in Europe.9,10,11,12,13
However, the scientific rationale for this regimen has never been published and may not be optimal.9 Cytisinicline’s mean elimination half-life of 4.8 hours supports a simplified regimen using 3 times daily administration.9,14 In a randomized phase 2b trial testing various doses and schedules for 25 days, 3 mg administered 3 times daily produced the highest biochemically confirmed continuous abstinence during 4 consecutive weeks after treatment ended (weeks 4 to 8) and was superior to placebo (30% vs 8%, P = .005).15 The 3-mg dose taken 3 times daily was well tolerated, achieved good treatment adherence, and was selected for use in phase 3 clinical trials.15
Because relapse commonly occurs early in a quit attempt, a treatment duration longer than 25 days might improve the effectiveness of the revised cytisinicline regimen.9,16 This randomized, double-blind, clinical trial compared the efficacy and tolerability of cytisinicline, 3 mg, administered 3 times daily vs placebo when administered for 6 weeks or 12 weeks.
Methods
This multisite, 3-group, double-blind, randomized phase 3 clinical trial evaluated the efficacy and tolerability of cytisinicline vs placebo, accompanied by behavioral support, for smoking cessation. The trial was approved by a centralized institutional review board. Participants provided written informed consent and were randomized from October 2020 through June 2021. Data collection ended in December 2021. Full protocol details are in the trial protocol (Supplement 1) and summarized here. The statistical analysis plan is in Supplement 2.
Setting and Participants
The trial was conducted at 17 sites widely distributed across the US, with the largest number of sites in the Southeast. Adults aged 18 years or older were eligible if they currently smoked 10 or more cigarettes per day, had expired air carbon monoxide (co) greater than or equal to 10 ppm, and were ready to set a date to quit smoking (Table 1 and Figure 1). Individuals were excluded if they used any noncigarette tobacco product (pipe tobacco, cigars, smokeless tobacco, hookah), electronic cigarettes, smoking cessation medication (bupropion, varenicline, nortriptyline, nicotine replacement product), or marijuana (smoked or vaped) in the 28 days before randomization or planned to use them during the study. Other exclusion criteria included uncontrolled hypertension; hepatic or kidney impairment; 3-month history of acute myocardial infarction, unstable angina, cerebrovascular incident, or hospitalization for congestive heart failure; moderate to severe depression symptoms (Hospital Anxiety and Depression Scale score ≥11)18; diagnosis of schizophrenia or bipolar disorder, current psychosis, suicidal ideation, or suicide risk (Columbia Suicide Severity Rating Scale)19; or a positive urinary screen for illicit drugs. (Full criteria are in the trial protocol in Supplement 1).
Table 1. Baseline Characteristics of Study Participants by Treatment Group.
| Demographic | |||
|---|---|---|---|
| Cytisinicline for 12 wk (n = 270) | Cytisinicline for 6 wk (n = 269) | Placebo (n = 271) | |
| Age, mean (SD), y | 53.3 (11.6) | 52.2 (11.2) | 52.0 (12.0) |
| Sex, No. (%) | |||
| Male | 135 (50.0) | 121 (45.0) | 112 (41.3) |
| Female | 135 (50.0) | 148 (55.0) | 159 (58.7) |
| Race, No. (%)a | |||
| American Indian/Alaska Native | 1 (0.4) | 2 (0.7) | 1 (0.4) |
| Asian | 1 (0.4) | 1 (0.4) | 1 (0.4) |
| Black or African American | 48 (17.8) | 40 (14.9) | 42 (15.5) |
| Native Hawaiian or Other Pacific Islander | 1 (0.4) | 1 (0.4) | 2 (0.7) |
| White | 216 (80.0) | 222 (82.5) | 221 (81.5) |
| Other | 3 (1.1) | 3 (1.1) | 4 (1.5) |
| Hispanic ethnicity, No. (%) | 23 (8.5) | 26 (9.7) | 19 (7.0) |
| Tobacco use, mean (SD) | |||
| Duration of smoking, y | 37.0 (12.9) | 36.3 (12.7) | 36.5 (12.6) |
| Cigarettes per day in the past 30 d | 19.4 (7.2) | 19.4 (7.3) | 19.4 (7.7) |
| Expired air carbon monoxide, ppm | 26.4 (14.5) | 26.3 (14.7) | 26.6 (13.8) |
| Fagerstrom Test for Nicotine Dependence scoreb | 5.6 (1.9) [n = 269] | 5.5 (1.8) [n = 267] | 5.6 (1.7) |
| Quitting history | |||
| Prior quit attempts, median (IQR) | 4 (2-6) | 4 (3-6) | 4 (2-6) |
| Prior cessation medication used, No. (%) | |||
| Nicotine replacement product | 174 (64.4) | 167 (62.1) | 171 (63.1) |
| Varenicline | 127 (47.0) | 113 (42.0) | 114 (42.1) |
| Bupropion | 57 (21.1) | 40 (14.9) | 56 (20.7) |
| Prior cessation behavioral support used, No. (%)c | 30 (11.1) | 25 (9.3) | 23 (8.5) |
| Comorbidities | |||
| Hospital Anxiety and Depression Scale total score, mean (SD)d | 5.5 (4.5) | 5.4 (3.7) | 5.5 (4.2) |
Race and ethnicity were assessed by a participant’s response to a fixed-category question.
Fagerstrom Test for Nicotine Dependence17 is a 6-item self-administered scale with a range of scores 0 to 10. Higher scores indicate greater physical dependence on nicotine, which is associated with less success achieving abstinence during a quit attempt.
Includes counseling support received in person, by phone, or via web.
Hospital Anxiety and Depression Scale18 is a 14-item self-administered scale, with a range of scores 0 to 42. Higher scores indicate more symptoms of anxiety and depression.
Figure 1. Screening, Randomization, and Follow-Up of Trial Participants in the Study of Cytisinicline for Smoking Cessation in Adults Who Smoked.
aA total of 159 participants did not meet inclusion criteria and 366 met exclusion criteria. A participant could be in both categories. The numbers of patients who were ineligible for various reasons are not shown because not every site screened all patients for all potential reasons for ineligibility.
bRandomization stratified by study site.
Recruitment and Assignment to Condition
At a screening visit, individuals provided written informed consent; completed a medical history, brief physical examination, and electrocardiogram and laboratory tests; agreed to a quit date 5 to 7 days after study drug initiation; and recorded the number of cigarettes smoked daily for 7 days. Baseline measures included race and ethnicity, assessed by a participant’s response to a fixed-category question, in order to explore whether these factors moderated treatment success. At a second visit, participants who met inclusion and exclusion criteria were randomly assigned to a study group, received brief smoking cessation counseling, set their quit date within 5 to 7 days, and started study medication the next day. A predetermined central computer-generated randomization sequence was used to assign participants (1:1:1) stratified by study site to receive placebo 3 times daily for 12 weeks, 3-mg cytisinicline 3 times daily for 6 weeks followed by placebo 3 times daily for 6 weeks, or 3-mg cytisinicline 3 times daily for 12 weeks (eFigure 1 in Supplement 3).
Interventions
The study medication was identical-appearing tablets containing 3 mg of cytisinicline or placebo taken orally 3 times daily for 12 weeks. Participants were followed up for 12 additional weeks after treatment ended. All participants received 10 minutes of brief smoking cessation behavioral support provided by trained counselors at each visit for up to 15 visits from randomization through week 12. Shorter sessions were offered at weeks 16, 20, and 24.
Assessments
Assessments after randomization were conducted at in-person visits on day 2, weekly from 1 to 12 weeks, and at weeks 16, 20, and 24. Participants who discontinued study drug prematurely were encouraged to remain in the study and complete all assessment visits. Smoking status was assessed by self-report of smoking abstinence since the last visit, measured weekly from weeks 2 through 12. A breath co level was measured at each visit. Verified abstinence for weeks 2 to 12 required self-reported nonsmoking since the last visit and a breath co level less than 10 ppm. Self-reported abstinence at weeks 16, 20, and 24 used the Russell Standard criteria of not smoking more than 5 cigarettes since the last visit.20 Verified abstinence at 16, 20, and 24 weeks also required a breath co level less than 10 ppm. Participants not meeting these criteria or with missing data were classified as smoking.
Safety was assessed by measurement of vital signs and participant self-report of adverse events and concomitant medications on day 2 and at weekly visits during treatment from weeks 1 to 12 and through an additional 12-week follow-up. Hematology and chemistry laboratory tests were done at weeks 1, 6, and 12. Electrocardiograms were done at weeks 6 and 12. Clinically significant adverse events or abnormalities were followed until resolution or end of study.
Outcome Measures
The study had 2 primary end points, which assessed whether cytisinicline produced greater biochemically confirmed continuous smoking abstinence when compared with placebo during the last 4 weeks of the 6-week treatment (weeks 3 to 6) and the last 4 weeks of the 12-week treatment (weeks 9 to 12). Trial statistical success was defined as either primary end point meeting statistical criterion. Participants were allowed 1 missed visit (ie, smoking status unknown) for analysis of the primary end point. The secondary outcome measure was verified continuous smoking abstinence from the last 4 weeks of cytisinicline or placebo treatment to week 24. This outcome required verified continuous abstinence from weeks 3 to 24 for the 6-week cytisinicline treatment group and from weeks 9 to 24 for the 12-week cytisinicline group. A third secondary outcome measure compared the risk of relapse to smoking between weeks 6 and 24 among participants assigned to cytisinicline who achieved sustained abstinence during weeks 3 to 6. These individuals were either switched to placebo at week 6 or continued cytisinicline to week 12. Other prespecified end points included comparing the difference between groups in verified 7-day point-prevalence abstinence at each visit from week 2 through week 24 and assessing for evidence of effect modification for subsets defined by baseline attributes. To assess cigarette craving between groups, the Brief Questionnaire of Smoking Urges (QSU-brief) was administered at clinic visits on day 0 and at weeks 1 to 6.21,22 Tolerability outcomes included the incidence of treatment-emergent serious and nonserious adverse events during treatment with cytisinicline or placebo and clinically significant changes in vital signs, laboratory tests, or electrocardiograms.
Statistical Analysis
Analyses for the 2 binary primary and secondary outcomes were based on exact analyses 2 × 2 tables that compared randomized groups, stratified by clinical site. Participants with missed assessments required for primary and secondary end points were classified as still smoking. A target sample of 750 participants (n = 250 per group) was computed and verified using simulations to provide 96% power for specifications of an overall 1-sided .025 type I error probability and abstinence probabilities of 7% for placebo and 19% for cytisinicline. The Hochberg procedure was used to control for primary outcome multiplicity.23 Sensitivity analyses included assessments of effect modification related to subsets defined by baseline attributes using a logistic regression model. Longitudinal analyses used mixed model for repeated measures methodology with a constrained model when using prerandomization data.24 Analyses of adverse events included all randomized participants who received at least 1 dose of study drug.
Results
Participants
Of 1345 individuals screened, 810 were eligible and randomized to 1 of 3 groups: 12 weeks of cytisinicline (n = 270), 6 weeks of cytisinicline plus 6 weeks of placebo (n = 269), or placebo (n = 271) (Figure 1). Demographic characteristics did not differ between screened individuals who were randomized or not randomized. Primary efficacy analyses included all 810 randomized participants. Analyses of adverse events (n = 809) excluded 1 participant in the placebo group who received no study medication. Follow-up visits ended in December 2021.
Individuals in all groups were comparable on baseline characteristics, including age, sex, race and ethnicity, smoking and quitting history, nicotine dependence,17 and anxiety and depression symptoms (Table 1). Participants smoked a mean of 19.4 cigarettes per day. Overall, 663 participants (81.9%) completed 12 weeks of study drug treatment (12-week cytisinicline group: 232 [85.9%], 6-week cytisinicline group: 217 [80.7%], placebo group: 214 [79.0%]). Study drug compliance was high: 79.3% of participants in the 12-week cytisinicline group, 76.6% in the 6-week cytisinicline group, and 69.3% in the placebo group took 90% or more of the study drug doses. Compliance with behavioral support was also high, with 92.8% of planned sessions completed by participants in the 12-week cytisinicline group, 89.5% in the 6-week cytisinicline group, and 86.8% in the placebo group. Follow-up assessments were completed by 618 participants (76.3%) at 24 weeks (12-week cytisinicline group: 225 [83.3%], 6-week cytisinicline group: 199 [74.0%], and placebo group: 194 [71.6%]). Participants who did and did not complete follow-up did not differ significantly in age, sex, or number of cigarettes smoked per day at baseline.
Efficacy
Biochemically confirmed continuous smoking abstinence during the last 4 weeks of treatment, the primary outcome measure, was significantly higher for cytisinicline compared with placebo at both treatment durations (Table 2). For 6-week cytisinicline treatment vs placebo, 25.3% vs 4.4% of participants were abstinent during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001). For 12-week cytisinicline treatment vs placebo, the difference was 32.6% vs 7.0% during weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001).
Table 2. Smoking Cessation Outcomes by Treatment Group.
| Outcome measure | No. (%) | Cytisinicline for 12 wk vs placebo | Cytisinicline for 6 wk vs placebo | ||||
|---|---|---|---|---|---|---|---|
| Cytisinicline for 12 wk (n = 270) | Cytisinicline for 6 wk (n = 269) | Placebo (n = 271) | Odds ratio (95% CI) | P value | Odds ratio (95% CI) | P value | |
| Biochemically confirmed continuous smoking abstinencea | |||||||
| Primary outcomes | |||||||
| Weeks 3-6b | 60 (22.2) | 68 (25.3) | 12 (4.4) | 8.0 (3.9-16.3) | <.001 | ||
| Weeks 9-12c | 88 (32.6) | 60 (22.3) | 19 (7.0) | 6.3 (3.7-11.6) | <.001 | ||
| Secondary outcomesd | |||||||
| Weeks 3-24 | 32 (11.9) | 24 (8.9) | 7 (2.6) | 3.7 (1.5-10.2) | .002 | ||
| Weeks 9-24 | 57 (21.1) | 37 (13.8) | 13 (4.8) | 5.3 (2.8-11.1) | <.001 | ||
Abstinence from cigarette smoking was defined as a self-report of no cigarettes since last visit that was confirmed by expired air carbon monoxide (co) <10 ppm. Participants with co ≥10 ppm or missing outcome data were counted as smoking.
Smoking abstinence reported and validated at weeks 3, 4, 5, and 6.
Smoking abstinence reported and validated at weeks 9, 10, 11, and 12.
Continued abstinence from cigarette smoking beyond the primary end point to week 24 was defined as a self-report of no cigarettes since last visit (through week 12 visit) or self-report of no more than 5 cigarettes since last visit at monthly visits (weeks 16, 20, and 24), with self-report confirmed by expired air co <10 ppm at each visit. Participants with co ≥10 ppm or missing outcome data were counted as smoking.
Continuous abstinence from the last 4 weeks of treatment through 6 months (secondary outcome measure) was significantly higher at both cytisinicline treatment durations vs placebo (Table 2). For 6-week cytisinicline treatment vs placebo, 8.9% vs 2.6% of participants were abstinent during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For 12-week cytisinicline treatment vs placebo, 21.1% vs 4.8% of participants were abstinent during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). eTable 1 in Supplement 3 provides relative risk and number needed to treat estimates based on exact analysis of the 2 × 2 table of group by binary outcome (unstratified because no evidence suggested clinical site effect modification). Confidence intervals were computed algebraically from exact ORs and 95% CIs.25
Among participants who were assigned to either cytisinicline group and who achieved continuous abstinence during weeks 3 to 6, the individuals who continued cytisinicline for an additional 6 weeks (12-week cytisinicline group) did not have a significantly different rate of relapse-free abstinence during weeks 6 to 24 compared with individuals in the 6-week cytisinicline group who switched to placebo at week 6 (10.4% vs 13.3%; OR, 1.31 [95% CI, 0.75-2.33]; P = .35). For this analysis, individuals who were not abstinent at weeks 3 to 6, 12, 16, 20, and 24 were regarded as having relapsed.
Figure 2 displays the weekly estimated prevalence probabilities of being abstinent. A participant who reported no cigarettes smoked in the last 7 days and provided biochemical confirmation was classified as abstinent. Both cytisinicline groups illustrated progressively increasing probabilities of abstinence over the first 6 weeks of treatment and had clinically meaningful higher probabilities than placebo throughout active treatment. The estimated ORs with 95% CIs for comparisons with placebo at every week, and in particular for the posttreatment follow-up weeks, did not include 1 (Figure 2).
Figure 2. Weekly Prevalence Probabilities of Biochemically Confirmed Tobacco Abstinence by Group.
At each week, participants reported whether cigarettes were smoked in the last 7 days. A participant was classified as abstinent for that week if no smoking was reported and was biochemically confirmed. Missing assessments were classified as nonabstinence in order to include all randomized. The prevalence probabilities and exact 95% CIs were estimated at each week.
Assessment of heterogeneity of subsets defined by baseline attributes are shown in eFigure 2 in Supplement 3. No evidence of effect modification was evident for the subgroups defined by age, sex, or number of cigarettes smoked per day.
The mean total cigarette craving score, using the QSU-brief, declined more rapidly between baseline and week 6 among participants who received cytisinicline for 6 or 12 weeks compared with placebo (eFigure 3 in Supplement 3). Confidence intervals for the effect estimates at weeks 1 to 6 excluded 0, providing evidence of a rapid and sustained effect.
Safety
Treatment-emergent adverse events were reported by 184 participants (68.2%) in the 12-week cytisinicline group, 172 (63.9%) in the 6-week cytisinicline group, and 166 (61.5%) in the placebo group (Table 3). The majority of adverse events were nonserious and mild to moderate in severity. Across all 3 groups, nausea, headache, abnormal dreams, and insomnia were the most common (>5%) adverse events, but only the incidences of abnormal dreams and insomnia were higher in the cytisinicline groups compared with placebo. Study drug discontinuation due to adverse events occurred in 16 (2.9%) of 539 participants receiving cytisinicline (6-week group: 2.2%, 12-week group: 3.7%), and 4 (1.5%) of 270 participants receiving placebo (Figure 1). Serious adverse events occurred in 18 (3.3%) of 539 participants who received cytisinicline and in 3 (1.1%) of 270 participants who received placebo (OR, 3.08 [95% CI, 0.98-13.18]) (Table 3). No serious adverse event was judged to be treatment-related, including the 1 death that occurred in the 6-week cytisinicline group.
Table 3. Summary of Adverse Events by Treatment Groupa.
| Outcome measure | No. (%) | ||
|---|---|---|---|
| Cytisinicline for 12 wk (n = 270) | Cytisinicline for 6 wk (n = 269) | Placebo (n = 270)a | |
| No. of participants with | |||
| Any treatment-emergent adverse event | 184 (68) | 172 (64) | 166 (62) |
| Any serious adverse eventb | 8 (3) | 10 (4) | 3 (1) |
| Any treatment-related serious adverse eventc | 0 | 0 | 0 |
| No. of treatment emergent adverse events | n = 494 | n = 459 | n = 359 |
| Mild | 303 (61) | 290 (63) | 239 (67) |
| Moderate | 178 (36) | 148 (32) | 114 (32) |
| Severe | 13 (3) | 21 (5) | 6 (2) |
| Most frequent treatment-emergent adverse eventsd | |||
| Insomnia | 26 (10) | 23 (9) | 13 (5) |
| Abnormal dreams | 21 (8) | 22 (8) | 8 (3) |
| Headache | 21 (8) | 18 (7) | 22 (8) |
| Nausea | 15 (6) | 16 (6) | 20 (7) |
| Constipation | 13 (5) | 16 (6) | 3 (1) |
| Anxiety | 15 (6) | 7 (3) | 5 (2) |
| Diarrhea | 12 (4) | 10 (4) | 15 (6) |
Analysis limited to participants who took at least 1 dose of study medication. Because 1 participant randomized to the placebo group (n = 271) took no study medication, the denominator for this analysis is 270).
Serious adverse event was defined as an adverse event that resulted in death or was life-threatening; required hospitalization or prolonged an existing hospitalization; resulted in persistent or significant disability, incapacity, or congenital abnormality; or which required medical intervention to prevent any of the above outcomes.
A serious adverse event’s relationship to treatment was judged by responsible investigator using best medical judgment and based on a reasonable temporal sequence from the time of study drug administration, and/or a known response pattern to the study drug; could not have been produced by other factors such as the participant’s clinical state, therapeutic intervention, or concomitant therapy; and either occurred immediately following study drug administration or improved on stopping the study drug.
Includes all treatment-emergent adverse events reported by 5% or more of participants in any study group. Listed in descending order by combined cytisinicline for 6 and 12 weeks.
Discussion
This multisite, placebo-controlled, phase 3, randomized clinical trial tested the efficacy and tolerability of a novel regimen of cytisinicline. Both 6- and 12-week schedules administered cytisinicline at a dose of 3 mg taken 3 times daily, combined with behavioral support, and both demonstrated robust efficacy for smoking cessation among adults who sought to quit smoking. Participants in the cytisinicline groups had 6- to 8-fold higher odds of continuous smoking abstinence at the end of treatment than participants receiving placebo plus behavioral support. The efficacy of cytisinicline treatment for both 6 and 12 weeks, compared with placebo, was sustained to 24-week follow-up and was consistently demonstrated in subgroups defined by baseline characteristics. At 24 weeks, this new regimen produced 1 additional person abstinent for every 6 people treated with cytisinicline for 12 weeks or for every 11 people treated for 6 weeks (eTable 1 in Supplement 3). Cytisinicline reduced nicotine craving and was well tolerated by participants, who adhered to the treatment schedule at a high rate, even though the trial was conducted during the early phases of the US COVID-19 pandemic.
Among cytisinicline-treated participants who achieved 4 weeks of tobacco abstinence by week 6, an additional 6 weeks of cytisinicline treatment, compared with stopping at week 6, did not lower a participant’s risk of relapse (ie, resuming smoking during weeks 6 to 24). However, point-prevalence abstinence rates in the group treated with cytisinicline for 12 weeks continued to increase after week 6 (Figure 2), suggesting that quitting continued to occur among participants who did not attain abstinence by week 6 and continued to receive cytisinicline. This appears to have contributed to those in the 12-week cytisinicline group achieving successful abstinence at weeks 9 to 12 compared with placebo. The observation that some participants who did not quit smoking when treatment started but achieved abstinence later during a period of ongoing treatment has also been reported with varenicline, which has pharmacological properties similar to cytisinicline, but it has not been observed with other smoking cessation pharmacotherapies.26,27
The effect size and absolute level of tobacco abstinence achieved with cytisinicline at 6-month follow-up in this trial were larger than the continuous 6-month abstinence rate in a previous placebo-controlled trial that used the drug’s traditional dosing and in a recent systematic review of cytisinicline clinical trials.11,28 This supports the hypothesis that a higher dose and longer treatment duration increases cytisinicline’s efficacy while maintaining acceptable tolerability. Indirect support also comes from an open-label, randomized trial of people who smoked and underwent lung cancer screening.29 In that trial, cytisinicline given for 40 or 84 days, plus smoking cessation counseling, was more effective than counseling alone, with 12-month verified continuous abstinence rates and adjusted ORs exceeding those achieved in the prior 25-day trial.11,29
Cytisinicline was directly compared with varenicline in 2 noninferiority trials. It was noninferior to varenicline for smoking cessation in the trial that included a cytisinicline maintenance dose through 12 weeks, but it failed to show noninferiority to varenicline in a trial that compared cytisinicline taken for 25 days vs varenicline taken for 84 days.13,30 In both trials, participants reported significantly fewer adverse events with cytisinicline than with varenicline. Cytisinicline administered for 25 days outperformed a nicotine patch used for 8 weeks in the 1 published trial directly comparing these drugs.12 That trial used a lower dose and shorter duration of cytisinicline than was tested in the current trial.
Limitations
This study had several limitations. First, it enrolled a predominantly White sample, limiting generalizability for other racial and ethnic groups. Second, it excluded participants with a diagnosis of serious mental illness, suicidal ideation, moderate to severe depression symptoms, recent unstable cardiovascular disease, and current marijuana or illicit drug use, limiting the generalizability of the findings to these groups. Third, adverse event reports were assessed for 24 weeks, but the trial was not large enough or long enough to detect uncommon adverse events. However, cytisinicline has been used for decades as a cessation aid by millions of people who smoke in Central and Eastern Europe and the 25-day regimen has a good safety record.9 Fourth, while participants were followed up for at least 12 weeks after study drug treatment ended, a longer durability of posttreatment abstinence cannot be ascertained from the trial. Fifth, the intensity of behavioral support and attention to treatment dosing in this trial likely exceeds what can be provided in typical health care settings.
Conclusions
This phase 3, multisite, placebo-controlled, randomized clinical trial, the first large trial conducted in the US, demonstrated that a novel regimen of cytisinicline, along with behavioral support, has robust efficacy and excellent tolerability as a treatment for tobacco dependence.
Trial Protocol
Statistical Analysis Plan
eFigure 1. ORCA-2 Study Design
eFigure 2. Continuous Abstinence at End of Treatment: Effect Modification
eFigure 3. Total Score of Brief Questionnaire of Smoking Urges Over Time, by Group
eTable. Biochemically Confirmed Continuous Smoking Abstinence by Arm
Data Sharing Statement
References
- 1.World Health Organization . WHO Report on the Global Tobacco Epidemic, 2019: Monitoring Tobacco Use and Prevention Policies. World Health Organization; 2019. [Google Scholar]
- 2.Jha P, Ramasundarahettige C, Landsman V, et al. 21st-Century hazards of smoking and benefits of cessation in the United States. N Engl J Med. 2013;368(4):341-350. doi: 10.1056/NEJMsa1211128 [DOI] [PubMed] [Google Scholar]
- 3.US Department of Health and Human Services . Smoking Cessation: A Report of the Surgeon General— Executive Summary. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2020. [Google Scholar]
- 4.Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507-2520. doi: 10.1016/S0140-6736(16)30272-0 [DOI] [PubMed] [Google Scholar]
- 5.Patnode CD, Henderson JT, Coppola EL, Melnikow J, Durbin S, Thomas RG. Interventions for tobacco cessation in adults, including pregnant persons: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2021;325(3):280-298. doi: 10.1001/jama.2020.23541 [DOI] [PubMed] [Google Scholar]
- 6.Rigotti NA, Kruse GR, Livingstone-Banks J, Hartmann-Boyce J. Treatment of tobacco smoking: a review. JAMA. 2022;327(6):566-577. doi: 10.1001/jama.2022.0395 [DOI] [PubMed] [Google Scholar]
- 7.Selby P, Zawertailo L. Tobacco addiction. N Engl J Med. 2022;387(4):345-354. doi: 10.1056/NEJMcp2032393 [DOI] [PubMed] [Google Scholar]
- 8.US Food and Drug Administration . Accessed August 15, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_ChantixTOC.cfm
- 9.Tutka P, Vinnikov D, Courtney RJ, Benowitz NL. Cytisine for nicotine addiction treatment: a review of pharmacology, therapeutics and an update of clinical trial evidence for smoking cessation. Addiction. 2019;114(11):1951-1969. doi: 10.1111/add.14721 [DOI] [PubMed] [Google Scholar]
- 10.Prochaska JJ, Das S, Benowitz NL. Cytisine, the world’s oldest smoking cessation aid. BMJ. 2013;347:f5198. doi: 10.1136/bmj.f5198 [DOI] [PubMed] [Google Scholar]
- 11.West R, Zatonski W, Cedzynska M, et al. Placebo-controlled trial of cytisine for smoking cessation. N Engl J Med. 2011;365(13):1193-1200. doi: 10.1056/NEJMoa1102035 [DOI] [PubMed] [Google Scholar]
- 12.Walker N, Howe C, Glover M, et al. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014;371(25):2353-2362. doi: 10.1056/NEJMoa1407764 [DOI] [PubMed] [Google Scholar]
- 13.Courtney RJ, McRobbie H, Tutka P, et al. Effect of cytisine vs varenicline on smoking cessation: a randomized clinical trial. JAMA. 2021;326(1):56-64. doi: 10.1001/jama.2021.7621 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Jeong SH, Newcombe D, Sheridan J, Tingle M. Pharmacokinetics of cytisine, an α4 β2 nicotinic receptor partial agonist, in healthy smokers following a single dose. Drug Test Anal. 2015;7(6):475-482. doi: 10.1002/dta.1707 [DOI] [PubMed] [Google Scholar]
- 15.Nides M, Rigotti NA, Benowitz N, Clarke A, Jacobs C. A multicenter, double-blind, randomized, placebo-controlled phase 2b trial of cytisinicline in adult smokers (the ORCA-1 Trial). Nicotine Tob Res. 2021;23(10):1656-1663. doi: 10.1093/ntr/ntab073 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Hughes JR, Keely J, Naud S. Shape of the relapse curve and long-term abstinence among untreated smokers. Addiction. 2004;99(1):29-38. doi: 10.1111/j.1360-0443.2004.00540.x [DOI] [PubMed] [Google Scholar]
- 17.Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström test for nicotine dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict. 1991;86(9):1119-1127. doi: 10.1111/j.1360-0443.1991.tb01879.x [DOI] [PubMed] [Google Scholar]
- 18.Stern AF. The Hospital Anxiety and Depression Scale. Occup Med (Lond). 2014;64(5):393-394. doi: 10.1093/occmed/kqu024 [DOI] [PubMed] [Google Scholar]
- 19.Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking cessation trials: proposal for a common standard. Addiction. 2005;100(3):299-303. doi: 10.1111/j.1360-0443.2004.00995.x [DOI] [PubMed] [Google Scholar]
- 21.West R, Ussher M. Is the ten-item Questionnaire of Smoking Urges (QSU-brief) more sensitive to abstinence than shorter craving measures? Psychopharmacology (Berl). 2010;208(3):427-432. doi: 10.1007/s00213-009-1742-x [DOI] [PubMed] [Google Scholar]
- 22.Cox LS, Tiffany ST, Christen AG. Evaluation of the brief Questionnaire of Smoking Urges (QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001;3(1):7-16. doi: 10.1080/14622200020032051 [DOI] [PubMed] [Google Scholar]
- 23.Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289-300. doi: 10.1111/j.2517-6161.1995.tb02031.x [DOI] [Google Scholar]
- 24.Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent variable in analyses of change from baseline in clinical trials? Stat Med. 2009;28(20):2509-2530. doi: 10.1002/sim.3639 [DOI] [PubMed] [Google Scholar]
- 25.Thomas DG, Gart JJ. A table of exact confidence limits for differences and ratios of two proportions and their odds ratio. J Am Stat Assoc. 1977;72:73-76. doi: 10.1080/01621459.1977.10479909 [DOI] [Google Scholar]
- 26.Jorenby DE, Hays JT, Rigotti NA, et al. A randomized controlled trial comparing the efficacy of varenicline, a novel α4β2 nicotinic acetylcholine receptor partial agonist, to bupropion and to placebo for smoking cessation. JAMA. 2006;296:56-63. doi: 10.1001/jama.296.1.56 [DOI] [PubMed] [Google Scholar]
- 27.Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010;121(2):221-229. doi: 10.1161/CIRCULATIONAHA.109.869008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Livingstone-Banks J, Fanshawe TR, Thomas KH, et al. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2023;5(5):CD006103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Pastorino U, Ladisa V, Trussardo S, et al. Cytisine Therapy Improved Smoking Cessation in the Randomized Screening and Multiple Intervention on Lung Epidemics Lung Cancer Screening Trial. J Thorac Oncol. 2022;17(11):1276-1286. doi: 10.1016/j.jtho.2022.07.007 [DOI] [PubMed] [Google Scholar]
- 30.Walker N, Smith B, Barnes J, et al. Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial. Addiction. 2021;116(10):2847-2858. doi: 10.1111/add.15489 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
Statistical Analysis Plan
eFigure 1. ORCA-2 Study Design
eFigure 2. Continuous Abstinence at End of Treatment: Effect Modification
eFigure 3. Total Score of Brief Questionnaire of Smoking Urges Over Time, by Group
eTable. Biochemically Confirmed Continuous Smoking Abstinence by Arm
Data Sharing Statement
