Key Points
Question
Is cytisinicline an effective and safe pharmacotherapy for smoking cessation and nicotine craving reduction?
Findings
In a replication randomized clinical trial of 792 adults who smoked 10 or more cigarettes daily and received behavioral support, both 6- and 12-week cytisinicline regimens were more effective than placebo, producing significantly higher continuous smoking abstinence rates than placebo at the end of drug treatment and through 24 weeks. Cytisinicline reduced nicotine cravings and was well tolerated.
Meaning
These results demonstrate the high smoking cessation efficacy and excellent tolerability of cytisinicline, confirm its ability to reduce nicotine craving, and support adoption of cytisinicline as a smoking cessation medication.
Abstract
Importance
New smoking cessation medication options are needed. Cytisinicline, a partial agonist at α4β2 nicotinic acetylcholine receptors, has demonstrated smoking cessation efficacy in 1 US trial. Additional evidence is needed.
Objective
To reproduce the findings of the efficacy and tolerability of cytisinicline compared with placebo for smoking cessation and to test its effect on nicotine craving as a mechanism of action.
Design, Settings, and Participants
This was a 3-group double-blind, placebo-controlled phase 3 replication randomized clinical trial (ORCA-3) conducted at 20 clinical trial sites in the US from January 2022 to March 2023. It compared 6 and 12 weeks of a novel cytisinicline regimen to placebo among adults who smoked 10 or more cigarettes daily and sought to quit. Participants were randomized (1:1:1) to 3-mg cytisinicline 3 times daily for 12 weeks; 3-mg cytisinicline 3 times daily for 6 weeks followed by placebo for 6 weeks; or placebo 3 times daily for 12 weeks. The follow-up period was 24 weeks, and all groups received behavioral support. Data analyses were performed from May 3, 2023, to March 20, 2024.
Interventions
Cytisinicline, 3 mg, 3 times daily for 12 weeks; cytisinicline, 3 mg, 3 times daily for 6 weeks followed by placebo for 6 weeks; or placebo 3 times daily for 12 weeks.
Main Outcomes and Measures
Biochemically verified (carbon monoxide <10 ppm) continuous smoking abstinence during the last 4 weeks of 6- and 12-week treatments (primary outcome) and from end of treatment to 24 weeks (secondary outcome); Questionnaire of Smoking Urges; incidence of adverse events.
Results
Of 792 participants randomized (mean [SD] age, 52.0 [11.8] years; 439 [55.4%] female; mean [SD] cigarettes/d, 20.4 [7.5]), 628 (79.3%) completed the trial. Primary and secondary outcomes were significantly higher for both cytisinicline groups vs placebo. For 6-week treatment, 39 cytisinicline participants (14.8%) vs 16 placebo participants (6.0%) were abstinent during weeks 3 to 6 (odds ratio [OR], 2.9; 95% CI, 1.5-5.6; P < .001). For 12-week treatment, 80 cytisinicline participants (30.3%) vs 25 placebo participants (9.4%) were abstinent during weeks 9 to 12 (OR, 4.4; 95% CI, 2.6-7.3; P < .001). Continuous abstinence rates for the 6-week treatment were 6.8% (cytisinicline) vs 1.1% (placebo) from weeks 3 to 24 . Continuous abstinence rates for the 12-week treatment were 20.5% (cytisinicline) vs 4.2% (placebo) for weeks 9 to 24. Reduction in craving at week 6 was greater for cytisinicline than placebo (−15.2 points [95% CI, −16.4 to −14.0] vs −12.0 points [95% CI, −13.5 to −10.5]; P < .001). Cytisinicline was well tolerated with no treatment-related serious adverse events.
Conclusions and Relevance
The findings of the ORCA phase 3 trial reaffirms the efficacy and tolerability of cytisinicline at both 6- and 12-week treatment for smoking cessation, with benefits extending through 24 weeks. As a mechanism of effect, cytisinicline mitigated nicotine craving.
Trial Registration
ClinicalTrials.gov Identifier: NCT05206370
This phase 3 replication randomized clinical trial reassesses the efficacy and tolerability of cytisinicline for smoking cessation and reducing nicotine craving.
Introduction
Cigarette smoking remains the leading cause associated with preventable mortality worldwide, contributing to an estimated 8 million premature deaths annually.1 Stopping smoking reduces tobacco-related morbidity and mortality and increases life expectancy.2,3 Nicotine dependence treatment using pharmacotherapy and behavioral support is effective.4 The US Food & Drug Administration (FDA) has approved nicotine replacement products, bupropion, and varenicline as smoking cessation aids; however, their long-term smoking cessation rates are modest, adverse effects can limit their use, and many individuals have already tried them without success.4,5,6,7 New options are urgently needed because no cessation medication has been approved for use in the US since 2006.8
Cytisinicline is a plant-based alkaloid that binds selectively to α4β2 neuronal nicotinic acetylcholine receptors, which mediate nicotine dependence.9 As a partial agonist, cytisinicline reduces nicotine craving and withdrawal symptoms, while as an antagonist, it reduces nicotine binding to neuronal nicotinic acetylcholine receptors, limiting nicotine’s reinforcing effects.9 The efficacy of cytisinicline compared to placebo and to nicotine patch has been demonstrated in clinical trials using a traditional dosing schedule with 1.5 mg taken 6 times daily and titrated downward over a 25-day treatment course.9,10,11,12 Cytisinicline may have similar efficacy compared to varenicline and have fewer adverse effects.12 The scientific rationale for traditional dosing of cytisinicline is unknown.9 We developed a novel dosing regimen based on cytisinicline pharmacokinetics with the goal of optimizing efficacy: 3 mg taken 3 times daily for 6 or 12 weeks.13,14
A phase 3 randomized double-blind clinical study (ORCA-2; NCT04576949) compared this dosing regimen, given for 6 or 12 weeks to placebo, with all participants receiving behavioral support.15 Both 6- and 12-week cytisinicline treatment durations demonstrated clinically robust and statistically significant efficacy for biochemically verified continuous tobacco abstinence during the last 4 weeks of treatment, and for continuous abstinence to 24 weeks.15
ORCA-2 was the first large cytisinicline randomized clinical trial conducted in the US.15 To confirm its results and support the cytisinicline application for FDA licensure, we undertook ORCA-3, a second phase 3 randomized clinical trial to test the efficacy and safety of cytisinicline for smoking cessation. This study reports the results and describes the effect of cytisinicline on cigarette craving and nicotine exposure as evidence of its mechanism of action.
Methods
This trial was reviewed and approved by the institutional review board of Advarra. The study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. Participants provided written informed consent. Full protocol details are provided in the trial protocol (Supplement 1) and the statistical analysis plan (Supplement 2).
Trial Design and Participants
ORCA-3, a multisite, 3-group, double-blind, randomized placebo-controlled clinical trial, tested the efficacy and safety of cytisinicline for smoking cessation using the dosing regimen of 3 mg 3 times daily for 6 or 12 weeks. The trial was conducted at 20 sites in 15 US states. Adults (≥18 years old) were eligible if they currently smoked 10 or more cigarettes per day, had expired air carbon monoxide (CO) of 10 ppm or greater, and were ready to set a date to quit smoking. Individuals were excluded if they had previously used cytisinicline; used bupropion, varenicline, nortriptyline, or any nicotine replacement product within 4 weeks of randomization or planned to use these medications during the study; had used any noncigarette nicotine product or smoked or vaped cannabis in the 14 days before randomization or planned to use during the study; or had a past 3-month history of acute myocardial infarction, unstable angina, stroke, cerebrovascular incident, or hospitalization for congestive heart failure; current uncontrolled hypertension (blood pressure ≥160/100 mm Hg); hepatic or kidney impairment; moderate to severe depression symptoms (Hospital Anxiety and Depression Scale score16 ≥11); current psychosis, suicidal ideation, or suicide risk (Columbia Suicide Severity Rating Scale17); or a positive urinary screen for illicit drugs. The CONSORT flow diagram is available as Figure 1. Participants were compensated for each study visit.
Figure 1. CONSORT Flow Diagram.
aRandomization stratified by study site.
bThere were 228 individuals screened who did not meet inclusion criteria and 380 who met exclusion criteria (could be in both categories). The numbers of potential participants who were ineligible for various reasons are not shown because not every site screened all patients for all potential reasons for ineligibility.
cIn the 12-week cytisinicline group, 1 participant died of a stab wound, 1 of hemorrhagic stroke, and 1 of a suspected opioid overdose; and in the 6-week cytisinicline group, 1 participant died of postsurgical complications.
dPhysicians typically withdrew a participant due to habitual noncompliance with study visits and/or diary completion, which made it difficult to adequately assess the participant’s safety to continue with the study.
Recruitment and Assignment to Condition
At the screening visit, 1395 individuals provided written informed consent; completed a medical history, physical examination, 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 self-reported demographic characteristics. At a second visit, participants who met inclusion criteria were randomly assigned to a treatment group, received brief smoking cessation counseling, set a quit date within 5 to 7 days, and started taking the study medication.
Randomization began in January 2022 using a predetermined central computer-generated randomization sequence assigned participants (1:1:1) stratified by study site to receive 3-mg cytisinicline 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 placebo 3 times daily for 12 weeks (Figure 1). All participants and study staff were blinded to study drug.
Interventions
The study drug was a tablet containing 3 mg of cytisinicline or placebo, taken orally 3 times daily for 12 weeks, starting the day after randomization. Participants also received up to 14 sessions of behavioral support (10 minutes duration) from trained counselors starting before randomization and continuing through week 12. Shorter sessions were offered at weeks 16, 20, and 24.
Assessments
After randomization, participants were assessed at in-person weekly visits during treatment (weeks 1-12) and at weeks 16, 20, and 24. Participants who discontinued the study drug prematurely were encouraged to remain in the study and complete all assessment visits. Smoking status, assessed by self-report since the last visit, was measured at visits from weeks 2 to 12.18 Breath CO level was measured at every visit. Verified abstinence required self-reported abstinence since the prior visit and a CO level less than 10 ppm. During the follow-up period (weeks 16, 20, and 24), continuous abstinence was assessed using the Russell Standard criteria of not smoking more than 5 cigarettes since the last visit verified with a breath CO level of less than 10 ppm.19 Participants who did not meet these criteria or had missing data were classified as smoking. Cigarette cravings were assessed at baseline and weeks 1 to 6 using the Brief Questionnaire of Smoking Urges (QSU-brief; range, 10-70) and 2 subscales, QSU-1 (questions 1, 3, 6, 7, 10; range, 5-50) and QSU-2 (questions 4, 8, 9; range, 3-30).20,21,22,23 Blood for analysis of concentrations of cotinine, a nicotine metabolite,24 was collected at baseline, then biweekly to week 12.
Safety was assessed by vital sign measurement and adverse event elicitation from participants at all visits during treatment and through week 24. Hematology and chemistry laboratory tests and electrocardiograms were performed at baseline and weeks 6 and 12. Clinically significant adverse events or abnormalities were followed up until resolution or end of study.
Outcomes Measures
The primary outcome, continuous abstinence during the last 4 weeks of treatment, was used to compare 12-week cytisinicline to placebo (assessed weeks 9-12) and 6-week cytisinicline to placebo (assessed weeks 3-6). Trial 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 outcome. Secondary outcomes measured were verified continuous smoking abstinence from the last 4 weeks of drug treatment to week 24 (weeks 3-24 for the 6-week cytisinicline group and weeks 9-24 for the 12-week cytisinicline group). Other prespecified end points included the difference between groups in verified 7-day point-prevalence abstinence and changes in serum cotinine at each visit during weeks 2 to 24. Safety outcomes included the incidence of treatment-emergent adverse events during treatment with cytisinicline or placebo and clinically significant changes in vital signs, laboratory tests, or electrocardiograms.
Statistical Analysis
The 2 binary primary outcomes and the secondary binary outcomes were analyzed using exact analyses of 2 × 2 tables comparing randomized groups to outcome with stratification by clinical site. Participants with missed assessments were classified as still smoking. The planned sample of 750 participants (n = 250 per group) was established using simulations to provide 96% power with specifications of an overall 1-sided 0.025 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.25 Longitudinal exploratory and sensitivity analyses used mixed model for repeated measures methodology with specification of unstructured covariance matrix; baseline data were not classified by randomized group when included.26 Analyses of adverse events included all randomized participants who received at least 1 dose of the study drug. Two-sided P <.05 was considered to be statistically significant. Data analyses were performed from May 3, 2023, to March 20, 2024, using SAS, version 9.4 (SAS Institute).
Results
The analyses included 792 participants (mean [SD] age, 52.0 [11.8] years; 439 [55.4%] female and 353 male [44.6%]) who smoked a mean (SD) of 20.4 (7.5) cigarettes per day. The total sample was randomized to 3 groups: 265 participants assigned to placebo, 263 to 6 weeks of cytisinicline plus 6 weeks placebo, and 264 to 12 weeks cytisinicline (Figure 1). Primary efficacy analyses were intent-to-treat and included all 792 randomized participants. Safety analyses (n = 785) excluded 7 participants who did not start treatment (3 in the placebo group, and 4 in the cytisinicline 12-week group). Follow-up visits ended in March 2023.
Baseline characteristics, including self-reported race and ethnicity and tobacco use history, are reported in Table 1 and were similar among the 3 study groups. Adherence to study treatment was high. Similar proportions of participants completed all 84 days of drug treatment: 204 (77.0%) placebo, 199 (75.7%) 6-week cytisinicline, and 206 (78.0%) 12-week cytisinicline. Participants completed 88.0% of behavioral support sessions in the placebo group, 89.5% in the 6-week cytisinicline group, and 89.0% in the 12-week cytisinicline group. Study completion, defined as attendance at the 24-week visit, was achieved by 628 randomized participants (79.3%; 209 to placebo [78.9%], 207 to 6-week cytisinicline [78.7%], and 212 to 12-week cytisinicline [80.3%]).
Table 1. Baseline Characteristics of Study Participants (N = 792), by Study Group.
| Characteristic | No. (%) | ||
|---|---|---|---|
| Placebo | 6-wk Cytisinicline + 6-wk placebo | 12-wk Cytisinicline | |
| Participants, No. | 265 | 263 | 264 |
| Age, mean (SD), y | 51 (11.4) | 52 (11.7) | 52 (12.3) |
| Sex | |||
| Female | 146 (55.1) | 142 (54.0) | 151 (57.2) |
| Male | 119 (44.9) | 121 (46.0) | 113 (42.8) |
| Racea | |||
| American Indian or Alaska Native | 1 (0.4) | 4 (1.5) | 0 |
| Asian | 0 | 2 (0.8) | 2 (0.8) |
| Black or African American | 51 (19.2) | 38 (14.4) | 50 (18.9) |
| Native Hawaiian or other Pacific Islander | 0 | 0 | 2 (0.8) |
| White | 210 (79.2) | 216 (82.1) | 205 (77.7) |
| Othera | 3 (1.1) | 3 (1.1) | 5 (1.9) |
| Hispanic ethnicitya | 17 (6.4) | 15 (5.7) | 13 (4.9) |
| Hospital Anxiety and Depression Scale total score, mean (SD)b | 5.8 (4.1) | 6.3 (4.5) | 6.5 (5.0) |
| Tobacco use, mean (SD) | |||
| Duration of smoking, y | 34.5 (12.4) | 35.7 (13.2) | 34.8 (13.6) |
| Cigarettes/d for 7 consecutive d | 20.0 (7.1) | 21.0 (7.9) | 20.0 (7.4) |
| Expired air carbon monoxide, ppm | 30.1 (17.5) | 29.4 (13.2) | 29.2 (12.9) |
| Serum cotinine level, ng/mL | 293.6 (136.8) | 303.6 (135.2) | 286.9 (117.7) |
| Fagerstrom Test for Nicotine Dependence scorec | 5.6 (1.9) | 5.9 (1.7) | 5.6 (1.9) |
| Tobacco quitting history | |||
| Prior attempts, median (IQR) | 4.0 (3.0-6.0) | 4.0 (2.0-5.0) | 4.0 (2.0-6.5) |
| Prior cessation medication used | |||
| Bupropion | 67 (25.3) | 51 (19.4) | 52 (19.7) |
| Nicotine | |||
| Lozenges | 30 (11.3) | 35 (13.3) | 26 (9.8) |
| Gum | 113 (42.6) | 99 (37.6) | 107 (40.5) |
| Patch | 160 (60.4) | 150 (57.0) | 132 (50.0) |
| Varenicline | 110 (41.5) | 105 (39.9) | 102 (38.6) |
Race and ethnicity were reported by each participant in response to a fixed-category question. Other included any race or ethnicity not listed.
Hospital Anxiety and Depression Scale16 is a 14-item self-administered scale, with a range of scores 0 to 42. Higher scores indicate more symptoms of anxiety and depression.
Fagerstrom Test for Nicotine Dependence18 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.
Cytisinicline Efficacy
The primary outcome measure, biochemically confirmed continuous smoking abstinence at the end of treatment, was significantly higher for both cytisinicline groups compared with placebo (Table 2). For 6-week treatment, 39 participants of the cytisinicline (14.8%) vs 16 of the placebo (6.0%) group were abstinent during weeks 3 to 6 (odds ratio [OR], 2.9; 95% CI, 1.5-5.6; P < .001). For 12-week treatment, 80 participants in the cytisinicline (30.3%) vs 25 in the placebo (9.4%) group were abstinent during weeks 9 to 12 (OR, 4.4; 95% CI, 2.6-7.3; P < .001).
Table 2. Smoking Cessation Outcomes, by Study Group.
| Biochemically confirmed cessationa | Study groups, No. (%) | 6-wk Cytisinicline vs placebo | 12-wk Cytisinicline vs placebo | ||||
|---|---|---|---|---|---|---|---|
| Placebo (n = 265) | 6-wk Cytisinicline (n = 263) | 12-wk Cytisinicline (n = 264) | Odds ratio (95% CI) | P valueb | Odds ratio (95% CI) | P valueb | |
| Primary outcome | |||||||
| Weeks 3-6c | 16 (6.0) | 39 (14.8) | 37 (14.0) | 2.9 (1.5-5.6) | < .001 | NA | NA |
| Weeks 9-12d | 25 (9.4) | 41 (15.6) | 80 (30.3) | NA | NA | 4.4 (2.6-7.3) | <.001 |
| Secondary outcomes | |||||||
| Weeks 3-24e | 3 (1.1) | 18 (6.8) | 24 (9.1) | 6.3 (1.9-34.6) | < .001 | NA | NA |
| Weeks 9-24e | 11(4.2) | 32 (12.2) | 54 (20.5) | NA | NA | 5.8 (2.9-12.5) | <.001 |
Abbreviations: NA, not applicable; ppm, parts per million.
Cessation (continuous abstinence) from cigarette smoking was defined as self-reported zero cigarettes since last visit that was confirmed by expired air carbon monoxide less than 10 ppm; those with expired carbon monoxide level of 10 ppm or higher or missing outcome data were counted as smoking.
Two-sided, calculated by exact computations with clinical site as a stratifier and no evidence of heterogeneity across sites.
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 self-reported zero cigarettes smoked since last visit (through week 12 visit) or self-reported 5 cigarettes or fewer since last monthly visit (weeks 16, 20, and 24), with self-report confirmed by expired air carbon monoxide level less than 10 ppm at each visit; those with 10-ppm or higher level or missing outcome data were counted as smoking.
The secondary outcome measure, continuous abstinence through 24 weeks, was also significantly higher in each cytisinicline group compared with placebo (Table 2). In the 6-week cytisinicline group, 18 participants (6.8%) were abstinent during weeks 3 to 24 compared with 3 participants (1.1%) in the placebo group (OR, 6.3; 95% CI, 1.8-34.6; P < .001). For the 12-week cytisinicline group, 54 participants (20.5%) were abstinent during weeks 9 to 24 compared with 11 participants (4.2%) in the placebo group (OR, 5.8; 95% CI, 2.9-12.4; P < .001).
eFigure 1 in Supplement 3 shows the weekly estimated prevalence probability of biochemically confirmed abstinence by group. Both of the cytisinicline groups demonstrated a progressive increase in weekly abstinence during the first 6 weeks of treatment that was significantly higher than placebo. In the 12-week cytisinicline group, the probability of weekly abstinence continued to increase from week 6 to 12 and remained significantly higher than placebo.
Craving and Serum Cotinine Levels
Cytisinicline treatment vs placebo significantly reduced mean QSU craving scores from baseline to week 6 (−15.2 [95% CI, −16.4 to −14.0] vs −12.0 [95% CI, −13.5 to −10.5]; P < .001) (Figure 2) and in both QSU subscale scores. The QSU-1 subscale, which measures the rewarding effects of nicotine intake,20,21 declined by −9.7 points (95% CI, −10.3 to −9.1) over 6 weeks in the cytisinicline group vs 7.6 points (95% CI, −8.4 to −6.9) in the placebo group (P < .001) (eFigure 2A in Supplement 3). The QSU-2 subscale, which assesses nicotine withdrawal effects,20,21 declined by −2.9 points (95% CI, −3.2 to −2.6) in the cytisinicline group over 6 weeks compared to −2.3 points (95% CI, −2.7 to −2.0; P = .01) in the placebo group (eFigure 2B in Supplement 3).
Figure 2. Reduction in Craving by Group Over Time per the Brief Questionnaire of Smoking Urges (QSU-brief)23 Scores.
During the first 6 weeks of treatment, mean cigarette craving per QSU-brief scores declined more among participants randomized to the pooled cytisinicline 6- and 12-weeks groups compared to placebo. Mixed-model repeated measures with unstructured covariance and with baseline as a repeated measure were used to estimate the mean at each visit; 95% CIs for the mean estimates are shown for all visits.
Participants in the cytisinicline and placebo groups who reported smoking abstinence at 6 or 12 weeks had similar reductions in serum cotinine levels from baseline. However, among participants who did not achieve smoking abstinence, cotinine levels declined significantly more in the cytisinicline groups than in the placebo groups. Participants in the 6-week cytisinicline group who did not quit by 6 weeks (n = 193) had a greater reduction in mean serum cotinine levels at week 6 than placebo group participants who did not quit (n = 213): −150.21 ng/mL (95% CI, −168.00 to −132.61) vs −38.26 ng/mL (95% CI, −55.11 to −21.42; P < .001) (eFigure 3A in Supplement 3). Participants in the 12-week cytisinicline group who did not quit at week 12 (n = 138) had a greater reduction in cotinine levels than placebo-treated participants who did not quit at week 12 (n = 188): −125.87 ng/mL (95% CI, −146.51 to −105.23) vs −31.03 ng/mL (95% CI, −48.72 to −13.35; P < .001) (eFigure 3B in Supplement 3).
Cytisinicline Safety
Treatment-emergent adverse events were reported by comparable proportions of participants across groups. The most common adverse events, reported by >5% of participants in the placebo, 6-week, and 12-week cytisinicline groups, respectively, were insomnia (7.6%, 11.0%, 11.9%), abnormal dreams (5.7%, 9.1%, 7.7%), nausea (7.3%, 9.5%, 6.9%), and headache (6.1%, 7.6%, 8.5%) (absolute values are available in Table 3). Study drug discontinuation due to adverse events occurred in 9 of 523 participants (1.7%) receiving cytisinicline (6-week group, 1.5%; 12-week group, 1.9%), and 3 of 262 participants (1.1%) receiving placebo. Serious adverse events occurred in 16 of 523 participants (3.1%) who received cytisinicline and in 8 of 262 participants (3.1%) who received placebo (Table 3). No serious adverse event was determined to be treatment related, including 4 deaths that occurred (1 in the 6-week and 3 in the 12-week cytisinicline groups), all 4 of which were considered unrelated or unlikely to be associated with the study drug.
Table 3. Summary of Adverse Events (AEs), by Study Groupa.
| Outcome measure | Participants, No. (%) | ||
|---|---|---|---|
| Placebo (n = 262) | 6-wk Cytisinicline (n = 263) | 12-wk Cytisinicline for (n = 260) | |
| Treatment-emergent AEs | 164 (62.6) | 170 (64.6) | 168 (64.6) |
| Serious treatment-emergent AEsb | 8 (3.1) | 8 (3.0) | 8 (3.1) |
| Serious treatment-related AEsc | 0 | 0 | 0 |
| Treatment-emergent AEs, severity | n = 235 | n = 242 | n = 239 |
| Mild | 121 (46.2) | 142 (54.0) | 124 (47.7) |
| Moderate | 100 (38.2) | 87 (33.1) | 98 (37.7) |
| Severe | 14 (5.3) | 13 (4.9) | 17 (6.5) |
| Most frequent treatment-emergent AEsd | |||
| Abnormal dreams | 15 (5.7) | 24 (9.1) | 20 (7.7) |
| Headache | 16 (6.1) | 20 (7.6) | 22 (8.5) |
| Insomnia | 20 (7.6) | 29 (11.0) | 31 (11.9) |
| Nausea | 19 (7.3) | 25 (9.5) | 18 (6.9) |
Analysis limited to participants who took at least 1 dose of study medication. Because 3 participants randomized to the placebo group (n = 265) and 4 participants randomized to the 12-week cytisinicline group (n = 264) took no study medication, the denominators for this analysis were 262 and 260, respectively.
Defined as an AE associated with death or that was life-threatening; required hospitalization or prolonged an existing hospitalization; resulted in persistent or substantial disability, incapacity, or congenital abnormality; or required medical intervention to prevent any of these outcomes.
Related to treatment was determined by researchers 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 after study drug administration or improved on cessation of study drug.
Includes all treatment-emergent AEs reported by 5% or more of participants in any study group. Listed in descending order by combined cytisinicline for 6 and 12 weeks.
Discussion
Reproducing previous findings, this second phase 3 multisite placebo-controlled randomized clinical trial (ORCA-3) found that both 6- and 12-week treatment with cytisinicline using a novel dosing regimen of 3 mg 3 times daily combined with substantial behavioral support demonstrated clinically meaningful and statistically significant efficacy for smoking cessation among adults who sought to quit smoking. Cytisinicline produced a 3- to 4-fold higher odds of smoking cessation vs placebo at the end of treatment, and an approximately 6-fold higher odds of smoking cessation continuing through 24-week follow-up. These results confirm the results of ORCA-2,15 which shared a similar study design but was conducted at different sites.
Both the ORCA-2 and -3 trials reported generally similar large effect size estimates of cytisinicline efficacy vs placebo for 6- and 12-week treatment durations. For 12-week cytisinicline treatment, the odds of abstinence at end of treatment (primary end point) were 6.3 in ORCA-2 and 4.4 in ORCA-3. The odds of abstinence sustained to 24 weeks were 5.3 in ORCA-2 and 5.8 in ORCA-3. For 6-week cytisinicline treatment, the odds of end-of-treatment abstinence were 8.0 in ORCA-2 and 2.9 in ORCA-3. For continuous abstinence sustained through 24 weeks, the ORs were 3.7 for ORCA-2 and 6.3 for ORCA-3. The largest difference between trials was the higher end-of-treatment abstinence rates and ORs in ORCA-2 compared with ORCA-3. COVID-19 pandemic−related restrictions may account for some of the difference. ORCA-2 was conducted while pandemic-related mandates were in place (October 2020-December 2021), whereas these restrictions and mandates were relaxed or absent when ORCA-3 was conducted (January 2022-March 2023). Smoking cessation soon after the quit date may have been facilitated by stay-at-home mandates that reduced external environmental smoking cues.
In ORCA-3, the point prevalence abstinence rates of participants assigned to 12 weeks of cytisinicline continued to rise throughout the active treatment period, suggesting that new quitting continued to occur with cytisinicline treatment beyond week 6 and contributing to higher tobacco abstinence rates during weeks 9 to 12 (eFigure 1 in Supplement 3). Similar results were seen in ORCA-2. Taken together, these results suggest that those who do not quit by weeks 3 to 6 may benefit from continuing cytisinicline for 12 weeks. An increase in point-prevalence abstinence with longer treatment has also been observed for varenicline, which has a similar mechanism of action, but not for other smoking cessation treatments.27,28
As anticipated for a nicotine partial agonist, cytisinicline treatment produced a significant reduction in mean craving scores compared to placebo through 6 weeks of treatment. Notably, craving levels were also significantly lower among all randomized participants, including those who continued to smoke while taking cytisinicline, indicating that cytisinicline effectively mitigates cravings even in those who do not quit. Furthermore, cotinine levels corroborated these findings, showing significantly lower cotinine levels among cytisinicline-treated participants who did not quit smoking at 6 or 12 weeks. These reductions suggest that among participants who did not quit, those receiving cytisinicline significantly decreased their smoking. These results underscore the potential of cytisinicline not only to reduce cravings but also to reduce combustible tobacco intake as a treatment option for people aiming to reduce their intake and, ultimately, quit.
Our findings of a progressive increase in quitting with ongoing treatment and a significant reduction in craving lend strong support to the hypothesis that cytisinicline acts as a partial agonist at the nicotine acetylcholine receptor.9 Most likely, cytisinicline-mediated antagonism of nicotine receptor binding reduces the reward of cigarette smoking, leading to reduced craving, self-administration of less nicotine, and increased quitting. This mechanism not only underscores the effectiveness of cytisinicline for smoking cessation but also highlights its potential utility in helping people quit other nicotine products, such as e-cigarettes. A prior randomized clinical trial demonstrated the end-of-treatment effectiveness of cytisinicline for vaping cessation.29
Cytisinicline was well tolerated in both of these phase 3 trials, with low adverse effects−related discontinuation rates in ORCA-2 (2.9% for 6-week cytisinicline, 2.2% for 12-week cytisinicline, and 1.5% for placebo)15 and ORCA-3 (1.7%, 1.9%, and 1.1%, respectively). Adherence to the 6- and 12-week cytisinicline regimes was also high in both trials, with most participants randomized to cytisinicline retained (6-week cytisinicline, 74.0% for ORCA-2 and 78.7% for ORCA-3; 12-week cytisinicline, 83.3% and 80.3%, respectively).
Both ORCA trials suggest that cytisinicline may be associated with a more favorable adverse effect profile than varenicline, a medication with a similar mechanism of action. This is consistent with the results of 2 prior randomized clinical trials comparing the 2 drugs, in which cytisinicline caused less nausea and fewer sleep disturbances.30,31
Limitations
Study limitations included the small representation of participants who were not White, limiting the generalizability of findings to other racial and ethnic groups and limiting the ability to test for subgroup differences. Study results cannot be generalized to people who smoke fewer than 10 cigarettes daily. Although people diagnosed with serious mental illness were not excluded, exclusion for suicidal ideation, moderate to severe depression symptoms, recent unstable cardiovascular disease, and current cannabis or illicit drug use makes it difficult to generalize the study findings to people with these co-occurring conditions. Abstinence was evaluated for 24 weeks and safety parameters evaluated for 12 weeks of treatment, precluding determination of longer-term benefits and exposure for safety parameters, although a long-term dosing study is currently underway. Lastly, study participants received a more intensive level of behavioral support than is typically found outside of a clinical trial.
Conclusions
This phase 3, multisite, placebo-controlled, randomized clinical trial is the second large trial conducted in the US to demonstrate that a novel regimen of 3-mg cytisinicline taken 3 times daily along with behavioral support has robust efficacy and excellent tolerability as a treatment for quitting smoking. Cytisinicline holds substantial promise, offering efficacy similar to varenicline but a more favorable adverse effect profile12 and addressing the limitations of treatments, such as nicotine replacement therapy and bupropion, which have lower efficacy or greater tolerability concerns. Changes in craving and cotinine biomarkers over time support the proposed mechanism of action of cytisinicline as a partial nicotine agonist. These findings also highlight the potential for cytisinicline to serve as a versatile tool for nicotine cessation, not only for traditional cigarettes but also for other nicotine delivery products.
Trial Protocol
Statistical Analysis Plan
eFigure 1. Weekly Point Prevalence Probabilities of Tobacco Abstinence, by Group.
eFigure 2A. QSU subscale 1: Total Score – All Randomized Set
eFigure 2B. QSU subscale 2: Total Score – All Randomized Set
eFigure 3A. Cotinine Change at 6 Weeks in Patients without Abstinence
eFigure 3B. Cotinine Change at 12 Weeks in Patients without Abstinence
Data Sharing Statement
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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. Weekly Point Prevalence Probabilities of Tobacco Abstinence, by Group.
eFigure 2A. QSU subscale 1: Total Score – All Randomized Set
eFigure 2B. QSU subscale 2: Total Score – All Randomized Set
eFigure 3A. Cotinine Change at 6 Weeks in Patients without Abstinence
eFigure 3B. Cotinine Change at 12 Weeks in Patients without Abstinence
Data Sharing Statement
