Study Oversight

The trial was conducted and monitored in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and is reported with fidelity to the protocol and statistical analysis plan included in the protocol14 available with the full text of this article at NEJM.org. The Health Research Council of New Zealand funded the trial, including the reimbursement of Quitline, which was engaged to recruit participants. Cytisine was supplied at no cost by the manufacturer, Sopharma. The research council, Sopharma, and the Extab Corporation had no role in the design of the trial, the collection, analysis, or interpretation of the data, or the writing of the report for publication. The protocol was approved by the New Zealand Multi-Region Ethics Committee and the Standing Committee on Therapeutic Trials. All participants provided oral informed consent. All authors were involved in the design and conduct of the trial and the writing of the manuscript. The first and second authors oversaw the conduct of the study, the seventh author performed all statistical analyses, and the first author supervised the writing of the manuscript.

Participants

This parallel-group, randomized, controlled, noninferiority trial was conducted in New Zealand.14 The first randomization was conducted on March 29, 2011, and the last follow-up took place on February 4, 2013. Smokers were recruited through the New Zealand national quitline. To be included in the study, participants had to be at least 18 years of age, daily smokers, and motivated to quit. Potential participants were excluded if they were pregnant or breast-feeding, were taking smoking-cessation medication, were enrolled in another cessation program or study, had self-reported pheochromocytoma, had a systolic blood pressure above 150 mm Hg, a diastolic blood pressure above 100 mm Hg, or both, had schizophrenia, or had had a self-reported cardiovascular event in the 2 weeks before study enrollment.

Randomization

Eligible participants who had called the quitline were randomly allocated, by computer, to nicotine-replacement therapy or cytisine in a 1:1 ratio. Randomization was stratified with the use of minimization according to sex, ethnicity (Maori, Pacific Islander, or non-Maori and non–Pacific Islander), and cigarette dependence, which was determined by means of the Fagerström Test of Cigarette Dependence, in which smokers were assigned to one of two groups: those with scores of 5 or lower, indicating lower dependence, and those with scores greater than 5, indicating greater dependence.15,16 Participants and researchers collecting outcome data were aware of treatment allocation.

Procedures

All participants were offered low-intensity telephone behavioral support (an average of three calls of 10 to 15 minutes each from Quitline advisors over a period of 8 weeks). Participants assigned to nicotine-replacement therapy received vouchers from Quitline that were redeemable from community pharmacies for nicotine patches (in doses of 7 mg, 14 mg, or 21 mg) and for gum (2 mg or 4 mg) or lozenges (1 mg or 2 mg) or both gum and lozenges at a cost of NZ$3 for an 8-week supply of each item (the equivalent of €2, or approximately $2.50 in U.S. dollars). The type and strength of nicotine-replacement therapy were determined by Quitline advisors in accordance with national smoking-cessation guidelines17 and participant preference. The cytisine group received a 25-day course of tablets by courier and were asked to reduce their smoking at their own pace during the first 4 days of treatment such that they were not smoking at all by the 5th day (i.e., their “quit date”). Participants followed the manufacturer’s recommended dosing regimen: days 1 through 3, one tablet every 2 hours through the waking day (up to six tablets per day); days 4 through 12, one tablet every 2.5 hours (up to five tablets per day); days 13 through 16, one tablet every 3 hours (up to four tablets per day); days 17 through 20, one tablet every 4 to 5 hours (three tablets per day); and days 21 through 25, one tablet every 6 hours (two tablets per day). Participants in the cytisine group also received the vouchers for nicotine-replacement therapy sent to participants in the nicotine-replacement therapy group. They were asked to take the cytisine tablets for 25 days. If they had not stopped smoking by that time, or if they required ongoing support to refrain from smoking after that time, they were to redeem the vouchers for nicotine-replacement therapy.

At baseline, data were collected on demographics, smoking history, concomitant medication, motivation to quit smoking (with a score of 1 indicating very low motivation and a score of 5 indicating very high motivation), symptoms of withdrawal and the urge to smoke (both assessed with the Mood and Physical Symptoms Scale, with symptoms rated on a scale of 1 to 5, with 1 indicating none and 5 the most severe, and the urge to smoke scored on a scale of 0 to 10, with higher scores indicating greater strength of the urge to smoke and a greater duration of these urges),18 alcohol use (assessed with the Alcohol Use Disorders Identification Test [AUDIT-C], rated on a scale of 0 to 12, with higher scores indicating a greater risk of alcohol dependence),19 and satisfaction with smoking (assessed with the modified Cigarette Evaluation Questionnaire, which included 12 subscales; in each subscale, a score of 1 indicated not at all satisfied and a score of 7 indicated extremely satisfied).20

The primary outcome was continuous abstinence from smoking (self-reported abstinence since quit day, with an allowance for smoking a total of five cigarettes or less,21 including during the previous 7 days) 1 month after quit day. Secondary outcomes assessed at 1 week and at 1, 2 and 6 months after quit day were self-reported treatment compliance (total number of cytisine tablets taken or the type, strength, and amount of nicotine-replacement therapy used); alcohol use19; motivation to quit; symptoms of tobacco withdrawal; and the strength of urges to smoke and the duration of these urges18; 7-day point prevalence for abstinence (no cigarettes, not a single puff, in the previous 7 days)21; continuous abstinence; smoking satisfaction20; concomitant medication; and, if still smoking, date returned to daily smoking and the number of cigarettes smoked per day. Self-reported adverse events were recorded at each follow-up call, coded in accordance with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification, and classified by a medical practitioner as nonserious or serious (defined as death, life-threatening, hospitalization, or otherwise medically important) and according to severity (mild — awareness of event but easily tolerated; moderate — discomfort extensive enough to cause some interference with usual activity; or severe — inability to carry out usual activity). All adverse events were reviewed by an independent data safety and monitoring committee. At 1 week and 1 month we also asked participants in the cytisine group whether they would recommend cytisine as a cessation aid.

Statistical Analysis

For our sample of 1310 people (655 per group), we assumed a loss of 20% to follow-up and a power of 90% at the one-sided significance level of 0.025 (the equivalent of a two-sided significance level of 0.05) to detect a 5% difference in 1-month quit rates between groups. The 1-month quit rate in the cytisine group was assumed to be 55%, midway between the estimate of 60% for varenicline8 and 50% for nicotine-replacement therapy.22 A noninferiority margin of difference between the group proportions was set at 5%.

Analyses were performed with SAS Software, version 9.3 (SAS Institute), and were guided by a prespecified plan. Noninferiority for the primary outcome was evaluated by observing whether the lower bound of the two-sided 95% confidence intervals for the risk difference in quit rates between the groups was above the noninferiority limit of −5. The primary analyses were carried out on an intention-to-treat basis (participants for whom outcomes were missing were assumed to be smoking). In the case that noninferiority was evident, assessment as to whether cytisine had effectiveness superior to that of nicotine-replacement therapy was carried out according to the same approach but was compared with a zero difference. Per-protocol analyses excluded participants who had missing data at 1 month or who had major protocol violations (e.g., death, pregnancy, withdrawal from the study, loss to follow-up, or noncompliance). Compliance in the cytisine group was defined as having taken 80% or more of the required number of tablets within 1 month after the quit date (i.e., 80 tablets or more). Compliance in the nicotine-replacement therapy group was defined as having used nicotine-replacement therapy at both 1 week and 1 month after the quit date. Participants with missing data were assumed to be noncompliant with the study regimen. Complete case analysis was also undertaken, and quit rates, relative risk, risk difference, and the number needed to treat were calculated. Treatment groups were compared with the use of chi-square tests and unadjusted and adjusted logistic regression modeling (adjusting for minimization factors and education).

In prespecified subgroup analyses, the consistency of effects was assessed with tests for heterogeneity for the primary outcome according to ethnicity (Maori vs. non-Maori), age (<40 years of age vs. ≥40 years of age), sex, and level of education (<12 years of schooling or no qualification vs. ≥12 years of schooling), type of cigarettes smoked (factory-made only, roll-your-own only, or factory-made and roll-your-own), and baseline AUDIT-C score (high vs. low). Post hoc subgroup analyses for the primary outcome were undertaken according to baseline level of cigarette dependence and use of nicotine-replacement therapy in the preceding 12 months. The change from baseline in symptoms of tobacco withdrawal (for abstainers), AUDIT-C score, and number of cigarettes smoked per day over time was assessed by means of repeated-measures mixed models adjusted for baseline value. Kaplan–Meier curves, the log rank test, and Cox proportional hazards regression analysis were used to measure time to first lapse from quit date (return to daily smoking).