Cytisine versus Nicotine for Smokin

Cytisine versus Nicotine for Smoking Cessation

Natalie Walker, Ph.D., Colin Howe, Ph.D., Marewa Glover, Ph.D., Hayden McRobbie, M.B., Ch.B., Ph.D., Joanne Barnes, Ph.D., Vili Nosa, Ph.D., Varsha Parag, M.Sc., Bruce Bassett, B.A., and Christopher Bullen, M.B., Ch.B., Ph.D.
N Engl J Med 2014; 371:2353-2362December 18, 2014DOI: 10.1056/NEJMoa1407764


Cytisine is a plant-based alkaloid found in members of the Leguminosae family. Like varenicline, cytisine is a partial agonist of nicotinic acetylcholine receptors (nAChRs), with an affinity for the α4β2 receptor subtype, and a half-life of 4.8 hours. Cytisine is a generic agent currently manufactured by Sopharma as Tabex and by Aflofarm Pharma as Desmoxan. It has been available both with and without prescription for smoking cessation since the 1960s, largely in Eastern Europe. Four systematic reviews report cytisine to be superior to placebo for short-term and long-term abstinence. When taken at the recommended dosage (1.5 to 9 mg per day for 25 days), cytisine is associated with no significant increase in adverse events as compared with placebo (20.5% vs. 19.6%), although gastrointestinal symptoms are more common (11.9% vs. 7.2%)
Cytisine remains relatively unknown outside Eastern Europe despite calls for licensing worldwidebecause of its proven benefits, low cost as compared with other cessation medications (cytisine, $20 to $30 for 25 days; nicotine-replacement therapy, $112 to $685 for 8 to 10 weeks; varenicline, $474 to $501 for 12 weeks), and low cost per quality-adjusted-life-year Given that no trials have compared cytisine with nicotine-replacement therapy, we designed a noninferiority trial to investigate whether cytisine was at least as effective as nicotine-replacement therapy. We hypothesized that 25 days of cytisine plus low-intensity behavioral support would be at least as effective as 8 weeks of nicotine-replacement therapy plus low-intensity behavioral support for smoking cessation.
METHODS
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 protocol 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. 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. 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), 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), 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). 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, 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 use; motivation to quit; symptoms of tobacco withdrawal; and the strength of urges to smoke and the duration of these urges; 7-day point prevalence for abstinence (no cigarettes, not a single puff, in the previous 7 days); continuous abstinence; smoking satisfaction; 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 theInternational 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 vareniclineand 50% for nicotine-replacement therapy.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 betwee