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Cytisine Hits Snag as Smoking Cessation Aid

— Herbal product had previously bested placebo and nicotine replacement in randomized trials

Ƶ MedicalToday
A box of Tabex (Cytisine) tablets next to an ashtray with one cigarette extinguished in it.

A generic drug widely used in Eastern European and Asian countries for smoking cessation took on the West's leading non-nicotine agent in a randomized trial, coming out on the short end, researchers said.

Cytisine for 25 days failed to meet criteria for noninferiority in comparison with varenicline (Chantix) given for 84 days in an open-label trial involving 1,452 smokers hoping to quit the habit, reported Ryan J. Courtney, PhD, of the University of New South Wales in Randwick, Australia, and colleagues in .

The finding was a major disappointment in that cytisine -- a plant alkaloid that, like varenicline, stimulates nicotinic acetylcholine receptors -- had previously been shown to be superior to and to in separate trials. Moreover, a trial involving some of the same researchers and reported earlier this year, in New Zealand, found that cytisine was more effective than varenicline.

But Courtney's group was clear that the new trial doesn't spell doom for cytisine. Extended dosing would be worth testing in a future study, they indicated. And the contrary results in the Maori trial might suggest that populations more accepting of "natural" products would respond better to cytisine than to varenicline.

Some of these questions could be answered in an with a proprietary cytisine formulation called cytisinicline, in which the agent is given for up to 12 weeks.

In its native form, cytisine has been in common use outside the West for some 50 years. As a partial agonist for nicotinic acetylcholine receptors, it reportedly suppresses nicotine cravings and withdrawal symptoms when people stop smoking cigarettes. The standard treatment interval has been 25 to 30 days, although Courtney and colleagues noted that this isn't necessarily optimal -- as a cheap plant derivative, it hasn't had the financial backing to test multiple dosing regimens as Big Pharma would do for a product that needs FDA approval. (Cytisine appears not to be carried by U.S.-based herbal supplement vendors, but it can be ordered online from overseas.)

For its part, varenicline first won FDA approval in 2006, with recommended dosing set at 12 weeks. It's not without controversy, of course -- including suicidality led to label warnings, although the FDA still . Then just last week, drugmaker Pfizer recalled nine lots of varenicline (which hadn't yet been shipped to pharmacies) . The FDA said it asked Pfizer to extend the recall "to the consumer level" because pills already sold could potentially have the same contamination, but the company didn't yet do so.

Nevertheless, varenicline has been the leading non-NRT drug for smoking cessation in the the Western world. For cytisine to stake a claim as an effective agent -- particularly in countries other than the U.S. that would want evidence of at least noninferiority for it to be included in national formularies -- a head-to-head trial in a Western-type population could help its case.

Hence, the Australian government sponsored the new trial, , which had no involvement from Pfizer or cytisine suppliers. Participants were daily smokers, recruited from ads in print, radio, and online media, as well as from a telephone quit line, who said they wanted to quit and weren't currently using other smoking-cessation pharmacotherapies. Some 5% were Aboriginal or Torres Strait Islanders. Half were men, and mean participant age was 43. Mean smoking intensity was 18 cigarettes per day; total smoking history in pack-years wasn't reported, but the mean starting age for smoking was 16. They were randomized 1:1 to the two study agents, unblinded for pragmatic reasons.

The trial's primary endpoint was smoking abstinence -- i.e., not having smoked more than five cigarettes in the past 6 months when evaluated at study month 7 -- as reported by participants and checked with a carbon monoxide (CO) breath test. Those lost to follow-up or who missed or failed the CO test were considered to be still smoking.

Not surprisingly, given that most cessation attempts fail, the primary endpoint was met by 11.7% of the cytisine group and 13.3% of the varenicline group. To be considered noninferior, the lower bound of the risk difference's one-sided 97.5% confidence interval had to be no more than -5%. In the end, the risk difference was -1.62% with a confidence interval of -5.02% to infinity. A secondary Bayesian analysis found only a 15% probability of noninferiority, with other statistical tests also pointing toward lower efficacy with cytisine.

Two findings did fall in cytisine's favor. First, when participants were contacted by phone at the end of 1 month -- at which point those in the cytisine group had finished dosing -- self-reported abstinence in the previous week stood at 42.5% with cytisine versus 32.3% for varenicline. That was one reason why Courtney and colleagues suggested a longer cytisine dosing period could be beneficial.

Also, adverse events were less common with cytisine. Across all events, those that were clearly more common with varenicline were abnormal dreams and nausea.

Serious events, almost all requiring hospitalization, also appeared more common with varenicline (32 people vs 17 with cytisine), but the difference was not statistically significant. These events made somewhat of a puzzle, showing no clear pattern. Twelve were orthopedic, whereas only five could be considered neuropsychiatric. However, one of the latter was a suicide attempt by a varenicline recipient with a mental illness history. (On the other hand, the previous trial comparing cytisine to standard NRT found more adverse events with the former.)

Courtney and colleagues acknowledged a number of limitations and cautions. Past research has shown that behavioral support in addition to pharmacotherapy boosts quit rates, but participants in the trial got almost nothing other than referral to a telephone quit line. Also, the CO breath test only identifies smoking within the past 24 hours, so its reliability for assessing long-term abstinence is questionable. And the open-label design could have led to biases in adherence and self-reported outcomes.

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    John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Disclosures

The study was funded by the Australian government.

Study authors reported relationships with Pfizer (varenicline's manufacturer), various manufacturers of cytisine, Juul Labs, and other commercial entities.

Primary Source

JAMA

Courtney RJ, et al "Effect of cytisine vs varenicline on smoking cessation: a randomized clinical trial" JAMA 2021; DOI: 10.1001/jama.2021.7621.