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A Randomized Controlled Trial

Serena Tonstad, MD, PhD; Philip Tønnesen, MD, PhD; Peter Hajek, PhD; Kathryn E. Williams, PhD; Clare B. Billing, MS; Karen R. Reeves, MD; for the Varenicline Phase 3 Study Group

JAMA. 2006;296:64-71.

Context  The majority of cigarette smokers who achieve abstinence relapse within the first year and require many attempts before achieving permanent abstinence. Evidence to support pharmacological treatment for relapse prevention is insufficient.

Objective  To determine whether smokers who quit after 12 weeks of treatment with varenicline, a selective 42 nicotinic acetylcholine receptor partial agonist, maintain greater continuous abstinence rates (defined as not a single "puff" of a cigarette) than placebo controls during an additional 12 weeks of treatment and until 52 weeks after treatment initiation.

Design, Setting, and Participants  Randomized controlled trial conducted at multiple medical clinics in 7 countries with follow-up to 52 weeks after study baseline. Of 1927 cigarette smokers recruited between April 2003 and February 2004 and treated for 12 weeks with open-label varenicline titrated to 1 mg twice per day, 1236 (64.1%) did not smoke, use tobacco, or use nicotine replacement therapy during the last week of treatment and 62.8% (n = 1210) were randomized to additional treatment or placebo.

Intervention  Participants were randomly assigned to receive either double-blind varenicline, 1 mg twice per day (n = 603), or placebo (n = 607) for an additional 12 weeks.

Main Outcome Measures  Carbon monoxide–confirmed continued abstinence during weeks 13 to 24 and weeks 13 to 52 of the study.

Results  The carbon monoxide–confirmed continuous abstinence rate was significantly higher for the varenicline group than for the placebo group for weeks 13 to 24 (70.5% vs 49.6%; odds ratio [OR], 2.48; 95% confidence interval [CI], 1.95-3.16; P<.001) as well as for weeks 13 to 52 (43.6% vs 36.9%; OR, 1.34; 95% CI, 1.06-1.69; P = .02). Adverse events reported in the open-label period were mostly mild; no difference in adverse events between varenicline and placebo was observed during the double-blind period.

Conclusions  Smokers who achieved abstinence for at least 7 days at the end of 12 weeks of open-label varenicline treatment and were randomized to receive an additional 12 weeks of varenicline treatment showed significantly greater continuous abstinence in weeks 13 to 24 compared with placebo. This advantage was maintained through the nontreatment follow-up to week 52. Varenicline may be an efficacious, safe, and well-tolerated agent for maintaining abstinence from smoking.

Trial Registration  clinicaltrials.gov Identifier: NCT00143286

Author Affiliations: Department of Preventive Cardiology, Ullevål University Hospital, and University of Oslo, Oslo, Norway (Dr Tonstad); Department of Pulmonary Medicine, University of Copenhagen, and Gentofte Hospital, Copenhagen, Denmark (Dr Tønnesen); Wolfson Institute of Preventive Medicine, Queen Mary, University of London, London, England (Dr Hajek); and Pfizer Global Research and Development, Groton, Conn (Drs Williams and Reeves and Mr Billing).

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