Efficacy and tolerability of varenicline, an α4 β2 nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose-response study with 40-week follow-up for smoking cessation in Japanese smokers

• Published in: Clinical therapeutics 2007, Vol.29 (6), p.1040-1056
• Main Authors: Nakamura, Masakazu, MD, Oshima, Akira, MD, Fujimoto, Yoko, MD, PhD, Maruyama, Nami, MSc, Ishibashi, Taro, MSc, Reeves, Karen R., MD
• Format: Article
• Language: English
• Subjects: Internal Medicine; Medical Education
• ISSN: 0149-2918
• DOI: 10.1016/j.clinthera.2007.06.012

Abstract Background: Varenicline, a selective α4 β2 nicotinic acetylcholine receptor partial agonist, has been developed specifically for smoking cessation. In Japan, 39.3% of men smoke and this is a major public health concern. Objective: The primary objective of this study was to evaluate the efficacy and dose-response relationship of varenicline in Japanese smokers. Methods: In this double-blind, placebo-controlled, randomized, parallel-group study, subjects were randomized to receive varenicline at 0.25 mg BID, 0.5 mg BID, 1 mg BID, or placebo for 12 weeks followed by a 40-week, nontreatment follow-up phase. The primary efficacy variable was the continuous abstinence rate (CAR), defined as no reported smoking (not even a puff) or other nicotine use and confirmed by end-expiratory carbon monoxide level ≤10 ppm, during the last 4 weeks of treatment (weeks 9–12). Secondary end points included CARs for weeks 9–24 and 9–52. Craving, withdrawal, and smoking satisfaction were determined by the Minnesota Nicotine Withdrawal Scale, the Brief Questionnaire on Smoking Urges, and the modified Cigarette Evaluation Questionnaire. The tolerability of varenicline was also evaluated. Results: Of 618 subjects who received treatment, 515 (83.3%) were classified as nicotine dependent (scoring ≥5 on the Tobacco Dependence Screener), and constituted the primary analysis group. Of these, 385 (74.8%) subjects were male, and the mean age was within the range of 39.0 to 40.2 years. Across treatment groups, subjects claimed to have smoked a mean of 23.1 to 24.9 cigarettes per day in the preceding 30 days, and the mean score on the Fagerström Test for Nicotine Dependence was within the range from 5.4 to 5.7. The CAR for weeks 9–12 was significantly higher for all doses of varenicline compared with placebo (39.5% [51/129]). The highest CAR of 65.4% (85/130) was achieved with varenicline 1 mg BID (odds ratio [OR] [95% CI] = 2.98 [1.78–4.99]; P < 0.001). The CAR for weeks 9–52 was significantly greater for varenicline 1 mg BID than placebo (34.6% [45/130] vs 23.3% [30/129]; OR [95% CI] = 1.81 [1.04–3.17]; P = 0.036). The CARs for weeks 9–24 at 0.25, 0.5, and 1 mg BID were 33.6% (43/128), 35.2% (45/128), 37.7% (49/130), and for weeks 9–52 at 0.25 and 0.5 mg BID were 27.3% (35/128) and 28.9% (37/128) but failed to reach significance versus the placebo (29.5% [38/129] for weeks 9–24 and 23.3% [30/129] for weeks 9–52). Treatment-emergent adverse events (AEs) were more prevalent among va