Efficacy and tolerability of varenicline, an α4β2 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

1040_ET_nakamura

6/29/07

9:52 AM

Page 1040

Clinical Therapeutics/Volume 29, Number 6, 2007

Efficacy and Tolerability of Varenicline, an α4β2 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 Masakazu Nakamura, MD1; Akira Oshima, MD2; Yoko Fujimoto, MD, PhD3; Nami Maruyama, MSc3; Taro Ishibashi, MSc3; and Karen R. Reeves, MD4 1Department

of Health Promotion and Education, Osaka Medical Center for Health Science and Promotion, Osaka, Japan; 2Department of Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka, Japan; 3Pfizer Global Research & Development, Tokyo, Japan; and 4Pfizer Global Research & Development, Groton, Connecticut ABSTRACT Background: Varenicline, a selective α4β2 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 endexpiratory 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 1040

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 varenicline-treated subjects (79.1% [121/153] at 0.25 mg The data in this manuscript were presented in part at the 2006 Scientific Sessions of the American Heart Association, November 12–15, 2006, Chicago, Illinois. Accepted for publication April 26, 2007. Express Track online publication June 22, 2007. doi:10.1016/j.clinthera.2007.06.012 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2007 Excerpta Medica, Inc.

Volume 29 Number 6

1040_ET_nakamura

6/29/07

9:52 AM

Page 1041

M. Nakamura et al. BID, 80.6% [125/155] at 0.5 mg BID, and 80.1% [125/156] at 1 mg BID) than placebo subjects (71.4% [110/154]). The 3 most prevalent AEs at varenicline 1 mg BID were nasopharyngitis (35.9% [56/156]), nausea (24.4% [38/156]), and headache (10.3% [16/156]), all of which were of mild or moderate intensity. Nausea was the only AE that appeared dose related (7.2% [11/153] at 0.25 mg BID, 9.7% [15/155] at 0.5 mg BID, and 24.4% [38/156] at 1 mg BID) versus placebo (7.8% [12/154]). Conclusions: Varenicline was associated with dosedependent improvement in smoking abstinence rates during the last 4 weeks of treatment and in the longer term over 40 weeks of nontreatment follow-up. The dose associated with the highest efficacy was varenicline 1 mg BID. (Clin Ther. 2007;29:1040–1056) Copyright © 2007 Excerpta Medica, Inc. Key words: smoking cessation, varenicline, Japan, nicotinic partial agonist.

INTRODUCTION Smoking is a known cause of significant morbidity and mortality worldwide, with almost 5 million individuals dying prematurely of diseases related to smoking per year worldwide.1 Cigarette consumption in Japan is among the highest in the world, amounting to >2500 cigarettes per person aged >15 years per year.1 Although the majority of Japanese smokers are men, with a 39.3% smoking prevalence in 2005, a new and worrying trend is that smoking rates in women have been rising.2 Smoking prevalence in Japanese women has risen from 9.4% in 1989 to 11.3% in 2005, a rise largely accounted for by the increase observed among younger women (in women aged 20–29 and 30–39 years, smoking prevalence has increased from 8.9% and 11.7%, respectively, in 1989 to 18.9% and 19.4% in 2005).2,3 Smoking is a major public health concern in Japan, and tobacco smoking accounted for an estimated 113,000 of 962,000 deaths in Japan in 2000.4 Annual health care costs of tobacco-related deaths and diseases in Japan are estimated at more than ¥1151.2 billion (US $9.5 billion), with societal costs exceeding ¥3700 billion (US $30.5 billion).5 Evidence suggests that smokers consume excess medical care, especially inpatient care, and efforts to reduce tobacco exposure are imperative to improve the health care and economic burden on Japanese society.6 Although Japan is June 2007

still lagging behind other countries, smoking control initiatives have recently been introduced that may lead to an increase in the number of individuals motivated to stop smoking. In Japan, nicotine-replacement therapies (NRTs) have been approved as aids for smoking cessation, with nicotine gums being available over the counter, while transdermal nicotine preparations require a prescription. All other forms of NRT, including nasal sprays, inhalers, sublingual tablets, and lozenges, are not approved for use in Japan either over the counter or by prescription. The NRTs promote smoking cessation by providing an alternate source of nicotine, allowing smokers to gradually decrease their nicotine use. A meta-analysis of 105 studies of NRT in a total of 39,503 subjects concluded that all commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler, and sublingual tablet) are effective, with an odds ratio (OR) (95% CI) for abstinence with NRT compared with either placebo or a nonNRT control group of 1.77 (1.66–1.88).7 The other primary smoking-cessation therapy is sustained-release (SR) bupropion. A meta-analysis of 31 studies in a total of 9940 subjects reported an OR (95% CI) for abstinence with bupropion SR monotherapy compared with either placebo or nonpharmacotherapeutic control of 1.94 (1.72–2.19).8 Given that bupropion SR is not licensed in Japan, leaving NRT gum and the transdermal patch as the only pharmacologic aids to smoking cessation in Japan, there is a need for the introduction of new pharmacotherapies with novel mechanisms of action for smoking cessation. Exposure to nicotine leads to a series of phenomena involving greater expression of nicotine receptors in the brain, development of tolerance to the physiologic effects of nicotine, dependence on nicotine, and withdrawal symptoms (eg, urge to smoke, negative affect, restlessness, increased appetite, insomnia) after smoking cessation.9,10 Evidence supports the role of the α4β2 nicotinic acetylcholine receptor (nAChR) in the reinforcing effects of nicotine use.11 Varenicline, a selective α4β2 nAChR partial agonist developed specifically for smoking cessation, is hypothesized to relieve nicotine craving and withdrawal effects while reducing the reinforcing effects of nicotine through its partial agonist mechanism of action.12,13 In the United States, a large (N = 1027), randomized, double-blind, placebo-controlled, 52-week study found significantly improved continuous abstinence 1041

1040_ET_nakamura

6/29/07

9:52 AM

Page 1042

Clinical Therapeutics rates (CARs) with varenicline 1 mg BID compared with bupropion SR 150 mg BID and with placebo at the end of 12 weeks of treatment, and higher CARs were evident for up to 1 year after treatment initiation.14 In this study, the CAR for the last 4 weeks of treatment (weeks 9–12) was 43.9% compared with 17.6% in the placebo group (P < 0.001) and 29.8% in the bupropion SR group (P < 0.001). Furthermore, 52 weeks after quitting, 23.0% of smokers taking varenicline remained abstinent compared with only 10.3% of placebo-group smokers (P < 0.001) and 14.6% taking bupropion SR (P = 0.004). A second, identically designed study in 1025 subjects had similar results.15 The present study was the first confirmatory trial of varenicline to be conducted in Japan. It was designed to evaluate the dose-response relationship of varenicline, over 3 doses, versus placebo for smoking cessation in Japanese smokers.

SUBJECTS AND METHODS Study Design A randomized, double-blind, placebo-controlled, parallel-group, Japanese multicenter (19 sites) study (ClinicalTrials.gov Identifier: NCT00139750) was conducted with the primary objective of comparing the efficacy of varenicline at doses of 0.25 mg BID, 0.5 mg BID, and 1 mg BID with placebo after 12 weeks of treatment. Secondary objectives included long-term efficacy of varenicline up to 40 weeks after the end of treatment. The safety profile and tolerability of varenicline were also evaluated. This study was conducted in accordance with the Declaration of Helsinki16 and was approved by the institutional review board at each of the 19 study sites and was conducted in compliance with International Conference on Harmonisation and Good Clinical Practice guidelines.17

Participants Japanese smokers aged between 20 and 75 years who were motivated to stop smoking and who had claimed to have smoked a mean of at least 10 cigarettes per day during the preceding year without a period of abstinence >90 days were eligible for the study. Women of childbearing potential were eligible if they were not pregnant or breastfeeding, and if they practiced effective contraception for at least 30 days prior to screening. Smokers with a history of serious diseases or diseases that required close follow-up (includ1042

ing cardiovascular, cerebrovascular, and pulmonary disease; cancer; significant hepatic or renal impairment; neurologic and psychiatric disorder) and those with significant laboratory abnormalities were not eligible for participation. Other exclusion criteria included a body mass index of <15 kg/m2 or >38 kg/m2, body weight <45 kg, history of drug (except nicotine) or alcohol abuse or dependence within the previous 12 months, and use of NRT within the previous 30 days. Study subjects who used tobacco products other than cigarettes (pipe tobacco, snuff, chewing tobacco, cigars) within 30 days prior to screening or who did not agree to abstain from use of these products during the study period were also excluded.

Interventions A screening visit was conducted 5 to 21 days prior to the baseline visit and subjects were enrolled into the study based on inclusion and exclusion criteria. During the screening visit, written informed consent was obtained, and the target quit date (TQD), the day on which the subject agreed to initiate smoking abstinence, was set to coincide with the first scheduled on-treatment visit. The Tobacco Dependence Screener (TDS),18 a scale from 0–10 used in the smokingcessation treatment service reimbursed by public health insurance in Japan, was used to diagnose nicotine dependence (score ≥5), and the degree of nicotine dependence was determined by the Fagerström Test for Nicotine Dependence (FTND, scale from 0–10, with higher scores indicating greater dependence).19 A medical history, smoking history, physical examination (including blood pressure, heart rate, and body weight), and 12-lead electrocardiogram (ECG) were also conducted. At the baseline visit, a computer-generated list of random numbers was used to assign subjects to receive 12 weeks of treatment with varenicline 0.25 mg BID, 0.5 mg BID, or 1 mg BID or placebo. All treatments were provided as tablets to be taken with 200 mL water. Treatment began on the evening of the baseline visit, and dose titration to full dose was implemented during week 1 (0.25 mg QD for 7 days in the 0.25 mg BID group, 0.5 mg QD for 7 days in the 0.5 mg BID group, and 0.5 mg QD for 3 days followed by 0.5 mg BID for 4 days in the 1 mg BID group), since earlier clinical study results suggested improved tolerability with initial dose titration.20 Double-blinding of subjects and investigators was maintained throughout the study using matching placebo tablets, including the Volume 29 Number 6

1040_ET_nakamura

6/29/07

9:52 AM

Page 1043

M. Nakamura et al. dose titration during week 1. Adherence to treatment was checked by counting leftover tablets or by interviews with subjects at weekly clinic visits during the treatment period. Subjects were given brief smoking-cessation counseling based on the US Agency for Health Care Policy and Research guidelines,21 lasting up to 10 minutes at each clinic visit, beginning at baseline and continuing until the end of treatment. An educational booklet on smoking cessation22 was distributed to subjects for review at baseline. The week-1 visit was scheduled to coincide with the TQD and set as the date that subjects were to initiate abstinence from smoking. Smokingcessation counseling (of up to 5 minutes) was also provided by telephone contact at TQD + 3 days. The nontreatment follow-up period was 40 weeks, with 6 clinic visits (weeks 13, 16, 24, 36, 44, and 52) and 5 telephone contacts (weeks 20, 28, 32, 40, and 48). Smoking-cessation counseling was also provided during this period, lasting up to 10 minutes at clinic visits and up to 5 minutes by telephone contacts.

Efficacy Evaluations The primary end point was the end-expiratory carbon monoxide (CO)–confirmed 4-week CAR for weeks 9–12, with no reported smoking (not even a puff) or other nicotine use. Smoking status was obtained, beginning at the week-1 visit, through selfreports of cigarette and other nicotine use since the last study visit and confirmed by measurement of endexpiratory CO concentration. Of the various biochemical markers used to confirm abstinence, such as nicotine, cotinine, CO, and thiocyanate, end-expiratory CO concentration was used because it is considered an appropriate measure for biochemical verification23,24 and is widely used in controlled clinical trials.25,26 Although end-expiratory CO cannot be used to detect the use of noncombustible sources of nicotine (eg, nicotine gum), all forms of tobacco and NRT were prohibited in this trial, as stated in the informed consent form signed by all subjects, and subjects were asked about usage at each clinic visit and telephone contact. End-expiratory CO levels were measured using a Micro Smokerlyzer (Bedfont Scientific Limited, Rochester, United Kingdom) following the subjects’ self-reported smoking status at each clinic visit from baseline to week 52 or early termination of treatment/ follow-up. A subject was determined to be a nonJune 2007

smoker if the end-expiratory CO concentration was ≤10 ppm. If CO levels were found to be >10 ppm, the subject was considered nonabstinent for the period associated with that measurement. The CAR was defined as the proportion of subjects confirmed to have achieved abstinence during the period. Subjects who discontinued the study were considered smokers for the remainder of the study. The end expiratory CO–confirmed CARs for weeks 9–24 and weeks 9–52 were also evaluated as secondary end points. End-expiratory CO–confirmed 7-day point prevalence (PP) of abstinence, defined as the proportion of subjects confirmed to have achieved abstinence during the past 7 days, was evaluated at week 2 through week 12, week 24, and week 52 to facilitate comparison with existing literature.27

Other Evaluations Three instruments were used to assess craving, withdrawal, and the reinforcing effects of smoking, beginning at the baseline visit—the Minnesota Nicotine Withdrawal Scale (MNWS),28–30 the Brief Questionnaire on Smoking Urges (QSU-Brief),30–32 and the modified Cigarette Evaluation Questionnaire (mCEQ).30,33,34 Nicotine-withdrawal symptoms were assessed with the MNWS scale. This scale comprised 9 items, categorized into 5 subscales (Urge to Smoke, Negative Affect, Restlessness, Increased Appetite, and Insomnia), in which withdrawal symptoms were rated on a scale of 0 (not at all) to 4 (extreme). Assessment occurred at each clinic visit from baseline to week 7, week 12, and week 13. The QSU-Brief assessed the urge to smoke (craving), using a 10-item scale rated from 1 (strongly disagree) to 7 (strongly agree), based on the total score as well as on 2 subscales, Factor 1 (5 items concerning the urge to smoke) and Factor 2 (3 items concerning relief from negative affect). It was completed at each clinic visit from baseline to week 7 and again at the week-12 visit. The mCEQ was used to assess the reinforcing effects of smoking. It was categorized into 5 subscales (Smoking Satisfaction, Psychological Reward, Enjoyment of Respiratory Tract Sensations, Craving Reduction, and Aversion) in which higher scores indicated stronger intensity of symptoms related to smoking effects on a 7-point scale (from 1 = not at all to 7 = extremely). It was administered weekly from baseline to week 7 and was completed only by those subjects who had claimed to have smoked since the previous assessment. 1043

1040_ET_nakamura

6/29/07

9:52 AM

Page 1044

Clinical Therapeutics

Tolerability Assessments Tolerability assessments included physical examinations, blood pressure, heart rate, body weight, ECG, laboratory tests, adverse events (AEs), and serious AEs (SAEs). An SAE was defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability or incapacity; or resulted in a congenital anomaly or birth defect. Blood pressure, heart rate, and body weight were measured at each clinic visit from baseline to week 52 or early termination of treatment/follow-up. Blood pressure and heart rate were measured in the upper portion of the dominant arm with the patient in the sitting position after an appropriate period of rest. ECGs were carried out at screening, baseline, week 2, and week 12, or early termination of treatment. Laboratory tests to determine clinical abnormalities included blood chemistry, complete blood count, and urinalysis. All observed or self-reported AEs during the treatment period and up to 7 days after the final dose were recorded in case-report forms and followed up until they resolved or to the study end.

Randomization/Statistical Methods Before randomization, subjects were stratified into 2 groups based on their diagnosis of nicotine dependence as determined by the TDS score at screening, as follows: those with TDS scores ≥5 (the nicotinedependent group) and those with TDS scores ≤4. Subjects in each group were randomized to 1 of the 4 treatment groups in a 1:1:1:1 ratio using a central procedure. The primary efficacy analyses of the primary and secondary end points (CAR at weeks 9–12, 9–24, and 9–52, and 7-day PP) were conducted in the nicotine-dependent group (all subjects who received ≥1 dose of study medication and had a TDS score ≥5); the primary tolerability analyses were conducted in the total group (all subjects who received ≥1 dose of study medication, regardless of TDS score). Efficacy analyses were also conducted in the total group, and tolerability analyses were also conducted in the nicotinedependent group. To detect differences at a significance level of 0.05 between varenicline 0.5 mg or 1 mg BID and placebo in the primary analysis population with at least 90% power (based on the results of an earlier varenicline dose-response study20), it was estimated that a mini1044

mum sample size of at least 480 nicotine-dependent smokers was required. Operationally, enrollment of smokers scoring ≤4 on the TDS was planned to be ended when the number of these subjects reached 200. Therefore, the maximum planned sample size was 680 subjects. The primary end point (CAR for weeks 9–12) was compared between each varenicline group and the placebo group using a logistic regression model that included dose and study center as categorical variables. To preserve the family-wise error rate, a stepdown procedure (1 mg BID > 0.5 mg BID > 0.25 mg BID vs placebo) was used for pairwise comparisons between the varenicline and placebo groups for the primary end point.35 Each test was carried out using a 2-sided type I error rate of 5%. A logistic regression model was also used to investigate a dose-response relationship over the 3 varenicline doses (secondary analysis). No adjustment for multiple comparisons was made for any of the secondary analyses. Similarly, a logistic regression model that included dose and study center as categorical variables was used to evaluate comparisons between the 3 doses of varenicline and placebo for the secondary end points (CAR for weeks 9–24 and weeks 9–52, and 7-day PP). Repeated-measures analysis was used to evaluate mean scores on the MNWS, QSU-Brief, and mCEQ. Summary statistics (responder rates for binary variables; mean and standard error for continuous variables) were calculated for each treatment group for each evaluation period.

RESULTS Subject Disposition and Baseline Characteristics A total of 619 subjects were enrolled and randomly assigned to receive varenicline 0.25 mg BID (153 subjects), 0.5 mg BID (156), 1 mg BID (156), or placebo (154). A total of 618 subjects received treatment; 1 subject originally assigned to the varenicline 0.5 mg group withdrew prior to treatment. Of the total group, 577 (93.4%) subjects completed the treatment and 510 (82.5%) completed the study (Figure 1). The 1 subject who did not receive study treatment was not included in these analyses. As this subject withdrew prior to treatment for reasons unrelated to the study and the decision to initiate treatment could not be influenced by knowledge of the assigned treatment, the intent-to-treat principle was preserved despite this exclusion. Volume 29 Number 6

1040_ET_nakamura

6/29/07

9:52 AM

Page 1045

M. Nakamura et al.

619 Subjects enrolled

Treatment assignment

153 Randomized to varenicline 0.25 mg BID

156 Randomized to varenicline 0.5 mg BID

156 Randomized to varenicline 1 mg BID

154 Randomized to placebo

1 Not treated 7 Discontinued treatment 2 Adverse events 5 Consent withdrawal 0 Other 146 Completed treatment

10 Discontinued treatment 3 Adverse events 5 Consent withdrawal 2 Other 145 Completed treatment

13 Discontinued treatment 5 Adverse events 7 Consent withdrawal 1 Other 143 Completed treatment

11 Discontinued treatment 3 Adverse events 8 Consent withdrawal 0 Other 143 Completed treatment

20 Discontinued during follow-up 5 Adverse events* 0 Consent withdrawal 15 Other† 0 Deaths 126 Completed study

17 Discontinued during follow-up 1 Adverse events* 3 Consent withdrawal 13 Other† 0 Deaths 128 Completed study

19 Discontinued during follow-up 2 Adverse events* 1 Consent withdrawal 15 Other† 1 Death‡ 124 Completed study

11 Discontinued during follow-up 1 Adverse events* 3 Consent withdrawal 7 Other† 0 Deaths 132 Completed study

153 Included in secondary efficacy and safety analyses

155 Included in secondary efficacy and safety analyses

156 Included in secondary efficacy and safety analyses

154 Included in secondary efficacy and safety analyses

Figure 1. Subject disposition in the total group. *Serious adverse events unrelated to treatment. †Primarily transferred to another study that evaluated 12 weeks of retreatment in those who failed to remain abstinent during weeks 9–12 in this study. ‡Traffic accident unrelated to treatment. Of the 618 subjects in the total group, 515 (83.3%) were classified as nicotine dependent (ie, scoring ≥5 on the TDS) and formed the primary analysis population for smoking-cessation efficacy (varenicline 0.25 mg BID, 128 subjects; 0.5 mg BID, 128; 1 mg BID, 130; or placebo, 129). Among these, 482 (93.6%) subjects completed the treatment and 426 (82.7%) completed the study (Figure 2). The treatment groups of the primary analysis population were well balanced with reJune 2007

spect to baseline characteristics and smoking history (Table I). 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 FTND in each group was within the range of 5.4 to 5.7.

Continuous Abstinence Rates The 4-week CARs for weeks 9–12 in the nicotinedependent group were significantly higher for all doses 1045

1040_ET_nakamura

6/29/07

9:52 AM

Page 1046

Clinical Therapeutics

516 Subjects defined as nicotine-dependent enrolled

Treatment assignment

128 Randomized to varenicline 0.25 mg BID

129 Randomized to varenicline 0.5 mg BID

130 Randomized to varenicline 1 mg BID

129 Randomized to placebo

1 Not treated 6 Discontinued treatment 2 Adverse events 4 Consent withdrawal 0 Other 122 Completed treatment

9 Discontinued treatment 3 Adverse events 5 Consent withdrawal 1 Other 119 Completed treatment

11 Discontinued treatment 5 Adverse events 6 Consent withdrawal 0 Other 119 Completed treatment

7 Discontinued treatment 3 Adverse events 4 Consent withdrawal 0 Other 122 Completed treatment

18 Discontinued during follow-up 5 Adverse events* 0 Consent withdrawal 13 Other† 0 Deaths 104 Completed study

15 Discontinued during follow-up 1 Adverse events* 3 Consent withdrawal 11 Other† 0 Deaths 104 Completed study

16 Discontinued during follow-up 2 Adverse events* 0 Consent withdrawal 13 Other† 1 Death ‡ 103 Completed study

7 Discontinued during follow-up 1 Adverse events* 1 Consent withdrawal 5 Other† 0 Deaths 115 Completed study

128 Included in primary efficacy analysis

128 Included in primary efficacy analysis

130 Included in primary efficacy analysis

129 Included in primary efficacy analysis

Figure 2. Subject disposition in the nicotine-dependent group. *Serious adverse events unrelated to treatment. †Primarily transferred to another study that evaluated 12 weeks of retreatment in those who failed to remain abstinent during weeks 9–12 in this study. ‡Traffic accident unrelated to treatment.

of varenicline than that for placebo, which was 39.5% (51/129) (Table II, Figure 3). The CAR increased with dose: 54.7% (70/128) with varenicline 0.25 mg BID (OR [95% CI], 1.88 [1.14–3.12], P = 0.013); 55.5% (71/128) with varenicline 0.5 mg BID (OR [95% CI], 1.94 [1.17–3.22], P = 0.01); and 65.4% (85/130) with varenicline 1 mg BID (OR [95% CI], 2.98 [1.78–4.99], P < 0.001). When the varenicline dose-response relationship in terms of the 1046

4-week CAR for weeks 9–12 was analyzed using a logistic regression model, the slope of the regression line was 0.98 (95% CI, 0.50–1.48), confirming a significant dose-response relationship (P < 0.001). The CARs for weeks 9–24 in the nicotine-dependent group (Table II, Figure 3) were not significant for any dose of varenicline compared with placebo. The CAR for weeks 9–52 was significantly higher for varenicline 1 mg BID than placebo (34.6% [45/130] vs Volume 29 Number 6

1040_ET_nakamura

6/29/07

9:52 AM

Page 1047

M. Nakamura et al.

Table I. Baseline characteristics and smoking status of the nicotine-dependent group. Varenicline 0.25 mg BID (n = 128)

0.5 mg BID (n = 128)

93 (72.7) 35 (27.3)

91 (71.1) 37 (28.9)

103 (79.2) 27 (20.8)

98 (76.0) 31 (24.0)

Age, mean (SD), y

40.2 (12.3)

39.0 (12.0)

40.1 (11.6)

39.9 (12.3)

No. of years smoked, mean (SD)

20.9 (11.5)

20.1 (11.3)

21.5 (11.3)

20.9 (11.4)

No. of cigarettes/d in past 30 d, mean (SD)

24.9 (10.3)

23.8 (10.5)

24.0 (9.8)

23.1 (8.8)

Previous quit attempts,* no. (%) 0 1 2 ≥3

50 (39.1) 44 (34.4) 15 (11.7) 19 (14.8)

40 (31.3) 42 (32.8) 20 (15.6) 26 (20.3)

42 (32.3) 41 (31.5) 18 (13.8) 29 (22.3)

51 (39.5) 44 (34.1) 16 (12.4) 18 (14.0)

FTND score,† mean (SD)

5.6 (2.1)

5.5 (2.1)

5.4 (2.1)

5.7 (1.8)

7.15 (1.58)

7.45 (1.39)

7.29 (1.39)

7.43 (1.44)

Characteristic Sex, no. (%) Male Female

TDS

score,‡

mean (SD)

1 mg BID (n = 130)

Placebo (n = 129)

FTND = Fagerström Test for Nicotine Dependence19; TDS = Tobacco Dependence Screener.18 *Including “cold turkey,” nicotine patch, nicotine gum, and counseling/self-help. † Scores range from 0 to 10, with higher scores indicating a higher degree of nicotine dependence. ‡ Scores range from 0 to 10, with nicotine dependence defined as a score ≥5.

23.3% [30/129]; OR [95% CI], 1.81 [1.04–3.17]; P = 0.036). In the total group, similar results for CAR for weeks 9– 12 (66.7% [104/156] vs 39.0% [60/154]; OR [95% CI], 3.23 [2.02–5.19]; P < 0.001 for varenicline 1 mg BID vs placebo) and a significant dose-response relationship (slope [95% CI], 1.03 [0.58–1.48]; P < 0.001) were obtained. For weeks 9–24, CAR for varenicline 1 mg BID was significantly higher than for placebo (40.4% [63/156] vs 28.6% [44/154]; OR [95% CI], 1.73 [1.07–2.80]; P = 0.025) and for weeks 9–52, CARs for both varenicline 0.5 mg BID and 1 mg BID were significantly higher than for placebo (32.9% [51/155] and 35.9% [56/156] vs 22.7% [35/154]; ORs [95% CI], 1.70 [1.02–2.85]; P = 0.041 and 1.96 [1.18–3.26]; P = 0.009, respectively).

7-Day Point Prevalence of Abstinence The 7-day PP for the nicotine-dependent group increased from week 3 and thereafter in all of the varenicline groups compared with the placebo group, and was the highest in the varenicline 1 mg BID group June 2007

at all time points (Figure 4). At the end of treatment (week 12), more participants were abstinent in each of the varenicline groups (0.25 mg BID, 64.1% [82/128] [OR, 2.17; P = 0.003]; 0.5 mg BID, 62.5% [80/128] [OR, 2.02; P = 0.006]; and 1 mg BID, 72.3% [94/130] [OR, 3.21; P < 0.001]) compared with the placebo group (45.7% [59/129]). At study end (week 52), 7-day PP remained higher in 2 of the 3 varenicline groups (0.25 mg BID, 39.1% [50/128] [OR, 1.71; P < 0.05]; 1 mg BID, 42.3% [55/130] [OR, 1.97; P = 0.012]) compared with placebo (27.9% [36/129]).

Measures of Craving, Withdrawal, and Smoking Reinforcement The effects of varenicline compared with placebo on craving, withdrawal, and smoking satisfaction, as determined by the MNWS, QSU-Brief, and mCEQ questionnaires, are shown in Tables III and IV for the nicotine-dependent group. Over weeks 1 through 7 (Table III), mean scores on the MNWS Urge to Smoke subscale were significantly lower with varenicline 0.25, 0.5, and 1 mg BID 1047

1048 70/128 (54.7) 71/128 (55.5) 85/130 (65.4) 51/129 (39.5)

Varenicline 0.25 mg BID

Varenicline 0.5 mg BID

Varenicline 1.0 mg BID

Placebo

–

2.98 (1.78–4.99)

1.94 (1.17–3.22)

1.88 (1.14–3.12)

OR (95% CI)

–

<0.001

0.01

0.013

P

38/129 (29.5)

49/130 (37.7)

45/128 (35.2)

43/128 (33.6)

(n/N [%])

–

1.47 (0.87–2.50)

1.33 (0.78–2.27)

1.22 (0.71–2.09)

OR (95% CI)

–

0.149

0.298

0.464

P

30/129 (23.3)

45/130 (34.6)

37/128 (28.9)

35/128 (27.3)

(n/N [%])

–

1.81 (1.04–3.17)

1.38 (0.78–2.46)

1.25 (0.70–2.23)

OR (95% CI)

n = number considered abstinent; N = number of evaluable subjects; OR = odds ratio for each treatment group compared with the placebo group.

(n/N [%])

Treatment

Weeks 9–52 CAR

–

0.036

0.265

0.446

P

9:52 AM

Weeks 9–24 CAR

6/29/07

Weeks 9–12 CAR

Table II. Continuous abstinence rates (CARs) in the nicotine-dependent group.

1040_ET_nakamura Page 1048

Clinical Therapeutics

Volume 29 Number 6

1040_ET_nakamura

6/29/07

9:52 AM

Page 1049

M. Nakamura et al.

70

Varenicline 1 mg BID (n = 130) Varenicline 0.5 mg BID (n = 128) Varenicline 0.25 mg BID (n = 128) Placebo (n = 129)

* †

60

‡

CARs (%)

50 40

§

30 20 10 0 ||

Weeks 9–24¶

Weeks 9–12

Weeks 9–52¶

Figure 3. Continuous abstinence rates (CARs) in the nicotine-dependent group. *P < 0.001; †P = 0.01; ‡P = 0.013; §P = 0.036, all compared with placebo; ||Clinic visits only, at which abstinence was confirmed by endexpiratory carbon monoxide ≤10 ppm; ¶Clinic visits (at which abstinence was confirmed as before) and telephone contacts.

Varenicline 1 mg BID (n = 130) Varenicline 0.5 mg BID (n = 128) Varenicline 0.25 mg BID (n = 128) Placebo (n = 129)

← Drug Treatment →

80 70

7-Day PP (%)

60 50 40 30 20 10 0 0

4

8

12

16

20

24

28

32

36

40

44

48

52

Week Figure 4. 7-Day point prevalence (PP) of abstinence in the nicotine-dependent group, as verified by end-expiratory carbon monoxide ≤10 ppm.

June 2007

1049

1040_ET_nakamura

6/29/07

9:52 AM

Page 1050

Clinical Therapeutics

Table III. Evaluation of withdrawal and craving symptoms reported in the nicotine-dependent group, as measured on the Minnesota Nicotine Withdrawal Scale (MNWS)28–30 and the Brief Questionnaire on Smoking Urges (QSU-Brief)30–32: Repeated-measures analysis for weeks 1–7.

No. of Subjects

Least Squares Mean (SE)

Difference vs Placebo, Mean (SE)

95% CI

P

MNWS–Urge to smoke Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

128 128 130 129

1.31 (0.072) 1.11 (0.073) 1.05 (0.071) 1.57 (0.072)

–0.26 (0.100) –0.46 (0.100) –0.51 (0.099) –

–0.45 to –0.06 –0.66 to –0.26 –0.71 to –0.32 –

0.01 <0.001 <0.001 –

MNWS–Negative affect Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

128 128 129 129

0.51 (0.046) 0.40 (0.047) 0.36 (0.046) 0.64 (0.046)

–0.13 (0.064) –0.24 (0.064) –0.28 (0.064) –

–0.25 to –0.00 –0.37 to –0.12 –0.41 to –0.15 –

0.046 <0.001 <0.001 –

MNWS–Restlessness Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

128 128 130 129

0.64 (0.059) 0.55 (0.059) 0.45 (0.058) 0.83 (0.058)

–0.19 (0.081) –0.28 (0.081) –0.38 (0.081) –

–0.35 to –0.03 –0.44 to –0.12 –0.54 to –0.22 –

0.018 <0.001 <0.001 –

MNWS–Increased appetite Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

128 127 129 129

1.17 (0.087) 1.15 (0.088) 0.95 (0.087) 1.03 (0.087)

0.14 (0.121) 0.12 (0.121) –0.09 (0.121) –

–0.09 to 0.38 –0.12 to 0.36 –0.32 to 0.15 –

0.238 0.319 0.481 –

MNWS–Insomnia Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

128 128 130 129

0.53 (0.057) 0.55 (0.058) 0.56 (0.057) 0.49 (0.057)

0.04 (0.079) 0.05 (0.079) 0.07 (0.079) –

–0.12 to 0.19 –0.10 to 0.21 –0.09 to 0.22 –

0.632 0.504 0.380 –

QSU-Brief–Total craving score Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

128 128 130 127

2.05 (0.084) 1.84 (0.084) 1.84 (0.083) 2.35 (0.084)

–0.30 (0.117) –0.51 (0.117) –0.51 (0.116) –

–0.53 to –0.07 –0.74 to –0.28 –0.74 to –0.28 –

0.012 <0.001 <0.001 –

QSU-Brief–Factor 1 Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

128 128 130 127

2.28 (0.096) 2.05 (0.096) 2.05 (0.095) 2.65 (0.096)

–0.37 (0.133) –0.60 (0.133) –0.60 (0.132) –

–0.63 to –0.11 –0.86 to –0.34 –0.86 to –0.34 –

0.006 <0.001 <0.001 –

QSU-Brief–Factor 2 Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

128 128 130 127

1.62 (0.067) 1.46 (0.067) 1.46 (0.066) 1.84 (0.067)

–0.22 (0.093) –0.38 (0.093) –0.38 (0.093) –

–0.40 to –0.04 –0.56 to –0.20 –0.56 to –0.19 –

0.019 <0.001 <0.001 –

Subscale/Treatment

1050

Volume 29 Number 6

1040_ET_nakamura

6/29/07

9:52 AM

Page 1051

M. Nakamura et al.

Table IV. Evaluation of the reinforcing effects of smoking in the nicotine-dependent group, as measured on the modified Cigarette Evaluation Questionnaire 30,33,34: Repeated-measures analysis for weeks 1–7.

No. of Subjects

Least Squares Mean (SE)

Difference vs Placebo, Mean (SE)

95% CI

P

Smoking satisfaction Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

105 98 92 104

2.79 (0.115) 2.42 (0.123) 2.34 (0.129) 3.09 (0.113)

–0.29 (0.159) –0.67 (0.163) –0.74 (0.168) –

–0.61 to 0.02 –0.99 to –0.35 –1.07 to –0.41 –

0.064 <0.001 <0.001 –

Psychological reward Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

105 98 93 104

2.09 (0.082) 1.91 (0.087) 1.79 (0.090) 2.33 (0.080)

–0.24 (0.112) –0.42 (0.115) –0.53 (0.118) –

–0.46 to –0.02 –0.64 to –0.19 –0.76 to –0.30 –

0.036 <0.001 <0.001 –

Enjoyment of respiratory tract sensations Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

105 98 92 104

2.34 (0.117) 2.23 (0.125) 1.81 (0.131) 2.80 (0.114)

–0.47 (0.161) –0.57 (0.166) –1.00 (0.171) –

–0.78 to –0.15 –0.90 to –0.25 –1.33 to –0.66 –

0.004 <0.001 <0.001 –

Craving reduction Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

105 98 92 104

2.88 (0.146) 2.76 (0.156) 2.70 (0.165) 3.15 (0.142)

–0.27 (0.200) –0.40 (0.207) –0.45 (0.214) –

–0.66 to 0.13 –0.80 to 0.01 –0.87 to –0.03 –

0.181 0.057 0.035 –

Aversion Varenicline 0.25 mg BID Varenicline 0.5 mg BID Varenicline 1 mg BID Placebo

105 98 93 104

1.80 (0.095) 1.70 (0.101) 1.92 (0.107) 2.30 (0.092)

–0.50 (0.131) –0.60 (0.135) –0.38 (0.139) –

–0.76 to –0.24 –0.86 to –0.33 –0.65 to –0.10 –

<0.001 <0.001 0.007 –

Subscale/Treatment

compared with placebo (P = 0.01, P < 0.001, and P < 0.001, respectively), and indicated less negative affect (P = 0.046, P < 0.001, and P < 0.001) and less restlessness (P = 0.018, P < 0.001, and P < 0.001). No significant differences in mean scores on the MNWS subscales of Increased Appetite and Insomnia were observed between the varenicline and placebo groups. The descriptive statistics of the MNWS subscale scores at week 13 were similar to week 12, suggesting no withdrawal effects following discontinuation of treatment. Results for the mean QSU-Brief scores over weeks 1 through 7 (Table III) suggested a similar effect of varenicline on the QSU-Brief total craving score to that observed by the MNWS. Mean scores in the June 2007

varenicline 0.25, 0.5, and 1 mg BID groups were all significantly lower than that in the placebo group (P = 0.012, P < 0.001, and P < 0.001, respectively). Similarly, analysis of QSU-Brief–Factor 1 (urge to smoke) and –Factor 2 (relief from negative affect) subcomponents indicated that all mean scores in the varenicline 0.25, 0.5, and 1 mg BID groups were significantly lower than those in the placebo group (Factor 1: P = 0.006, P < 0.001, and P < 0.001; Factor 2: P = 0.019, P < 0.001, and P < 0.001). Finally, analysis of the mean mCEQ scores over weeks 1 through 7 (Table IV) found that varenicline was associated with significantly reduced scores on the subscale of Smoking Satisfaction at 0.5 and 1 mg BID compared with placebo (both doses, P < 0.001), 1051

1040_ET_nakamura

6/29/07

9:52 AM

Page 1052

Clinical Therapeutics Psychological Reward at 0.25, 0.5, and 1 mg BID (P = 0.036, P < 0.001, and P < 0.001, respectively), Enjoyment of Respiratory Tract Sensations at 0.25, 0.5, and 1 mg BID (P = 0.004, P < 0.001, and P < 0.001), Craving Reduction at 1 mg (P = 0.035), and Aversion at 0.25, 0.5, and 1 mg BID (P < 0.001, P < 0.001, and P = 0.007, respectively).

Tolerability The percentage of subjects in the total group who experienced all-causality, treatment-emergent AEs was higher in the varenicline groups (0.25 mg BID, 79.1% [121/153]; 0.5 mg BID, 80.6% [125/155]; and 1 mg BID, 80.1% [125/156]) than in the placebo group (71.4% [110/154]) (Table V). The AEs that occurred in ≥5% of subjects in any treatment group are reported in Table VI. The 3 most prevalent AEs at varenicline 1 mg BID were nasopharyngitis (35.9% [56 / 156]), nausea (24.4% [38/156]), and headache (10.3% [16/156]). The incidence of nausea in the varenicline groups was dose dependent: 7.2% (11/153) at 0.25 mg BID, 9.7% (15/155) at 0.5 mg BID, and 24.4% (38/156) at 1 mg BID. Most AEs were of mild or moderate intensity; only 2 AEs were reported as severe (cholecystitis in 1 subject in the varenicline 0.25 mg BID group, subarachnoid hemorrhage in 1 subject in the placebo group). SAEs developed in 5 (3.3%) of 153 subjects in the varenicline 0.25 mg BID group, 2 (1.3%) of 155 subjects in the 0.5 mg BID group, 3 (1.9%) of 156 subjects in the 1 mg BID group, and 3 (1.9%) of 154 subjects in the placebo group. Two of the SAEs were considered treatment related: 1 case of cholecystitis in the vareni-

cline 0.25 mg BID group, which resolved after laparoscopic cholecystectomy, and 1 case of angina pectoris in the 1 mg BID group, which resolved after discontinuation of treatment. One death occurred due to a traffic accident during the nontreatment follow-up period in a subject in the varenicline 1 mg BID group. AEs that led to study discontinuation occurred in 3 (2.0%) of 153 subjects in the varenicline 0.25 mg BID group (1 subject with nausea; 1 with peritonitis and cholecystitis; and 1 with diarrhea, vomiting, and sensory disturbance), 4 (2.6%) of 155 subjects in the 0.5 mg BID group (1 subject with hemorrhoids and rectal prolapse; 1 with conjunctivitis; 1 with pituitary hemorrhage, vomiting, and headache; and 1 with diarrhea, nasopharyngitis, and headache), 5 (3.2%) of 156 subjects in the 1 mg BID group (1 subject feeling abnormal; 1 with nausea; 1 with angina pectoris; 1 with ovarian hematoma; and 1 with nausea and asthenia), and 3 (1.9%) of 154 subjects in the placebo group (1 subject with subarachnoid hemorrhage; 1 with contusion; and 1 with rash), all of which resolved after termination of treatment (Table V). Across all treatment groups, the proportion of subjects who had a temporary suspension of treatment due to AEs ranged from 9.7% (15/154) to 13.5% (21/155) (Table V), although these subjects returned to full dosing and continued in the trial. The AE profile in the nicotine-dependent group was similar to that in the total group. In 4 subjects in the total group, a total of 5 laboratory test abnormalities were reported as treatmentrelated AEs. In the varenicline 1 mg BID group, 1 subject had both elevated aspartate aminotransferase (197 IU/L) and alanine aminotransferase (175 IU/L),

Table V. Summary of all-causality, treatment-emergent adverse events (AEs)* in the total group. Values are no. (%). Varenicline

Variable Any AEs Discontinuations due to AEs Temporary suspension of treatment due to AEs

0.25 mg BID (n = 153)

0.5 mg BID (n = 155)

1 mg BID (n = 156)

Placebo (n = 154)

121 (79.1) 3 (2.0)

125 (80.6) 4 (2.6)

125 (80.1) 5 (3.2)

110 (71.4) 3 (1.9)

18 (11.8)

21 (13.5)

18 (11.5)

15 (9.7)

*All observed or volunteered AEs, regardless of the suspected causal relationship to study treatment, reported between the start of treatment and any time up to 7 days after administration of the last dose.

1052

Volume 29 Number 6

1040_ET_nakamura

6/29/07

9:52 AM

Page 1053

M. Nakamura et al.

Table VI. All-causality, treatment-emergent adverse events (AEs)* in ≥5% of the total group. Values are no. (%). Varenicline

AE Nasopharyngitis Headache Constipation Diarrhea Nausea Influenza Seasonal allergy Upper abdominal pain

0.25 mg BID (n = 153)

0.5 mg BID (n = 155)

1 mg BID (n = 156)

Placebo (n = 154)

66 (43.1) 16 (10.5) 13 (8.5) 13 (8.5) 11 (7.2) 7 (4.6) 9 (5.9) 3 (2.0)

79 (51.0) 18 (11.6) 12 (7.7) 7 (4.5) 15 (9.7) 5 (3.2) 4 (2.6) 9 (5.8)

56 (35.9) 16 (10.3) 12 (7.7) 1 (0.6) 38 (24.4) 9 (5.8) 5 (3.2) 12 (7.7)

59 (38.3) 4 (2.6) 8 (5.2) 1 (0.6) 12 (7.8) 9 (5.8) 10 (6.5) 10 (6.5)

*All observed or volunteered AEs, regardless of the suspected causal relationship to study treatment, reported between the start of treatment and any time up to 7 days after administration of the last dose.

and another had elevated blood bilirubin (2.1 mg/dL). In the varenicline 0.5 mg BID group, 1 subject had elevated blood creatinine (1.27 mg/dL), and in the varenicline 0.25 mg BID group, 1 subject had elevated alanine aminotransferase (94 IU/L). These events were considered mild in intensity. Increases in body weight were evident in all treatment groups including the placebo group and were not dose dependent. The mean (SE) increases in weight from baseline to week 12 for all subjects who completed the treatment period were varenicline 0.25 mg BID, 1.21 kg (0.15); varenicline 0.5 mg BID, 1.32 kg (0.17); varenicline 1 mg BID, 1.22 kg (0.14); and placebo, 0.71 kg (0.15). The mean (SE) increases in weight from baseline to week 12 for all subjects who succeeded in quitting were comparable among the treatment groups: varenicline 0.25 mg BID, 1.37 kg (0.19); varenicline 0.5 mg BID, 1.38 kg (0.24); varenicline 1 mg BID, 1.37 kg (0.17); and placebo, 1.48 kg (0.22).

DISCUSSION The current study suggests that varenicline, an α4β2 nAChR partial agonist, has significant efficacy for smoking cessation in Japanese smokers defined as nicotine dependent by scoring ≥5 on the TDS. Results for the primary end point, the CARs for weeks 9–12, were significantly higher for all doses of varenicline over placebo at the end of treatment. Efficacy was evident in a dose-dependent manner, with the highest June 2007

abstinence rate observed in the varenicline 1 mg BID group for both primary and secondary efficacy measures. In the varenicline 1 mg BID group, 65.4% of subjects achieved continuous abstinence during the last 4 weeks of treatment compared with 39.5% in the placebo group (OR, 2.98), and 34.6% of subjects who received varenicline 1 mg BID remained continuously abstinent from week 9 through week 52 compared with 23.3% of placebo subjects (OR, 1.81). CARs at end of treatment and week-52 follow-up were similar when the total group, including smokers with TDS scores of ≤4, was considered. Results for the less conservative measure of smoking cessation, the 7-day PP, supported these continuous abstinence measures. The unique activity of varenicline was reinforced by additional measures. Based on the mean scores on the MNWS Urge to Smoke subscale and the QSUBrief, all doses of varenicline were associated with a reduced urge to smoke compared with placebo. Mean scores on the Negative Affect and Restlessness MNWS subscales were also significantly lower with varenicline treatment compared with placebo, suggesting a reduction in withdrawal symptoms. Results of the mCEQ subscales support the idea that varenicline reduces smoking satisfaction. This characteristic of varenicline treatment may help to decrease the reinforcing effects of nicotine. Similar effects were observed in the US studies.14,15 Overall, varenicline was well tolerated. In the total group, the incidences of AEs were higher in the 1053

1040_ET_nakamura

6/29/07

9:52 AM

Page 1054

Clinical Therapeutics varenicline groups (79.1%–80.6%) than in the placebo group (71.4%), and most were considered mild or moderate in intensity, with 12 (2.6%) subjects treated with varenicline discontinuing the study. The incidence of nausea in the 1 mg BID dosing group was lower (24.4%) than that reported in the US studies (29.4% and 28.1%),14,15 which suggests a favorable tolerability profile of varenicline in Japanese smokers for the dosing regimens used in this 12-week study. A limitation of the study design was that inclusion/ exclusion criteria limited the study population to relatively healthy subjects, excluding smokers with unstable diseases and psychiatric disorders. Consequently, extrapolation of these results to the general population requires some caution. The CARs for weeks 9–12 and weeks 9–52 observed in the present study at the varenicline 1 mg BID dose were higher than those reported in the 2 US studies of varenicline.14,15 However, this was also true for the placebo group in this study compared with the US studies, and the treatment effect for varenicline defined by the absolute differences in CARs between varenicline 1 mg BID and placebo were similar for all studies (present study CAR difference for weeks 9–12, 25.9% vs 26.3%14 and 26.3%15 in the US studies; present study CAR difference for weeks 9–52, 11.3% vs 12.7%14 and 13.5%15 in the US studies). The efficacy of varenicline in both this present study and the 2 US studies are reflected in the ORs for quitting on varenicline 1 mg BID compared with placebo. In this study, the OR for weeks 9–12 was 2.98, and for the 2 US studies the ORs were 3.8514 and 3.85.15 Similarly, for weeks 9–52 the OR was 1.81 in this study, and in the US studies the ORs were 2.6614 and 3.09.15 CARs may have been influenced by differences in smoking-cessation environments in Japan and the United States. There is a longer history of promotional strategies to encourage smoking cessation in the United States than in Japan. Consequently, the majority of smokers in US studies had previously experienced failed quit attempts, with ~15% of subjects making their first quit attempt.15 In contrast, in the current Japanese study, ~35% of subjects were making their first serious attempt to quit. Successful tobacco control is thought to result in a higher dependence among the remaining smokers due to selective quitting by smokers with lower dependence.36 However, the mean number of cigarettes smoked per day and FTND between the US and the Japanese studies were compa1054

rable. Thus, differences in smoking-cessation environments may have had minimal influence on the difference in the reported CARs. Another consideration is better treatment compliance and the high enthusiasm in both the investigators and the study participants in an environment with limited pharmacotherapies available for smoking cessation compared with the United States. This could explain the greater study retention rate in both the treatment phase of the present study (93.3% for varenicline and 94.6% for placebo in the nicotinedependent group) compared with the US studies (75.8%14 and 74.2%15 for varenicline; 65.3%14 and 62.5%15 for placebo), as well as the nontreatment phase (80.6% for varenicline and 89.1% for placebo in the nicotine-dependent group) in this study compared with the US studies (70.0%14 and 61.0%15 for varenicline; 60.0%14 and 54.3%15 for placebo). A higher retention rate suggests that more subjects received treatment and counseling during the nontreatment follow-up phase, allowing an accurate evaluation of the abstinence rate in a study design in which all subjects who discontinued treatment and followup were assumed to be smokers.

CONCLUSIONS The results of this study suggest that varenicline, the first in a new class of compounds developed for smoking cessation, was an efficacious and well-tolerated therapy in nicotine-dependent smokers within this Japanese study population. In a dose-dependent manner, treatment with varenicline for 12 weeks was associated with improved smoking-abstinence rates measured during the last 4 weeks of treatment as well as long-term abstinence in the 40-week follow-up period. Varenicline was generally well tolerated, with mild or moderate nausea as the main dose-dependent AE.

ACKNOWLEDGMENTS The Varenicline Japanese Phase 2b Study Group included the following principal investigators: Makoto Koizumi (Koizumi Pulmonology and Internal Medicine Clinic, Hokkaido); Akemi Konishi (Kobari General Hospital, Chiba); Hisakuni Sekino (Sekino Hospital, Tokyo); Yukio Suzuki (Kitasato Institute Hospital, Tokyo); Isamu Hirata (Hideshima Hospital, Tokyo); Hakuzan Tajima (Tajima Clinic, Tokyo); Toshikazu Nagakura (Yoga Allergy Clinic, Tokyo); Minoru Nozaki (Swing Nozaki Clinic, Tokyo); Hirotaka Volume 29 Number 6

1040_ET_nakamura

6/29/07

9:52 AM

Page 1055

M. Nakamura et al. Nagashima (Ohsaki Heart Clinic, Tokyo); Akio Kubo (Kubo Clinic, Kanagawa); Hidenori Nakamura (Seirei Hamamatsu General Hospital, Shizuoka); Ichiro Otani (Midorigaoka Hospital, Osaka); Kenjiro Nakamura (Tenjin Sogo Clinic, Fukuoka); Wataru Ikematsu (Kobori Building Clinic, Fukuoka); Hideyuki Ikematsu (Hara-Doi Hospital, Fukuoka); Yukikuni Sakata (PS Clinic, Fukuoka); Hiroyuki Saito (Saito Clinic, Saga); Keiji Oka (Oita Oka Hospital, Oita); and Yosuke Nakamura (Nakamura Hospital, Oita). The study was funded by Pfizer Inc. (ClinicalTrials. gov Identifier: NCT00139750). Drs. Nakamura and Oshima were the primary study investigators, had full access to all study data, and had the final responsibility for the decision to submit the results for publication. Dr. Nakamura has received research contracts from Pfizer Japan Inc. (Tokyo, Japan), Novartis Pharma K.K. (Tokyo, Japan), and Sanofi-Aventis K.K. (Tokyo, Japan), and a research grant from Pfizer Research Foundation (Tokyo, Japan). Dr. Oshima has received research contracts from Pfizer Japan Inc. Editorial assistance was provided by Christopher Grantham, PhD, Envision Pharma, Horsham, United Kingdom.

REFERENCES 1. Mackay J, Eriksen M, Shafey O. The Tobacco Atlas. 2nd ed. American Cancer Society; 2006. 2. Ministry of Health Labour and Welfare. National Health and Nutrition Survey for 2005 [MHLW Web site]. Available at: http://www.mhlw.go.jp/houdou/2007/05/ h0516-3a.html. Accessed June 2, 2007. 3. Ministry of Health Labour and Welfare. National Nutrition Survey for 1989 [Japan Health Promotion & Fitness Foundation Web site]. Available at: http://www.health-net.or.jp/ tobacco/product/pd100000.html. Accessed June 2, 2007. 4. Peto R, Lopez AD, Boreham J, Thun M. Mortality from smoking in developed countries 1950–2000. 2004 Revision [Clinical Trials Service Unit Web site]. Available at: http://www.ctsu.ox.ac.uk/~tobacco/. Accessed April 20, 2007. 5. Institute for Health Economics and Policy. Report on the cost-benefit analyses on tobacco control policies [IHEP Web site]. Available at: http://www.ihep.jp/. Accessed April 20, 2007. 6. Izumi Y, Tsuji I, Ohkubo T, et al. Impact of smoking habit on medical care use and its costs: A prospective observation of National Health Insurance beneficiaries in Japan. Int J Epidemiol. 2001;30:616–621; discussion 622–623.

June 2007

7. Silagy C, Lancaster T, Stead L, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2004;3:CD000146. 8. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2007;4:CD000031. 9. US Dept of Health and Human Services. The health consequences of smoking: Nicotine addiction: A report of the Surgeon General. Washington, DC: Government Printing Office; 1988. DHHS publication (CDC) 88-8406. 10. Henningfield J, Schuh L, Jarvik M. Pathophysiology of tobacco dependence. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven; 1995:1715–1729. 11. Maskos U, Molles BE, Pons S, et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature. 2005;436:103–107. 12. Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: An alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem. 2005;48:3474–3477. 13. Rollema H, Chambers LK, Coe JW, et al. Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology. 2007;52:985–994. 14. Jorenby DE, Hays JT, Rigotti NA, et al, for the Varenicline Phase 3 Study Group. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: A randomized controlled trial [published correction appears in JAMA. 2006;296:1355]. JAMA. 2006; 296:56–63. 15. Gonzales D, Rennard SI, Nides M, et al, for the Varenicline Phase 3 Study Group. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustainedrelease bupropion and placebo for smoking cessation: A randomized controlled trial. JAMA. 2006;296:47–55. 16. World Medical Association. Declaration of Helsinki ethical principles for medical research involving human subjects [WMA Web site]. Available at: http://www.wma.net/e/ policy/b3.htm. Accessed June 4, 2007. 17. International Conference on Harmonisation. The ICH process for harmonisation of guidelines [ICH Web site]. Available at: http://www.ich.org/cache/compo/276–254-1. html. Accessed June 4, 2007. 18. Kawakami N, Takatsuka N, Inaba S, Shimizu H. Development of a screening questionnaire for tobacco/ nicotine dependence according to ICD-10, DSM-III-R, and DSM-IV. Addict Behav. 1999;24:155–166. 19. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The Fagerstrom Test for Nicotine Dependence: A revision of the Fagerstrom Tolerance Questionnaire. Br J Addict. 1991;86:1119–1127. 20. Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor

1055

1040_ET_nakamura

6/29/07

9:52 AM

Page 1056

Clinical Therapeutics

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

partial agonist, varenicline, for smoking cessation. Arch Intern Med. 2006;166:1571–1577. Fiore MC. Treating tobacco use and dependence: An introduction to the US Public Health Service Clinical Practice Guideline. Respir Care. 2000; 45:1196–1199. National Cancer Institute. Clearing the Air: Quit Smoking Today. Washington, DC: National Institutes of Health; 2003. NIH publication 03-1647. SRNT Subcommittee on Biochemical Verification. Biochemical verification of tobacco use and cessation. Nicotine Tob Res. 2002;4:149–159. West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking cessation trials: Proposal for a common standard. Addiction. 2005;100:299–303. Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med. 1997;337: 1195–1202. Gonzales D, Bjornson W, Durcan MJ, et al. Effects of gender on relapse prevention in smokers treated with bupropion SR. Am J Prev Med. 2002;22:234–239. Hughes JR, Keely JP, Niaura RS, et al. Measures of abstinence in clinical trials: Issues and recommendations [published correction appears in Nicotine Tob Res. 2003;5:603]. Nicotine Tob Res. 2003;5:13–25. Hughes JR, Hatsukami D. Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry. 1986;43:289–294. Cappelleri JC, Bushmakin AG, Baker CL, et al. Revealing the multidimensional framework of the Minnesota Nicotine Withdrawal Scale. Curr Med Res Opin. 2005;21:749–760. Ohishi T, Green J, Nakamura M, Ohashi J. Development of Japanese version of smoking cessation questionnaires. Jpn Pharmacol Ther. 2005; 33:141–156. Cox LS, Tiffany ST, Christen AG. Evaluation of the Brief Questionnaire of Smoking Urges (QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001;3:7–16.

1056

32. Cappelleri JC, Bushmakin AG, Baker CL, et al. Multivariate framework of the Brief Questionnaire of Smoking Urges. Drug Alcohol Depend. 2007;May 7 [E-pub ahead of print]. 33. Rose JE, Behm FM, Westman EC. Nicotine-mecamylamine treatment for smoking cessation: The role of pre-cessation therapy. Exp Clin Psychopharmacol. 1998;6:331–343. 34. Cappelleri JC, Bushmakin AG, Baker CL, et al. Confirmatory factor analyses and reliability of the modi-

fied cigarette evaluation questionnaire. Addict Behav. 2007;32:912– 923. 35. Ruberg SJ. Dose response studies. II. Analysis and interpretation [published correction appears in J Biopharm Stat. 1996;6:375]. J Biopharm Stat. 1995;5:15–42. 36. Fagerstrom KO, Kunze M, Schoberberger R, et al. Nicotine dependence versus smoking prevalence: Comparisons among countries and categories of smokers. Tob Control. 1996;5:52–56.

Address correspondence to: Masakazu Nakamura, MD, Department of Health Promotion and Education, Osaka Medical Center for Health Science and Promotion, 1-3-2, Nakamichi, Higashinari-ku, Osaka 5370025, Japan. E-mail: [email protected] Volume 29 Number 6