In this randomized, double-blind, placebo-controlled multinational study, smokers interested in quitting were randomized to the standard dose of varenicline or placebo. They were free to choose to quit at any time between Days 8 and 35 (Weeks 2–5) after starting treatment (i.e., following drug titration that took place within the first week). The aim was to assess the efficacy and safety of 12 weeks of varenicline 1 mg twice daily (b.i.d.) versus placebo in aiding cessation within this flexible quit date setting and included a 12-week follow-up period without medication.
Clinic visits occurred weekly until Week 12 then at Weeks 13, 16, 20, and 24. Telephone contact was made at Weeks 14, 18, and 22. At each visit, subjects were queried about their potential quit date, the number of cigarettes smoked per day, and their quit attempts since the last visit. A quit attempt was defined as a self-reported attempt that lasted for at least a few hours with the conviction to quit permanently and included both spontaneous and planned attempts. Cessation was monitored by self-report and was confirmed by ≤10 ppm expired carbon monoxide (CO). At each clinic or telephone contact, subjects received brief (up to 10 min) smoking cessation counseling, consistent with Agency for Healthcare Research and Quality guidelines (Fiore et al., 2008
). At baseline, subjects received the Clearing the Air: Quit Smoking Today
(National Cancer Institute [U.S.], 2003
) self-help booklet. As in previous varenicline studies, subjects were encouraged to continue in the study even if they discontinued medication or failed to stop smoking.
To facilitate cross-study comparisons, the same major outcomes were used as in previous varenicline studies, i.e., continuous abstinence from Weeks 9–12 and Weeks 9–24.
Randomization and Interventions
A predefined, central, computer-generated randomization sequence assigned subjects in a 3:1 ratio to receive either varenicline or placebo (block size: 4, stratified by center). A 3:1 randomization was chosen to promote rapid enrollment because the efficacy of varenicline has been established and it is commercially available. Varenicline subjects were titrated to the full dose during the first week: 0.5 mg once daily for 3 days then 0.5 mg b.i.d. for 4 days. Those randomized to placebo received matched placebo dosing with identical appearance to varenicline.
In order to preserve the blind of the investigative centers, subjects, and sponsor, no unblinded data listings and tables were produced, other than for the Data Monitoring Committee, until data from the non-treatment follow-up period had been entered into a database and cleaned.
Setting and Subjects
The study was conducted at 33 centers across 14 countries (Argentina, Brazil, Canada, China, Czech Republic, France, Germany, Hungary, Italy, Mexico, Republic of Korea, Taiwan, United Kingdom, and United States), between September 22, 2008 and December 10, 2009. Sites included research centers, private practice offices, and research clinics. Many centers in multiple countries were used in order to increase the external validity of the trial and to facilitate expeditious recruitment. Enrollment per center varied from 9 (1.4%) to 43 (6.5%) subjects with 17 centers enrolling between 16 and 20 subjects.
Inclusion and exclusion criteria were similar to the varenicline registration studies (Gonzales et al., 2006
; Jorenby et al., 2006
). Male and female smokers were eligible for the study if they were aged between 18 and 75 years, had smoked ≥10 cigarettes/day during the previous year with no longer than 3 months abstinence during that time, and were motivated to stop smoking.
Subjects were excluded from the study if they had used a nicotine replacement product, bupropion, clonidine, or nortriptyline within the past 3 months or had taken varenicline previously. Subjects were also excluded for serious or unstable psychiatric disorders in the past 6 months or on the basis of medical history. This encompassed current depression or depression diagnosed or treated within the past 12 months; any history of suicidal ideation or suicidal behavior in the past 5 years; past history of—or present—psychosis, panic attacks, or anxiety disorders; or bipolar disorder. It also excluded those with a history of drug (except nicotine) or alcohol abuse/dependence within the past 12 months and those with a positive urine drug screen for drugs of abuse/potential abuse not prescribed for the treatment of a medical condition.
Outcomes and Follow-up
The primary efficacy objective was to compare 12 weeks of varenicline 1 mg b.i.d. with placebo for smoking cessation in the setting of subject self-selected quit date. The primary efficacy endpoint was 4-week continuous abstinence for Weeks 9–12. The key secondary efficacy endpoint was continuous abstinence from Weeks 9 to 24. Additional secondary endpoints included the 7-day point prevalence of abstinence at Weeks 12 and 24 and time to first quit attempt.
Adverse events were recorded and subsequently systematized using the Medical Dictionary for Regulatory Activities
(MedDRA). Additionally, at each contact, two neuropsychiatric assessments were conducted: interviewer–administration of the Columbia Suicide-Severity Rating Scale (C-SSRS; Posner, Oquendo, Gould, Stanley, & Davies, 2007
) to assess suicidal ideation and behavior and self-administration of the Patient Health Questionnaire (PHQ-9; Kroenke, Spitzer, & Williams, 2001
) to assess depression/depressed mood.
Logistic regression models were used to assess primary and key secondary endpoints. The model included treatment and center as independent variables. The type 1 family-wise error rate of .05, for the analyses of the primary and key secondary endpoints, was preserved using a step-down procedure. The hierarchy of comparisons was (1) 4-week continuous abstinence for Weeks 9–12 and (2) continuous abstinence for Weeks 9–24. For these endpoints, expanded logistic regression models were used to assess the center by treatment interaction. The primary efficacy analysis population was all subjects randomized to treatment. Subjects who discontinued the study were assumed to be smokers from the point of discontinuation to end of study. In the case of missed visits during the evaluation periods for continuous abstinence (Weeks 9–12 and 9–24), a subject was considered abstinent if they reported they had not smoked or used nicotine products “since the last visit” at the first visit after the missing visit(s). Missing CO measurements did not disqualify the subject for abstinence endpoints. All statistical testing was two sided and used a .05 level of significance (no adjustment for multiplicity was used other than for the primary and key secondary endpoints).
The Kaplan–Meier method was used to analyze the time to first quit attempt, defined as the number of days from the first dose of study medication to the date of the first quit attempt based on subjects who took at least one dose of study medication. Subjects who did not report quit attempts within the quit window, or who had missing data, were classified as censored, and their time to first quit attempt was set to Day 35.
Expanded logistic regression models were used to assess the impact of country and baseline characteristics on the primary and key secondary outcomes. The sample size calculation was based on a two-group continuity-corrected Pearson chi-square two-sided test with a .05 significance level and a 3:1 randomization ratio of varenicline to placebo. Assuming true continuous abstinence rates of 0.24 for Weeks 9–12 and 0.18 for Weeks 9–24 for placebo and continuous abstinence rates of 0.46 for Weeks 9–12 and 0.31 for Weeks 9–24 for varenicline, a sample size of 652 subjects was calculated. This provided at least 90% power to detect a difference between the varenicline and placebo groups for the primary and key secondary endpoints.