From August 2008 to July 2009, we recruited daily users of smokeless tobacco into this double blind, placebo controlled, randomised, multicentre, parallel group clinical trial in Norway (seven sites: one at a specialist smoking cessation clinic; six in primary care) and Sweden (nine sites: one at a specialist smoking cessation clinic; five in primary care; three in secondary care hospitals). Participants were recruited almost exclusively through newspaper advertising. Our primary objective was to examine the efficacy of varenicline 1 mg twice daily compared with placebo for cessation of smokeless tobacco after 12 weeks of treatment. Secondary objectives included evaluations of efficacy for a further 14 weeks of follow-up after treatment and safety through the treatment period and four weeks after the last dose.
To be included, men and women aged ≥18 had to be using smokeless tobacco containing nicotine (at least eight times a day during the previous year with no period of abstinence in the three months before screening) but be motivated to stop use of all tobacco products. They had to be prepared to adhere to the protocol and provide informed consent. Women of childbearing age were included if they were not pregnant or breast feeding and had agreed to practise effective contraception for at least one month before and for the duration of the trial.
Exclusion criteria included use of any other nicotine containing products other than smokeless tobacco during the previous three months (participants’ exhaled carbon monoxide had to be ≤10 ppm at screening); use of varenicline, bupropion, or nicotine replacement treatment within the previous three months; use of any other investigational drug from 30 days before to 30 days after the study; history of drug or alcohol misuse within the past 12 months; or any serious psychiatric or medical condition (for example, depression) or treatment with any drugs that might interfere with the outcome of the trial or interpretation of safety or efficacy evaluations.
Eligible participants were randomised to one of two parallel treatment arms in a 1:1 ratio (varenicline:placebo) by using a telephone interactive voice response system (IVRS). Participant identification numbers were allocated in the numerical order in which participants were accepted to the study. Study investigators contacted the IVRS to obtain participants’ identification numbers and double blinded randomised allocations. The dose of varenicline was titrated up during the first week (0.5 mg once daily for three days, then 0.5 mg twice daily for four days), followed by 1 mg twice daily through week 12. Participants randomised to placebo followed the same dosing regimen with matching placebo tablets. Participants were instructed to take tablets orally with water. Compliance with treatment was documented at all study visits and at the end of treatment visit during week 12.
Participants were instructed to set a target quit date during days 8 to 28 after initiation of treatment. Because of the lack of guidelines for behavioural support or counselling for cessation of smokeless tobacco, participants were offered brief behavioural support or counselling at the discretion of the investigator and in accordance with local standard practice. In most cases participants were given simple advice and helpful tips, together with discussion of any topics or concerns raised by the participants. The potential health risks of smokeless tobacco were discussed only in response to a query from a participant.
Baseline assessments occurred during the first visit and included assessment of demography, medical history, concomitant use of drugs, physical examination, blood pressure, heart rate, and body weight. The latter was reassessed at weeks 12 and 26. We obtained each participant’s history of smoking and use of smokeless tobacco and used a modified Fagerström test for nicotine dependence (modified for use of smokeless tobacco, see appendix 1 on bmj.com). Each question had an associated score, and the total score achieved by the participant determined their level of nicotine dependency.
Use of smokeless tobacco was assessed weekly at weeks 9-12 and again at week 26 with a self completion questionnaire, modified from one designed for and implemented in previous varenicline studies to collect information about nicotine use. Abstinence from smokeless tobacco was confirmed by measurement of salivary cotinine at baseline and reassessed weekly from weeks 9-12 and at week 26. Participants whose cotinine concentration was >15 ng/ml at any given time point were classified as non-responders (using smokeless tobacco or another form of nicotine containing product) for the corresponding end point, even if they reported abstinence from tobacco.
To assess safety and tolerability of varenicline in smokeless tobacco users, investigators recorded all adverse events, either observed or reported by participants, including details on severity (mild, moderate, or severe), as well as the investigators’ expert medical opinions on the relation of the adverse events to the study treatment. These adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events were recorded from the time of the first dose of study treatment up to 28 days after the last dose was taken. For all adverse events, the investigators determined the outcome of the adverse event and whether any specific adverse events met the criteria for classification as a serious adverse event. A serious adverse event was defined as any adverse event that was life threatening; caused death; resulted in new admission to hospital or prolonged an existing stay; led to a persistent or severe disability or incapacity; resulted in a congenital anomaly or birth defect; or required medical or surgical intervention to prevent one of these outcomes listed. Serious adverse events could also include any adverse event that the sponsor or investigators considered serious enough to be classified as such. If any adverse events or their sequelae persisted, follow-up was required until resolution or stabilisation occurred at a level acceptable to the investigator and sponsor.
Participants could withdraw from the study themselves or at the discretion of the investigators or sponsor (for example, for safety, behavioural, or administrative reasons). Whenever possible, every effort was made to document participants’ outcomes such as abstinence, reasons for withdrawal, and safety status. If a participant withdrew from the trial and also withdrew consent for disclosure of future information, no further evaluations were performed, and no additional data were collected.
The primary efficacy end point was the continuous abstinence rate over the last four weeks of study treatment (weeks 9-12), defined as proportion of participants who reported abstaining from smokeless tobacco during the indicated period confirmed by cotinine measurements during clinic visits. Secondary end points included long term continuous abstinence rate (weeks 9-26), seven day point prevalence of abstinence (defined as the proportion of participants who abstained from smokeless tobacco for the seven days before the end of treatment (week 12) and the end of the study (week 26)), and the safety and tolerability of varenicline versus placebo for 12 weeks of treatment.
Analyses included all participants who took at least one dose of study medication. Participants who discontinued the study were classified as still using smokeless tobacco for the remainder of the study. Efficacy end points were analysed with logistic regression models with terms for study centre and treatment group. Significance tests for the treatment comparison (varenicline v placebo) were performed at the two sided 0.05 level, and the 95% confidence intervals were two sided.
The study was designed to have at least 90% power to detect a difference between varenicline and placebo, assuming a response rate for the four week continuous abstinence rate of 0.35 and 0.20, respectively (relative risk 1.75), with a two sided significance of 0.05.
We conducted exploratory analyses to assess whether treatment effects varied according to baseline salivary cotinine concentration and baseline score on a modified Fagerström test. We used logistic regression models to analyse the four week and long term continuous abstinence rates with additional terms for baseline salivary cotinine concentration or baseline modified Fagerström test score and their interaction with treatment. The cotinine scores were defined as 1=<361 ng/ml, 2=361-499 ng/ml, and 3=≥500 ng/ml (the upper limit of quantification for salivary cotinine concentrations was 500 ng/ml). Cotinine scores were assigned because the upper level of quantification was 500 ng/ml and almost 60% of participants had baseline cotinine values in excess of this. The scores were chosen to represent a ratio of about 1:1:2 of participants and were tested for simple linear relations to the outcomes. Possible scores on the modified Fagerström test ranged from 1 to 10 (observed scores ranged from 3 to 10). We determined Spearman’s non-parametric rank correlation for the baseline modified Fagerström test total scores versus the baseline salivary cotinine scores.