Design
This is a single-blind, randomized controlled trial of mass distribution of free Nicotine Replacement Therapy to Canadian smokers. A two-stage recruitment process will be employed, in the context of a general population survey with two follow-ups (8 weeks and 6 months). Random digit dialing of Canadian home telephone numbers and an initial interview will identify households with adult (age 18 or over) smokers who smoke 10 or more cigarettes a day. One individual from each household who is willing to take part in a smoking study that involves three interviews, with saliva collection for 3-HC/cotinine ratio measurement at baseline and saliva cotinine verification at 8-week and 6-month follow-ups will be randomly selected (according to most recent birthday). Willing participants will be offered a $20 honorarium for completing the baseline and each of the 8-week and 6-month follow-ups. Verbal consent will be obtained as the initial contact is by telephone.
As part of the baseline survey, eligible subjects will be identified for the second stage of the recruitment process and will be randomized into experimental and control conditions to receive versus not receive nicotine patches. Eligibility will be determined by a series of questions regarding hypothetical interest in nicotine patches to quit smoking (including willingness to have nicotine patches sent to their home) and having no contraindications for using NRT. A randomized half of the eligible subjects will be assigned to the experimental condition and asked for their permission to have nicotine patches sent to their home. These subjects will have 5 weeks of nicotine patches sent to their homes to help them quit smoking. Subjects in the control condition will not be offered nicotine patches. Only subjects in the randomized controlled trial will be followed-up at 8 weeks and 6 months. See Figure 1 for a CONSORT diagram of the proposed study design.
Ethical approval
The research methods to be used in this study have been approved by the standing ethics review committee of the Centre for Addiction and Mental Health.
Participants - inclusion and exclusion criteria
Participants will be recruited using a general population telephone survey of Canadian residents. A two stage recruitment procedure will be employed.
Criteria for Participation in baseline survey
Participation in the baseline recruitment survey will be restricted to current smokers, age 18 and above, who smoke 10 or more cigarettes per day, who are interested in being involved in a smoking study, and who are willing to answer three sets of questions: now, after 8 weeks and after 6 months. In addition, participants must be willing to provide a saliva sample for cotinine analysis at each time point (sent by mail [14, 15]; note that 97% of cotinine samples collected by mail were usable in these studies).
Criteria for Assignment to the Randomized Controlled Trial
As part of the baseline survey, all subjects will be asked a series of questions to assess their level of interest in receiving free NRT: "The Ministry of Health is considering different ways to help people stop smoking. One option would be to provide interested smokers with free Nicotine Patches. If Nicotine Patches were offered for free, would you be interested in receiving them?" Those who say "yes" will then be asked if they would use the nicotine patch to quit smoking. Those who say "yes" to this question will be asked if they would begin to use the patch within 1 week of receiving it. A "yes" to this question will lead to being asked if they would be willing to have the Patch sent to their home. These questions have been used in a previous survey and form the basis of the sample size estimate for the present study [10]. Finally, as part of the demographic section of the survey, subjects will also be asked questions regarding health conditions contraindicating NRT use (i.e., being pregnant, intending to become pregnant, or breastfeeding; having a serious heart or circulation problem, not including high blood pressure). Subjects will be eligible for the randomized controlled trial if they are interested in NRT, would use it to quit within 1 week of receipt, are willing to have the NRT sent to their home, and have no health contraindications for the use of NRT. Subjects who meet all these eligibility criteria will then be randomly assigned to the experimental or control condition.
Although some participants will report that they have used NRT in the past, they will not be excluded from the study due to prior NRT use because the intent is to evaluate the impact of NRT in the full range of potential community participants. In addition, our previous research has indicated that prior use of NRT is actually positively related to current interest in using NRT again [10]. Thus, one of the secondary analyses of this study will test the moderating hypothesis that prior use of NRT is negatively related to future success with NRT when it is offered for free.
Interventions
Experimental condition
A randomized half of the subjects meeting baseline criteria and expressing an interest in receiving free nicotine patches, willingness to use the Patches within a week to quit smoking, interest in having the patches sent to their home, and meeting criteria for eligibility to receive NRT (i.e., no health contraindications) will be randomly assigned to the experimental condition (the remainder will be assigned to the control condition). Subjects in the experimental condition will be asked, at the end of the baseline survey, if they want to be sent a free, 5-week supply of Nicotine Patches. Those who say "yes" will have the NRT mailed to their home the week after their baseline interview. As is employed in the Ontario mass distribution of NRT initiative [12], a 5-week program of nicotine patches will be sent (3 weeks of Step 1 [21 mg of nicotine]; 1 week of Step 2 [14 mg of nicotine]; 1 week of Step 3 [7 mg of nicotine]). Once randomly assigned to this condition, subjects will be counted as part of the experimental condition whether they agree to accept the NRT or not (intent-to-treat approach).
The 5-week program of nicotine patches was chosen for pragmatic reasons, which balanced a limited budget to supply the NRT and conduct a large population survey, and because of findings from literature regarding effective treatment duration. A recent Cochrane review evaluating the efficacy of NRT has revealed no differences in treatment effect between trials offering up to eight weeks of nicotine patch treatment and those offering longer treatments [16]. Furthermore, several trials evaluating usage patterns of free nicotine patches offered to smokers through a Smokers' Quitline have shown no differences in 7- and 12-month quit rates between individuals receiving 2, 4, 6, or 8-week supplies of free nicotine patches [17, 18]. These findings however, are inconsistent with two other studies demonstrating higher quit rates among Smokers' Quitline callers receiving 8 weeks versus 2 weeks of free nicotine patches [19], and 6 weeks versus 4 weeks of free NRT [20]. Given the apparent inconsistencies in the literature surrounding effective treatment duration of mailed out free NRT, we chose a middle of the road approach of 5 week nicotine patch program.
Control condition
Subjects randomly assigned to the control condition will not be asked, at the end of the baseline survey, if they want free nicotine patches sent to their homes. An advantage of the design procedure to be employed in this trial is that respondents in the control condition will not have the expectation that they will receive NRT. Thus, their smoking outcomes at 8-week and 6-month follow-ups will reflect a true natural history comparison to the outcomes of subjects in the experimental condition.
An alternate control condition would be to provide subjects with placebo patches. However, the objective of this trial is to test the question, "does mailed distribution of free NRT (in the form of the nicotine patch) lead to increased quit rates among Canadian smokers?" This objective is a pragmatic one and requires the random assignment of offering free NRT to some and nothing to others. Whether the impact of the NRT is due to the active ingredient or due to a placebo effect is irrelevant to this objective. Thus, the most appropriate control condition is one where subjects receive nothing, and further, have no expectation that they would receive anything.
Content of Baseline Interview
The primary purpose of the baseline interview is to assess eligibility for the randomized controlled trial. Specifically, subjects will be asked of their interest in receiving free NRT, its use within one week of receipt, and health contraindications for NRT use. In addition, other questions will also investigate the following: a) subjects' heaviness of smoking [21], b) number and duration of past quit attempts, c) past use of NRT, d) current life stressors, e) motivation to quit smoking, f) past and present drug use, g) level of alcohol intake (AUDIT-C) [22], h) presence of mental health disorders diagnosis, and e) a series of demographic characteristics such as age, gender, ethnicity, marital status, education and employment status.
Content of 8-week and 6-month follow-up interviews
At 8-week and 6-month follow-ups, subjects who have not quit will be asked how many cigarettes per day they currently smoke and their intentions to quit smoking; how soon after waking they smoke their first cigarette; and if, since their baseline interview, they have stopped smoking for even one day because they were trying to quit. Subjects in the experimental condition will be asked to evaluate their experiences with NRT and to elaborate on their efforts to quit smoking. Specifically, at 8-weeks subjects will be asked if they received the NRT; how soon after receipt they began to use it; how much of it (if any) they used; if relevant, why they did not use any or all of it; whether or not they experienced any withdrawal symptoms and which ones; and what challenges they encountered to quitting/reducing. At 6-months, subjects will be asked whether or not they purchased additional NRT to help in their quit effort (what type and how much); whether or not they plan to purchase more NRT to quit or maintain their non-smoking; if they have smoked in the past 30 days or reduced from baseline, what benefits they have noticed; what supports they had for quitting; and what additional resources they sought to help them quit. These questions will be asked after the core smoking status outcome measures have been assessed. Subjects in the control condition will also be asked about their use of NRT but the questions will be framed to reflect purchase of NRT from sources other than this ongoing study. Subjects in both conditions will also be asked about their use of other smoking cessation aids.
Validation of self-report by saliva cotinine samples
Several studies have demonstrated the utility of collecting saliva cotinine samples by mail using the same Salivette sampling method proposed for this study [14, 15]. While clinically tobacco exposure is measured by quantifying cotinine in either plasma or urine, salivary cotinine is a reliable measure of nicotine or tobacco exposure that is widely used in both clinical and epidemiological or population-based studies [23–25]. Participants will be asked to collect their saliva sample at baseline and on the day they complete their follow-up interviews (saliva collection kits mailed several days following baseline interview and one week before each follow-up interview is due, along with a reminder letter about the upcoming telephone interview). At baseline, the saliva sample will allow for the calculation of the 3-HC/cotinine ratio to test the moderating hypothesis of nicotine metabolism rate on success at tobacco cessation using nicotine patches. Collection of saliva samples at follow-up periods will allow for the verification of smoking abstinence.
Randomization
Recruitment is conducted using a Random Digit Dialing survey with computer assisted telephone interview (CATI) technology. At the end of the baseline interview, eligible subjects will be allocated to experimental and control conditions using a simple randomization without replacement built into the CATI program (no stratification or minimization given the large proposed sample size in this trial).
Blinding
Interviewers will be blind to subjects' condition because they will be using the CATI technology. As the first parts of the 8-week and 6-month follow-ups are identical for experimental and control conditions, they will not know the intervention condition to which a subject belongs until questions specific to the use of NRT are asked near the end of the surveys (i.e., after the primary outcome measures are assessed). Further, while it is possible that a participant might 'unblind' themselves to an interviewer by volunteering that they used the nicotine patch, this is still unlikely to have an impact as the interviewers will be part of a separately contracted telephone survey research firm and will not be aware of the hypotheses of this research trial.
Outcome Measures
Primary outcome measures
The primary outcome measure will be 30 day point prevalence of abstinence at 6 months, validated by saliva cotinine samples.
Secondary outcome measures
Secondary outcome measures are: (1) 7 day point prevalence of smoking abstinence at 8 weeks post-baseline; (2) reduction in smoking since baseline; (3) compliance with the full 5-week course of nicotine patches provided to experimental condition; (4) challenges with quitting/reducing smoking; and (5) purchase and use of NRT and smoking cessation aids at follow-up periods.
Data Analysis
Power analysis
Quit rates for those who use nicotine patches have been obtained from several sources, including systematic reviews by Fiore et al. [26] and a Cochrane review by Stead and colleagues [16]. Both these reviews indicate a 10% increase in tobacco cessation rates upon using nicotine patches as compared to placebo at 6-month follow-up. This 10% increase is roughly in concordance with the 30 day point prevalence rate for abstinence observed at the 6-month follow-up point of the STOP mass distribution demonstration trial (9%; note that this trial had no control group so the results reflect pre-post changes in smoking rates) [12]. However, we recognize that both of these estimates are probably too large for a pragmatic randomized controlled trial because the impact of interventions is often smaller in real world settings (and pre-post estimates, such as those found in the STOP Study, can also be inflated). Thus, we have chosen to power our trial based on the assumption that our quit rate will be half as large (i.e., a 5% increase in quit rates in the experimental condition versus the control at 6-month follow-up). Finally, we can estimate a 3.7% baseline rate of smoking cessation at 6-month follow-up in a general population sample using findings from the 2008 Canadian Tobacco Use Monitoring Survey (CTUMS) [3]. Given these results, we predict that the subjects in the control condition will display a 3.7% quit rate and subjects in the experimental condition will display a 8.7% quit rate at 6-month follow-up.
Using these assumptions, a power analysis was conducted; this indicated that a total of 403 respondents would be needed per condition to detect a 5% difference at a significance level of .05 with a power of 80% (estimate calculated with continuity correction factored in) [27]. Thus, we have chosen an ideal sample size of approximately 800 respondents in order to conduct appropriate analyses.
Based on our previous research using a similar research design, albeit with problem drinkers rather than smokers [28, 29], a 20% attrition between baseline and 6-month follow-up can be expected (the most important follow-up for this study); this would mean that a sample size of 1,000 respondents would be needed at baseline to take part in the randomized trial. Similar follow-up rates have been obtained for smokers in the Ontario Tobacco Survey, indicating that a 20% attrition rate estimate is also reasonable for smokers [30].
From a recent survey of current smokers [10] we know that 62% of 10 or more cigarettes a day smokers say that they would be interested in receiving NRT. Note that the 62% proportion is slightly different from the 58.9% previously reported from this same survey. This is because the proportion reported here for the purposes of generating a sample size estimate was calculated using unweighted data and employs only those smokers from this pilot survey who currently smoke 10 or more cigarettes per day (rather than all smokers who smoked 10 or more cigarettes per day at some point in their life as is employed in the published paper).
Further, from this same survey, we know that 57% of those interested in free NRT say that they would use this NRT to quit, state they would start using it within a week, and would also be willing to have it sent to their homes. Finally, results from this same pilot survey indicate that approximately 14% of those willing to have NRT sent to their homes would screen out due to health contraindications (heart or circulatory problems not including high blood pressure; currently pregnant, intending to become pregnant or breastfeeding) [10]. Note that this estimate of health contraindications is an overly conservative one as the question on heart or circulatory problems asked about lifetime experience. Thus, it is likely that less than 14% of potential subjects will be excluded for this reason. However, we will use the 14% figure in this estimate in order to ensure an adequate sample size.
In conclusion, in order to conduct this trial, we would need to recruit approximately 3,000 respondents at baseline who smoke 10 or more cigarettes per day and who are also willing to take part in an 8-week and a 6-month follow-up with saliva sample collection by mail at each time point (note: saliva samples only collected for the 1,000 participants at baseline who will take part in the randomized trial).
Analysis Plan
The primary analyses will employ manual stepwise logistic regressions. Specifically, dependent measures will be 30 day point prevalence abstinence at 6-month follow-up and 7 day point prevalence abstinence at 8-week follow-up. Separate logistic regression analyses will be conducted for each time point (validated by saliva cotinine sample). In the primary analyses, subjects lost to follow-up will be assumed to be active smokers. In Step one of the logistic regression, experimental condition will be entered as a dummy coded variable (0 = control condition; 1 = experimental condition). This step will test the primary hypothesis regarding the impact of sending free NRT on quit rates. Steps two and three of the logistic regression will involve adding interaction terms to test the mediator and moderator hypotheses (3-HC/cotinine ratio, compliance with NRT use, prior use of NRT; main effects terms entered in Step two and interaction terms entered in Step three). Sex difference analyses will be conducted in a similar manner (i.e., is there an interaction effect of subjects' sex by receipt of NRT on abstinence rates at 6-month follow-up?). As part of these primary analyses, we will also conduct a chi-square test to explore whether there is differential loss to follow-up between experimental conditions. Further we will replicate the primary analyses with all subjects with missing data excluded from the analyses. If the results are the same between the analyses where the missing data is excluded and where subjects lost to follow-up are assumed to still be current smokers, then we can safely assume that there is no differential attrition between conditions (or, at least none that impacted on the outcome of the trial).
Subgroup analyses will examine quit rates among subjects within the experimental and control conditions who: (a) are slow versus fast nicotine metabolizers as measured by the 3-HC/cotinine ratio; (b) report using all 5 weeks of the free NRT they were sent as compared with those who do not use all 5 weeks; (c) had used NRT for a quit attempt at least once before participation in the proposed study as compared with those who had never used NRT before; and (d) are male or female (to assess any interaction by sex). Further, we will compare subjects in the experimental condition who used the NRT to just those subjects in the control condition who did not use any NRT during the same time period (i.e., they did not obtain NRT from other sources). Finally, using just the baseline data (N = 1,000), we will relate the 3-HC/cotinine ratio to patterns of smoking and prior use of NRT.
