Aim:
To evaluate the effectiveness, safety, and acceptability of combination treatment (cytisine plus nicotine e-cigarettes) compared to monotherapy (cytisine only or nicotine e-cigarettes only) on six-month smoking abstinence.
Trial design:
A single-blind, pragmatic three-arm, parallel group, pragmatic, community-based randomized trial.
Eligibility criteria:
Eligible participants must be daily smokers who live in New Zealand, are aged ≥18 years, and have no contraindications to the study treatment. Participants must be motivated to quit smoking within the next two weeks, be able to provide online consent, have daily access to a mobile telephone that can text and have access to the internet via a computer or smart phone. Participants must also be willing to use cytisine or an e-cigarette or both products to help quit smoking. Full details of inclusion and exclusion criteria are provided later in this trial registration.
Recruitment:
Participants will be recruited from throughout New Zealand using multi-media advertising, with targeted promotion to reach indigenous Māori, Pacific and low socio-economic groups given their disproportionately higher smoking prevalence. Advertisements will direct potential participants to a trial website where they can read the participant information sheet. A two step-consent process will be used. First, interested participants will be asked for on-line consent to complete an online screening questionnaire to determine their eligibility for the trial and verify their phone number. Second, eligible and interested participants will then provide online consent to enter the trial.
Baseline information:
Baseline data will then be collected via the online platform, and will include: demographic data, smoking history, cigarette dependence, motivation to quit, withdrawal symptoms and craving, cannabis use, alcohol use, self-reported comorbidities, concomitant medication, and health-related quality of life. Full details on the baseline data are provided later in this trial registration. The participant will then be asked to click the ‘randomization’ button, whereupon they will be immediately randomized and informed of their allocated intervention.
Randomization:
Participants will be assigned a unique registration number allocated by a central computer, following details submitted via the study website. Eligible participants will be randomized via computer (3:3:2 ratio) to one of three trial groups using stratified block randomization (block sizes of eight), and stratified by ethnicity (Māori, non-Māori). The randomization sequence will be generated by the trial statistician, and centrally managed and concealed until the point of randomization.
Blinding:
This is a single-blind trial as participants will be aware of the intervention to which they have been allocated, and data collection by the trial research assistants will include questions specific to use of participants allocated treatment. Except for the trial statistician, the trial steering committee members will remain blinded to treatment allocation until analyses are complete. The statistical analysis plan will be finalized and uploaded to the trial registry prior to the first participant being randomised.
Interventions:
Participants will be randomized to either 12 weeks of: 1) cytisine plus nicotine e-cigarette, 2) cytisine; or 3) nicotine e-cigarette. Participants allocated cytisine will be instructed to follow the manufacturer’s 25-day dosing regimen. However, a maintenance dose of cytisine will be added for day 26 to week 12. Full details of the dosing regimen are provided later in this trial registration. Participants allocated a nicotine e-cigarette will be instructed to follow the manufacturer’s instructions for use, with ad libitum use over 12 weeks. The e-cigarette device used in the trial will be the ‘UpOX’, a closed pod system with a 3% nicotine salt (30mg/mL). A tobacco flavour e-liquid will be provided as this is the usual flavour chosen by smokers when they are transitioning away from tobacco. Participants will be advised that they should try and use only the product provided, but if they are finding the nicotine strength is not sufficiently addressing their carvings (or the flavour is distasteful) they are free to try alternative nicotine strengths or flavours, but that this will be at their own cost). Participants will be asked at follow-up about any switching of products. Participants allocated both cytisine and a nicotine e-cigarette will be instructed to follow the manufacturer’s instructions for use (as mentioned above). All participants will also receive a evidence-based, text-message behavioral support program. This theoretically-based text message program will provide smoking cessation advice and motivation to support individuals to quit smoking and maintain cessation. The program includes 2-way functionality to support individuals during cravings. Regular, text messages providing smoking cessation advice, tips to cope with cravings, advice on avoiding smoking triggers, and motivational support will be delivered over a six-month period (five messages a day for six weeks, then three per week until the end of the 26th week – i.e., six-month follow-up). All 12-weeks of trial products will be couriered to participants immediately after randomization, at no cost to participants. The courier company will notify the study center immediately after the courier pack has been delivered, which will trigger the scheduling of the ‘quit date’ (day 0) follow-up call and the start of the text message behavioural support program.
Follow-up:
Participants will be asked to begin their treatment the day after they receive their courier pack and to reduce their smoking ad libitum over the first four days of treatment so that they are not smoking at all by the fifth day (‘quit date’). Participants will be called on their quit date to verify they are quitting on that day (and to collect outcome data). If a participant states that they are not quitting on the scheduled ‘quit date’, they will be given one chance to reset their quit date within the next seven days, with this date becoming their new ‘quit date’ (which will trigger the scheduling of all subsequent follow-up calls). For participants who are unable to be contacted at quit date, their ‘quit date’ will be set in the system as six days after they received their courier pack (which will trigger the scheduling of all subsequent follow-up calls). Participants will be advised to continue with their allocated treatment irrespective of any lapses back to smoking. Further follow-up calls will be made at one, three and six months after their quit date to collect outcome data. Approximately two thirds of participants will also be contacted 12 months after their quit date to collect outcome data.
Outcome data:
The primary outcome is six-month carbon-monoxide verified continuous abstinence from smoking (i.e. smoking ≤ five cigarettes since quit date). Outcomes collected at three, six, and 12 months post-quit date include other cessation outcomes, treatment use, acceptability, and adverse events. Full details on the outcome data are provided later in this trial registration.
Trial power:
A sample size of 800 (N=300 in the cytisine group, N=300 in the cytisine plus nicotine e-cigarette group, and N=200 in the nicotine e-cigarette group) will provide 90% power at two-sided p=0.05 to detect an absolute difference of 13% in six-month smoking abstinence rates between the combination treatment group and the cytisine group, and 16% difference between the combination treatment group and the nicotine e-cigarette group (taking account of multiple testing). The predicted difference is based on trial evidence for six month verified continuous abstinence quit rates of 9% for nicotine e-cigarettes, 12% for cytisine, and 25% for combination cessation treatment (averaged). The sample size accounts for a 28% loss-to-follow-up at six months.
Statistical analysis:
All statistical analyses will be performed using SAS version 9.4 (SAS Institute Inc. Cary NC), and R. Data analyses will be specified a priori in a statistical analysis plan prepared by the trial statistician and posted on the trial registry prior to the first participant recruitment. No interim analyses will be undertaken. All analyses will be conducted for the following comparisons, 1) cytisine plus nicotine e-cigarettes vs cytisine and 2) cytisine plus nicotine e-cigarettes vs nicotine e-cigarettes. The main analyses will be carried out on an intention-to-treat basis, with multiple imputation analysis performed to account for missing data using the fully conditional specification logistic regression method (data will be assumed to be missing at random).
