Design and Oversight

We conducted a two-group, pragmatic, multicenter, individually randomized, controlled trial. National Health Service (NHS) stop-smoking services are available free across the United Kingdom.6 This trial was conducted in three service sites from May 2015 through February 2018. The Health and Lifestyle Research Unit that delivers the service for two London boroughs (Tower Hamlets and City of London), along with the Leicester and East Sussex services, recruited participants and delivered the interventions. Participating services included trial information in their advertising. Participants were also recruited through social media. Adult smokers were invited to participate if they were not pregnant or breast-feeding, had no strong preference to use or not to use nicotine replacement or e-cigarettes, and were currently not using either type of product.

The trial was approved by the National Research Ethics Service (reference number, 14/LO/2235). Collective unblinded data were seen only for the purposes of the meetings of the data monitoring and ethics committee. Data analyses were conducted with blinding to treatment assignments. All the authors contributed to the trial design, participated in the interpretation of the data, vouch for their completeness and accuracy, and made the decision to submit the manuscript for publication. All the authors vouch for the fidelity of the trial to the protocol, available at NEJM.org.

Procedures

Smokers were provided with trial information, prescreened for eligibility, and, if eligible, invited to a baseline session. There, eligibility was confirmed, written informed consent and baseline data were obtained, and participants set up their quit date (normally the following week).7

Randomization took place on the quit date to limit differential dropout. Randomization sequences (1:1 ratio in permuted blocks of 20, stratified according to trial site) were generated with the use of a pseudorandom number generator in Stata software and were embedded into an application that only revealed the next treatment assignment once a participant had been entered into the database.

Product use started immediately after randomization. All the participants received the same multisession behavioral support as per U.K. stop-smoking service practice.7,8 This support involved weekly one-on-one sessions with local clinicians, who also monitored expired carbon monoxide levels for at least 4 weeks after the quit date.

Participants were contacted by telephone at 26 and 52 weeks. Interviewers asked about product use and thus were aware of the treatment assignments. Participants who reported abstinence or a reduction in smoking of at least 50% at 52 weeks were invited back to provide a carbon monoxide reading. Participants were compensated £20 ($26 U.S.) for their travel and time at the 52-week validation visit.

Nicotine-Replacement Group

Participants were informed about the range of nicotine-replacement products (patch, gum, lozenge, nasal spray, inhalator, mouth spray, mouth strip, and microtabs) and selected their preferred product. Use of combinations was encouraged, typically the patch and a faster-acting oral product. Participants were also free to switch products. The way that nicotine replacement was provided differed slightly among trial sites (see the Supplementary Appendix). Supplies were provided for up to 3 months, as per standard practice. The cost to the NHS of a 3-month supply of a single nicotine-replacement product is currently approximately £120 ($159 U.S.).

E-Cigarette Group

A starter pack, called One Kit (Aspire, U.K. Ecig Store), was provided to facilitate initial use and teach participants how to use refillable e-cigarette products, along with one 30-ml bottle of Tobacco Royale flavor e-liquid purchased from U.K. Ecig Store, containing nicotine at a concentration of 18 mg per milliliter. The kit had a 2.1-ohm atomizer and 650-mAh battery. During the trial, the company discontinued this kit, so One Kit 2016 (Innokin, U.K. Ecig Store), with a 1.5-ohm atomizer and 1000-mAh battery, was used for 42 participants. Participants were asked to purchase their future e-liquid online or from local vape shops and to buy a different e-cigarette device if the one supplied did not meet their needs. They were encouraged to experiment with e-liquids of different strengths and flavors. Those who were unable to obtain their own supply were provided with one further 10-ml bottle, but this was not offered proactively. Participants received oral and written information on how to operate the e-cigarette.

The original One Kit, including five atomizers, U.K. adapter, spare battery, and e-liquid, was purchased wholesale for £19.40 ($26 U.S.). The cost of One Kit 2016, including the same extras, was £30.25 ($40 U.S.).

Participants in the e-cigarette group and those in the nicotine-replacement group were asked to sign a commitment to not use the nonassigned treatment for at least 4 weeks after their quit date. This was to minimize contamination between the trial groups.

Measures

At trial visits, the following data were recorded: smoking status, expired carbon monoxide level (at baseline, 4 weeks, and 52 weeks), use and ratings of trial products, ratings of withdrawal symptoms (weeks 1 through 6), adverse reactions (presence or absence of nausea, sleep disturbance, and throat or mouth irritation), and respiratory symptoms (presence or absence of shortness of breath, wheezing, cough, and phlegm). The Supplementary Appendix provides further details of trial measures.

The primary outcome was 1-year sustained abstinence, calculated in accordance with the Russell Standard9 as a self-report of smoking no more than five cigarettes from 2 weeks after the target quit date, validated biochemically by an expired carbon monoxide level of less than 8 ppm at 1-year follow-up and not contradicted by any previous self-report or validation result. Carbon monoxide validation is the standard measure in trials assessing nicotine-containing products (see the Supplementary Appendix). Participants who died (one in each group) were excluded. Participants who were lost to follow-up or did not provide biochemical validation were classified as not being abstinent in the primary analysis.

Secondary abstinence outcomes included sustained abstinence from 26 to 52 weeks, at 4 weeks, and at 26 weeks and the percentage of participants without sustained abstinence from 26 to 52 weeks who reduced their cigarette consumption by at least 50%. We also assessed 7-day abstinence at 4, 26, and 52 weeks. In addition, we compared the trial groups with respect to relapse rate and time to relapse and with respect to the measures listed above.

Statistical Analysis

We calculated that a sample of 886 participants would provide the trial with 95% power (at a two-sided alpha level of 0.05) if the true percentages of 1-year abstinence were 23.8% in the e-cigarette group and 14.0% in the nicotine-replacement group (relative risk, 1.7). Since trial setup, the abstinence rate in stop-smoking service clinics declined to 10%, but the sample of 886 participants would provide 85% power if the percentages were 17.0% and 10.0% in the respective groups.

The primary and secondary abstinence outcomes were analyzed by regression of smoking status at each time point onto trial group. Primary analyses were adjusted for trial center to account for the stratification factor. In sensitivity analyses, each model was further adjusted for baseline covariates selected with the use of stepwise regression. Binary regressions were conducted by means of the generalized linear model with binomial distribution and logarithmic link to estimate the relative risk for e-cigarettes as compared with nicotine-replacement therapy.

To assess the effect of missing data on the primary outcome, we conducted four prespecified sensitivity analyses, which excluded participants who did not attend at least one behavioral-support session, excluded participants who used the nonassigned product for at least 5 consecutive days, excluded participants who did not complete the 52-week follow-up, and imputed missing information with the use of multiple imputation by chained equations.10 Missing data were imputed for 136 participants in each group, and 50 data sets were imputed.

We also estimated mean differences and 95% confidence intervals between trial groups in product ratings and in change scores between baseline and follow-up time points in withdrawal symptoms, as well as between-group differences in the percentage of participants who had adverse reactions or respiratory symptoms, using binomial regression with adjustment for trial center (see the statistical analysis plan, available with the protocol at NEJM.org). Analyses were conducted with the use of Stata software, version 15 (StataCorp).