Title: A randomised controlled trial to examine the efficacy of e-cigarettes compared with nicotine replacement therapy, when used within the UK stop smoking service
Funder: Department of Health and Social Care

Abstract: Background Electronic cigarettes (EC) closely mimic the sensory aspects of smoking while delivering levels of nicotine comparable to that delivered by oral nicotine replacement products [9, 10]. Their use is gaining in popularity [11-13], with smokers using them as a safer alternative to tobacco or for smoking cessation [11, 14, 15]. Nicotine itself is relatively harmless; the risks of smoking are linked to poisonous chemicals contained in the smoke from a burning cigarette. The tobacco control community are divided on their opinions of EC, but there is agreement that more data are urgently needed on whether EC match the efficacy of other existing treatments in helping smokers quit or reduce smoking. Several studies have suggested that EC have a substantial potential as a stop-smoking treatment but no study has compared it to a standard intensive treatment so far. EC are cheaper than nicotine replacement therapy (NRT; and the other prescription non-nicotine smoking cessation medicines), and hold greater appeal to smokers [1, 7]. There are few other smoking cessation treatment improvements on the horizon and EC are the most promising current development awaiting objective scrutiny. Health care commissioners need to know if they are as effective as NRT when used with the support routinely provided by the UK stop-smoking service (SSS). This proposal aims to provide this information. Design Randomized controlled trial. Setting Two SSS that provide evidence-based treatment to smokers who are typically highly dependent and from economically deprived backgrounds. Strategy for research and modelling A straightforward trial comparing EC to no treatment is not ethically acceptable and it will also not clarify the value of EC in the current treatment landscape. Smokers will be randomized to usual care (UC) including standard NRT or EC. Both groups will receive multi-session behavioural support. Target population 886 smokers seeking help who are 18 years or older, not currently pregnant or breast-feeding and can read/write/understand English. Health technologies being assessed EC are battery-powered devices that provide inhaled doses of nicotine by delivering a vaporized liquid nicotine solution in propylene glycol or glycerol. No tobacco, smoke, or combustion is involved in their operation and no clinically significant levels of any harmful chemicals have been detected in EC vapour [5]. We will provide a starter-kit to participants in the EC arm. We have consulted EC users who advise that the flavour and strength of the refill liquid is an important but very personal choice. Therefore we will direct people to select and purchase their own refill liquid. This will (a) ensure that people use a refill liquid they like; (b) reflect what happens in ‘real life’; and (c) avoid giving the EC arm an advantage of free treatment when some people in the UC arm will have to pay a prescription charge. Recruitment Smokers seeking help will be recruited from local SSS and by advertisements in local papers. Procedure Prospective participants will attend a screening session and those eligible will provide informed consent, demographic data and details of smoking history, and be randomised to one of the two study arms. Usual Care (UC) arm Participants will be assisted in selecting NRT of their choice as per usual practice. The NRT will be provided on letter of recommendation to supply (a local scheme for supplying NRT) for up to three months, as per standard practice. Participants will attend 6 weekly support sessions and attend follow-up appointments at 6 and 12 months. EC arm Participants will be given an EC starter-kit. They will be provided with instructions on how to operate the EC. An information sheet written by experienced EC users will also be provided. Participants will be encouraged to try different refill e-liquids and provided with details of suppliers of e-liquids. Support and follow-up contacts will be identical to those in the UC arm. Measurement of outcomes and costs The primary outcome will be abstinence at one year defined as per Russell Standard [8]. Secondary outcomes will include abstinence at 4-weeks and 6 months, smoking reduction in participants who did not achieve full abstinence, ratings of the treatment, adverse events, and the cost-efficacy of the interventions. An intention to treat analysis will be used with participants lost to follow-up included as non-abstainers [8]. Sample size The 12-month validated abstinence rate associated with UC is expected to be 14% [18]. To detect an 8% increase in abstinence rates at 1-year (i.e. 14% to 22%, RR=1.57, power = 85%, alpha = 0.05) a total of 886 participants (443 in each group) are required. Project timetables: Study set up – 6 months, recruitment period – 21 months, completion of follow-ups – 12 months, data analysis and study write-up – 3 months, total 42 months. Recruitment strategy We will recruit smokers via SSS over 21 months. Currently each service treats around 380 smokers per year (approximately 1330 in total over 21 months). If two thirds will be interested in taking part in this study, 886 participants will be recruited over 21 months with no additional recruitment initiatives. We will, however, also conduct additional recruitment by advertising in local papers. This was an effective method of recruitment in our previous trials. However, given the non-traditional nature of EC, we propose to conduct a 6-month internal pilot in the first year to evaluate recruitment rate and study acceptability.

Lay abstract: One in five UK adults continues to smoke. About half who try to quit without support will not manage to stop for even a week, and less than 5% make it to a year. Smokers are much more likely to quit successfully when they utilize Stop Smoking Services (SSS). However, only about 5% of smokers access these services. The electronic cigarette (EC) is becoming increasingly popular among smokers as a means of reducing or stopping smoking. In the UK, awareness of EC among smokers has increased from 60% in 2010 to 80% in 2012, and in the same period the proportion of smokers trying them had almost tripled (5.5% to 15%) [11]. Relieving the desire to smoke and help in cutting down the number of cigarettes smoked are seen as key advantages of the EC, particularly among heavy smokers. EC closely mimic the sensory aspects of smoking while delivering in a smoke-like mist, levels of nicotine comparable to that delivered by nicotine gum or patch. Nicotine itself is relatively harmless; the risks of smoking are linked to poisonous chemicals contained in the smoke from a burning cigarette. No clinically significant levels of any harmful chemicals have been detected in EC vapour [5]. We already know that EC can alleviate urges to smoke, but do not know if they are as effective in helping smokers quit as the existing stop-smoking medicines (for example, nicotine replacement treatment, NRT). One study found EC as effective as nicotine patches, but it used an EC model with low nicotine delivery, mailed the treatments to smokers and did not provide any face-to-face support, and the quit rates were low [19]. Because EC are popular and inexpensive compared to SSM, it is important to find out if EC match SSM in efficacy. If they do, this will open a way to attracting more smokers to treatment, and to reduce its costs. This is a proposal to compare the efficacy of EC to existing nicotine replacement treatment (NRT). We will recruit 886 smokers who want help to quit and randomly assign them to receive either standard NRT of their choice, or an EC. Both treatments will be combined with a 6-session behavioural support programme that is tried and tested [20]. We have consulted with EC users who have recommended we use a second generation EC (these do not look like cigarettes and are more reliable for nicotine delivery) and let users choose their own e-liquid strength and flavour so that this reflects how EC are used in ‘real life’. We will provide participants with an EC starter pack but they will then be encouraged to buy their own e-liquid. People in the usual care group access their NRT on a letter of recommendation to supply (a local scheme for supplying NRT) on a weekly basis for the first 4 weeks, as per standard practice, and pay prescription charges if applicable. All participants will be followed up at 6 and 12 months, and those reporting abstinence at 12 months or who have reduced the number of cigarettes they smoke per day by half will have a carbon-monoxide (CO) breath test to confirm this. The main outcome will be sustained, CO validated abstinence from smoking at a year. We will also collect information on NRT/EC use, side effects, and reduction in consumption of regular cigarettes. Finally the cost of the two interventions will be compared. If EC were found to be as effective as existing treatment, this will have immediate clinical implications in improving the reach and reducing the cost of stop smoking treatments and potentially saving the lives of many smokers.

Research activity codes: 6.1 PHARMACEUTICALS;6.3 MEDICAL DEVICES
Health categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;RESPIRATORY;STROKE