Randomized Trial of Electronic Cigarettes With or Without Nicotine in Smoking Cessation.

A Randomized, Placebo Controlled, Double Blind, Double Dummy, Multicenter Trial Comparing Electronic Cigarettes With Nicotine to Varenicline and to Electronic Cigarettes Without Nicotine.

Background:

Electronic cigarettes (EC) mainly containing nicotine (88-95 % of users) are widely and growingly used worldwide. It is estimated that there were 1.7 million daily users in France in 2016. Although the number of publications about its use is increasing exponentially, there are no evidence based, unbiased, head-to-head comparison data about its efficacy as an aid to smoking cessation. As of today, only two head-to-head randomized studies have been published, both reported negative results at the main endpoint but they used first and second generation EC delivering nicotine with low or unknown bioavailability. Recent EC deliver nicotine with largely improved bioavailability.

One of the randomized studies compared EC with and without nicotine to nicotine patch and reported similar smoking cessation rate at main outcome. However, there is no published, double blind study comparing EC use with a well-studied, licensed smoking cessation medication.

Superiority of EC with nicotine compared to EC without nicotine and to a reference smoking cessation medication while collecting also straightforward information about safety, would allow proposing EC with nicotine to the large population of smokers who intend to quit and situate it among the approved smoking cessation treatments.

The clinical study's hypothesis:

EC containing nicotine can be considered as a nicotine replacement therapy having, probably, a better bioavailability of nicotine than the marketed pharmaceutical NRTs, first line medications of smoking cessation. It is therefore of interest to compare EC containing nicotine to EC without nicotine but also to a reference medication with demonstrated efficacy in smoking cessation. We hypothesize that EC with nicotine provides a higher smoking abstinence rate than EC without nicotine and may be as good as varenicline, our reference medication.

This is a randomized, placebo controlled, multicenter, double dummy, parallel groups, phase III type pivotal trial.

Included participants are randomly assigned to one of the 3 groups:

A) Control group: Electronic cigarette without nicotine (ECwoN) plus placebo tablets of varenicline: placebo condition B) Experimental group: Electronic cigarette with nicotine (ECwN) plus placebo tablets of varenicline: ECwN condition C) Reference group: ECwoN plus varenicline tablets: varenicline condition Ratio: A:B:C= 1:3:3 Each participant uses an EC and 2x2 tablets per day. Group allocation is stratified by age at cut off of 45 years.

Enrolment is initiated by two ways:

• Potential participants aware of the study register at the study's recruitment website; call in or send an email followed by a phone screen. The screening starts with the participant's information about the study's aims, constraints, benefits and risks. A maximum one week delay of reflection is allowed if the potential participant is asking for a delay to sign his/her consent form.

After screening, an appointment for the inclusion visit is provided at the closest investigation center.

• Referred or self-referred potential participants consulting for smoking cessation are proposed an inclusion visit.

The participant is informed that in this study, the smoking cessation shall occur within 15 days following the signature of the written consent.

Baseline visit = inclusion visit = V0 The Inclusion visit can immediately follow the screening visit if the participant does not need time for reflection.

The investigator checks the inclusion and exclusion criteria and if the participant is conform to them, the investigator collects informed written consent from the participant and he/she is included in the trial. The randomization can immediately follow the inclusion.

A target quit date (TQD) is defined together with the participant. The TQD defines the date when the randomized participant stops smoking. This is the starting date of the post-quit period. Start of treatment should occur within 7 days after the randomization visit.

All treatments are launched one week before the TQD. During this period smoking conventional cigarettes is allowed.

Follow-up visits : Visit 1 to Visit 6 Target quit date (TQD) should occur between 7 and 15 days after randomization. The first post-quit date visit (Visit 1)is at Week 2 after TQD i.e. 3 weeks after treatment initiation = Day 21 after treatment initiation.

Visit 2 is at Week 4 after TQD i.e. 5 weeks after treatment initiation = Day 35 after treatment initiation.

Visit 3 is at Week 8 after TQD i.e. 9 weeks after treatment initiation = Day 63 after treatment initiation.

Visit 4 is at Week 10 after TQD i.e. 11 weeks after treatment initiation = Day 77 after treatment initiation.

Visit 5 is at Week 12 after TQD i.e. 13 weeks after treatment initiation = Day 91 after treatment initiation.

Visit 6 is at Week 24 after TQD i.e. 25 weeks after treatment initiation = Day 175 after treatment initiation.

The visits should be realized +/- 5 days with respect to the planned date of the visits.

End of study visit The end of research visit is the Visit 6, at week 24 after TQD. This visit is identical to the previous follow up visits.

Inclusion Criteria:

1. Smokers smoking at least 10 cigarettes/day (factory made or roll-your-own) in the past year
2. Aged 18 to 70 years
3. Motivated to quit defined as a score > 5 on a visual rating scale ranging from 0 (not motivated at all) to 10 (extremely motivated)
4. Signed written informed consent
5. Understanding and speaking French
6. Women of childbearing age can be included if they use an effective contraceptive method: either hormonal contraception or an intrauterine device started at least one month before the first research visit
7. Individual affiliated to a health insurance system as defined by the sponsor (except Aide Médicale d'État =AME)
8. Previous failure of nicotine replacement therapy for smoking cessation

Exclusion Criteria:

1. any unstable disease condition within the last 3 months defined by the investigator as major change in symptoms or treatments such as 1.1.recent myocardial infarction, 1.2.unstable or worsening angina 1.3.severe cardiac arrhythmia 1.4.unstable or uncontrolled arterial hypertension 1.5.recent stroke 1.6.cerebrovascular disease 1.7.obliterative peripheral arterial disease 1.8.cardiac insufficiency 1.9.diabetes 1.10.hyperthyroidism 1.11.pheochromocytoma 1.12.severe hepatic insufficiency 1.13.history of seizures 1.14.severe depression 1.15.chronic obstructive pulmonary disease (COPD)
2. any life threatening condition with life-expectancy of less than 3 months
3. alcohol use disorder defined as a score ≥ 10 on the AUDIT-C questionnaire
4. abuse of or dependence on illegal drugs in the last 6 months revealed by the medical history
5. regular use of tobacco products other than cigarettes
6. current or previous (last 6 months) use of electronic cigarette
7. pregnant women
8. breastfeeding women
9. protected adults
10. current or past 3 months participation in another interventional research
11. current or past (last 3 months) use of smoking cessation medication such as varenicline, bupropion, nicotine replacement therapies
12. known lactose intolerance (placebo tablets contain lactose)
13. hypersensitivity to the active substance or to any of the excipients
14. known severe renal failure