Berlin 2019.

Study name	Randomized, placebo‐controlled, double‐blind, double‐dummy, multicentre trial comparing electronic cigarettes with nicotine to varenicline and to electronic cigarettes without nicotine: the ECSMOKE trial protocol
Methods	3‐arm randomized, placebo‐controlled, multicentre, double‐blind, double‐dummy, parallel groups, phase III type trial Setting: Smoking cessation clinics of both academic and community hospitals Recruitment is either local (a) directly by the centres or centralized (b) using a web page and a centralized study‐specific phone number and email address People who smoke intending to quit smoking are recruited by advertisement in pharmacies, physicians’ offices situated in the catchment area of each investigator’s centre, by local newspapers and in public places of the centres’ healthcare facilities Candidates to participate can register by the study’s website, unique email address and phone number. Registration is followed by a phone screening before dispatching to the study centres. Only 1 person by household will be recruited
Participants	Estimated enrolment: 650 participants Inclusion criteria: People who smoke, at least 10 cpd (factory‐made or roll‐your‐own) in the past year Aged 18 – 70 years Motivated to quit, defined as a score > 5 on a visual rating scale ranging from 0 (not motivated at all) to 10 (extremely motivated) Signed written informed consent Understanding and speaking French Women of childbearing age can be included if they use an effective contraceptive method: either hormonal contraception or an intrauterine device started at least 1month before the first research visit Individual affiliated to a health insurance system Previous failure of NRT for smoking cessation Exclusion criteria: Any unstable disease condition within the last 3 months defined by the investigator as major change in symptoms or treatments, such as recent myocardial infarction, unstable or worsening angina, severe cardiac arrhythmia, unstable or uncontrolled arterial hypertension, recent stroke, cerebrovascular disease, obliterative peripheral arterial disease, cardiac insufficiency, diabetes, hyperthyroidism, pheochromocytoma, severe hepatic insufficiency, history of seizures, severe depression, COPD Any life‐threatening condition with life expectancy of < 3 months Alcohol use disorder defined as a score ≥ 10 on the Alcohol Use Disorders Identification Test (AUDIT)‐C questionnaire (see below) Abuse of or dependence on illegal drugs in the last 6 months, revealed by medical history Regular use of tobacco products other than cigarettes Current or previous (last 6 months) use of EC Pregnant women Breastfeeding women Protected adults Current or past 3 months participation in another interventional research Current or past 3 months use of smoking cessation medication such as varenicline, bupropion, NRTs Known lactose intolerance (placebo tablets contain lactose) Hypersensitivity to the active substance or to any of the excipients Known severe renal failure
Interventions	A) EC without nicotine (ECwoN) plus placebo tablets of varenicline (0.50mg) administered by oral route: placebo condition; B) EC with nicotine (ECwN) plus placebo tablets of varenicline: ECwN condition. V C) Reference: ECwoN plus 0.5 mg varenicline tablets: varenicline condition. Varenicline administered according to the marketing authorization E‐cigarette details: EC device Mini iStick kit (20 W) Eleaf, clearomiser: GS Air M with resistance of 1.5 ohm. To keep the blinding, the clearomizer’s Pyrex window is of grey Colour not allowing to distinguish the coloration of the e‐liquid containing nicotine. Liquid for EC is manufactured by GAIATREND SARL (www.gaiatrend.fr/fr/) All participants will be delivered a short manual and a video specifically developed for this study explaining the use of EC. At each visit, participants receive verbal counseling about the use of the EC device and answers to their questions about handling the EC device Behavioural support: Brief behavioral smoking cessation counseling for all participants is administered at all visits by the investigators specialized in smoking cessation. It is based on the national guidelines for smoking cessation Treatment duration: 1 week + 3 months
Outcomes	Week 2, 4, 8, 10, 12, 24 after target quit day Primary outcome: Continuous smoking abstinence rate (CAR) (abstinence from conventional/combustible cigarettes) during the last 4 weeks (weeks 9 – 12) of the treatment period of 3 months Secondary outcomes: Safety profile PPA rate CAR confirmed by urinary anabasine concentration Changes in cpd consumption Craving for tobacco and withdrawal symptoms with respect to baseline
Starting date	17 October 2018
Contact information	Ivan Berlin, ivan.berlin@aphp.fr
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