Efficacy, Safety and Toxicology of Electronic Nicotine Delivery Systems as an aid for smoking cessation: The ESTxENDS multicentre randomized controlled trial

Cigarette smoking is the leading cause of preventable death in Switzerland. Recently, electronic nicotine delivery systems (ENDS or e-cigarettes) have become popular with smokers who want to switch from tobacco cigarettes to ENDS to reduce their exposure to toxic compounds or to stop smoking. 

Only two rigorous RCTs have been published so far. They have promising, yet inconclusive results, as they were based on small samples. The safety and potential adverse effects of ENDS are also largely unknown. While the aerosol the users inhale appears safe in laboratory conditions, the difference in exposure to toxicants and their effects on the body between smokers who quit (with or without ENDS) and those who use ENDS for a long time have not yet been assessed in an RCT. 

We aim to test ENDS on: 

1. The efficacy for cigarette smoking cessation and reducing the number of cigarettes smoked over 6 months of follow-up
2. The safety of ENDS on adverse events
3. The effect of ENDS on reducing exposure to inhaled toxic compounds
4. The effect of ENDS on health-related outcomes

Our hypotheses are that ENDS are a safe alternative to cigarette smoking. They help smokers quit smoking, reduce their exposure to toxic compounds released by tobacco cigarettes, and improve markers of oxidative stress and risk factors for heart disease and respiratory symptoms. 

We plan to include 1172 smokers in a pragmatic RCT that will add ENDS to smoking cessation counselling (SCC), and compare ENDS to SCC alone. 

Our main outcome will be continuous smoking cessation after target quit date at 6-month follow-up, with blinded assessment and biochemical verification by exhaled carbon monoxide (CO) and urinary anabasine levels. In intention to treat analyses, assuming a 5% lost to follow-up, we will have 80% power at two sided α of 5% of detecting a 7% absolute increase in smoking cessation rate (from 12% to 19%, RR 1.6, assuming ENDS are as efficacious as nicotine replacement therapy (NRTs) plus SSC. 

Participants in the intervention arm will receive free ENDS, nicotine-containing e-liquids ad libitum, and technical support for using ENDS. Participants in both arms will receive SCC in four sessions over two months over the phone, and be allowed to use NRTs and other smoking cessation help. In order to minimize attrition in the control group, we will provide members with the intervention after the 6-month follow-up visit. 

At baseline and 6-month follow-up, we will distribute questionnaires and perform a battery of clinical tests, including tests for cardiovascular risk factors (blood pressure, lipids, and glucose; body mass index), determine urinary biomarkers for tobacco-specific nitrosamines (TSNAs), nicotine metabolites (nicotine, cotinine, anabasine), metabolites of polycyclic aromatic hydrocarbons (PAHs) (1-hydroxypyrene, 1-and 2-naphthol) and oxidative stress markers in urine (8-hydroxy-2'-deoxyguanosine and 8-iso-prostaglandin F22α).