Title: Efficacy and Mechanism Evaluation - Effectiveness of Electronic Cigarettes compared with varenicline for smoking cessation in patients with COPD and effect on the Lungs (EME-ECAL study)
Funder: Medical Research Council

Abstract: Background: Smoking cigarettes is associated with long-term, negative health effects causing cancers and smoking related lung diseases, such as chronic obstructive pulmonary disease (COPD). These effects are created by the harmful contents of cigarette smoke. Toxins in cigarette smoke can directly damage the lung, alter how immune cells in the lung work (making them less effective at clearing infection but more likely to damage healthy lung) and cause persistent inflammation. These are known as cigarette smoke related “signals of harm”. Ultimately, as more lung tissue is damaged, chronic cigarette smoke exposure leads to lung diseases, such as COPD. Once COPD is established, giving up smoking is the only way to slow the progression of the disease and quitting reduces these signals of harm. It is imperative that smokers with COPD quit but despite medical advice, around 1/3 of COPD patients continue to smoke._x000D_ Current smoking cessation treatments have a poor quit rate and most people start to smoke again. Often patients have tried to stop by using nicotine replacement therapies (NRT), such as patches and gums, but only 10-20% are able to quit and 80% go back to smoking within a year, due to the addictive nature of the nicotine in tobacco._x000D_ E-cigarettes (ECs) are a potential alternative cessation treatment. ECs deliver nicotine to the lungs in a vapour, without burning tobacco and some patients have used ECs to quit smoking. Recent studies have found ECs are more effective than NRTs in helping healthy smokers to quit, more than doubling the quit rate after 1year compared to NRTs. However, 80%of those who quit using ECs, still continued to vape after 1year. _x000D_ Some COPD patients are now trying to quit smoking using ECs, however ECs have not been tested against the current gold standard treatment to aid smoking cessation, Varenicline (Champix™), to see which is the most effective means of helping people quit smoking._x000D_ Although using ECs appears less harmful than cigarettes, recent evidence from our group and others have highlighted potential negative effects of using ECs including damaging lung immune cells and causing inflammation in the short-term. The long-term effects of ECs on the lung are unknown. _x000D_ Patients and healthcare professionals are unsure whether to use or recommend ECs to help current smokers quit._x000D_ Research questions:_x000D_ 1. Are ECs more effective in helping COPD patients to quit smoking than the current best therapy (Varenicline)?_x000D_ 2. What is the impact on health of using either ECs or Varenicline to stop smoking? _x000D_ Methods: The ECAL trial will assess how effective ECs are as a smoking cessation treatment in comparison to Varenicline in COPD patients. We will use biological readouts implicated in lung damage as signals of harm, such as numbers of immune cells, markers of tissue damage, inflammation and levels of toxins present in the blood in patients who quit but continue to vape, those who quit with Varenicline and those who continue to smoke. _x000D_ Dissemination: Two PPI collaborators helped us co-create this project plan and will be members of our PPI group which will decide on the most effective strategies to translate our findings in a meaningful way to COPD patients, the general public and healthcare professionals._x000D_ Impact: This study will help inform clinical advice, patient choice and provide more information about the place of ECs in the UK healthcare system and beyond.

Lay abstract: Hypothesis: E-cigarettes (EC) will be more effective than Varenicline as a smoking cessation aid in patients with COPD but the mechanism of cessation in those randomized to EC will be associated with higher levels of immune cell recruitment, inflammatory mediator release and toxicant exposure than those randomized to Varenicline _x000D_ Background_x000D_ Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) and around 35% of patients remain smokers. Smoking cessation is the only known strategy that slows the accelerated decline in lung function. Current smoking cessation treatments have poor efficacy and over 80%return to smoking within a year of attempting to quit. _x000D_ EC are non-medical devices that vaporise nicotine-containing liquids. Many people including COPD patients have used them successfully to stop smoking. However, there remain unanswered questions about their effectiveness and potential beneficial/harmful effects. This has led to significant confusion by healthcare professionals and patients as to their use, despite PHE’s support for EC. _x000D_ A recent trial showed ECs were superior to nicotine replacement therapy in smokers to achieve cessation. 80% of participants that switched from smoking to EC, continued to vape at 1year, thus becoming chronic EC users with persistent nicotine addiction._x000D_ Although ECs are likely to be less harmful than cigarette smoke, we and others have described ECs related harm. In vitro studies at pharmacologically relevant vapour concentrations demonstrate cellular toxicity and inflammation. _x000D_ Our HTA funded trial, ECAL, a multicentre randomised controlled trial in 1250 COPD patients, will compare the effectiveness of ECs versus Varenicline for smoking cessation. The primary outcome of the trial is biochemically confirmed abstinence from smoking at 52wks._x000D_ _x000D_ Aims and objectives_x000D_ To compare the consequences of attempted cessation using EC vs Varenicline in COPD patients, we will compare inflammatory and toxicant signal from baseline to study end (52wks), thus assessing how the inflammatory and toxicant signal alters if people quit smoking using Varenicline, quit but continue to use ECs or return to smoking._x000D_ _x000D_ Research objectives:_x000D_ 1. Compare cellular inflammation in blood total and differential cell count (full blood count) in relation to the effects of randomisation and subsequent successful smoking cessation (SSCE)_x000D_ _x000D_ 2. Assess sequential changes is markers of inflammation known to be associated with COPD (destructive proteases, cytokine levels, antimicrobial peptides in blood, Luminex) in relation to the effects of randomisation and SSCE_x000D_ _x000D_ 3.Determine changes in toxicant burden (plasma, LC-MS) in relation to the effects of randomisation and SSCE. _x000D_ _x000D_ Timeline_x000D_ Total study length is 36mths and will closely align with the timescale of the ECAL trial(detailed in the Gantt chart)._x000D_ _x000D_ Impact/Dissemination_x000D_ We anticipate that EC will be more successful that varenicline for COPD patient smoking cessation but that continued use of EC may drive inflammation and potentially COPD progression. The results will inform us about whether to recommend smoking cessation with EC and then a phased withdrawal of EC to prevent ongoing damage. Dissemination will occur through manuscript publication and presentation at national and international conferences. Our PPI/E collaborators are central to dissemination through workshops, social media, executive reports and public meetings.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;5.3 MEDICAL DEVICES
Health categories: RESPIRATORY