Secondary analysis of adverse event data from a randomised placebo-controlled trial of e-cigarettes for smoking reduction

Background The adverse event (AE) profile of e-cigarette use for smoking reduction remains poorly characterised. This study compared AE profiles of nicotine-containing e-cigarettes with non-nicotine e-cigarettes and a non-aerosol cigarette substitute (CS) in a smoking reduction trial. Methods We conducted secondary analysis of AEs from a double-blind randomised controlled trial involving 520 adults assigned to e-cigarettes containing 0, 8 or 36 mg/mL nicotine or a CS for 24 weeks. AEs were coded using Common Terminology Criteria for Adverse Events version 4.0 and assessed for frequency, severity, seriousness and relatedness. In addition to all reported AEs regardless of relatedness, we examined study-related AEs, defined as those rated by the Medical Monitor as possibly, probably or definitely related to study product or study procedures. Cumulative incidence was calculated over 24 weeks. Risk differences (RDs) and 95% CIs were estimated for frequently reported AEs (≥1% overall) comparing e-cigarettes versus CS and nicotine versus non-nicotine e-cigarettes. Fisher’s exact test with multiplicity adjustment assessed significance. Results All reported and study-related AEs were predominantly mild. No study-related AEs were serious and four participants discontinued because of study-related AEs (one in 0 mg/mL; three in 36 mg/mL). At 24 weeks, cumulative incidence of first study-related AE was highest in 36 mg/mL (37.0%) and 8 mg/mL (35.2%) groups, followed by 0 mg/mL (23.4%) and CS (2.5%) groups. For study-related AEs, e-cigarette groups had higher risks of cough (RD, 8.5%; 95% CI 5.6% to 11.3%), headache (RD, 5.4%; 95% CI 3.3% to 7.6%) and sore throat (RD, 5.4%; 95% CI 3.2% to 7.6%) than CS, with consistent findings for all reported AEs. Study-related cough was significantly more common with nicotine-containing than non-nicotine e-cigarettes (RD, 8.1%; 95% CI 3.4% to 12.8%). Conclusions All study products were generally well tolerated; however, cough, headache and sore throat were more frequent with e-cigarettes than CS, while study-related cough was more common with nicotine-containing than non-nicotine e-cigarettes.