A randomized comparative effectiveness trial of nicotine pouches for cigarette substitution: A question of public health

PROJECT SUMMARY Commercial cigarette smoking is a modifiable risk factor implicated in one-third of all cancer deaths. Nicotine is the chief addictive agent causing sustained smoking, but diverse tobacco products (e.g., e-cigarettes, FDA- approved nicotine replacement) allow nicotine self-administration on a continuum of harm. Public health gains

could be substantial if people who use the most harmful products (i.e., combusted cigarettes) switch to a less harmful nicotine product. Nicotine pouches – microfiber sachets containing powered nicotine but no tobacco leaf – are a new class of oral tobacco products rapidly growing in popularity. Switching from cigarettes to

nicotine pouches is likely to be health-promoting because pouches are not combusted and contain fewer harmful and potentially harmful chemicals than other tobacco products. However, we currently know very little about how readily people who smoke will adopt nicotine pouches, how effectively pouches can substitute for

cigarettes when smokers are trying to avoid smoking, the importance of nicotine dose in effective cigarette substitution, and the mechanisms that may promote or hinder product transition. To address these key gaps, we will enroll 284 adults who smoke daily and are not planning to quit in the next 30 days in a randomized

controlled trial (RCT). Participants will be randomly assigned to receive: 1) 3-mg nicotine pouches; 2) 6-mg nicotine pouches; 3) nicotine mini-lozenges (2- or 4-mg); or 4) no study product. Participants receiving a study product (nicotine pouches or nicotine mini lozenges) will be asked to use them for 4 weeks, an initial

experimentation week, and then for a 3-week switching trial where they will be asked not to smoke their usual cigarettes and instructed instead to use their study product (if assigned one). Before and after the switching trial, participants will come to the clinic following overnight abstinence and will use their assigned product (if

any) during a 30-minute sampling test to assess the duration of product use, subjective evaluations of study products, and suppression of craving and withdrawal symptoms under controlled conditions. During the 4 weeks of the study, participants will use a smartphone app to record, in real-time, each time they use

cigarettes (primary outcome) or a study product. For a random daily subset of use events, participants will answer additional questions about the context of their use (e.g., affect, any restrictions on smoking) and potential mechanisms driving use (e.g., withdrawal alleviation, satisfaction). Participants will also complete 3

daily prompted random assessments to characterize non-use contexts. This innovative, rigorous, and timely research will provide critical information regarding: (a) the potential impact of providing nicotine pouches on smokers’ use of combusted cigarettes, (b) whether nicotine dose influences the ability of pouches to replace

cigarette use, (c) whether pouches substitute for cigarettes more effectively than FDA-approved nicotine mini lozenges, and (d) product usage patterns and effects that may promote or hinder cigarette substitution These data could inform regulatory policy decisions regarding the potential public health impact of nicotine pouches.