Study procedures
At screening, participants underwent testing to ensure that they met all inclusion and no exclusion criteria and completed tobacco and nicotine product use history questionnaires and the Fagerstrom Test for Cigarette DependenceUpon completion of the product familiarisation, participants began an eight-day study period in which they used one of eight assigned study products on each day. The order in which participants used the study products was set by a predetermined randomisation sequence produced using a computer generated pseudo-random permutation procedure (SAS version 9.4). The randomisation code was produced based on a Williams Latin square design for an 8 × 8 crossover study with eight sequences and four participants per sequence.Before the product use sessions on each study day, participants were required to abstain from using any nicotine or tobacco products for a period of at least 12 h. On the day participants were randomised to smoke their usual brand cigarettes, participants smoked a single cigarette by taking ad libitum puffs over a period of 10 min. During this session, the number of puffs taken was counted. If the cigarette was finished before the end of the 10-min session no further cigarette smoking was allowed and the time the product was finished was recorded. Participants did not smoke combustible cigarettes using the fixed-puff regime, as the purpose of this regime was to isolate the impact of different protonating acid combinations contained in the prototype e-liquids on resulting PK profiles. On the days participants were randomised to use the study e-cigarettes, participants underwent two product use sessions. The first session used a “fixed-puff” regimen (one puff every 30 s for 10 min, 21 total puffs), which was followed by a six-hour period of nicotine abstinence. After this period, participants underwent a further product use session in which they took ad libitum puffs over a 10-min period, during which puffs were counted. The purpose of the ad libitum regime was to evaluate the resulting PK profiles for the prototype e-liquids and combustible cigarette products under participants’ typical usage patterns.For all product use sessions (excluding the familiarisation session), blood samples for nicotine pharmacokinetic analysis were taken before, during and after product use. After completion of blood sampling on each study day, participants were allowed to use their own nicotine products (combustible cigarettes and/or e-cigarettes) ad libitum until 12 h prior to the next product use session. After the last study day, participants were discharged from the clinic site and a follow-up phone call was conducted with all participants 5–7 days after discharge.