4.1. Study Cohort and Design
The two different experimental approaches of single centre, four-arm semi-blind pilot studies included 20 different young, active smokers in each of the two approaches. The trial was designed as a crossover. The participants had no obligations between each visit regarding smoking or vaping. The participants were randomised by drawing pieces of paper out of a closed envelope for the order of the four different study arms on the first visit (The first approach consisted of four different study arms: (a) HTP 2.2 (Philip & Morris—New York, NY, USA; flavour “Bronze”, 0.5 mg nicotine per heet), (b) a commercial tobacco cigarette (Cig) (Marlboro Gold, Philip & Morris, New York, NY, USA; 0.5 mg nicotine), (c) e-cigarette with nicotine (ECig (+)) (DIPSE, Oldenburg, Germany, eGo-T CE4 vapouriser (third generation), 3.3 volts, 1.5 ohms, and 7.26 watts; 20 mg/mL, tobacco flavour), and (d) e-cigarette without nicotine (ECig (−)) (DIPSE, Oldenburg, Germany, eGo-T CE4 vapouriser (third generation), 3.3 volts, 1.5 ohms, and 7.26 watts; 0 mg/mL, tobacco flavour). Arms (c) and (d) were blinded by a person not involved in the investigators’ team. Therefore, both the investigators and participants were unaware of the kind of liquid used. The second approach also consisted of four different study arms: (a) HTP 2.2 (Philip & Morris, New York, USA; flavour “Bronze”, 0.5 mg nicotine per heet), (b) a commercial tobacco cigarette (Cig) (Marlboro Gold, Philip & Morris, New York, NY, USA,; 0.5 mg nicotine), (c) a JUUL™ e-cigarette (JUUL, San Francisco, USA) with the first-generation technology equipped with a JUUL™ pod of the flavour “Virginia Tobacco” (JUUL group, San Francisco, USA; 20 mg/mL nicotine), and (d) e-cigarette without nicotine (ECig (−)) (0 mg/mL, tobacco flavour). In the second experimental approach, blinding was not possible due to the two different types of e-cigarettes. As an example, the flowchart in Additionally, neither the investigator nor the probands had any influence on the experimental sequence in both approaches. The use of HTPs was explained to the participants following the instructions made by an IQOS store. Furthermore, the participants were asked to smoke the cigarette as normal. During the study, smokers who were inexperienced in the use of e-cigarettes or HTPs were trained using e-cigarettes by an experienced e-cigarette user. All of them had to vape the e-cigarette with a minimum of a puff every 30 s for 10 puffs, in accordance with other publications [