Caponnetto 2013a

Methods	Design: 3‐arm double‐blind randomized controlled trial: EC with 7.2 mg nicotine for 12 weeks; same for 6 weeks followed by 5.2 mg for 6 weeks: EC with no nicotine for 12 weeks Recruitment: Newspaper advertisements Setting: Outpatient clinic, Italy Inclusion criteria: Smoked at least 10 cpd for past 5 years; age 18 ‐ 70; in good health; not currently or intending to quit smoking in the next 30 days Exclusion criteria: symptomatic cardiovascular or respiratory disease; regular psychotropic medicine use; current or past history of alcohol abuse; use of smokeless tobacco or NRT; pregnant or breast feeding.
Participants	Total N: 300 36% women, mean age 44 (SD 12.5), mean cpd 20 (IQR: 15 ‐ 25) Lost to follow‐up at 12 months Grp A: N = 35/100 Grp B: N = 37/100 Grp C: N = 45/100 No participants discontinued intervention
Interventions	EC presented as a healthier alternative to tobacco smoke and could be freely used, ad libitum (up to 4 cartridges per day) for 12 weeks, as a tobacco substitute EC used: 'Categoria' (model 401) with disposable cartridges Grp A: 12 weeks of 7.2 mg capsules ('Original') Grp B: 6 weeks 7.2 mg ('Original') then 6 weeks 5.4 mg ('Categoria') Grp C: 12 weeks of 0 mg ('Original') Baseline visit and up to 7 follow‐up visits to receive more cartridges, hand in diaries, measure CO and vital signs
Outcomes	Abstinence at 12 months (complete self‐reported abstinence from tobacco smoking since previous visit at 6 months, confirmed with CO < 7 ppm at 12 months) ≥ 50% reduction in baseline cigarettes at 12 months Recorded AEs thought to be related to tobacco smoking and EC at baseline and at each study visit (7 follow‐up visits over 12 weeks, plus at 24 and 52 weeks)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, block size 15 (5:5:5 ratio)
Allocation concealment (selection bias)	Low risk	Randomization carried out by pharmacy, who did not have direct contact with the participants
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind. “Blinding was ensured by the identical external appearance of the cartridges. The hospital pharmacy was in charge of randomization and packaging of the cigarettes”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Biochemical validation used
Incomplete outcome data (attrition bias) All outcomes	Low risk	211 (70.3%) and 183 (61%) attended 6‐ and 12‐month follow‐up (at 12m, 35% lost in 7.2 group; 37% lost in 5.4 group; 45% lost in no‐nicotine group)
Selective reporting (reporting bias)	Unclear risk	Unclear if original intention was to combine groups A+B or not. In sample size calculation they compared A+B with C, but results are not reported in this way