Cobb 2021.

Study characteristics
Methods	Design: Randomized parallel‐assignment double‐blind trial Setting: USA (Penn State Medical Center in Hershey, Pennsylvania (n=300). Virginia Commonwealth University in Richmond, Virginia (n=220)  Recruitment: Community advertisements Study start date: June 2015; Study end date: June 2018.
Participants	Total N: 520 (though Veldheer paper only reports 263) N per arm: 130 per arm Inclusion criteria: age 21‐65; smoke > 9 cigarettes per day ; smoke regular filtered cigarettes or machine‐rolled cigarettes with a filter; CO measurement > 9 ppm at baseline; not planning to quit in the next 6 mths; interested in reducing cigarette consumption; no serious quit attempt in last mth, or use of FDA‐approved smoking cessation medication (varenicline, bupropion (used specifically as a quitting aid), patch, gum, lozenge, inhaler, and nasal spray). Exclusion criteria: unstable or significant medical condition in the past 12 mths (recent heart attack or some other heart conditions, stroke, severe angina including high blood pressure if systolic > 159 or diastolic > 99 observed during screening); immune system disorders, respiratory diseases (exacerbations of asthma or COPD, require oxygen, require oral prednisone), kidney (dialysis) or liver diseases (cirrhosis), or any medical disorder/medication; use of any non‐cigarette nicotine delivery product (pipe, cigar, dip, chew, snus, hookah, e‐cigs, strips, sticks) in the past 7 days; uncontrolled mental illness or substance abuse or inpatient treatment for these in the past 6 months; difficulty providing blood samples; no surgery requiring general anaesthesia in the past 6 weeks; use of EC for ≥5 in the past 28 days or any use in the past 7 days; use of marijuana or any illicit drug/prescription drugs for non‐medical use daily/almost daily, or weekly in the past 3 mths per NIDA Quick Screen; hand‐rolled, roll‐your‐own cigarettes; allergy to propylene glycol /vegetable glycerin; pregnancy/breastfeeding. 58% women; mean age 47; mean cpd 18; mean FTND: Not specified Motivated to quit: Interested in reducing cigarette intake but not planning to quit in next 6 months EC use at baseline: None
Interventions	EC: Cartridge For 24 weeks: 1) Cigarette substitute: QuitSmart cigarette substitute ‐ plastic tube looks like a real cigarette, designed to provide the same draw resistance as a smoker's usual cigarette. No drug delivery. 2 cigarette substitutes and a product manual are provided to participants following randomization and replacement products are provided throughout the intervention period (24 weeks). At baseline, associated user manual, research staff explain how to use product. Reduction goal to 50% at weeks 0 and 1, 75% at weeks 2 and 4, continue reducing onwards from there 2) EC with no nicotine: EGO e‐cigarette. Cartomizers containing 0 mg/mL nicotine provided throughout the intervention period (24 weeks) Associated user manual, research staff explain how to use product. 3) As (2) but 8 mg/mL nicotine 4) As (2) but 36 mg/mL nicotine
Outcomes	0, 1, 2, 4, 8, 12, 16, 20, 24, 28, and 36 weeks. Provision of the condition‐specific product lasted for 24 weeks (intervention period). There was a 12‐week follow‐up period after the intervention period for each condition (36 weeks). NNAL collected at baseline 4, 12 & 24 weeks Cessation: (a) intent‐to‐treat, self‐reported 7‐day point prevalence cigarette abstinence (PPA), biochemically confirmed by exhaled CO<10ppm (7‐day PPA) for each visit up to 24 weeks after randomization (last visit of randomized phase of the trial), with those not attending visits counted as smoking. Additional outcomes included (b) self‐reported 28 or more days of cigarette abstinence at week 24 (biochemically validated by exhaled CO < 10 ppm at weeks 20 and 24), (c) the number (%) of participants in each group who reported at least one full day without smoking a cigarette (no biochemical verification), from week 1 to week 24, and (d) the total number of days on which participants self‐reported being abstinent from cigarettes from week 1 to week 24. “tobacco‐related toxicant exposure to the potent lung carcinogen NNK, as indexed by the sum of its urinary metabolite 4‐(methylnitrosamino)‐ 1‐(3‐pyridyl)‐1‐butanol (NNAL) and its glucuronides (total NNAL; pg/mg creatinine) collected at randomisation and at 4, 12, and 24 weeks.” urine cotinine (ng/mg creatinine) at 4, 12 and 24 weeks glutathione and 8‐Isoprostanes Exhaled CO was measured at each in‐person visit Pulmonary function tests were done at randomisation, 4, 12, 24, and 36 weeks Self‐reported number of cigarettes smoked per day and daily study product use were assessed at each in‐person visit using a 7‐day timeline follow‐back procedure supplemented with paper diaries completed daily Adverse events and serious AEs Blood pressure, Heart rate  Other outcomes measured Drug/Alcohol Measures: Alcohol AUDIT‐C; NIDA Quick Screen Cigarette Measures: MNWS; confidence to quit, Stage of Change, Environmental smoke, Smoking urges, 7‐day TLFB & Current Tobacco Use Cigarette Dependence Study product dependence and measures Psych Measures: Kessler 6; Perceived stress; CES‐D Health Measures: Interheart, Clinical COPD Questionnaire Biomeasures: Waist/Hip Ratio, Weight Blood Samples: Complete Metabolic Panel, Hematology Panel, Lipid panel, C‐Reactive Protein.
Study funding	This research was supported by grants P50DA036105 and U54DA036105 from the National Institute on Drug Abuse of the National Institutes of Health and the Center for Tobacco Products of the US Food and Drug Administration. Data collection was supported by UL1TR002649 at Virginia Commonwealth University and by UL1TR002014 at Penn State University from the National Center for Advancing Translational Sciences of the National Institutes of Health. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the US Food and Drug Administration.
Author declarations	COC reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. JF reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study, and grants, personal fees, and non‐financial support from Pfizer, outside of the submitted work. AAL reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. JMY reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. LK reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. SV reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. CB has previously undertaken trials of electronic cigarettes for smoking cessation (with electronic cigarettes purchased from an online retailer [NZVAPOR], electronic cigarette liquid for one trial purchased from Nicopharm, Australia, and nicotine patches supplied by the New Zealand Government via their contract with Novartis [Sydney, Australia]). Neither NZVAPOR nor Nicopharm have links with the tobacco industry. None of these parties had any role in the design, conduct, analysis, or interpretation of the trial findings, or writing of this publication. TE reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study, and is a paid consultant in litigation against the tobacco industry and also the electronic cigarette industry and is named on one patent for a device that measures the puffing behaviour of electronic cigarette users and on another patent for a smartphone application that determines electronic cigarette device and liquid characteristics. M‐SY reports grants from the National Institute on Drug Abuse and the US Food and Drug Administration, during the conduct of the study.
Notes	Study listed as ongoing study Lopez 2016 in the 2016 review update and as Veldheer 2019 in 2020 and April 2021 updates Cessation data from Foulds which is pre‐print only
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The study statistician (M‐SY) prepared site‐specific randomisation lists using the sample function in R version 3.2.0 (blocks of eight).  These lists were uploaded onto a study‐specific website that interfaced with the data collection and management system (REDCap)."
Allocation concealment (selection bias)	Low risk	“Once a participant has been confirmed eligible for randomization, a computer procedure will assign the participant to the next condition on the list automatically.” 'Only unmasked researchers at each site with no participant contact accessed their list to prepare cartomisers for dispensing.’
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Not blinded for non‐EC arms but given similar level of support/product, so performance bias judged unlikely
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not blinded for non‐EC arms but given similar level of support/product, so differential misreport judged unlikely
Incomplete outcome data (attrition bias) All outcomes	Low risk	"188 (36%) of 520 participants were lost to follow‐up by week 24; attrition did not differ by group (39 [30%] of 130 in the cigarette substitute group, 56 [43%] of 130 in the ENDS with 0 mg/mL nicotine group, 49 [38%] of 130 in the ENDS with 8 mg/mL nicotine group, and 44 [34%] of 130 in the ENDS with 36 mg/mL nicotine group; P = 0·15)."
Selective reporting (reporting bias)	Low risk	All specified outcomes available or being written up