Veldheer 2019.

Study characteristics
Methods	Design: Randomized parallel‐assignment double‐blind trial Setting: USA (2 sites) Recruitment: Community advertisements Study start date: June 2015; Study end date: June 2018.
Participants	Estimated enrolment: 520 Total N: 263 in this analysis (520 planned overall; THIS INCLUDES ONLY THOSE FOLLOWED UP AT 1 AND 3 MONTHS) N per arm: sub: 72; EC: 191 Inclusion criteria: Age 21 ‐ 65 Smoke > 9 cigarettes per day for at least 1 year Smoke regular filtered cigarettes or machine‐rolled cigarettes with a filter CO measurement > 9 ppm at baseline No serious quit attempt in the prior 1 month. This includes use of any FDA‐approved smoking cessation medication (varenicline, bupropion (used specifically as a quitting aid), patch, gum, lozenge, inhaler, and nasal spray) in the past 1 month as an indication of treatment‐seeking Not planning to quit in the next 6 months Interested in reducing cigarette consumption Willing to attend visits weekly and monthly over a 9‐month period (not planning to move, not planning extended vacation, no planned surgeries) Read and write in English Able to understand and consent Exclusion criteria: Pregnant and/or nursing women Unstable or significant medical condition in the past 12 months (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 that may affect participant safety or biomarker data 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 History of difficulty providing or unwilling to provide blood samples (fainting, poor veins, anxiety) No surgery requiring general anaesthesia in the past 6 weeks Use of an e‐cig for 5 or more days 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 months per NIDA Quick Screen Use of hand‐rolled, roll‐your‐own cigarettes Known allergy to propylene glycol or vegetable glycerin Other member of household is currently participating/participated in the study 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 E‐cigarette use at baseline: None
Interventions	EC: Cig‐a‐like For 24 wks: 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	Months 1, 3, 6, 9; (only 1 and 3 month available at time of extraction) Cessation: Conventional tobacco product use measured but measures not clear Adverse events and biomarkers: Adverse events Lung function Blood pressure, pulse CO, “exhaled breath condensate biomarkers of oxidative stress, glutathione and 8 Isoprostanes” – incl. carcinogenic nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone [NNK; via its metabolite NNAL (4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol) in urine], expired air carbon monoxide (CO), and nicotine (via its metabolite cotinine in urine) Other outcomes measured: Weight Cotinine Tobacco use
Study funding	This study was funded by the National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA) under Award Number P50DA036105. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or FDA. The project [publication] was supported by CTSA award No. UL1TR000058 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
Author declarations	JF has done paid consulting for pharmaceutical companies involved in producing smoking cessation medications, including GSK, Pfizer, Novartis, J&J, and Cypress Bioscience. TE is a paid consultant in litigation against the tobacco industry and is named on a patent application for a device that measures the puffing behavior of electronic cigarette users. There are no competing interests to declare for other authors
Notes	Preliminary data from RCT; full results not yet available EC arms pooled in preliminary data available to us at time of writing Authors provided outcome data; Study listed as ongoing study Lopez 2016 in the 2016 review update
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “the assignment codes are made from separate randomization lists created in advance by the statistician for each site stratum.”
Allocation concealment (selection bias)	Low risk	Quote: “Once a participant has been confirmed eligible for randomization, a computer procedure will assign the participant to the next condition on the list automatically.”
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	Unclear risk	Dataset only includes those followed up at 1 and 3 months, which excludes 140 participants; breakdown by arm not provided
Selective reporting (reporting bias)	High risk	Results paper just preliminary results with all EC arms collapsed. Protocol and NCT record list different outcomes and study lengths.