Hatsukami 2020.

Study characteristics
Methods	Design: randomized trial Recruitment: Media advertisements Setting: Clinic visits in community, USA Study start date: 25 November 2014; Study end date: 2 December 2018
Participants	Total N: 264 N per arm: Usual brand: 36; AD‐E: 76; CS‐E: 76; CS‐NRT: 76. Inclusion criteria: At least 18 years of age Smoking at least 5 cpd for the past year with a breath CO at least 10 ppm or NicAlert test = level 6 if CO less than 10 ppm In stable physical and mental health Exclusion criteria: A serious quit attempt in the past 3 months Recent (< 3 months) alcohol or drug abuse problems Regular use of other nicotine or tobacco products (e.g. > 9 days per month to minimize confounding effects of these products on biomarker outcomes) Planning to quit smoking in the next 3 months Chronic conditions affecting results of biomarker analyses (e.g., liver disease) Currently using NRT or other cessation medications Pregnant, planning to become pregnant, or breastfeeding 49% women; mean age 45.2; mean cpd 15.2; mean FTND 3.4 E cigarette use at baseline: Not reported Motivated to quit: Initially uninterested
Interventions	EC: Cig‐a‐like, but the only cig‐a‐like product with high nicotine content Usual brand arm: Purchased their own usual brand of cigarettes; at end of clinical trial phase (week 8), offered ECs or NRT for up to 8 weeks, with a choice of product and no specific instructions for use EC AD‐E arm: Use EC whenever you like instead of a cigarette; can smoke as many or as few cigarettes as you want EC CS‐E arm: Complete substitution with e‐cigarettes (i.e. “you will stop smoking cigarettes and use only e‐cigarettes”) The primary e‐cigarette product was Vuse Solo (4.8% nicotine, manufactured by RJ Reynolds, Inc). Initially a choice of Blu cigarettes (cartridge‐based system, marketed previously by Lorillard) and Fin (prefilled tanks system, manufactured by Fin Branding Group) was offered; but because Vuse attained the highest market share during the early phase of the study, switched exclusively to Vuse. Participants could choose 1 of 4 flavors: tobacco, mint, menthol, and berry. Participants were provided 7 cartridges a week with the option of returning to the clinic before their next visit to obtain additional cartridges if needed. All products provided free to the participants. All unused products and used EC cartridges were collected at each visit CS‐NRT arm: Complete substitution with 4 mg nicotine gum or lozenge, with the participant choosing what product they would like to use (i.e. “you will stop smoking cigarettes and use only nicotine gum or lozenge”). The 4 mg was down‐titrated to 2 mg if adverse side effects were experienced. Nicotine gum came in mint, cinnamon, and fruit flavors, while the nicotine lozenge was mint or cherry flavors. All these products were provided free to the participants and unused products were collected at each visit Behavioural support: CS‐E arm and CS‐NRT arm: received brief counseling on how to avoid smoking cigarettes
Outcomes	2‐week baseline period (weeks −1 and 0); Week 1, 2, 3, 4, 6 and 8 Adverse events and biomarkers: Urinary total nicotine equivalents (total nicotine + total cotinine + total 3′‐hydroxycotinine; TNE) Exhaled CO Urinary 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol and its glucuronides (total NNAL, biomarker for NNK) Urinary phenanthrene tetraol (PheT, an indicator of carcinogenic polycyclic aromatic hydrocarbons) Urinary metabolites of VOCs (mercapturic acids)—2‐cyanoethylmercapturic acid (CEMA, biomarker for acrylonitrile), 3‐hydroxypropylmercapturic acid (3‐HPMA, biomarker for acrolein), 3‐hydroxy‐1‐methylpropylmercapturic acid (HMPMA, biomarker for crotonaldehyde/methylvinyl ketone), 2‐hydroxypropylmercapturic acid (2‐HPMA, biomarker for propylene oxide), and N‐acetyl‐S‐(carbamoylethyl)‐L‐cysteine(AAMA, biomarker for acrylamide) A safety check for adverse events was conducted at a week‐20 follow‐up Blood pressure, heart rate and oxygen saturation Other outcomes measured: Cessation (< 6 months)
Study funding	"supported by grants U19CA157345 from the National Cancer Institute (DKH/PS), UL1 TR000062 and UL1 TR002494 from the National Center for Advancing Translational Science of the National Institutes of Health, and T32 DA007097 from the National Institute of Drug Abuse (EM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies"
Author declarations	"RJC is a member of the FDA Tobacco Products Scientific Advisory Committee. PGS serves or has served as an expert witness in tobacco company litigation on behalf of plaintiffs"
Notes	New for 2020 update. AD‐E arm not included in this review Additional data provided from authors.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not blinded and some interventions contained different levels of support
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not blinded but all relevant outcomes for our analyses were objective
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “There was a significant difference in dropout rates across groups following study entry (p = .041), with the highest dropout rates observed in the complete substitution groups, particularly in the NRT group…” AD‐E: Week 1 = 73/76; Week 2 = 73/76; Week 4 = 69/76; Week 6 = 66/76; Week 8 = 65/76 = 85% CS‐E: Week 1 =69/76; Week 2 = 67/76; Week 4 = 66/76; Week 6 = 61/76; Week 8 = 58/76 = 69.7% CS‐NRT: Week 1 =72/76; Week 2 = 65/76; Week 4 = 60/76; Week 6 = 57/76; Week 8 = 53/76 = 69.7% UB: Week 1 = 35/36; Week 2 = 35/36; Week 4 = 33/36; Week 6 = 33/36; Week 8 = 32/36 = 88.8%
Selective reporting (reporting bias)	Low risk	Table in supplementary section describes that heart rate, blood pressure and oxygen levels were measured, but findings not reported in paper; however, provided by authors upon request