Walele 2018.

Study characteristics
Methods	Design: RCT (short‐term, Cravo 2016) followed by cohort study (Walele 2018) in which all participants were given nicotine EC Recruitment: Community Setting: 2 centres in the UK (Covance Clinical Research Unit Ltd, Leeds and Simbec Research Ltd, Wales) Study start date: December 2013; Study end date: December 2016
Participants	420 participants Inclusion criteria differ per study phase: Cravo 2016 (short‐term RCT): 21 ‐ 65 years of age BMI 18 ‐ 35 kg/m2 5 ‐ 30 cigarettes per day for at least 1 year (self‐reported) in good health (determined by medical history, a physical examination, a 12‐lead ECG, lung function tests and clinical laboratory evaluations) Established people who smoke (urinary cotinine ≥ 3 and exhaled CO ≥ 6 ppm) Additional criteria for Walele 2018 (participants from Cravo 2016): Participants assessed by PI as being compliant in Cravo 2016 (e.g. having attended outpatient visits and having been compliant with study procedures) Participants had to be willing to use the study product as the only nicotine‐containing product for the duration of the study, and, as deemed by PI, had to have no clinically significant abnormalities in 12‐lead electrocardiogram, vital signs, spirometry and clinical laboratory assessments in the preceding study In addition, participants who were assigned to the conventional cigarette (CC arm) in Cravo 2016 had to be established people who smoke CCs, which was assessed by urinary cotinine levels (a score of 3 and above on a NicAlert™ test strip was considered positive), eCO levels (a readout > 6 ppm was considered positive) and by review of a smoking history questionnaire Exclusion criteria: Cravo 2016: Use of NRT, snuff or chewing tobacco in 14 days previous, or intended to use during study Trying to stop smoking or considering quitting Clinically‐significant illness or disorder, history of drug or alcohol abuse within 2 years prior to study start Woman of “childbearing potential” unwilling to use “acceptable contraceptive measure” during study Walele 2018 (participants from Cravo 2016): People who had taken or received any form of NRT, snuff or chewing tobacco during the previous study or intended to use it during this study, were excluded People with relevant illness history People with history of drug or alcohol abuse People with lung function test or vital signs considered unsuitable People who are trying to stop smoking Women who are pregnant, or unwilling to use acceptable contraceptive method for the duration of the study Cravo 2016 Total N: 419 randomized, 408 analyzed (excludes 11 who were excluded prior to any product use) N per arm: EVP: 306; Control: 102 45% women; mean age 34.6; Mean cpd: most 11 ‐ 20 cpd (56% int, 62% control); Mean FTND: most moderate (57% int, 54% cont) Motivated to quit: No E‐cigarette use at baseline: Not excluded based on prior EC use Walele 2018 Total N: 209 (147 pre‐EVP group; 62 pre‐CC group) 45% women; mean age 36.6; mean cpd 2.6 (data from figure): Not reported; FTND: Not reported Motivated to quit: As reported for Cravo 2016 E‐cigarette use at baseline: Not reported
Interventions	EC: Cig‐a‐like Cravo 2016 EC: EVP prototype (2.0% nicotine), developed by Fontem Ventures B.V. (Amsterdam, the Netherlands). Instructed to only use EVP for study period. It consisted of a rechargeable battery (voltage range of 3.0e4.2 V), an atomiser and a capsule (small cartridge) containing e‐liquid. The capsules were replaceable and the battery and atomiser were reusable. Could choose between two different e‐liquids, which differed solely in their flavor: a menthol‐flavored e‐liquid with 2.0% nicotine (2.7 mg nicotine/capsule) and a tobacco‐flavored e‐liquid with 2.0% nicotine (2.7 mg nicotine/capsule) Control: Used their own usual conventional cigarette brand Walele 2018 E‐cigarette details: Commercially available Puritane™ (closed system EVP) consists of a lithium‐ion rechargeable battery and a replaceable cartomiser comprising of an e‐liquid reservoir pre‐filled by the manufacturer, a heating element and a mouthpiece; 1.6% nicotine (16 mg/g) Available in tobacco or menthol. 2 weeks before baseline, participants had a familiarization session with Puritane™, where they could see and try the EVP
Outcomes	Cravo 2016: Weeks 1, 2, 4, 6, 8, 10 and 12 Walele 2018: starting on the last day of the previous trial): Months 1, 2, 3, 6, 9, 12, 15, 18, 21 and 24 Study centre visits for assessments Adverse events and biomarkers: “adverse events” (coded using Medical Dictionary for Regulatory Activities version 16.1, 2013, collected via diary cards and questionnaires) vital signs (systolic and diastolic blood pressure, pulse rate and oral temperature) lung function (FEV, FEF, PEF, FEV) urine biomarkers (nicotine equivalents (NEQs: nicotine, cotinine, nicotine‐N‐glucuronide, cotinine‐Nglucuronide, trans 3’‐hydroxycotinine and trans 3’‐hydroxycotinine glucuronide); S‐PMA; 3‐HPMA; PG; total NNAL (NNAL þ NNAL‐glucuronide)); exhaled CO blood COHb Other outcomes measured: Number of conventional cigarettes smoked EVP capsules used ECG (categorized them as normal, abnormal‐not clinically significant (NCS) or abnormal‐clinically significant (CS)) MWS‐R (revised Minnesota Nicotine Withdrawal Scale) QSUBrief (Brief Questionnaire of Smoking Urges) questionnaires clinical chemistry (blood levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma‐glutamyl transferase (GGT), sodium, potassium, chloride, calcium, inorganic phosphate, glucose, urea nitrogen (BUN), total bilirubin, creatinine, total protein, albumin, cholesterol (HDL, LDL, and total));clinical haematology (white blood cell count (WBC), red blood cell count (RBC), hemoglobin, hematocrit (PCV), mean cell volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), platelet count, differential WBC);urinalysis (pH, protein, glucose, ketones, urobilinogen, blood and specific gravity)
Study funding	Cravo 2016 "This work was funded and supported by Fontem Ventures B.V. Imperial Brands plc is the parent company of Fontem Ventures B.V. the manufacturer of the EVP prototype used in this study" Walele 2018 "This work was funded and supported by Fontem Ventures B.V. Imperial Brands Group plc is the parent company of Fontem Ventures B.V., the manufacturer of the EVP used in this study"
Author declarations	Cravo 2016 "Dr. Cravo has nothing to disclose. Mrs Martin reports personal fees from Fontem Ventures B.V. during the conduct of the study; personal fees from Tobacco and pharmaceutical industries outside the submitted work. Dr. Sharma reports other from Fontem Ventures B.V. during the conduct of the study. Dr. Bush reports other from Fontem Ventures B.V. during the conduct of the study. Mrs Savioz reports personal fees from Fontem Ventures B.V. during the conduct of the study; personal fees from Tobacco and pharmaceutical industries outside the submitted work. Mr Craige has nothing to disclose. Mr Walele has nothing to disclose." Walele 2018 (copied from Transparency documents) "Dr. Koch reports other from Fontem Ventures B.V., during the conduct of the study; Dr. Martin reports personal fees from Fontem Ventures B.V., during the conduct of the study; personal fees from Tobacco and pharmaceutical industries, outside the submitted work; Dr. O'Connell has nothing to disclose. Dr. Bush reports other from Fontem Ventures B.V., during the conduct of the study; Dr. Savioz reports personal fees from Fontem Ventures B.V., during the conduct of the study; personal fees from Tobacco and pharmaceutical industries, outside the submitted work; Dr. Walele has nothing to disclose."
Notes	Sponsor: Imperial Tobacco Group PLC Study listed as ongoing studies NCT02029196 and NCT02143310 in 2016 review update. Treated as single study in this review due to including the same participants, and no time lag between studies "The same subjects who participated in our previous clinical trial (ClinicalTrials.gov, #NCT02029196) conducted in the same centres, with another EVP (Cravo et al., 2016), were invited to participate the study by Walele 2018. All volunteering subjects were assigned to switch to using Puritane™, a closed system EVP, for two years, starting on the last day of the previous trial (End of Study [EoS] visit), which corresponded to the baseline visit of Walele 2018."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomisation was performed using an Interactive Web Response System (IWRS; Almac Clinical Technologies)”
Allocation concealment (selection bias)	Low risk	Quote: "Randomisation was performed using an Interactive Web Response System (IWRS; Almac Clinical Technologies)”
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label, no blinding, differential levels of support/product use so performance bias cannot be ruled out
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label, no blinding, with differential levels of support/product use and subjective outcomes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Cravo: 286/306 int (4.5% ltfp) and 101/102 (1% ltfp) control completed study but all who received product included in analysis. In EVP group, 14 withdrew consent, 2 experienced AEs, 1 death, 3 “other”. CC group 1 AE Walele 2018: High 209/387 enrolled for study Walele 2018. A total of 102 participants (48.8%; EVP: 75/145 (51%); CC: 27/61 (43.5%) completed the study
Selective reporting (reporting bias)	Low risk	Cravo 2016: Low All anticipated outcomes reported (study registered prior to study completion) Walele 2018: Low All anticipated outcomes reported (study registered prior to study completion)