Methods

Design: 3-armed RCT; with all participants then assigned to nicotine EC (treated as cohort in this review)

Recruitment: advertisement on university website, flyers on university campuses, emails to personnel, and advertisement in local newspaper

Setting: community and laboratory, Belgium

Study start date/end date: not stated

Participants

Total N: 48 provided data

Randomized to: EC1 16; EC2 17; control 17

Inclusion criteria: smoke ≥ 3 yrs; ≥ 10 cpd; not intending to quit in the near future but willing to try a less unhealthy alternative

Exclusion criteria: diabetes; severe allergies; asthma or other respiratory diseases; psychiatric problems; dependence on chemicals other than nicotine; pregnancy; breastfeeding; hypertension; CV disease; currently using any kind of smoking cessation therapy; prior use of EC

56% women, mean age 44, mean cpd 19, mean FTCD 5.79, all unwilling to quit with no baseline EC use

Interventions

EC: Refillable

Intervention: 2 intervention groups (EC1 and EC2) provided with EC and instructed to use EC or smoke ad libitum (EC1 group provided with Joyetech eGO-C, EC2 group provided with Kanger T2-CC) and provided guidance on EC use. For both types, provided 30 mL bottles of tobacco-flavoured e-liquid (Dekang “Turkish Blend”), containing 18 mg/mL of nicotine. 4 bottles at baseline replenished at 4 weeks, keep any remaining after 8 weeks

Control: 6 bottles for 2 months at week 8 (half offered EC1, half offered EC2); no guidance on use

Outcomes

3 lab sessions over 2 months (weeks 1, 4, and 8), plus online questionnaires, further follow-up at 3 and 6 m after last lab session

Cessation: measured but definition not provided, validated with eCO 5 ppm or less

Adverse events and biomarkers: eCO, salivary cotinine measured during lab sessions. Also collected craving and withdrawal symptoms via lab sessions, “benefits and complaints”, mood, EC usage

Study funding

"No external funding for this study was obtained. Electronic cigarettes and e-liquids were purchased at E-cig4U (`t Rond 10, 4285 DE Woudrichem, The Netherlands; http://www.e-cig4u.nL) with balances of previous research funds obtained by Frank Baeyens."

Author declarations

The authors declare no conflict of interest.

Notes

Randomization was for short-term outcomes only.

Additional data provided from authors

Random sequence generation (selection bias)

Low risk

Block randomization was performed by using a randomization tool available on the website www.randomizer.org.

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Unblinded but as this review only included data on objective measurements and not cessation, judged unlikely to affect outcomes

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Unblinded but as this review only included data on objective measurements and not cessation, judged unlikely to affect outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

36 out of 48 completed follow-up (11/16 in EC1 group, 12/17 in EC2 group, 13/17 in control group)

Selective reporting (reporting bias)

Unclear risk

Outcome reporting somewhat non-traditional; for example, collecting complaints but not explicitly adverse events, and incidence of AEs not reported. Unable to find prospectively registered protocol

Methods

Randomized, parallel-assignment, open-label trial

Setting: 5 sites in Switzerland: Bern, Geneva, Lausanne, St Gallen, Zurich

Recruitment: free and paid advertisements (lay press, social media, healthcare facilities, on public transport)

Study July 2018 to June 2021 (NCT record April 2022)

Participants

Total: 1246 (intervention group 622, control group 624)

47% female; mean age 41.1 (median age 38 (IQR 29 to 51)); median cigarettes per day 15 (IQR 10 to 20); FTND 4.3 (SD 2.3)

Inclusion criteria:

• Informed consent as documented by signature
• Persons aged 18 or older
• Currently smoking 5 or more cigarettes a day for at least 12 months
• Willing to try to quit smoking within the next 3 months
• Persons providing a valid phone number, a valid email address, and/or a valid postal address

Exclusion criteria:

• Known hypersensitivity or allergy to contents of the e-liquid
• Participation in another study with investigational drug within the 30 days preceding the baseline visit and during the present study where interactions are to be expected
• Women who are pregnant or breastfeeding
• Intention to become pregnant during the course of the scheduled study intervention, i.e. within the first 6 months of the study
• Persons having used ENDS regularly in the 3 months preceding the baseline visit
• Persons having used nicotine replacement therapy (NRT) or other medications with demonstrated efficacy as an aid for smoking cessation such as varenicline or bupropion within the 3 months preceding the baseline visit
• Persons who cannot attend the 6-month follow-up visit for any reason
• Cannot understand instructions delivered in person or by phone, or otherwise unable to participate in study procedures

E-cigarette use at baseline: not using e-cigarette regularly in last 3 months. 15.4% of the control and 17.2% of the intervention group had previously used an e-cigarette.

Motivated to quit: ‘wanted to set a quit date’. Eligible participants asked to set a quit date.

Interventions

a) ENDS (vaporizer/e-cig) and smoking cessation counselling will receive:

• ENDS and nicotine-containing e-liquids, which they will be allowed to use ad libitum. Two e-cigarette starter kits (Innokin Endura T20-S) and 5 spare 0.8-ohm coils. Participants could choose among 6 flavours (2 tobacco, 1 menthol, and 3 fruity) and 4 nicotine concentrations (19.6 mg, 11 mg, 6 mg, and 0 mg per millilitre). Trial nurses gave participants no more than 10 e-liquid bottles at the baseline visit.
• Smoking cessation counselling: provided in person at the first clinical visit and then over the phone at the target quit date 1 week later and again at weeks 2, 4, and 8 after the target quit date. After 6 months, participants will be asked to come to a final clinical visit.
• Participants will be allowed to additionally use nicotine replacement therapy. NRT is not free.

b) Control group will receive smoking cessation counselling only as provided for a). Participants will be allowed to additionally use nicotine replacement therapy.

Outcomes

Baseline and 6 months

Primary outcome: continuous smoking abstinence at 6 months post-quit date measured by:

• Self-report of having smoked no cigarettes from quit date, validated by urinary levels of anabasine. If anabasine is missing, validation by exhaled carbon monoxide (CO)

Secondary outcomes:

• Continuous smoking abstinence at 6 months post-quit date
  • Self-report of having smoked no cigarettes from quit date, validated by urinary levels of NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol). If NNAL is missing, validation by urinary levels of anabasine or exhaled carbon monoxide (CO).
• Self-reported smoking abstinence allowing a 2-week grace period at 4, 8 weeks, and 6 months post-quit date.
• Validated smoking abstinence allowing a 2-week grace period at 6 months post-quit date:
  • validated by urinary levels of anabasine; if anabasine is missing validation by exhaled CO;
  • validated by urinary levels of NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol); if NNAL is missing, validation by urinary levels of anabasine or exhaled CO.
• Self-reported smoking abstinence allowing up to 5 cigarettes at 1, 2, 4, 8 weeks, and 6 months post-quit date.
• Validated smoking abstinence allowing up to 5 cigarettes at 6 months post-quit date:
  • validated by urinary levels of anabasine; if anabasine is missing validation by exhaled CO;
  • validated by urinary levels of NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol); if NNAL is missing, validation by urinary levels of anabasine or exhaled CO.
• Self-reported 7-day PPA at 1, 2, 4, 8 weeks, and 6 months post-quit date.
• Validated 7-day PPA at 6 months post-quit date
  • Confirmation of having smoked no cigarettes in the past 7 days, validated by urinary levels of anabasine. If anabasine is missing validation by exhaled CO.
  • Confirmation of having smoked no cigarettes in the past 7 days, validated by urinary levels of NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol). If NNAL is missing, validation by urinary levels of anabasine or exhaled CO.
• Number of cpd at baseline, target quit date, 1, 2, 4, 8 weeks, and 6 months post-quit date, self-reported.
• Change in number of cpd at baseline, 6 months post-quit date, self-reported. Successful reduction defined as 50% reduction in cpd.
• Use of any other smoking cessation products (NRT) at 1, 2, 4, 8 weeks, and 6 months post-quit date, self-reported.
• Withdrawal at baseline and 6 months assessed with the Minnesota Tobacco Withdrawal Scale (MTWS-R).
• Fagerström Test for Nicotine Dependence at baseline and 6 months.
• Swiss EQ-5D at baseline and 6 months.
• Use of any ENDS at 1, 2, 4, 8 weeks, and 6 months post-quit date, self-reported.
• Respiratory symptoms (COPD Assessment Test).
• AEs defined as any untoward medical occurrence in participants who are administered an intervention during clinical investigation; these events were not necessarily caused by the intervention. Study nurses proactively collected AEs at each FU visit; participants could report AEs to the research team at any time.
• SAE defined as any event that: required inpatient treatment of at least 24 hours or extended a current hospital stay; caused permanent or significant incapacity or disability; was life-threatening or caused death; caused a congenital anomaly or birth defect. Collected proactively at each FU visit. Participants could report SAEs at any time.
• Study product use baseline to 6-month FU.

Study funding

For Auer 2024: Supported by a grant (173552) from the Swiss National Sci[1]ence Foundation, a grant (19.017477) from the Swiss Tobacco Prevention Fund, a grant (KFS4744-02-2019) from Swiss Cancer Research, and Lunge Zürich.

Author declarations

The funding bodies had no role in the trial design; the collection, monitoring, analysis, or interpretation of the data; or the writing of the manuscript. There was no industry involvement in the trial.

Reto Auer, Stephanie Baggio, Florent Baty, Aurelie Berthet, Philip Briggmann, Rodrigo casagrande Tango, Martin Feller, Anja Frei, Moa Haller, Nancy Hopf, Jean-Paul Humair,Isabelle Jacot Sadowski, Julian Jakob, Nicolas Rodondi, Nicolas Sambiagio, Anna Schoeni, Alexandra Strassmann, Mirah Stuber, Kali Tal do not have any interests to disclose.

Ivan Berlin: speaker at meetings (Pfizer). Member DSMB phase II trial Kinnov therapeutics.

Martin Brutsche: invited scientific talks (Astra Zeneca Schweiz). Scientific advisory board GlaxoSmithKline. Head of Department Kantonsspital. Consultant Merck Sharp & Dohme. Consultant Novartis Pharma AG.

See: https://www.nejm.org/doi/suppl/10.1056/NEJMoa2308815/suppl_file/nejmoa2308815_disclosures.pdf

Notes

Linked trial registry IDs: NCT03603340; NCT03603353; NCT03612336; NCT03612375; NCT03612453; NCT03612544; NCT03632421; NCT03938298. Based on the common study name ESTxENDS study, we assume that the listed trial IDs and the numerous listed references are linked to one study. However, limited information is currently available and we will revisit this as necessary as more information becomes available.

The abstract reports "participants in the control group will receive smoking cessation counselling only. Participants will be allowed to additionally use NRT." As NRT was not provided by the study, we classed this comparator arm as "behavioural support only."

Random sequence generation (selection bias)

Low risk

An automated, centralized, online randomization system in a protected environment at the Clinical Trials Unit in Bern, Switzerland, then generated randomization sequences in a 1:1 ratio.

Allocation concealment (selection bias)

Low risk

An automated, centralized, online randomization system in a protected environment at the Clinical Trials Unit in Bern, Switzerland, then generated randomization sequences in a 1:1 ratio.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Blinding was not possible as a placebo was not provided in the comparator group

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Cessation biochemically verified

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data on smoking status and serious adverse events at 6 months were available for 90.8% of participants. Less than 20% difference and less than 50% attrition

Selective reporting (reporting bias)

Low risk

Outcomes reported

Methods

RCT

Center for Alcohol and Addiction Studies, Brown University School of Public Health, USA

Participants

45 participants

EC: N = 18; ONP: N = 18; CC: N = 9

Mean age 50.1 (SD 10.7); average CPD 13.9 (SD 10.1)

Inclusion criteria: household income < 250% federal poverty level (FPL); past 6 months daily smoking of ≥ 5 cigarettes/day (exhaled CO ≥ 6 ppm at baseline); willingness to substitute combustible cigarettes for EC or NPs; aged 21+ years

Exclusion criteria: intention to quit smoking during the next 30 days or current or past 30-day engagement in smoking cessation; current use of EC or NP ≥ 4 days per month or self-report of primarily using tobacco products that are not combustible cigarettes; hospitalization for a psychiatric issue in the past 30 days or visible instability; heart-related event in the past 30 days; pregnancy

Note: Cannabis use will be assessed but not excluded.

For full list, see NCT record.

Inclusion based specific population characteristic: lower socioeconomic status, household income < 250% federal poverty level

No EC use at baseline.

Not motivated to quit.

Interventions

EC: 4th generation electronic cigarette device and disposable cartridges (5% nicotine e-liquid cartridges)

Nicotine pouch, 4 mg

Arm 1: Electronic cigarette

Participants in this experimental condition will be provided with a 4th generation EC device (VUSE Alto) and disposable cartridges. Participants will be provided with EC and 5% nicotine e-liquid cartridges (pods) for 8 weeks and encouraged at in-person and phone assessments to use the EC any time they would normally smoke. Participants will be able to choose one of two e-liquid flavours (tobacco, menthol) at baseline.

Arm 2: Nicotine pouch

Participants in this experimental condition will be provided with nicotine pouches.

Participants will be provided with on! 4 mg nicotine pouches for 8 weeks and encouraged at in-person and phone assessments to use the nicotine pouches any time they would normally smoke. Participants will be able to choose one of two nicotine pouch flavours (tobacco, mint) at baseline.

Arm 3: No intervention: smoking-as-usual

Participants in this assessment-only condition will continue smoking-as-usual.

All groups were advised to quit smoking at the end of the study with a brief advice and a handout on how to contact the Quitline.

Outcomes

Baseline, 8 weeks

Change in cigarettes per day from baseline to week 8. Within and between-group difference in past week average cigarettes per day assessed using timeline follow-back (TLFB)

Change in cigarette dependence from baseline to week 8

Cigarette abstinence at week 8. Past week any-use of cigarettes assessed using timeline follow-back (TLFB)

Change in carbon monoxide; cotinine; NNAL; 8-isoprostane from baseline to week 8

Change in carbon monoxide reported.

Feasibility and acceptability

Study funding

“The study is funded by the Brown University Office of Vice President Research. The authors JCA, DDM, and JSA are partially or fully funded by an NIH-funded Center of Biomedical Research Excellence (COBRE) (P20GM130414).”

Author declarations

“JSA serves as a consultant and has equity in the start-up company Qnovia. This is a start-up company developing smoking cessation prescription medications through the FDA. They currently do not have a product that is available for sale. The other authors have no conflict of interest to disclose.”

Notes

Avila 2024 moved to new study in 2025. NCT record (NCT05327439) was added to ongoing studies in 2022 update

Random sequence generation (selection bias)

Low risk

“Participants were randomized using a computer-generated randomization program stratified by sex and age”

Allocation concealment (selection bias)

Low risk

“Randomization was conducted by the same re search assistants who enrolled participants in the study, and both participants and research assistants were not blinded to the study condition.”

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

2 arms received equally intensive interventions (EC or pouch). Control arm not equally intensive.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

CO - “assessed via Smokerlyzer”

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Low at 8 weeks: EC 14/18= 77.8%; ONP 12/18 = 66.7%; CC 7/9 = 77.8%. Data is at 8 weeks. [Would be high for ONP at 16 weeks]

Selective reporting (reporting bias)

High risk

Urine and blood samples were not analysed.

Methods

Design: randomized, parallel-assignment, double-blind trial

Recruitment: outpatient pulmonary and primary care clinics, Tobacco Treatment Service, referrals from medical providers

Setting: Hospital outpatient and primary care clinics, USA

Study start date: October 2014; Study end date: June 2014

Participants

Total N: 40

N per arm: non-nicotine: 20; nicotine EC: 20

Inclusion criteria: ≥ 18 years; ≥ 1 cpd; willing to quit smoking

Exclusion criteria: unstable psychiatric or medical conditions requiring hospitalization within the past 4 months; acute coronary syndromes or stroke within the past 30 days; history of allergic reactions to adhesives; women who were pregnant, nursing, or not practising effective contraception; current use of an EC for the purpose of stopping tobacco cigarette smoking

Women: 52.5%; mean age: 53 mean cpd: 17 mean FTND: 5.9; motivated to quit

E-cigarette use at baseline: not reported

Interventions

EC: Refillable

Both groups received standard care (8 weeks nicotine patch and counselling) and were randomized to nicotine EC or non-nicotine EC.

EC: eGO style EC (650 mAh battery, EVOD clearomizer, 3.7 V, 1.8 Ω single bottom coil), provided with e-liquid purchased from an online vape shop (0 mg/mL or 24 mg/mL nicotine strength, 70/30 propylene glycol/vegetable glycerin, tobacco flavour); instructed to use it as needed as a substitute for tobacco to try to satisfy cravings to smoke. If the patch alone proved adequate to prevent withdrawal and smoking cravings, the participant was advised not to use the EC. Additional EC devices, replacement coils, and liquid were provided as needed for the first 8 weeks of the study.

Outcomes

Questionnaires and CO measurements taken at baseline, treatment visits at week 2, 4, 6, 8, and follow-up at week 24

Cessation: 7-day point prevalence abstinence, eCO ≤ 6 ppm

Adverse events and biomarkers: side effects were measured, although it is unclear whether a questionnaire with prespecified symptoms was used

Spirometry and FeNO at baseline and 6-month follow-up

Other outcomes: change in reported number of cpd at weeks 8 and 24; change in per cent predicted FEV1 and FVC from baseline to week 24, and EC use patterns

Study funding

"Funding for this study was provided by the Yale School of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine and the National Heart, Lung, and Blood Institute grant T32HL007778. NHLBI had no role in the study design, collection, analysis, or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication."

Author declarations

"Dr. Toll received a grant from Pfizer for medicine only for a research study, and he receives funding as an expert witness in litigation filed against the tobacco industry. Dr. Chupp received grants from NIH, Genetech, Glaxo Smith Kline, Astra Zeneca/Medimmune and Boston Scientific. He received consulting/speaking fees from Genetech, Astra Zeneca/Medimmune, Mannkind, and Boston Scientific. There are no other conflicts of interest for the remaining authors."

Notes

New for 2020 update. Study listed as ongoing study NCT02498145 in 2016 review update

Additional data provided from authors

Random sequence generation (selection bias)

Low risk

Quote: “Participants were randomized using a random number generator with 1:1 blocked randomization (block size n = 8).”

Allocation concealment (selection bias)

Unclear risk

Both groups received standard care (nicotine patch and counselling) and were randomized to: nicotine EC or non-nicotine EC (no further detail given).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: “Treatment assignment was blinded to both the investigators and participants”.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

CO biochemically validated

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: “The study had a modest loss to follow-up (20%) at week 24.”

Number lost to follow-up in each group was not reported in the paper.

Week 24 retention rate: Nicotine EC group: 19/20 (95%); non-nicotine EC group: 13/20 (65%); > 20% difference between groups

Selective reporting (reporting bias)

Low risk

Outcomes reported align with those listed in the clinicaltrials.gov record (registered 2015; prior to study completion in 2016).

Methods

Individually randomized, blinded, 2-arm trial

Setting: 39 general practices, England

Recruitment: primary care registries

Participants

325 (164 intervention; 161 intervention)

47.4% female; mean age 57.8; mean cpd 20.1; mean FTCD 4.2

Inclusion criteria: current smoker ≥ 10 ppm for exhaled CO and smokes a minimum of 8 cigarettes/8 grams of tobacco per day (including pipe, cigars, or tobacco roll-ups) with no intention of stopping immediately or seeking cessation support. Diagnosed with 1 or more of the following chronic conditions: ischaemic heart disease, peripheral vascular disease, hypertension, diabetes mellitus (Type 1 and Type 2), stroke, asthma, COPD, chronic kidney disease, depression, schizophrenia, bipolar disorder or other psychoses. Informed consent. ≥ 18 years

Exclusion criteria: GP believes that switching to EC would not benefit the patient, given their current medical condition; currently using EC, NRT or other cessation therapies (e.g. bupropion, nortriptyline, or varenicline); plans to stop smoking before or at the annual review; currently enrolled in another smoking-related study or other study where the aims of the studies are incompatible; cannot consent due to mental incapacity; pregnancy, breastfeeding

Interventions

EC type: refillable

Control: no additional support beyond standard care

Intervention: practitioners gave brief advice about EC and offered participants a free EC for the purpose of switching from smoking to vaping. The instruction was to reduce their smoking. If the offer was accepted, participants received: a starter pack containing an Aspire PockeX all-in-one e-cigarette, 2 x 0.6 ohm coils and 1 x 1.2 ohm coil, 3 nicotine e-liquids in 18 mg/mL (blueberry, menthol) and 12 mg/mL (mixed fruit) strengths and an accompanying practical support booklet developed by the study team. The practical support booklet contained information on how to set up the device, correct ways to vape, common issues with use and a list of local vape shops. It included motivational support to reinforce practitioners’ advice about EC, including the benefits of cutting down on cigarettes through e-cigarette use and addressing perceived risks and concerns. It included links to a study-dedicated website with video demonstrations on how to use EC and testimonials. Participants could opt into receiving an introductory telephone call from an experienced vaper in the first week of receiving their EC, to guide them on technical aspects of EC use (not behavioural support). Thereafter, participants could contact the vaper by telephone for up to 2 months after receiving their kit.

All: practitioners offered routine smoking cessation support to all participants. Although this varied across practices, standard care typically involved brief advice about stopping smoking and assistance to do so either by referral to the NHS stop-smoking services or offer of pharmacotherapy. If the participant declined standard care, they were randomized by the practitioner to either the intervention or control arm. In the control arm, participants received no further support beyond standard care.

Outcomes

0 months, consultation visit, 2 months post-consultation, 8 months post-consultation

"Patients attended four visits at their GP practice: a baseline visit, a therapeutic visit (‘annual review’) with their GP or nurse and two follow-up visits two months and eight months post-consultation."

Primary outcomes:

• 7-day PPA from smoked tobacco at 2 months, defined as complete self-reported abstinence from smoking – not even a puff – in the past 7 days, accompanied by a salivary anabasine concentration of < 1 ng/mL

If there are technical issues with the analysis of saliva samples (e.g. if there is not enough saliva present in the sample for anabasine analysis), we will use exhaled CO as verification of abstinence (CO < 10 ppm).

(Deviation from Statistical Analysis Plan: CO used due to imprecision of values for anabasine)

• Reduction in cigarette consumption at 2 months, defined as at least a 50% reduction in self-reported cigarettes per day on each of the last 7 days at 2 months compared with baseline consumption, accompanied by evidence of reduced smoke intake indicated by a CO measurement lower than baseline

Secondary outcomes:

• 7-day PPA measured at 8 months, biochemically confirmed by an exhaled CO of < 10 ppm
• 6-month prolonged abstinence using the Russell standard criteria, defined as smoking < 5 cigarettes between 2- and 8-month follow-ups, confirmed by an anabasine concentration of < 1 ng/mL at 2 months and an exhaled CO concentration of < 1 ng/mL at 8 months if CO measurement unavailable
• Mean change in salivary anabasine concentration and CO from baseline to 2 months
• Percentage reduction in self-reported cigarettes per day from baseline to 2 months; and from baseline to 8 months

SAEs and AEs reported. AEs: throat/mouth irritation; cough; headache; palpitations; nausea; dry mouth; dizziness; shortness of breath; stomach pain

Study funding

NIHR Postdoctoral Fellowship and NIHR School for Primary Care Research funded randomized controlled trial

Author declarations

All authors declare no competing interests.

Random sequence generation (selection bias)

Low risk

Quote: "Participants were randomised to intervention or control with a 1:1 allocation ratio. A randomisation list was generated by the trial statistician using the current version of Stata and validated by a second statistician within the Primary Care Clinical Trials Unit (PC-CTU). The randomisation was stratified by practice and used varying block sizes to ensure allocation concealment."

Allocation concealment (selection bias)

Low risk

Quote: "The randomisation list was passed to someone independent of the trial who created the randomisation envelopes. The trial statisticians were blinded to the treatment allocation during analyses."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the trial, GPs and practice nurses were aware of the participant’s treatment allocation to ensure that the correct intervention was given. Therefore, practitioners who delivered the intervention could not be blinded to treatment.

While participants knew whether they had been offered support to cut down by using an e-cigarette or not by their GP or nurse, the participant was not informed that the study investigated this specifically and, therefore, was in some respects blind to allocation.

Groups not matched for face-to-face contact time

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: “7-day point-prevalence abstinence from smoked tobacco at two months, defined as complete self-reported abstinence from smoking – not even a puff – in the past seven days, accompanied by a salivary anabasine concentration of < 1 ng/mL” or exhaled CO as verification of abstinence (CO < 10 ppm)"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

At 8 months: control 144/161; intervention 148/164

Selective reporting (reporting bias)

Low risk

Used CO above anabasine, but reported both

(Deviation from Statistical Analysis Plan: CO used due to imprecision of values for anabasine)

All predefined outcomes listed in the published protocol and clinical trial register were reported.

Methods

Design: "A mixed methods study"

Recruitment: recruited patients with COPD, aged 21 to 75, listed as current smokers in the NYU Langone Health electronic health record by phone, mail, and MyChart

Participants: patients with COPD

Setting: NYU, USA

Study start date: not reported

Participants

Total N: 48

Inclusion criteria: moderate COPD (based on the COPD Assessment Test score (CAT)); interested in quitting

Exclusion criteria: not reported

Female 54%; mean age 60 (SD 8.2)

E-cigarette use at baseline: not reported

Motivated to quit: yes

Interventions

EC: no detail reported

Arm 1 EC

Arm 2 NRT

Both groups: over 12 weeks, participants received 5 counselling sessions and were asked about their COPD symptoms, CC use, EC use, and nicotine withdrawal symptoms. We used Ecological Momentary Assessment (four text messages/day) to assess current EC/NRT and CC use.

Outcomes

12 weeks

Combustible cigarette use measured

Dyspnoea

COPD symptoms

Mixed methods study assessing the relationship between race/ethnicity and switching from CC to EC; evaluated whether it is mediated by social norms, risk perception, and overall opinions of CC and EC

Study funding

Not reported

Author declarations

Not reported

Notes

Student presentation

New to 2022 update

Random sequence generation (selection bias)

Unclear risk

No detail: “We randomized participants to EC or nicotine replacement therapy (NRT) for switching from CC.”

Allocation concealment (selection bias)

Unclear risk

No detail

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Two active interventions. No detail

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No detail

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Still collecting data. Outcome data not reported. Numbers not reported

Selective reporting (reporting bias)

Unclear risk

Still collecting data

Methods

Design: pragmatic, open-label, single-centre, 2-arm randomized controlled trial

Recruitment: withdrawal service in Melbourne, Australia

Setting: substance use disorder treatment setting, and following discharge, community setting, Melbourne, Australia

Study start date: 1 August 2017; Study end date: April 2019

Participants

Total N: 100

N per arm: EC intervention = 50; NRT control = 50

Inclusion criteria: ≥ 18 years; tobacco smoker on entering the residential service; capacity to consent and able to understand the participant materials

Exclusion criteria: used an END containing nicotine in the past month; pregnancy/breastfeeding; currently enrolled in another study; scheduled to be transferred to a long-term rehabilitation unit following discharge from the residential withdrawal unit.

Inclusion based on specific population characteristics: participants were discharged from a smoke-free alcohol or other drugs (AOD) residential withdrawal service.

32% women; mean age 40.9; mean cpd 21

Motivated to quit: median (SD) = 7.3 (2.4) on the 1 to 10 scale with 10 "highly motivated"

Interventions

EC: Refillable

Up to an hour training session, information pack. Innokin Endura T22 starter kit and refill liquid (Nicophar). 4-week supply of liquid nicotine, with further supplies of liquid nicotine mailed twice at 4- week intervals. Dosing schedule of e-liquid dependent nicotine dependence score: high-nicotine-dependence category assigned initial 4-week e-liquid supply (total 8 × 10 ml bottles) consisting of: 2 × 10 ml bottles of 18 mg e-liquid and 6 × 10 ml bottles of 12 mg e-liquid. The second and third batches = 8 × 10 ml bottles of 12 mg e-liquid only. Participants scoring in the moderate- and low-dependence categories: three 4-week supplies of 8 × 10 ml bottles of 12 mg e-liquid. Participants given 1-week supply of nicotine patches for use while getting used to the EC.

NRT control: information pack, 12 weeks NRT on the same schedule as for ENDs. 4-week supply of patches plus a nicotine spray and inhaler, followed by refills including patches plus inhaler, gum, and lozenges.

Both groups received proactive referral to quitline counselling (call-back service), which provides calls on pre-discharge and on days 1, 3, 7, 14, and 28 post-discharge, with an emphasis on relapse prevention. Counsellors trained on the use of ENDs

Outcomes

Week 6, 12; self-report

Adverse events collected

Other outcomes measured:

• Acceptability and feasibility of interventions
• Treatment adherence
• Cigarettes smoked per day - Heaviness of Smoking Index
• Frequency of cravings
• Minnesota Nicotine Withdrawal Scale (MNWS)
• 10-item Kessler Psychological Distress Scale (Kessler-10)
• Quitting self-efficacy, motivation to quit and the Heaviness of Smoking Index were assessed at baseline.

Study funding

"The study is supported by a VicHealth Innovation Research Grant (2016–0096). AG is supported by a post-doctoral fellowship from the Heart Foundation. ALB is supported by an Australian National Health and Medical Research Council (NHMRC) senior research fellowship and a Faculty of Health and Medicine, University of Newcastle Gladys M Brawn senior research fellowship. BB is supported by an Australian NHMRC career development fellowship (GNT1063206) and a Faculty of Health and Medicine, University of Newcastle Gladys M Brawn career development fellowship."

"This study was supported by a VicHealth Innovation Research Grant (2016-0096)."

Author declarations

"The authors declare that they have no competing interests."

"None to declare."

Notes

New for 2020 update; additional data originally provided by authors and subsequently published

Random sequence generation (selection bias)

Low risk

Quote: “Upon completing the baseline survey, participants were randomised 1:1 to an intervention via a computer-sequenced 4–6 block randomisation embedded in the tablet device software.”

Allocation concealment (selection bias)

Low risk

Quote: “At the end of the baseline survey, participants will be randomised 1:1 to an intervention via a computer-sequenced 4–6 block randomisation embedded in the iPad.”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “Participants were informed of their intervention group by the RA and provided with a training session of up to one hour.”

“Due to the nature of the intervention, neither participants nor staff can be blinded to allocation. However, the data safety monitoring committee and the statistician responsible for the data analysis will be blinded.”

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No biochemical validation, self-report data

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: “At 6 and 12-weeks, 63 participants (63%) and 50 participants (50%) were followed up, respectively. While slightly higher retention rates were evidenced in the VNP group at 6-weeks (68% vs 58% in NRT group; P = 0.30), there were no differences between groups at 12-weeks (25 re-contacted in both arms; i.e. 50%).”

Selective reporting (reporting bias)

Low risk

Unpublished findings provided by authors reported on all outcomes mentioned in the protocol.

Methods

RCT

Project NEAT: A randomized controlled trial to examine the efficacy of vaporised nicotine products and telephone quitline support compared with nicotine replacement therapy and telephone quitline support when used following discharge from residential withdrawal services

Setting: Australia (New South Wales, Queensland, Victoria)

Recruitment 4 hospital sites: Belmont Hospital, Belmont; St Vincent's Hospital, Darlinghurst; Turning Point Drug and Alcohol Centre, Richmond; Royal Brisbane & Womens Hospital, Herston

Participants

Target sample size: 926

Inclusion criteria: Aged 18 or over. Daily tobacco smoker (10 or more cigarettes) on entering withdrawal unit. Accessing treatment from participating services. Want to quit smoking in the next 30 days. Capacity to consent and understand the participant materials and follow the study instructions and procedure (e.g. sufficient English language ability and not too unwell as judged by medical staff).

Exclusion criteria: Pregnant or breastfeeding. Enrolled in another study. Scheduled to be transferred to a long-term residential rehabilitation service following discharge from the withdrawal unit. Used VNP (containing nicotine) in the last 30 days. Currently engaged in Quitline’s call-back services. No ready access to a phone

Willing to quit smoking: yes

Interventions

Condition 1: vaporised nicotine products and Quitline

Condition 2: current best practice treatment for tobacco smoking (combination nicotine replacement therapy and Quitline)

Outcomes

9 months after inpatient withdrawal unit discharge:

• Self-reported 7 months continuous abstinence from tobacco smoking
• Biochemically verified 7-month continuous abstinence from tobacco smoking

3 and 9 months after inpatient withdrawal unit discharge:

• 30-day point prevalence abstinence
• 7-day point prevalence abstinence
• Abstinence from all nicotine/tobacco products

Study funding

National Health and Medical Research Council of Australia for funding the trial with a Project Grant (GNT1160245), Canberra ACT 2601

Author declarations

CB declares grants for research from the New Zealand Ministry of Health, Health New Zealand, Health Research Council, Wake Forest University, and Education New Zealand, and support for travel to scientific meetings from Kenvue Asia, University of Edinburgh, and the Society for Research on Nicotine and Tobacco, for which he has served as President and Board member. All other authors declare no competing interests.

Notes

Moved to new in 2026.

Random sequence generation (selection bias)

Low risk

Randomisation, embedded in a REDCap database, was immediately triggered by the completion of the baseline survey. An independent statistician with no further involvement in the trial produced the randomisation schedule using a permuted block randomisation procedure, with random blocks of size four or six, stratified by site, and equal allocation ratios for the two treatment groups.

Allocation concealment (selection bias)

Unclear risk

Single blind. Participants were not aware of their study arm. Researchers were aware of which arm participants were allocated to. "Participants were immediately notified of their group allocation by the research assistant"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Interventions equally intensive. Single blind. Participants were not aware of their study arm. Researchers were aware of which arm participants were allocated to. "Participants were immediately notified of their group allocation by the research assistant." "Researchers collecting outcome data were masked to treatment group." Both groups had same Quitline behavioural counselling on discharge

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Self-report. CO verification was planned (changed due to covid).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

EC arm: 114/179 (63.7%) at 9 mth FU. NRT arm: 115/184 (62.5%) at 9 mth FU

Selective reporting (reporting bias)

Low risk

In clinical record state will collect data on: CC abstinence; number of cigarettes smoked; cravings; withdrawal symptoms; time to relapse; abstinence from all nicotine/tobacco products. Reported in paper: CC abstinence; SAE. Appendix CC abstinence; abstinence from all nicotine/tobacco products; CPD; craving; withdrawal; time to relapse. Measurement procedure changed as a result of COVID from verified abstinence to self-reported. "The protocol lists number of subsequent quit attempts among those who relapsed as a secondary outcome; however, this question was removed from follow-up surveys before roll-out to reduce participant burden."

Methods

Design: 3 parallel groups RCT

Recruitment: people who smoke recruited from the community, via newspaper advertisements

Setting: research unit, New Zealand

Study start date: 6 September 2011; study end date: 5 July 2013

Participants

Total N: 657. 289 nicotine EC (NEC), 295 patch, 73 non-nicotine EC (PEC)

Inclusion criteria: ≥ 18 years; smoked 10 or more cpd over past year; wanted to stop smoking

Exclusion criteria: pregnancy and breastfeeding; using cessation medicines or using other support to quit; heart attack, stroke, severe angina in the last 2 weeks; poorly controlled medical disorder; allergies, other chemical dependence

62% women, mean age 42, ⅓ NZ Maori, smoking 18 cpd, mean FTND score 5.5

Motivated to quit

E-cigarette use at baseline: not specified

Interventions

EC: Cig-a-like

Randomized to Nicotine EC (NEC), PATCH, or Placebo EC (PEC) use for 13 weeks (from 1 week prior to TQD)

• NEC: Elusion brand 16 mg cartridges; sent product via courier
• PATCH: 21 mg/24-hour patch; sent voucher to exchange for NRT at pharmacy (dispensing costs covered)
• PEC: as per EC, but 0 mg cartridges

All participants referred to Quitline and received an invitation to access phone- or text-based support. This was accessed by ≤ 40% of participants.

Outcomes

Sustained (≤ 5 cigarettes allowed) validated (exhaled breath CO < 10 ppm) abstinence at 6 months

≥ 50% self-reported reduction in baseline cigarettes at 6 months

Participants reporting any adverse events

Proportion of AEs that were serious

Proportion of unrelated AEs

Study funding

Health Research Council of New Zealand

Author declarations

"We declare that we have received no support from any companies for the submitted work and have no non-financial interests that might be relevant to the submitted work. ML, via his company Health New Zealand, previously did research funded by Ruyan (an e-cigarette manufacturer). CB and HM have done research on Ruyan e-cigarettes funded by Health New Zealand, independently of Ruyan. HM has received honoraria for speaking at research symposia, has received benefits in kind and travel support from, and has provided consultancy to, the manufacturers of smoking cessation drugs. NW has provided consultancy to the manufacturers of smoking cessation drugs, received honoraria for speaking at a research meeting and received benefits in kind and travel support from a manufacturer of smoking cessation drugs. JW has provided consultancy to the manufacturers of smoking cessation medications."

Notes

Accessed support: NEC: 115/289; PATCH: 106/295; PEC: 26/73

Random sequence generation (selection bias)

Low risk

Computerized block randomization

Allocation concealment (selection bias)

Low risk

Computerized via study statistician

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

NEC and PEC were blind to treatment condition in relation to one another. No blinding for NEC/PEC vs PATCH conditions, but as NEC and PATCH were both active treatments, performance bias judged unlikely

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biochemical validation used

Incomplete outcome data (attrition bias)
All outcomes

Low risk

22% lost to follow-up (all considered to be smoking). Patch group had a higher loss to follow-up and withdrawal than EC (loss to follow-up 17% NEC, 27% patches, 22% PEC). However, minimal differences in per-protocol and ITT analyses

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported

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

Study start date: April 2010; Study end date: April 2012

Participants

Total N: 300

Inclusion criteria: smoked ≥ 10 cpd for past 5 years; age 18 to 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; pregnancy or breastfeeding

36% women; mean age 44 (SD 12.5); mean cpd 20 (IQR: 15 to 25)

Not currently or intending to quit smoking in the next 30 days

E cigarette use at baseline: not specified

Interventions

EC: Cig-a-like

EC presented as a healthier alternative to tobacco smoke and could be freely used, ad libitum (up to 4 cartridges a 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)

Study funding

"This research was supported by a grant-in-aid from Lega Italiana AntiFumo. The study sponsor had no involvement in the study design, collection, analysis, and interpretation of data, the writing of the manuscript or the decision to submit the manuscript for publication. RP and PC are currently funded by the University of Catania, Italy. The e-cigarette supplier had no involvement in the study design, collection, analysis, and interpretation of data, the writing of the manuscript or the decision to submit the manuscript for publication."

Author declarations

"RP has received lecture fees and research funding from Pfizer and GlaxoSmithKline, manufacturers of stop smoking medications. He has served as a consultant for Pfizer and Arbi Group Srl, the distributor of the CategoriaTM e-Cigarette. The other authors have no relevant conflict of interest to declare in relation to this work."

Notes

Additional data provided from authors

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, which did not have direct contact with the participants

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double-blind

Quote: “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 12 m, 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 were not always reported in this way.

Methods

Design: randomized non-inferiority switching trial

Setting: Italy

Recruitment: recruited among hospital/university staff, via social media, or through word of mouth

Study start date: May 2019. Study end date May 2020

Participants

220 healthy people who smoke tobacco cigarettes

EC arm 110, HTP arm 110

% female: EC arm 70% (63.6), HTP arm 56% (50.9). Mean age 41.3 (EC arm 41.3 (SD 16.9), HTP arm 41.3 (SD 16.1)). Mean CPD: EC arm 22.8 (10.9), HTP arm 22.6 (SD 10.1). Mean FTND: EC arm 6 (SD 2.2), HTP arm 5.8 (SD 2.1)

Motivated to quit: No

Interventions

E-cigarettes (EC) arm: JustFog Q16 Starter Kit consisting of a battery and a 1.9-mL refillable tank fitted with a 1.6-Ohm nichrome coil, 16 mg, 3 flavours 50% propylene glycol/40% vegetable glycerin/10% H2O. EC study arm, 50.9% (56/110) chose Puff Riserva Country, 30.9% (34/110) chose Puff Riserva Tuscan, and 18.2% (20/110) chose Puff Artic e-liquid.

Heated Tobacco Products (HTPs) arm: IQOS 2.4 Plus consisting of a pen-like holder into which a tobacco stick is inserted and heated, and a battery case to recharge the holder after each use. IQOS 2.4 Plus was the only HTP available on the Italian market when this trial was designed. The device is to be used with tobacco sticks specifically processed and manufactured for IQOS (named HEETS). Participants could choose from 3 varieties of tobacco sticks (HEETS Amber, rich tobacco; HEETS Yellow, smooth tobacco; and HEETS Turquoise, menthol-flavoured tobacco), which were available for sale on the Italian market at the time of the study. HTP study arm, 56.4% (62/110) chose HEETS Amber, 33.6% (37/110) chose HEETS Yellow, and 10.0% (11/110) chose HEETS Turquoise tobacco sticks.

Both groups: “Motivational counseling was offered throughout the study to maximize study product adherence, to favor transition away from combustible tobacco cigarettes, and to prevent relapse back to smoking.”

Outcomes

12-week study. Follow-up 24 weeks. Baseline, 1, 2, 4, 8, 12, and 24 weeks.

Biochemically verified self-reported continuous abstinence at 12 weeks from the previous visit. Continuous abstinence rate (CAR) weeks 4 to 12). Abstinence from smoking was defined as eCO-verified (< 10 ppm). 7-day point prevalence of abstinence at week 12.

Secondary outcomes include: smoking reduction from baseline, adoption rates and product acceptability, tolerability, changes in step test values and in the level of selected biomarkers of exposure in exhaled breath (i.e. eCO) and in spot urine samples

A follow-up visit at 24 weeks to review product usage and smoking behaviour under naturalistic conditions of use

Study funding

NCT record: Collaborators: Philip Morris Société Anonyme

Caponnetto 2020: This research is supported by an Investigator-Initiated Study award by Philip Morris Products Société Anonyme (PMI.IIS.2016.006).

Author declarations

EM, DS and RP are full-time employees of the University of Catania, Italy. PC, MC and RE are fixed-term researchers at University of Catania, Italy. MM is a fixed-term researcher at Centro per la Prevenzione e Cura del Tabagismo, University of Catania. BB is a full-time employee of ARNAS Garibaldi, Catania, Italy. AP is a full-time employee of Casa di Cura Musumeci-Gecas, Gravina di Catania, Italy. UP is a full-time employee of Ospedale “San Vincenzo” - Taormina, Italy.

In relation to his work in the area of tobacco control, RP has received lecture fees and research funding from Pfizer and GlaxoSmithKline, manufacturers of stop smoking medications. He has also received support from The Consumer Advocates for Smoke-free Alternatives (CASAA) for publication and open access costs of one paper. He has also served as a consultant for Pfizer, Global Health Alliance for treatment of tobacco dependence, ECITA (Electronic Cigarette Industry Trade Association, in the UK), Arbi Group Srl., and Health Diplomats (consulting company that delivers solutions to global health problems with special emphasis on harm minimization). Lectures fees from a number of European electronic cigarette industry and trade associations (including FIVAPE in France and FIESEL in Italy) were directly donated to vapers advocacy no-profit organizations. He is also currently involved in the following pro bono activities: scientific advisor for LIAF, Lega Italiana Anti Fumo (Italian acronym for Italian Anti Smoking League) and for The Consumer Advocates for Smoke-free Alternatives (CASAA); Chair of the European Technical Committee for standardization on “Requirements and test methods for emissions of electronic cigarettes” (CEN/TC 437; WG4).

The other authors have no conflict of interests to declare.

Notes

Random sequence generation (selection bias)

Low risk

NCT record: The randomization sequence will be computer-generated by using blocks size of 5, with an allocation ratio of 1:1 for each of the study products (IQOS, JustFog-EC). This was not reported in the paper.

Allocation concealment (selection bias)

Low risk

From Caponnetto 2020: “assignment to one of the two groups must be made on the basis of a simple list. The “dummy” randomization list will be generated by the statistician through an SAS program (Statistical Analysis System Version 9.4). The randomization list will consist of 220 numbers of 3 digits in the form nnn (where “nnn” is a sequential number from 001 to 220). In derogation from the protocol (Study Design and Study Plan section) and in order to make it impossible to identify the subject's own arm to be randomized (before the number is assigned), the size of the blocks will not be 4 but will be variable in blocks of 4 and 6. The sequence of blocks will also be randomized and blind.”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

“Obviously, product assignment could not be blinded, and strong product preference (IQOS-HTP vs JustFog-EC) could have introduced an allocation bias.” Authors aware of a strong product preference

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Self-reported AEs. VO2 max measured by the Chester step test. eCO measured

Incomplete outcome data (attrition bias)
All outcomes

Low risk

EC 101/110 12 weeks; 94/110 at 24 weeks

Selective reporting (reporting bias)

High risk

Study completed in May 2020 but 24-week outcome data not reported in publication or in the trial register record in which 12-week outcomes were reported

Methods

Design: randomized, parallel-assignment, open-label trial

Recruitment: recruitment from local urban community in southeastern USA, using various media outlets

Setting: community, southeastern USA

Study start date: November 2014; Study end date: May 2016

Participants

Total N: 68

N per arm: Control group: 22; ENDS group: 46 (split into 2 non-randomized groups: BluCig 16 mg: 25; BluCig 24 mg: 21)

Inclusion criteria:

• Age 18+ years
• Current smoker of ≥ 5 cpd for ≥ 1 year
• No recent history of cardiovascular distress, COPD, cancer (any non-dermatologic), or uncontrolled diabetes mellitus
• Neither pregnant nor breastfeeding (verified)
• Absence of any major current psychiatric impairment, including current alcohol/drug abuse/dependence
• Current, active use of email
• At least some concern for health effects of smoking (> none at all on a Likert scale)
• Not used any ENDS product in the past 6 months
• Never purchased an ENDS product

Exclusion criteria:

• Use of non-cigarette tobacco products (e.g. cigarillos) in the last 30 days
• Current use of any smoking cessation medications
• Current enrolment in a smoking cessation treatment study

Women: 59.7%; mean age: 42.2; mean cpd: 15.3; heaviness of smoking (0 to 6): 2.9

EC use: Control: 9%; ENDS 16 mg group: 4%; ENDS 24 mg group: 33%

Motivation to quit smoking in next month (0 to 10): Control: 4.0; ENDS 16 mg: 5.0; ENDS 24 mg: 4.4

Interventions

EC: Cig-a-like

Intervention: At study start, choice of tobacco or menthol flavour Blu Starter Pack EC, with 16 mg/mL nicotine. Midway through study, the manufacturer of Blu altered the product and discontinued availability of the device, replaced with BluPlusþ, with 24 mg/mL nicotine. 3-week sampling period, given up to 7 cartridges at each of 3 weekly visits. Instructions on usage "kept minimal to preserve naturalistic intent." The study team suggested that ENDS could be used "as you wish, to cut down or quit smoking, help manage smoking restrictions, or both."

Control: own brand of cigarettes

Outcomes

Weeks 2, 3, 4, 8, 12, and 16

Carbon monoxide, NNAL

Other outcomes: cessation (< 6 months), product evaluation, EMA

Study funding

"Support was provided by NIH R21 DA037407 (to M.J. Carpenter), P01 CA200512 (to K.M. Cummings, M.J. Carpenter, and M.L. Goniewicz), UL1 TR001450, and P30 CA138313. M.L. Goniewicz's laboratory is supported via P30 CA016056. B.W. Heckman is supported via K12 DA031794 and K23 DA041616. T.L. Wagener's effort is partially supported by the Oklahoma Tobacco Research Center, which is funded by the Oklahoma Tobacco Settlement Endowment Trust."

Author declarations

"M.L. Goniewicz is a consultant/advisory board member for Johnson & Johnson. K.M. Cummings reports receiving a commercial research grant from and is a consultant/advisory board member for Pfizer Inc., and has provided expert witness testimony for various plaintiffs in lawsuits involving cigarette manufacturers. No potential conflicts of interest were disclosed by the other authors."

Notes

New for 2020 update. Listed as ongoing study NCT02357173 in 2016 review update. Additional data provided from authors

In all, 25 participants (54%) received the Blu Starter Pack (16 mg), and 21 participants (46%) received BluPlusþ (24 mg); no switches were made within participants. Note: this is not included in our analysis of higher v lower as assignment to nicotine dose was not done at random; 24 mg and 16 mg merged in our main analysis

Random sequence generation (selection bias)

Unclear risk

Quote: “Randomization to group was stratified by motivation to quit in the next 30 days (0–6 vs. 7–10 on a VAS scale) but proportioned 2:1 (ENDS:control) to increase precision estimates for e-cigarette uptake and usage.”

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not blinded and included non-active control

Blinding of outcome assessment (detection bias)
All outcomes

High risk

CO biochemically verified, but abstinence not used as outcome in this review, so rated based on adverse event reporting. Self-report, no blinding of participants

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Retention rate:

Week 4: control:19/22 (86%); ENDS 16 mg: 23/25 (92%); ENDS 24 mg: 20/21 (95%)

Week 16: control: 16/22 (73%); ENDS 16 mg: 19/25 (76%); ENDS 24 mg: 15/21 (71%)

Selective reporting (reporting bias)

Unclear risk

Not specified

Other bias

Low risk

Midway through the study, the manufacturer of Blu altered the product and discontinued availability of the device, replaced with BluPlusþ, with 24 mg/mL nicotine, again offered in both tobacco and menthol flavourings, and with improved battery duration (4-watt battery for both devices). In all, 25 participants (54%) received the Blu Starter Pack (16 mg), and 21 participants (46%) received BluPlusþ (24 mg); no switches were made within participants. The change in product (IRB approved) allowed us the unexpected opportunity to assess what impact, if any, the change in product design had on study outcomes. Note that the manufacturer, style of device, and packaging did not change, nor did our messaging to participants. The only difference was the strength of product. Thus, trial outcomes are reported across 3 groups: control versus 16 mg versus 24 mg ENDS. We have not rated this as high risk of bias as our analyses did not compare on nicotine strength and both nicotine arms were combined in our main analysis.

Methods

Design: RCT

Setting: USA

Recruitment: participants will be recruited nationally, but a subset (N = 120) will be recruited locally to allow for biomarker collection.

Study start date: 24 May 2018. Study end date: 8 September 2022

Participants

Total N: 638

427 = NJoy Pre-Filled Tank

211 = control

53.6% female; mean age 42.3 (SD = 11.5), 68.5% white (18.5% black; 14.1% Hispanic), 30.9% ≤ HS education, and moderately dependent (mean Heaviness of Smoking Index = 14.8; SD = 7.2)

Motivated to quit: limited interest in quitting smoking (mean motivation to quit on 0 to 10 VAS = 4.3; SD = 3.2; 24.1% making quit attempt in prior year). There is no requirement to quit smoking in this study, nor is there any requirement to use e-cigarettes.

Inclusion criteria: Age 21+; current smoker; regular use of email OR capacity to receive SMS text and internet access; additional smoking and health criteria determined at screening; minimal history of vaping

Interventions

E-cigarette: NJoy Pre-Filled Tank, 3 mL pre-filled tank, 15 mg/mL of nicotine. E-cigarette samples are inclusive of a battery and self-contained tanks of assorted flavours to last up to 4 weeks. Minimal instructions on use. Continue smoking their usual cigarettes as much or as little as they would like.

Control arm: no intervention. Participants will not receive an NJOY electronic cigarette to sample and will continue smoking their usual cigarettes as much or as little as they would like.

Outcomes

Baseline, 1, 2, 3, 4, 12, 24 weeks

1. Uptake. Mean days of use over 4-week sampling period (study enrolment through end of 4-week intervention)
2. Conversion. Percentage of participants who purchase an e-cigarette (study enrolment through end of 6-month follow-up)
3. Smoking cessation. Point prevalence abstinence from conventional smoking (6-month follow-up)
4. AEs categorised as mild, moderate, or severe. The AEs most commonly reported were: cough, headaches, increased phlegm. Information collected between study enrolment and 6-month FU.
5. SAEs information collected between study enrolment and 6-month FU.
6. Study product use at 4, 12, and 24 weeks

Participants will be asked to provide smoking diary data, captured electronically, daily for 4 weeks. More substantive phone assessment will track smoking and related behaviours at baseline (day 0) and +10, +17, and +24 days (weekly during initial 3 weeks, following brief lag for delays in product mailing), and at +1, +3, and +6 months.

Study funding

Funding: NCI R01 210625

Author declarations

Neither the tobacco industry nor any e-cigarette manufacturer provides support of any kind for this study.

Random sequence generation (selection bias)

Low risk

"Randomization occurred via stratified, mixed block design, stratifying on local vs. national enrollment and on desire to quit smoking: 0–6 vs. 7–10 on a VAS scale."

Allocation concealment (selection bias)

Low risk

Allocation was uploaded into REDCap meaning the research team were blinded to the sequence.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open-label with comparator group with minimal control. Randomization did not include any masking.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Self-reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

EC: 292/427 (68%)

Control: 163/211 (77%)

Selective reporting (reporting bias)

Low risk

All relevant prespecified outcomes provided by authors

Methods

RCT

12 week study. Randomization: computerized urn randomization

Setting: Brown University, USA

Participants

N = 35

HIV positive CC smokers, who are not ready or willing to quit smoking.

Mean age 54.4 [13.2] years, 30.1 % female, 62.9 % White

Inclusion Criteria: diagnosed with and engaged in care for HIV (defined as at least one HIV clinic medical appointment within the past six month period. At least 18 years of age. Smoke at least 5 cigarettes per day for longer than one year. Exhaled CO greater than 5 at BL

Exclusion Criteria: intention to quit smoking in the next 30 days. Using pharmacotherapy for smoking cessation. Using electronic cigarettes more than 2 days/week. Unstable medical or psychiatric condition (defined as hospitalization). Medical contraindications to nicotine (unstable angina, uncontrolled hypertension, or recent cardiovascular event, including hospitalization). Psychotic symptoms. Substance use disorder other than nicotine dependence.Past-month suicidal ideation or past-year suicide attempt. Pregnant or nursing.

Specific population characteristic: HIV positive

Motivated to quit smoking: No.

EC use at baseline: No.

Interventions

1) EC arm. Standardized Research Electronic Cigarette. 6-weeks of free EC (a standardized form developed by the NIH) and encouraged to use them whenever they would smoke a regular cigarette.

2) Control arm. Continue to smoke their usual brand of CC.

At week 6, all participants receive advice to stop smoking and referral to the RI Department of Health Quitline (a state-funded smoking cessation resource/program), if desired.

Outcomes

Baseline, weekly for 6 weeks, 12 weeks

Change, weekly to week 6: CC use, heart and lung function (e.g. BP).

Change from baseline to 6 weeks: CO, serum biomarkers, toxicant levels (e.g.NNAL), pulmonary function (Forced expiratory volume in 1 sec (FEV1)).

Study aims to assess: 1) the feasibility and acceptability of EC distribution in people with HIV; 2) the effect of EC use on smoking behaviors; and 3) the change in cardiopulmonary symptoms and biomarkers in smokers who transition from CC to EC use.

Study funding

Research reported in this publication was supported by the National Institute Drug Abuse (NIDA) of the National Institutes of Health under Award Number U01DA045514 (Cioe/Tidey). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was facili tated by the Providence/Boston Center for AIDS Research (P30AI042853). Research reported in this publication was supported by the Clinical Laboratory Core of the COBRE Center for Addiction and Disease Risk Exacerbation, funded by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20-GM130414.

Author declarations

Dr Eissenberg has been a paid consultant in litigation against the tobacco industry and the electronic cigarette industry and is named on one patent for a device that measures the puffing behavior of electronic cigarette users and on a patent application for a smartphone app that determines electronic cigarette device and liquid characteristics. The other authors have no conflicts of interest to declare.

Notes

Moved to new in 2026. Ongoing study added 2025

Random sequence generation (selection bias)

Low risk

"A computerized urn randomization was used to ensure the groups were balanced on sex at birth, Fagerström Test of Cigarette Dependence (Fagerstrom, 2012) (FTCD) score, (0–5 low; 6–10 high), and menthol/non-menthol usual brand."

Allocation concealment (selection bias)

Low risk

Participants and study staff were unaware of the group to which the participant has been assigned until allocation was complete. Once allocation complete not possible to blind as participants and study staff aware whether allocated a SREC or continuing to use own brand cigarette.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Interventions were not equally intensive. Not blinded. FU appointments (including blood samples) were equally intensive.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

CO and biomarkers (serum markers of inflammation and coagulation) were biochemically verified. FEV measured.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

SREC arm 13/17 (77%). Control 14/18 (78%) at FU (12 weeks)

Selective reporting (reporting bias)

Low risk

Physiologic measures (e.g. CO, FEV) reported to 6 weeks (SREC provided to 6 weeks). In supplementary materials reported as generalized estimating equations. Data not reported as raw numbers. Some outcomes reported as mean change in NCT record (CO, FEV1) to 6 weeks. Abstinence reported to 6 weeks. 12 week AE data reported.

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 to 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 months; interested in reducing cigarette consumption; no serious quit attempt in last month, 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 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; 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 months per NIDA Quick Screen; hand-rolled, roll-your-own cigarettes; allergy to propylene glycol/vegetable glycerin; pregnancy/breastfeeding

58.8% women; mean age 46.2; 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, and 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 randomization, 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 and 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, haematology 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

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, 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, 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

Methods

RCT. 2 group open-label RCT w/ blinded outcome ascertainment

Setting: community setting, New South Wales, Australia.

Participants

1045 adults who smoked daily, were willing to quit smoking, and were receiving a government pension/allowance (proxy for social disadvantage).

Interventions

Nicotine EC 524 (2 died 522 included in primary analysis)

NRT single form (gum OR lozenge) 524 (1 died 523 included in primary analysis)

Nicotine EC: Participants received up to an 8-week supply of nicotine e-liquid to use in 2 vaporizing devices: i) a tank device (Innokin Endura T18) with 18 mg/mL nicotine freebase liquid and ii) a pod device (alt.) with 40 mg/mL nicotine salt liquid. Each type of e-liquid was provided in 3 flavors (tobacco, menthol, and fruit)for the first 4-week supply. Participants could choose to use 1 orbothdevices and select between 1 or multiple flavors in their second 4-week supply. 8 week intervention. All participants received behavioral support via automated text messages for 5 weeks comprising 93 general and 19 treatment-specific messages. Final telephone interview ($40 AUD/$26 USD reimbursement). (CO) breath test ($40 AUD/$26 USD reimbursement)

NRT single form (gum or lozenge): This is either nicotine gum OR lozenge. "Choice of 4 mg of nicotine gum or lozenges (mint flavor) at baseline for their first 4-week supply. During check-in calls, they could choose to switch products for their second 4-week supply. They received up to an 8-week supply of gum or lozenges (maximum daily dosage, 15 pieces)." 8 week intervention. All participants received behavioral support via automated text messages for 5 weeks comprising 93 general and 19 treatment-specific messages. Final telephone interview ($40 AUD/$26 USD reimbursement). (CO) breath test ($40 AUD/$26 USD reimbursement)

Outcomes

2 month (8 week) intervention. 7 month FU

Participants self-reported 6-month continuous abstinence asked to complete a carbon monoxide (CO) breath test.

Study funding

Project Grant 1127390 from the Australian National Health and Medical Research Council. All study medications were purchased by the research team.

Author declarations

Disclosure forms are available with the article online.

Alexandra Aiken, Anthony Shakeshaft, Bridget Howard, Daniel Barker, Felix Naughton, Michael Farrell, Nick Zwar, Piotr Tutka, Richard Mattick, Robyn Richmond, Veronica Boland, and Wayne Hall do not have any interests to disclose at this time.

Colin Mendelsohn book sales and honoraria for lectures. Stop Smoking Start Vaping, published by Aurora Press. Support for attending meetings or other travel. Pfzer Australia. Wholelife Pharmacy & Healthfoods. World Vape Show.

Coral Gartner employed by the University of Queensland.

Dennis Petrie employed by Monash University. Grants from Australian Research Council, Department of Health, Australian Government, Department of Social Services, Australian Government, National Health and Medical Research Council.

Hayden McRobbie employed University of New South Wales. Grant National Health and Medical Research Council.

Ron Borland grants from National Health and Medical Research Council and National Institutes of Health.

Ryan Courtney grants from Department of Health, Australian Government, National Health and Medical Research Council, National Heart Foundation of Australia.

Notes

Moved to new in 2026

Random sequence generation (selection bias)

Low risk

"participants were randomly assigned to the VNP or NRT group in a 1:1 ratio. Allocations used a permuted block design(block sizes of 12 and 16) in a pre-generated randomization list embedded in the contract research organization’s data collection system (UNICOM Intelligence). Only the independent statistician at the contract research organization had access to the pre-generated randomization list."

Allocation concealment (selection bias)

Low risk

Contract research organization interviewers were blinded to participants’ treatment allocations at 7-month follow-up. Participants and Trial Coordinating Centre staff could not be blinded to treatment allocation. Data analysis was completed with blinding to treatment groups.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Interventions equally intensive. Participants and Trial Coordinating Centre staff could not be blinded to treatment allocation.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Self reported abstinence was CO confirmed.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

EC arm: 449/524 (86%) completed 7 month FU. NRT arm 417/524 (80%) completed 7 month FU.

Selective reporting (reporting bias)

Low risk

Protocol: 6 mth abstinence (CO confirmed); self-reported 7 day pp abstinence; reduction in number of CC smoked; AEs; SAEs; use of study product at FU; lapses; change in tobacco withdrawal symptoms; change in financial stress; change in mental distress; use of quit services or products (quitline, quit aids); other health resources used; changes in respiratory symptoms; EC user experience.

Other bias

Low risk

Randomization and masking occurred as per protocol (trial fidelity) with the exception of a single protocol deviation. The protocol deviation resulted in 10 participants being incorrectly assigned to the VNP group
by default. The University of New South Wales HREC approved the corrective action of excluding these participants from analyses (see Appendix A in the Study Protocol and Statistical Analysis Plan), leaving a total sample of 1045participants to analyze after removal of 3 participants who had died (as per the Russell Standard).

Methods

RCT. A multicentre, cluster-randomized controlled trial
Setting: 32 centres across 6 areas in Great Britain: Scotland; Wales; London; South-East England; South-West England and East England

Participants

Enrolment: 477.

Inclusion criteria: currently accessing homeless centre services and actively engaging with the service; > 18 years; self-reported daily smoking, then biochemically verified

Exclusion criteria: never- and ex-smokers; currently using a smoking cessation aid; unable to provide written consent; not known to centre staff; allergic to any of the e-liquid ingredients (EC arm only); pregnant

Interventions

EC: refillable

Two-arm cluster randomised controlled trial. 32 homeless centres.

Arm 1: EC arm. 16 clusters. 239 participants
Delivery of the EC intervention was as per feasibility study. Centre staff provided EC arm participants with a tank-style refillable EC starter kit (e.g. the PockeX as used in feasibility study or similar model determined via our PPI work), a choice of nicotine strength e-liquids (12 mg/mL and 18 mg/mL) and flavours (tobacco, menthol or fruit) and an EC fact-sheet. E-liquids (5 x 10 mL bottles per week) will be supplied for 4 weeks at weekly intervals by centre staff.

Arm 2: Control/comparator group (usual care). 16 centres. 238 participants.
Usual care (UC). Very brief advice (VBA) to quit (in the form of an ‘NHS choices’ leaflet adapted for this population as used in feasibility study) and signposting to the local SSS.

All participants (intervention and control) were offered a GBP 15 Love2Shop gift card (which could not be used for tobacco or alcohol purchases) for each follow-up appointment attended.

Outcomes

Baseline, 4, 12, and 24 weeks

Primary outcome measure

Current primary outcome measure as of 27/07/2022:
Sustained CO-validated smoking cessation at 24 weeks using the Russell Standard for cessation trials and intention-to-treat analysis (i.e. no more than 5 cigarettes since 2 weeks from baseline, validated by expired CO < 8 ppm

Secondary outcome measures

Current secondary outcome measure as of 27/07/2022:

1. Smoking reduction at 24 weeks
2. 7-day point prevalence quit rates at 4, 12, and 24 weeks self-reported and validated by expired CO < 8 ppm
3. Changes in the frequency of risky smoking practices (e.g. sharing cigarettes, smoking discarded cigarettes)
4. Cost-effectiveness of the intervention measured using a service use questionnaire and the EQ-5D-5L (4, 12, 24 weeks)
5. Fidelity of intervention implementation
6. Mechanisms of change measured quantitatively via questions (e.g. attitudes and perceptions of e-cigs)
7. Contextual influences and sustainability telephone interviews

Study funding

This study was funded by the National Institute for Health and Care Research (NIHR132158). The views expressed are those of the authors and not necessar ily those of the NIHR or the Department of Health and Social Care.

Author declarations

FP, AF, RB, EW, LM, DR, AV, CM, JL, JB, AE, PH, AT, SP, JL, BG and SC declare no competing interests. LD has acted as a paid consultant for Johnson & Johnson who manufacturer smoking cessation medications. KS has acted as a paid consultant for ThriveTribe who deliver stop smoking services and Pharmastrat Ltd a healthcare consulting company who deliver stop smoking services. CN has received an honorarium from Vox Media for filming a ’nicotine explainer’ on the role of nicotine in addiction. LB is seconded part time to Scottish Government as their Chief Social Policy Adviser and in that role serve as Senior Responsible Officer for the Place and Wellbeing Programme

Notes

New to included studies in 2026. Added to ongoing studies in 2022.

Random sequence generation (selection bias)

Low risk

Randomisation of clusters (1:1; using various block sizes) to EC or usual care (UC) was generated in Stata by the trial statistician, concealed from researchers. "Centres (clusters) were randomly allocated (1:1) to the EC intervention (n = 16) or UC (n = 16) using a predefined randomisation list generated by the trial statistician using Stata version 17. To ensure balance between arms, the randomisation list consisted of block sequences of varying size, withheld from the research team to avoid allocation bias. The tested and validated list was automated into REDCap (an electronic data capture tool hosted at the trials unit Kings College London) by the database programmer. Randomisation was not stratified by region as this may have led to selection bias (i.e. where researchers could predict allocation of final centres based on previous allocations in that region)." "One centre withdrew consent after randomisation but before recruitment commenced and was therefore excluded and replaced with a new centre (randomised using a biased coin approach)."

Allocation concealment (selection bias)

Low risk

"Researchers and centre staff were blinded to allocation until after centres had consented to participate in the trial and expressions of interest (EOIs) from participants had been gained (where possible). Arm allocation was revealed to centre staff during intervention training and concealed to participants until after consent and baseline assessment."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Similar face to face contact. Interventions different intensity.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

CO verified abstinence

Incomplete outcome data (attrition bias)
All outcomes

High risk

EC arm 162/239 (68%). UC arm 111/236 (47%)

Selective reporting (reporting bias)

Low risk

Clinical record registered protocol. Outcomes reported.

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

Two study phases.

Inclusion criteria differ per study phase:

Cravo 2016 (short-term RCT), inclusion: 21 to 65 years; BMI 18 to 35 kg/m²; 5 to 30 CPD for ≥ 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); 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; relevant illness history; history of drug or alcohol abuse; lung function test or vital signs considered unsuitable; 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 to 20 cpd (56% intervention, 62% control); mean FTND: most moderate (57% intervention, 54% control)

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 2 different e-liquids, which differed solely in their flavour: a menthol-flavoured e-liquid with 2.0% nicotine (2.7 mg nicotine/capsule) and a tobacco-flavoured 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 cartomizer 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)
• 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), haemoglobin, haematocrit (PCV), mean cell volume (MCV), mean cell haemoglobin (MCH), mean cell haemoglobin 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 others from Fontem Ventures B.V. during the conduct of the study. Dr. Bush reports others 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 others 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 others 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

This study has been renamed to Cravo 2016*. Cravo 2016* reports an RCT.

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 2016), were invited to participate in 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*."

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 and 101/102 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)

Methods

Design: non-blinded, within-participant cross-over

Recruitment: advertisements placed in newspapers, online, and in local vape shops, and received CAD 295 for participating in the study

Setting: Kitchener−Waterloo and Toronto, Ontario, Canada

Study start date: September 2015. Study end date: NR

Participants

Total N: 48

29.2% female; mean age 35.9 (SD 11.7); mean cpd NR; dual EC users at baseline; not motivated to quit

Inclusion criteria: > 18+ years; dual users of tobacco cigarettes and EC

Exclusion criteria: serious intentions to quit smoking in the next 6 months; tobacco products, NRT, any smoking cessation medications, participation counselling programmes for smoking cessation in the past 7 days; serious cardiac health issues; heart attack or stroke within the last 3 months; cancer within the last year; asthma, chronic obstructive pulmonary disease, a seizure disorder, or any life-threatening medical conditions with a prognosis of ≤ a year; history of psychosis, schizophrenia, bipolar disorder, or suicidal thoughts

Interventions

EC: own choice (mainly tank)

3 consecutive 7-day periods in which the use of tobacco cigarettes and e-cigarettes was experimentally manipulated

4 study conditions: dual use (e-cigarette and tobacco cigarette); tobacco cigarette; E-cigarette; no product use

Virtually all dual users reported using tank systems (92%) and e-cigarettes with nicotine (94%).

To control for order effects, participants were randomly assigned to 1 of 2 condition orders, A or B.

Following the baseline condition of dual use:

Group A participants switched to e-cigarette use, then to tobacco cigarette use, and finally to no product use.

Group B participants switched to tobacco cigarette use, then to e-cigarette use, and finally to no product use.

Outcomes

Baseline (visit 1) and after each of the 7-day periods (visit 2 (week 1), visit 3 (week 2), visit 4 (week 3))

Carbon monoxide

Urinary concentration of cotinine

Urinary concentrations of 1-hydroxypyrene (1-HOP) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)

Study funding

This research was supported by an Ontario Ministry of Health and LongTerm Care Health System Research Fund grant (#06697 awarded to DH). Additional support was provided by the Canadian Institutes of Health Research (CIHR), the Vanier Canada Graduate Scholarship (CDC), a CIHR and Public Health Agency of Canada, Applied Public Health Chair (DH), and an Ontario Institute for Cancer Research Investigator Award (GTF).

Author declarations

MLG reports grants from and served as an advisory board member to pharmaceutical companies that manufacture smoking cessation drugs. DH has provided paid expert testimony in tobacco litigation on behalf of governments and class-action plaintiffs on issues related to tobacco product science and regulation. The other authors have no competing interests to declare.

Random sequence generation (selection bias)

Unclear risk

No details of randomization method given

Allocation concealment (selection bias)

High risk

No blinding

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All followed up

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Methods

Design: RCT

Recruitment: participants were recruited to 10 clinical sites via site databases and using IRB-approved radio and print ads.

Setting: USA

Study start date: 17 January 2017. Study end date: 6 November 2018

Participants

Total N: 450

EC Test group 1: classic (tobacco) = 150

EC Test group 2: menthol = 150

Control = 150

Inclusion criteria: smoked ≥ 10 years, smoked an average of ≥ 10 manufactured cigarettes pd for 12 months. Willing and able to replace their cigarettes for 12 weeks with the assigned test e-Vapor product. Age 30 to 65 years.

Exclusion criteria: health condition that would jeopardize the safety of the participant or impact the validity of the study results; currently taking medication for depression, asthma or diabetes

For a full list of inclusion and exclusion criteria, see publication.

Female 51%; mean age 44.4 (SD 9.73); mean CPD 17.6 (SD 4.95)

Interventions

EC: cartridge

Arm 1 Experimental: Test 1 EC classic (tobacco)

Exclusive ad libitum use of test product MarkTen Bold Classic (test product 1) 4.0% nicotine by weight without use of any other type of tobacco/nicotine-containing product, for the entire duration of study participation. This replaced test e-Vapor Product NuMark LLC, MarkTen® XL Bold CLASSIC* (as no longer sold).

Arm 2 Experimental: Test 2 EC menthol

Exclusive ad libitum use of test products MarkTen Bold Menthol (test product 2) 4.0% nicotine by weight

Arm 1 and 2 participants were to completely replace their cigarettes with the test EVPs. Participants had 7 days to switch to EVPs prior to clinic visits.

Arm 3 No Intervention: control

Assigned to continue smoking their own brand cigarettes under ad libitum conditions

Outcomes

Baseline, weeks 1, 3, 6, 9, and 12

Baseline weeks 1, 6 and 12 (blood and urine). Weeks 1, 3, 6, 9, and 12 (eCO)

Lung function was assessed at screening, baseline, at week 12 of study 1, (and at weeks 18 and 24 of study 2): FEV1, per cent of predicted FEV1, FVC, percent of predicted FVC, FEV1/FVC, and percent of predicted FEV1/FVC, forced expiratory flow at 25% to 75% (FEF).

NNAL urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (ng/g creatinine), WBC, COHb, HDLC

Adverse events (AEs) and medications were recorded and monitored throughout the study.

Study funding

This study was funded by Altria Client Services LLC.

(Altria is the parent company of Philip Morris USA (producer of Marlboro cigarettes), John Middleton, Inc., U.S. Smokeless Tobacco Company, Inc., and Philip Morris Capital Corporation.)

Author declarations

All authors were employees of Altria Client Services LLC at the time of the study.

Notes

Paper reported 2 studies; only 1 study was eligible.

New to 2022 update

Random sequence generation (selection bias)

Unclear risk

Randomised – no further information in paper or supplementary materials

Allocation concealment (selection bias)

Unclear risk

No detail provided

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open-label

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No detail provided

Incomplete outcome data (attrition bias)
All outcomes

Low risk

< 50% attrition

Selective reporting (reporting bias)

Low risk

Outcomes reported

Methods

Design: 3-arm RCT

Recruitment: community

Setting: Canada

Study start date: November 2016. Study end date: September 2019

Participants

Total N: 376; nicotine e-cigarettes = 128; non-nicotine e-cigarettes = 127; counselling (control) = 121

47% female; mean age 52.66; mean cpd 21; mean FTND 6 (SD 2)

Motivated to quit: yes

Inclusion criteria: active smoker, ≥ 10 CPD for past year; ≥ 18 years; motivated to quit according to the Motivation To Stop Scale (MTSS) (level 5 or higher); provide informed consent in English or French; available for follow-up (1 year)

Exclusion criteria: medical condition with a prognosis < 1 year; current or recent cancer (≤ 1 yr in remission); pregnancy/breastfeeding; current/ recent use of any pharmacotherapy or behavioural therapy for smoking cessation (e.g. NRT, bupropion, varenicline, or counselling); any EC use (nicotine/non-nicotine) in past 60 days, or ever use of any EC ≥ 7 days consecutively; psychosis, schizophrenia, or bipolar disorder; ≤ 1 month following myocardial infarction, life-threatening arrhythmia, severe or worsening angina pectoris, or cerebral vascular accident; illegal drug use past yr (excluding marijuana); planned use of tobacco products other than conventional cigarettes (e.g. cigarillos, cigars, snuff, shisha, etc.) or marijuana during the study period

Interventions

EC: Cig-a-like

Nicotine e-cigarettes plus counselling:

12 weeks of e-cigarettes. Rechargeable base with prefilled, disposable, tobacco-flavoured liquid cartridges (15 or 0 mg nicotine/mL), which were produced specifically for use in clinical studies (purchased from NJOY Inc, Scottsdale, Arizona). 21 cartridges at baseline with additional cartridges supplied as needed. Nicotine and non-nicotine e-cigarettes were identical in appearance. Instructed to be used as desired. No schedule for e-cigarette tapering, but participants were aware that they would return their e-cigarettes after 12 weeks.

Participants received individual smoking cessation and relapse prevention counselling (minimum 30 minutes at baseline, 10 minutes during telephone follow-ups, and 15 to 20 minutes at clinic visits). Individualized quit plans.

Non-nicotine e-cigarettes plus counselling:

As above with 0 mg nicotine/mL in liquid cartridge

Counselling (control):

Participants received individual smoking cessation and relapse prevention counselling (minimum 30 minutes at baseline, 10 minutes during telephone follow-up, and 15 to 20 minutes at clinic visits). Individualized quit plans.

Outcomes

Follow-up was conducted by telephone at weeks 1, 2, 8, and 18, and at clinic visits at weeks 4, 12, 24, and 52.

Self-reported smoking (7-day recall), adherence, and adverse events (AEs) were assessed during follow-up contacts

Biochemically-validated 7-day point prevalence smoking abstinence at 4, 12, and 24 weeks, defined as self-reported abstinence in the past 7 days with exhaled carbon monoxide < 11 ppm

At baseline: cpd; FTND; Glover-Nilsson Smoking Behavioral Questionnaire (to assess behavioural dependence on smoking); and Beck Depression Inventory II (BDI-II; to assess depressive symptoms)

Study funding

This trial was funded by the Canadian Institutes of Health Research (CIHR; funding reference No. 133727 and 155969). Both nicotine e-cigarettes and non-nicotine e-cigarettes were purchased from NJOY Inc (Scottsdale, Arizona)

Author declarations

Dr Eisenberg reported receiving educational grants from Pfizer Inc for providing continuing medical education in cardiology. Dr Wilderman reported receiving financial compensation from Pfizer Inc for his involvement in a smoking cessation study using varenicline. Dr Filion reported receiving salary support from the Fonds de Recherche du Quebec, a William Dawson Scholar award from McGill University, and personal fees from Institut National D’excellence en Santé et Services Sociaux. No other disclosures were reported.

Notes

New cessation and adverse event data for 2021 update. Previously listed as NCT02417467 (included with SAE data only)

Random sequence generation (selection bias)

Low risk

Eligible participants were randomized via an online central randomization system. The system used a computer-generated randomization list containing permuted blocks of 6 and 9, stratified by centre.

Allocation concealment (selection bias)

Low risk

Participants, investigators, and study personnel were blinded to nicotine content in the e-cigarette groups. Quote: "Eligible participants were randomized via an online central randomization system. The system used a computer-generated randomization list containing permuted blocks of 6 and 9, stratified by center."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants, investigators, and study personnel were blinded to nicotine content in the e-cigarette groups.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Participants, investigators, and study personnel were blinded to nicotine content in the e-cigarette groups.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Low numbers lost to follow-up, treated as ITT

Selective reporting (reporting bias)

Low risk

Due to a prolonged and unforeseen delay in e-cigarette manufacturing, enrolment was paused on 27 September 2019, and then terminated on 14 November 2019. Given reduced power, the timing of the primary endpoint was changed from 52 weeks to 12 weeks on 04 December 2019. No 12-month follow-up but this was for manufacturing reasons and was reported

Methods

Design: RCT

Setting: USA

Participants

11

EC = 4; NRT = 7

Veterans who meet DSM criteria for tobacco use disorder

18% female; mean age 52.6; mean cpd 26.4; mean FTND 7.5; 64% African American

Interventions

EC type: cartridge

Arm 1: Electronic cigarettes 16 mg cartridge. Arm 2: NRT (16mg patch)

Participants attended thrice-weekly visits during the first 2 weeks (week 1-“baseline” with participants smoking ad libitum) and attended 5 visits during the third week (week 3-“efficacy” with participants smoking as little as possible while using NRT or E-cigs)

Outcomes

Baseline, 3 visits during week 1 and week 2, 5 visits during week 3.

Self-reports of cigarettes smoked in last 24 hours, confirmed by breath CO levels and salivary cotinine

Study funding

This work was conducted at and supported by resources at the MEDVAMC, including a MEDVAMC Research Enhancement Seed Grant.

Author declarations

NS

Notes

Study information extracted from conference abstract only

Random sequence generation (selection bias)

Unclear risk

Quote: “Veterans were randomized to either NRT (16 mg patch; N = 7) or E-cigs (16 mgcartridge; N = 4).” No further information provided

Allocation concealment (selection bias)

Unclear risk

No information provided

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

No blinding, but active interventions provided to both arms

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "CO levels and salivary cotinine were recorded during each visit.' 'Self-reports of cigarettes smoked in last 24 h, and this was confirmed by significant reductions of breath CO levels by NRT (t = 3.7, P = 0.01) and E-cigs (t = 3.9, P = .03)."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information provided

Selective reporting (reporting bias)

Unclear risk

No protocol or clinical trial record available to determine whether all prespecified outcomes were reported

Methods

Design: RCT

Setting: Netherlands, online

Recruitment

Study start date: recruited March 2020 to July 2020

Participants

N = 331

Intervention = 157; control = 174

% female: 59.8%; mean age: 49.0 (SD 13.2); mean CPD: 12.6 (cigarettes per week 83.3/7); mean FTND: 3.8 (2.6) Intervention 4.1 (2.6), Control 3.5 (2.5)

Inclusion criteria were that participants are at least 18 years old, have sufficient command of the Dutch language, have necessary internet literacy to use the intervention, have smoked tobacco in the past 7 days, and are motivated to quit tobacco smoking within 5 years.

EC use at baseline: overall 33/331 (10%). Intervention 17 (10.8); control 16 (9.2)

Motivated to quit: yes. Within next 5 years

Interventions

Digital computer-tailored smoking cessation intervention

Arm 1: intervention condition

Participants in the intervention condition will receive tailored information on e-cigarettes based on 5 items. The computer-tailored intervention will be based on the I-Change model.

Arm 2: control condition

The control condition will not receive tailored information about e-cigarettes.

Outcomes

Baseline, 6 months

Number of tobacco cigarettes smoked in the past 7 days; average number of tobacco cigarettes smoked per day; 7-day point prevalence tobacco abstinence; 7-day point prevalence e-cigarette abstinence

Smoking cessation methods; determinants of decision-making; process evaluation

Study funding

National Institute for Public Health and the Environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM)

Author declarations

No conflicts of interest declared

Random sequence generation (selection bias)

Unclear risk

Stated randomized, but the process was not described in the paper, protocol, or record

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Online, so participants would be unlikely to be aware of other participants

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Self-reported abstinence

Incomplete outcome data (attrition bias)
All outcomes

Low risk

139/157 intervention

138/174 control

Selective reporting (reporting bias)

Low risk

Stated investigating the hypothesis of whether intervention arm smokeless at 6 months

Methods

Design: double-blind RCT

Recruitment: people who smoke were recruited from an outpatient opioid-maintenance clinic in West Virginia, USA

Setting: outpatient opioid-maintenance clinic in West Virginia, USA

Study start date/Study end date: not reported

Participants

Total N: 25; N per arm: placebo (non-nicotine): 11; active (18 mg/mL nicotine): 14

Inclusion criteria:

• ≥ 18 years of age
• Report smoking ≥ 10 cpd for ≥ 1 year
• Report a current interest in quitting smoking

Exclusion criteria:

• Reported regular use of any nicotine/tobacco product other than cigarettes, including EC, or were already engaged in attempts to quit smoking

Inclusion based on specific population characteristics: people who smoke who were currently receiving a buprenorphine/naloxone combination in sublingual form, and had maintained sobriety from opioids and all other illicit substances for at least 90 consecutive days as verified via urinalysis

73.0% women; mean age 32.5; mean cpd 22; mean FTND 5.8

Motivated to quit: Quit ladder score (range 1 to 10): 5.6 average

Interventions

EC: Refillable

Compared nicotine (18 mg/mL) to non-nicotine EC

Second-generation EC consisted of the eGo-T battery (900mAh, 3.3 V constant output) (Joyetech; Irvine, CA) and the Kanger mini Protank-II, 1.5 ml Pyrex glass tank with a drip tip and atomizer head coils (KangerTech; China), choice between tobacco (n = 15) and menthol (n = 10) flavoured liquid (2-week supply). Participants were then trained in EC device operation, including assembly, liquid filling, manual battery operation, and cleaning/storage. Practised puffing on EC in the presence of a team member, and asked questions if needed. Participants instructed to use their ECIG ad libitum every day for 2 weeks.

Outcomes

Baseline (day 1), 14 days, 28 days for clinic measures. Data also collected via text messages over 2-week intervention period

Withdrawal/side effects: every evening during the 2-week intervention period, participants rated a variety of effects possibly experienced as a result of nicotine/tobacco withdrawal and/or use of the ECIG: nausea, dizziness, throat irritation/soreness, cough, dry mouth, headache, shortness of breath, irritability/frustration/anger, craving/urge to smoke, and other. Each item was rated on a continuous scale that ranged from 0 (not at all) to 100 (extremely).

Expired air CO

Other outcomes: self-reported cigarette and EC use; readiness to quit at day 1, 14, and 28

Study funding

Not reported

Author declarations

Not reported

Notes

New for 2020 update

Random sequence generation (selection bias)

Unclear risk

Quote: “Using a mixed factorial, simple randomization, double-blind study design, participants were assigned to one of two ECIG conditions…” (No further details given)

Allocation concealment (selection bias)

Unclear risk

No details on allocation given

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: “double-blind study design”, no further detail given

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: “double-blind study design”, no further details given

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: “…80.6% completed the two-week intervention (n = 14 active; n = 11 placebo), and 70.9% also completed the follow-up session (n = 13 active; n = 9 placebo).”

Active follow-up completion rate: 13/14 = 93%; placebo follow-up completion rate: 9/11= 82%

N.B. 6 participants were disqualified post-randomization:
Quote: “Of those individuals who were screened for the study, 93.9% were enrolled (n = 18 active; n = 13 placebo); two individuals who were ineligible provided an expired air CO level < 10 ppm. Six of the enrolled participants (n = 4 active and n = 2 placebo; n = 5 tobacco flavour and n = 1 menthol flavour) were disqualified for responding to 7 or fewer days of text messages.”

Selective reporting (reporting bias)

Unclear risk

All measures listed were reported: self-reported cigarette use, text message-based cigarette use, e-cig use, expired air CO, readiness to quit ladder, withdrawal/side effects

No study protocol or clinical trial record available to confirm all intended outcome measures were reported.

Methods

Design: prospective, randomized controlled trial with a parallel, non-randomized preference cohort

Recruitment: participants were recruited from local advertisements, smoking cessation databases, and visits to local businesses, as well as via the Scottish Primary Care Research Network

Setting: single tertiary research centre, UK

Study start date: August 2016; Study end date: July 2018

Participants

Total N: 114 in “final evaluable dataset” (145 recruited into the trial)

N per arm: tobacco cigarettes (TC): 40; EC nicotine (16 mg): 37; EC nicotine-free: 37

Inclusion criteria: ≥ 18 years of age who had smoked ≥ 15 cigarettes/day for at least 2 years; free from established CV disease, diabetes, and chronic kidney disease (and not on medication for those conditions); willing to stop tobacco cigarettes for period of study if required and not to use EC if required.

Exclusion criteria: pregnant/breastfeeding; not abstaining from sex or using effective contraception; medication for CVD; history of CVD (excluding hypertension), diabetes, active malignancy or chronic renal disease; nut allergy; participation in another clinical trial (other than observational trials and registries) with an investigational product and/or intervention within 30 days before visit 1.

65.4% women; mean age 46.9; mean cpd 18.7

Motivated to quit: TC group: no; EC nicotine (16 mg): yes; EC nicotine-free: yes

Interventions

EC: Cig-a-like

EC nicotine (16 mg) arm: EC containing 16 mg nicotine (Vapourlites Starter Kit with XR5 16 mg nicotine cartomizer; Vapourlites, Peterlee, United Kingdom)

EC nicotine-free arm: nicotine-free EC plus nicotine flavouring (Vapourlites Starter Kit with 0 mg nicotine cartomizer)

(non-randomized) TC arm: continued their usual daily smoking habits and did not use EC for the 4-week period of the trial

Outcomes

Week 4

Adverse events and biomarkers: BP, heart rate, adverse events

Other outcomes measured: endothelial function, oxidised low-density lipoprotein, high-sensitivity C-reactive protein, tissue plasminogen activator, and platelet activation inhibitor-1

Study funding

"The VESUVIUS (Vascular Effects of Regular Cigarettes Versus Electronic Cigarette Use) trial was funded by the British Heart Foundation (grant PG/15/64/31681); and supported by Immunoassay Biomarker Core Laboratory, University of Dundee, the Tayside Medical Sciences Centre, and the NHS Tayside Smoking Cessation Service. The funder had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit for publication."

Author declarations

"Dr. Donnan has received research grants from AbbVie, Shire, and Gilead Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose."

Notes

New for 2020 update

Random sequence generation (selection bias)

Low risk

Consented participants who were willing to quit smoking were randomized to one of the EC arms in a 1:1 fashion using a centrally controlled web-based good clinical practices– compliant randomization system to either: 1) EC containing 16 mg nicotine; or 2) nicotine-free EC plus nicotine flavouring because it was considered by the institutional ethics committee as ethically unacceptable to randomize those who were willing to quit smoking into a smoking arm. Those unwilling to consider quitting smoking continued in the parallel preference TC cohort.

Allocation concealment (selection bias)

Low risk

Central randomization

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not specified

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Not blinded and AE/SAE data are self-report only. For other outcomes, low risk as objectively measured:

Quote: “Patients fasted overnight and measurements were conducted at baseline and 1 month according to the International Brachial Artery Reactivity Task Force guidelines (19) by a single operator (M.H.) blinded to study allocation at a single site.”

“Pulse wave velocity and augmentation index were measured at baseline and 1 month by a single operator (M.H.) blinded to study allocation.”

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Number randomized not provided per group

Quote: “A total of 145 patients were recruited into the trial. A final number of 114 patients (40 TC, 37 EC-nicotine, 37 EC-nicotine-free) completed both visits.”

Selective reporting (reporting bias)

Low risk

Clinical trial record lists: change in FMD; change in oxidized LDL; change in PAI-1; change in hs-CRP; change in pulse wave velocity; change in tissue plasminogen activator; change in augmentation index @ 75 bpm

All reported in the paper

Methods

Design: multicentre, pragmatic randomized controlled trial to examine the efficacy of e-cigarettes compared with nicotine replacement therapy

Recruitment: participants attending UK stop-smoking service and via social media

Setting: UK National Health Service stop-smoking services

Study start date: 1 April 2015; study end date: 31 March 2018

Participants

Total N: 886

N per arm: EC: 439; NRT: 447

Inclusion criteria:

• Adults who smoke (aged 18 years or over) with no strong preference to use or not to use nicotine replacement or e-cigarettes, and were currently not using either type of product
• Able to read/write/understand English

Exclusion criteria:

• Pregnant or breastfeeding
• Strong preference to use or not use NRT or EC, currently not using either type of product

48% women; median age 41; median cpd 15 ; mean FTND 4.6; 41.5% reported past use of ECs

Motivated to quit: not reported

Interventions

EC: Refillable

NRT: Informed of range of NRT products (patch, gum, lozenge, nasal spray, inhalator, mouth spray, mouth strip, and microtabs) and selected preferred product, encouraged to use combination. Participants free to switch products. Supplies provided for up to 3 months

EC: Starter pack (1 Kit, Aspire UK) provided along with 30 mL bottle of Tobacco Royale flavour e-liquid, concentration 18 mg/mL. Participants showed how to use and asked to purchase future e-liquid online or from local vape shops and to buy different EC device if the 1 provided did not meet their needs. Encouraged to experiment with e-liquids of different strengths and flavours. If unable to obtain own supply, provided with further 10-mL bottle (not proactively offered). Oral and written info on how to operate EC

Both arms received multi-session behavioural support as per UK stop-smoking service practice (one-to-one sessions weekly with local clinicians, exhaled CO monitored for at least 4 weeks post-TQD); signed behavioural contract not to use other therapy for at least 4 weeks

Outcomes

Weeks 4, 26, and 52

Cessation: sustained and biochemically validated CO < 8 ppm

Adverse events and biomarkers: “adverse reactions”: presence or absence of nausea, sleep disturbance and throat and mouth irritation, and respiratory symptoms (presence or absence of shortness of breath, wheezing, coughing, and phlegm), death

Other outcomes measured:

• Use and ratings of trial products
• Rating of withdrawal symptoms (weeks 1 to 6)
• Reduction of cigarette consumption
• Cost-effectiveness

Study funding

“Supported by the National Institute for Health Research (NIHR) Health Technology Assessment Programme (project number, 12/167/135) and by a grant (A16893) from the Cancer Research UK Prevention Trials Unit.”

Author declarations

From ICJME disclosure forms: “Miss Natalie Bisal has nothing to disclose. Dr. Dawkins reports personal fees from Johnson & Johnson, outside the submitted work; Dr. Goniewicz reports personal fees from Johnson and Johnson, outside the submitted work; Dr. Hajek reports grants and personal fees from Pfizer, outside the submitted work; Ms. Li reports grants from NCCHTA, during the conduct of the study; Dr. McRobbie reports grants from NIHR HTA programme, during the conduct of the study; personal fees from Pfizer, personal fees from Johnson & Johnson, outside the submitted work; Dr. Myers Smith has nothing to disclose. Dr. Parrott has nothing to disclose. Dr. Pesola has nothing to disclose. Mrs Anna Phillips-Waller has nothing to disclose. Dr. Przulj reports grants from Pfizer, outside the submitted work; Dr. Ross has nothing to disclose. Dr. Sasieni has nothing to disclose. Ms. Wu has nothing to disclose."

Notes

New for 2020 update, listed as ongoing study ISRCTN60477608 in 2016 review update

Note higher use of allocated product at 12 m in intervention group compared to control group: “Among participants with 1-year abstinence, 80% (63 of 79) were using e-cigarettes at 52 weeks in the e-cigarette group and 9% (4 of 44) were using nicotine replacement in the nicotine-replacement group.”

Random sequence generation (selection bias)

Low risk

Quote: “Randomization took place on the quit date to limit differential dropout. Randomization sequences (1:1 ratio in permuted blocks of 20, stratified according to trial site) were generated with the use of a pseudorandom number generator in Stata software and were embedded into an application that only revealed the next treatment assignment once a participant had been entered into the database.”

Allocation concealment (selection bias)

Low risk

Refer to 'Random sequence generation'

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Not blinded, but as both arms contained active interventions, performance bias judged unlikely

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biochemical validation used

Incomplete outcome data (attrition bias)
All outcomes

Low risk

At 12 months:

EC arm: 356/439

NRT arm: 342/447

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported

Methods

Design: RCT multicentre

Participants: pregnant smokers (12 to 24 weeks gestation) who smoke daily and are interested in stopping smoking

Setting: maternity services across the UK. 23 hospital sites across England and one National Health Service Stop Smoking Service in Scotland

Recruitment: Recruitment was managed by research midwives in England and by the Stop Smoking Service in Scotland. Participants were identified from patient records and sent study information and invitation letters or invited via telephone, email or text; approached in person when attending antenatal hospital appointments; referred by community midwives or stop-smoking advisors; or self-referred via posters advertising the study at the sites’ antenatal clinics.

Study start date: 1 May 2017. Study end date: 26 November 2020

Participants

Total N: 1140

EC arm: 571

NRT arm: (nicotine patches) 569

Inclusion criteria:

12 to 24 weeks pregnant, daily smoker, wants help with stopping smoking. Willing to be randomized to use either NRT or EC and agreeing to use only the allocated stop-smoking product for at least the first 4 weeks of their quit attempt

Exclusion criteria:

Allergy to nicotine skin patches. Current daily use of NRT or e-cigarettes, and serious medical problems or high-risk pregnancy

Inclusion based on specific population characteristics: pregnant women

Female 100%; mean age 27; mean CPD 10

E-cigarette use at baseline: no

Motivated to quit: yes

Interventions

EC: Refillable

Arm 1: EC

Participants were sent an EU Tobacco Product Directive-compliant refillable e-cigarette starter kit (One Kit by the UK E-cig Store), together with two 10 mL bottles of tobacco-flavoured e-cigarette liquid (1.8% nicotine; 70% propylene glycol and 30% vegetable glycerol), a pack of 5 replacement coils, and an instruction leaflet (Supplementary Data, Appendix 5). Further supplies of e-cigarette liquid were posted on request for up to 8 weeks. A lower-strength e-cigarette liquid (1.1%) and e-cigarette liquid with fruit flavour were available as alternatives. Participants were encouraged to source e-cigarette liquids of the strength and flavour they liked, as well as different e-cigarette devices, and arrange their own supplies after 8 weeks if needed. The cost of the kit provided by the study was GBP 22.75 and the cost of e-cigarette liquid was up to GBP 24 for an 8-week supply.

Products used during the initial 4 weeks (n = 344) # * N (%): refillable e-cigarettes 324 (94.2%); cig-a-like 1 (0.3%); cartridge/pod 1 (0.3%); information missing 18 (5.2%)

Nicotine strength N (%): 0 mg/mL 7 (2.0); 1 to 10 mg/mL 47 (13.7); 11 to 20 mg/mL 199 (57.9); information missing 91 (26.5)

Arm 2: NRT - Nicotine patches

Participants were sent an initial 2-week supply of Nicorette Invisi 15 mg 16 h nicotine patches with manufacturer instruction leaflets and instructed to apply patches every day upon waking, and remove them before bedtime. Further supplies were posted on request for up to 8 weeks. A lower strength patch (10 mg 16 h) was available as an alternative. Participants were encouraged to access further supplies themselves via their general practitioner or local Stop Smoking Service. This could be patches and/or other NRT products such as nicotine chewing gum, inhalator or mouth spray, to use in addition to the patch alone if needed. In the United Kingdom, pregnant women who smoke receive NRT free of charge.

Behavioural support was given that accompanied both study arms.

Participants received 6 phone calls from stop-smoking advisors who followed the practice of the UK Stop Smoking Service 61.

Outcomes

Baseline, weeks 1 to 4 after target quit date (TQD) (phone call), end of pregnancy (EOP) at least 6 months (saliva and CO), 3 months post-partum (phone call)

Cessation: saliva samples and carbon monoxide readings collected

AEs and SAEs

Continued use of study product

Flavours

EC nicotine strength

Study funding

The study was funded by the National Institute of Health Research, Health Technology Programme (ref. no. 15/57/85). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. For part of the trial, F.P. was supported by Cancer Research UK (grant no. C8162/A25356).

Author declarations

P.H. provided consultancy to and received research funding from Pfizer. D.P. received research funding from Pfizer. H.M. has received honoraria for speaking at smoking cessation educational events and sitting on an advisory board organized by Pfizer. All other authors have no competing interests.

Notes

New to 2022 update

Random sequence generation (selection bias)

Low risk

Quote: "An independent statistician developed the randomization sequence using permuted block randomization with a block size of at least 6 and a maximum of 12".

Allocation concealment (selection bias)

Low risk

Quote: "The randomization list was accessible only to the independent statistician, on a secure server. Researchers conducting randomization used the database application to inform the participants of their study arm allocation. Researchers conducting follow-up calls were blind to treatment allocation until the follow-up contact was made".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants received equally intensive interventions.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Researchers conducting follow-up calls were blind to treatment allocation until the follow-up contact was made. Once contact was made and the trial application was opened, condition-specific questions were visible on the computer screen. The trial statistician was blind to participant allocation until the analysis of the primary and secondary outcomes was complete. This was achieved by extracting and importing into Stata only the baseline characteristics, study arm and smoking status variables in the first stage of the analysis. Variables coding treatment adherence and product use were extracted only after the primary and secondary outcome analyses were completed".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

EC arm 515/571; NRT arm 495/569

Selective reporting (reporting bias)

Low risk

Analysis prespecified

Methods

Design: randomized clinical trial

Recruitment: eligible participants were employees and their spouses at 54 companies that used Vitality wellness programmes.

Setting: online resources via workplace setting (54 companies), USA

Study start date: first phase of recruitment October 2014, second phase November 2015 (to meet recruitment target); study end date: 20 April 2017

Participants

Total N: 6006

N per arm: usual care: 813; free e-cigarettes: 1199; free cessation aids: 1588; reward incentives plus free cessation aids: 1198; redeemable deposit plus free cessation aids: 1208

Inclusion criteria:

• At least 18 years old
• Reported current smoking on a health risk assessment within the previous year
• Employees and their spouses that used Vitality wellness programmes

Exclusion criteria:

• Participants who express wanting to opt out of this programme

51.1% women; median age 44; median cpd 10

E-cig use at baseline: 10.7% current use; 23.1% past but not current use; 39.7% never used ECs

Motivated to quit: unselected sample (total sample): 9.2% no plan to quit; 61.6% want to quit later; 27.7% want to quit/need help

Interventions

EC: Cig-a-like

a) Usual care:

Standardized Vitality programme aimed at promoting tobacco cessation. This programme includes existing employee benefits for quitting and the use of text/email messages to encourage tobacco cessation.

b) as (a), plus free EC:

Free NJOY e-cigarettes (including battery sticks, a USB charger, and up to 20 chambers with 1.0% to 1.5% nicotine per week in participants’ chosen flavours). Use of all products was free until 6 months after the quit date.

c) as (b) plus access to free NRT, bupropion or varenicline

d) as (c) plus incentives across 6 m for testing negative for tobacco use

e) as (c) plus provide money at start and lose money from this fund if they do not test negative across 6 m

Outcomes

Months 1, 3, 6, and 12

Cessation: sustained smoking abstinence for 6 months, biochemical validation (urine cotinine, anabasine and blood carboxyhaemoglobin)

Other outcomes measured: costs

Study funding

"Supported by a grant from the Vitality Institute to the University of Pennsylvania Center for Health Incentives and Behavioral Economics."

Author declarations

"Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Check these and: Dr. Troxel reports others from VAL Health, outside the submitted work. Dr. Volpp reports grants and personal fees from CVS Health, personal fees from VAL Health, grants from Humana, grants from Merck, grants from Weight Watchers, grants from Hawaii Medical Services Association, grants from Oscar Health Insurance, outside the submitted work. All of the other authors state that they have nothing to disclose."

Notes

New for 2020 update. Study listed as ongoing study NCT02328794 in 2016 review update

Only arms (a) and (b) included in our analyses

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

High risk

Not blinded and different amounts of support given to each group

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biochemical validation

Incomplete outcome data (attrition bias)
All outcomes

High risk

At 12 months, very low numbers completed biochemical validation. Submitted a sample n = CG: 1, free e-cigs; 4, free cessation: 5, rewards: 14, deposits: 16

Selective reporting (reporting bias)

Low risk

Expected outcomes reported and checked with trial registration

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: ≥ 18 years of age; smoking ≥ 5 cpd for the past year with a breath CO ≥ 10 ppm or NicAlert test = level 6 if CO < 10 ppm; in stable physical and mental health.

Exclusion criteria: 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); using NRT or other cessation medications; pregnancy/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, they switched exclusively to Vuse. Participants could choose 1 of 4 flavours: 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 flavours, while the nicotine lozenge was mint or cherry flavours. 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 counselling 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 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

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 = 0.04), 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 the supplementary section notes that heart rate, blood pressure, and oxygen levels were measured, but findings not reported in paper; however, provided by authors upon request

Methods

RCT

3 NCT trials data pooled: NCT04092387; NCT04090879; NCT04092101

NCT04092387. Low nicotine content cigarettes in vulnerable populations: women of reproductive age.

NCT04090879. Low nicotine content cigarettes in vulnerable populations: affective disorders.

NCT04092101 . Low nicotine content cigarettes in vulnerable populations: opioid use disorder.

All: Start Sept 2019. Estimated completion Jan 2024.

Setting: Johns Hopkins University, the University of Vermont, and Brown University, USA

Recruitment: Participants were recruited through newspaper and online advertisements and word of mouth.

Inclusion based on specific population characteristic: At risk populations (affective disorders; opioid use disorder; reproductive age females with lower educational levels).

EC use at baseline. Used EC in past 30 days = 42 (12.9 SD)

Motivated to quit: not planning to quit in the next 30 days

Participants

Total N: 326 (3 trials)

Normal nicotine content tobacco cigarette only = 83 (70 at week 8; 67 at week 16)

VLNC = 85 (66 at week 8; 66 at week 16)

VLNC + EC tobacco flavour (TF) =74 (60 at week 8; 57 at week 16)

VLNC + EC preferred flavour (PF) = 84 (72 at week 8; 70 at week 16)

74.5% female (one of the three studies only recruited females). Mean age 40.09 (10.79 SD). Mean CPD 17.4 (8.87 SD). Mean FTND 5.09 (2.21 DS). Used EC in past 30 days = 42 (12.9 SD).

NCT04092387: Estimated enrolment 246. Inclusion criteria: Female; 21 to 44 years old, maximum educational attainment of graduating high school.

NCT04090879: Estimated enrolment 232 participants. Inclusion criteria: current diagnosis of an affective disorder.

NCT04092101: Estimated enrolment: 310. Inclusion criteria: Maintained on opioid medication methadone or buprenorphine treatment (methadone or buprenorphine treatment).

Shared inclusion criteria: 21 years and over (US legal age for purchasing cigarettes), 5 or more CPD in the past year, CO 8 ppm or higher, no psychiatric conditions with potential to interfere with study completion, sufficient literacy, no adverse health changes in the past 90 days, no use of EC daily or other tobacco products besides commercial cigarettes on 10 or more days in the past 30 days, and access to a computer or telephone for remote assessments (smart phone provided if necessary).

Shared exclusion criteria: prior regular use of VLNC cigarettes; plans to quit smoking in the next 30 days; a quit attempt in the past 30 days resulting in more than 3 days of abstinence; use of smoking cessation medications in the past 30 days; exclusive use of roll-your-own cigarettes; positive test result for drugs other than cannabis; binge drinking on 10 or more days in the past 30 days; abnormal vital sign measurements; positive COVID-19 symptoms or test result; recent suicidal ideation or suicide attempt; participation in another research study in the past 30 days; and cohabitation with another participant in the current study.Pregnant or breastfeeding,

Interventions

1) Normal nicotine content tobacco cigarette only (15.8 mg nicotine/g tobacco)

2) VLNC tobacco cigarette only (0.4 mg nicotine/g tobacco)

3) VLNC tobacco cigarette + EC tobacco flavour

4) VLNC tobacco cigarette + EC preferred flavour

Participants will be asked to use only their assigned study products for 16 weeks.

EC: (JUUL; Juul Labs) with pods containing 5% nicotine by weight. ECs were purchased from JUUL Labs. Those assigned to e-cigarettes participated in an orientation session and received a manual on device operation and storage. Participants received a supply of e-liquid pods sufficient to substitute for baseline smoking (1-pod/pack of cigarettes). EC flavours: tobacco flavour or preferred flavours. Preferred flavours arm: 8 flavors (classic tobacco, Virginia tobacco, crème brûlée, cucumber, fruit medley, mango, menthol, and mint) from which participants selected 3 preferred flavors. Participants selected 3 preferred flavors. Preferred flavors could be changed once during the study.

VLNC tobacco cigarette. During the first baseline visit, participants received free usual-brand cigarettes for use during the subsequent week to establish baseline CPD. The supply was 150% of self-reported CPD to accommodate increases. Participants received the first supply of study cigarettes at the second baseline visit. Participants received twice the number of cigarettes used during baseline to accommodate smoking increases or missed visits.

Normal nicotine content tobacco cigarette (15.8 mg nicotine/g tobacco). The National Institute on Drug Abuse provided study cigarettes with nicotine content averaged across menthol and non menthol cigarettes. Cigarettes were identical in appearance. Assignment to menthol or non menthol cigarettes was based on participant preference. During the first baseline visit, participants received free usual-brand cigarettes for use during the subsequent week to establish baseline CPD. The supply was 150% of self-reported CPD to accommodate increases. Participants received the first supply of study cigarettes at the second baseline visit.

Outcomes

Baseline, weekly for 16 weeks.

AEs & SAEs. CPD. CO, NNAL, anatabine, biomarkers of tobacco toxicant exposure, brain function and structure, and airway inflammation (fractional nitric oxide concentration in exhaled breath (FeNO)). Urine at week 8 and 16 for: Urine specimens analyzed for cotinine (nicotine metabolite), anatabine (tobaccoalkaloid), and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, a tobacco-specific N-nitroasmine and carcinogen). Heart rate, BP.

Study funding

This project was supported by Tobacco Centers of Regulatory Science grant U54DA036114 from the NIDA/NIH and FDA (Dr Higgins), Centers of Biomedical Research Excellence grant P30GM149331 from the National Institute of General Medical Sciences (Dr Higgins), and Institutional Training Award T32DA007242 from NIDA/NIH (DrsHeilandHiggins).

Author declarations

Dr Tidey reported receiving a grant from the National Institute on Drug Abuseof theNationalInstitutes of Health (NIDA/NIH) during the conduct of the study and grants from the NIH outside the submitted work. Dr Klemperer reported receiving a grant from the NIH/NIDA and US Food and Drug Administration (FDA) during the conduct of the study. No other disclosures were reported.

Notes

Higgins new to 2025 update. NCT records new to 2022 update as ongoing studies.

Random sequence generation (selection bias)

Unclear risk

“Participants were allocated equally across 1 of 4 experimental conditions using block randomization, stratified by study site and menthol cigarette preference:”

Allocation concealment (selection bias)

Low risk

Protocol: “The Administrative Core will maintain the randomization schedule and the link between the alphabetic code and treatment assignment securely. A second sealed copy will be secured in a separate building to protect against loss related to fire or other unforeseen events. The University of Vermont will be responsible for removing all identifying information from cigarettes received from the Research Triangle Institute (RTI), labeling each carton with a blind code, assigning product using this blind code based on the randomization schedule being provided by the UVM Biostatistics Core, and shipping cigarettes and e-cigarettes to each site as needed based on recruitment.” (Quote from protocol)

From paper:“Cigarettes and e-cigarettes were studied under double-blind and open-label conditions, respectively.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Arms were equally intensive.

Cigarettes and e-cigarettes were studied under double-blind and open-label conditions, respectively.

“The nicotine doses will be identified by letter code and only Administrative Core personnel with no participant contact will have the link between thestatistician’s letter code and dose assignments. There will be no blinding of e-cigarette conditions.”

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Measured (CO), Urine analysis for NNAL and anatabine

Incomplete outcome data (attrition bias)
All outcomes

Low risk

At 16 weeks: NNC = 67/83; VLNC = 66/85; VLNC + EC (TF) = 57/74; VLNC + EC (PF) = 70/84

Selective reporting (reporting bias)

Low risk

Reported CPD, cessation (to 16 weeks), SAE, AE, CO, NNAL, anatabine. Authors are working on a publication that will include the other measures ( heart rate and BP measures)

Other bias

Unclear risk

3 different populations

Methods

Design: pilot RCT

Recruitment: recruited via the Newcastle Dental Hospital and by primary care practitioners working in the north-east England region

Setting: dental clinical research facility (DCRF), located in the Newcastle Dental Hospital, Newcastle upon Tyne, UK

Study start date: 20 September 2016; study end date: 31 July 2018

Participants

Total N: 80

N per arm: Intervention group: 40; control group: 40

Inclusion criteria:

• Aged over 18 years old; smoker (≥ 10 cigarettes/day)
• Willing and able to come to the DCRF for the required study visits
• Having a minimum of 16 natural teeth (excluding third molars)
• Being diagnosed with periodontitis

Exclusion criteria:

• Having used an e-cigarette for more than 2 days in the last 30 days
• Infectious or systemic diseases that may be unduly affected by participation in this study
• Haemodynamically unstable
• Patients taking the medication adenosine (due to drug interaction risk)
• Lack of capacity to be able to consent to the research project or inability to follow study instructions, or both
• Participation in a dental research study within the previous 20 days
• Pregnant by medical history, or nursing
• Received any non-surgical periodontal therapy other than a routine scale and polish in the last 6 months
• Currently undergoing or requiring extensive dental, orthodontic or implant treatment, or treatment for peri-implantitis

Inclusion based on specific population characteristics: periodontitis

52.5% women; mean age 44.36; mean cpd 17.4; mean FTND 5

Motivated to quit: not selected on motivation and not reported

E-cigarette use at baseline: not currently using an e-cigarette, or not having used 1 for more than 2 days in the last 30 days

Interventions

EC: Refillable

All participants given standard stop-smoking advice (10 to 15 minutes in duration) and offer of referral to stop-smoking services

Intervention: given EC starter kit (Vype eTank clearomizer) and brief training on its use by a dentist. Provided with an approximately 2-week supply of e-liquid (20 ml) with a choice of flavour (Blended Tobacco, Crisp Mint, Dark Cherry and Vpure (flavourless)) and nicotine strength (0 mg/mL, 6 mg/mL, 12 mg/mL, 18 mg/mL) and information on where to buy more. EC intervention delivered directly following the standard stop-smoking advice and was expected to be 10 to 15 minutes in duration.

Control group: no further intervention

Outcomes

Months 1 and 6; self-report and biochemical validation of smoking status

Cessation: rates of continuous eCO-verified smoking abstinence at 6 months were calculated following the Russell Standard (RS6)

Adverse events and biomarkers: expired air CO, adverse events monitored at each study visit

Other outcomes measured:

• Feasibility outcomes
• Oral health outcomes
• Smoking behaviour outcomes comprised: self-reported tobacco and e-cigarette use, eCO, e-salivary cotinine, salivary anabasine, FTND and Mood and Physical Symptoms Scale

Study funding

"Richard Holliday is funded by a National Institute for Health Research Doctoral Research Fellowship (DRF-2015-08-077). This paper presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care."

Author declarations

"The authors declare that they have no competing interests."

Notes

New for 2020 update

Random sequence generation (selection bias)

Low risk

Randomization was performed using a secure password-protected web-based system.

Allocation concealment (selection bias)

Low risk

Quote: "The randomisation allocation schedule will be generated by a statistician with no other involvement in the study to achieve concealment of allocation."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Nature of study precluded blinding; different levels of support across intervention arms

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biochemical validation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Attrition < 50%

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported.

Methods

RCT

Recruitment: smoking cessation clinic of second cardiology department of National and Kapodistrian University of Athens, Attikon General Hospital

Setting: hospital smoking-cessation unit, Greece

Study start date: NS

Participants

N = 40; Arm 1 e-cigarette n = 20; Arm 2 conventional tobacco cigarette n = 20

80% female; mean age 44.8 (SD 11.3); mean cpd: 25.8 (C-cig 25.5 (SD 9.3), E-cig: 26.2 (SD 9.1))

Inclusion criteria: smokers without cardiovascular disease, who used to smoke 25.8 ± 9.2 conventional cigarettes per day of their choice

Exclusion criteria: abnormal renal function; hepatic failure (bilirubin > 2 mg/dL); active malignancy; people treated with drugs that affect platelet function; history of coronary artery disease or peripheral artery disease; history of cardiomyopathy; thrombocytopenia (PLTs < 100 × 109 /L); anaemia (HCT < 28%); alcohol or drug abuse; age < 21 years; pregnancy; risk factors for cardiovascular disease

Interventions

EC: Refillable

E-cig: second-generation e-cig device and popular in Greek Market e-liquid (NOBACCO eGo Epsilon BDC 1100, eGo battery, 1100 mAh, operating at 3.9 V - propylene glycol 74.3%, glycerin 20%, flavouring 4.5%, nicotine 1.2%/12 mg/mL)

Outcomes

Baseline, 4 months: exhaled CO concentration; blood pressure

Also, cpd; platelet function by Platelet Function Analyzer PFA-100 and Light Transmission Aggregometry; pulse wave velocity; plasma malondialdehyde levels as oxidative stress index

Study funding

"There was no funding for this study".

Author declarations

"The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."

Random sequence generation (selection bias)

Low risk

Table of random numbers as reproduced from the online randomization software www.graphpad.com/quickcalcs/index

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not possible

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Only CO outcomes used here, which were objectively measured

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All followed up (confirmed via contact with authors)

Selective reporting (reporting bias)

Unclear risk

No protocol or clinical trial record available to confirm whether all prespecified criteria were reported

Methods

Design: RCT

Setting: Smoking Cessation Clinic of Second Cardiology Department of National and Kapodistrian University of Athens, Attikon General Hospital, Greece

Participants

40

Inclusion criteria: current smokers without cardiovascular disease

Interventions

EC type: NS

Conventional cigarette (conv-cig) or an electronic cigarette (e-cig) with nicotine concentration 12 mg/dL for 1 month

Outcomes

a) Perfused boundary region (PBR) of the sublingual arterial micro vessels (range 5 to 25 micrometres), a marker inversely related with glycocalyx thickness

b) Pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIX)

c) Platelet function by 2 different methods, namely the novel Platelet Function Analyzer PFA-100 and the traditional Light Transmission Aggregometry (LTA)

d) Exhaled CO level (ppm) as a smoking status marker

e) Plasma malondialdehyde (MDA) levels, as an oxidative stress burden index

Study funding

Funding acknowledgement: type of funding source: none

Author declarations

NS

Notes

Information extracted from a conference abstract

Random sequence generation (selection bias)

Unclear risk

No detail given

Quote: "40 current smokers (mean age 48 years±5) without cardiovascular disease were randomized to smoke either a conventional cigarette (conv-cig) or an electronic cigarette (e-cig) (electronic cigarette fluid with nicotine concentration of 12 mg/dL) for one month."

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

NS

Selective reporting (reporting bias)

High risk

Results reported in summary form, not fully, with only some significant changes reported. Information taken from a conference abstract only

Methods

RCT

Setting: smoking cessation clinic, Greece. National & Kapodistrian University of Athens, Attikon University Hospital, 2nd Cardiology Department, Athens, Greece

Recruitment: subjects attending smoking cessation clinic

Participants

N= 100

EC arm = 25; Heat not burn cigarette arm = 25; Control arm = 50

% female: EC = 51%; Heat not burn cigarette = 55%; CC = 53%.

Age: EC: 45 ± 8 years; Heat not burn cigarette 46 ± 14 years; CC 48 ± 5 years.

Mean CPD: EC: used 27 ± 10 cigarettes/day, 28 ± 10 pack-years; Heat not burn cigarette: 26 ± 8 cigarettes/day, 30 ± 8 pack-years; CC: Used 27 ± 9 cigarettes/day, 29 ± 9pack-years.

Inclusion: CC user.

Motivated to quit: yes

Interventions

Refillable EC; Heat not burn cigarette; Control arm

Outcomes

Baseline, 1 month.

CO.

Smoking status was verified by measuring the concentration of exhaled carbon monoxide [(e CO) (ppm), Bedfont Scientific, Maidstone, Kent UK]

Endothelial glycocalyx thickness measured by Perfused Boundary Region (PBR)

Study funding

Reported as: 'None'.

Author declarations

None

Notes

New to 2025 update

Random sequence generation (selection bias)

Unclear risk

State that study is randomised but no detail is provided.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

EC & heat not burn cigarettes equally intensive.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Concentration of exhaled carbon monoxide [(e CO) (ppm), was measured by Bedfont Scientific, Maidstone, Kent UK].

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not reported.

Selective reporting (reporting bias)

Unclear risk

Reported as stated in abstract. No clinical record or protocol.

Methods

Design: randomized controlled trial

Recruitment: not specified

Setting: hospital, Greece

Study start date/Study end date: not specified

Participants

Total N: 54

N per arm: arm 1: 27; arm 2: 27

Inclusion criteria: ≥ 10 cpd; motivation to quit; hospitalized with acute coronary syndrome (ACS); ≥ 18 years

Exclusion criteria: prior EC use; history of neuropsychiatric disorders; prior varenicline use or use of smoking cessation pharmacotherapy at time of ACS; cardiogenic shock or renal impairment; hepatic impairment prior to ACS; excessive alcohol use or current use of marijuana or non-cigarette tobacco products

Inclusion based on specific population characteristics: People who have experienced acute coronary syndrome

65% women; mean age 52; mean cpd 21; mean FTND 5.6

Motivated to quit: yes

E-cigarette use at baseline: no prior EC use

Interventions

EC: information on whether cig-a-like or refillable not provided

Both arms given "low intensity counselling"

Intervention 1: 12-week use of EC 12 mg/mL nicotine

Intervention 2: 12-week varenicline

Outcomes

Weeks: 4, 12, 24

Cessation: 7-day PP at 24 weeks, self-report

Adverse events and biomarkers: unclear how these were reported. Abstract says no SAEs, poster implies this may have just been CV or neuropsychiatric SAEs. Abstract says nothing about AEs but nausea and sleeping disorders given in table in poster. Implies (S)AEs collected during treatment period only

Other outcomes measured: not specified

Study funding

Not reported

Author declarations

Not reported

Notes

New for 2020 update. Abstract and poster only; limited data available

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

Low risk

Not specified but equal amounts of contact and support between arms so performance bias judged unlikely

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Self-report only but equal amounts of contact between arms; no reason to suspect differential misreport

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not specified

Selective reporting (reporting bias)

Unclear risk

Abstract/poster only so not able to judge

Other bias

High risk

Abstract and poster only. Two different figures presented for quit rate in EC arm (no difference in those presented in varenicline arm) between abstract and poster. Poster percentage aligns with figure, so using that (16.5%) as opposed to abstract figure (32.5%). Contacted authors but no reply. Calculated n quit based on percentages but unclear what denominators were; EC calculates back to whole number for EC but not for varenicline.

Methods

RCT

Setting: hospitals, UK

West Park Hospital; Bradford District Care NHS Foundation Trust; Sheffield Clinical Commissioning Group

Participants

N= 43 [The target was 72]

EC kit arm = 21; Control (usual care) = 22

39.5% female; mean age 45.2 (SD=12.7); mean CPD 19.6 (10.9). Strength of urges to smoke = 3.4 (mean), (1.0 SD). Past year EC use for smoking cessation = 27.9% (n=12). Past yr quit attempt = 37.2% (n=16)

Inclusion criteria: receiving treatment for a mental illness; > 18 years; smoker; willing to attempt to quit

Exclusion criteria: inpatient admission in the last 3 months according to their health care record; smokers using EC; participating in other smoking cessation trials; being treated for comorbid drug or alcohol problems; Alzheimer’s disease or dementia; pregnancy or breastfeeding.

Specific population: All participants had a diagnosed mental health condition and were receiving treatment in primary or secondary care

Motivated to quit: willing to quit (Motivated to quit smoking 5.2 mean (1.7 SD) (motivation score 1-7, higher score = higher motivation))

EC use at baseline:

Interventions

EC: Aspire PockeX electronic cigarette

EC starter kit : third- generation e-cigarette (Aspire PocketX) with a four-week supply of a choice of: a) nicotine strength e-liquid (3 options: 6mg/ml, 10mg/ml, 18mg/ml) and b) flavours (tobacco, fruit, menthol) as an adjunct to usual care. Verbal explanation and demonstration, and information leaflet on how to use the EC.

Control arm: usual care.

Usual care arm. Minimum standard this would involve evidence-based Very Brief Advice to stop smoking, comprising the three As (Ask and record smoking status; Advice on the best way of quitting and; Act on patient response to build confidence) and referral to in-house or external specialist stop smoking services.”Encouraged to condider quitting, set a quit date within a week after randomisation, or reduce cigarette consumption. Possibly offered NRT as part of usual care.

Both arms: “To support engagement, all participants (both in intervention and control group) received a £10 love2shop voucher for completing the baseline assessment and a £10 love2shop voucher for completing the 1-month follow-up assessment.”

Outcomes

Baseline, 2 to 4 weeks. Baseline and 4 weeks reported in Kale 2025.

Primary outcome measure:

1. Feasibility and acceptability outcomes: consenting rate and recruitment frequency.
2. Clinical (smoking-related) outcomes: continuous abstinence assessed at 1 month will be defined as not having smoked in the 2 weeks prior to follow-up, verified by a CO reading below 10 ppm

Secondary outcome measures:

1. Feasibility and acceptability outcomes. Characteristics of ‘usual care’ in different locations will also be noted, recording 2 interactions of patients with CMHTs or GPs at each site at baseline and using short pro-forma with control group participants at 1-month follow-up.
2. Clinical (smoking-related) outcomes: Self-reported abstinence 2 to 4 weeks from enrolment or target quit date (whichever is later) will be recorded at 1-month follow-up. The change in cigarette consumption (and reduction in exhaled breath CO reading) from baseline to 1-month follow-up will be calculated in both intervention and control group participants.
3. Clinical (mental health-related) outcomes
4. Cost-effectiveness
5. SAE and AE

Number of AEs and SAEs provided by author

Study funding

"This work was supported by Yorkshire Cancer Research (Y433). DK receives salary support from Cancer Research UK (PRCRPG-Nov21\100002). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Funders were not involved in the collection, management, analysis, and interpretation of data; writing of the report; or in the decision to submit the report for publication."

Author declarations

"LS has received honoraria for talks, unrestricted research grants and travel expenses to attend meetings and workshops from manufactures of smoking cessation medications (Pfizer; J&J) and has acted as paid reviewer for grant awarding bodies and as a paid consultant for health care companies. All authors declare no financial links with tobacco companies, e-cigarette manufacturers, or their representatives."

Notes

New to 2025 update. Ongoing study added to 2022 update

Random sequence generation (selection bias)

Low risk

“intervention allocation was determined by computer block-randomisation”

Allocation concealment (selection bias)

Low risk

“Randomisation occurred after consent to take part in the study had been obtained via opening of consecutively numbered opaque envelopes containing information about allocation.”

“Allocation was concealed until after completion of the baseline questionnaire.”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Interventions were not equally intensive . “Participants and researchers and clinical staff administering the intervention could not be blinded due to the nature of the intervention and study design. As follow-up questionnaires differed for intervention and control groups, outcome assessment was only blinded to researchers for questionnaires self-completed online rather than over the phone. However, the study’s statistician was blinded to participants’ allocation.” Some blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

AEs & SAEs are used in this review, self-reported is usual for these measures. Other data collected by questionnaire - high.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

At 4 weeks, both <50%: EC = 15/21; Control = 12/22

Selective reporting (reporting bias)

Low risk

Outcomes reported.

Methods

Design: 2-centre, randomized, controlled, switching, open-label, parallel-group, clinical confinement study

Higher versus lower nicotine study

Setting: USA. Two clinical research sites (Overland Park, KS and Minneapolis, MN), contracted by Altasciences Clinical Research as the contract research organization (CRO)

Recruitment: potential participants completed a pre-screening telephone interview and also attended a screening visit at the clinical research site within 30 days before study entry.

Study start date: April 2017. Study end date: September 2017

Participants

125 randomized:

Kanobe 2022 reports EC Vuse Solo arm

EC (Vuse Solo) group: 35

Female 42.9% female; mean age 41.2 years; mean CPD: 18.3 (SD 10.9); mean FTND: 6.1 (SD 1.6)

Kanobe 2023 reports on Vuse Vibe and Vuse Ciro arms:

37 Vuse Vibe group: 37

37 Vuse Ciro group: 37

35.6% (32) female; mean age 40

[Abstinence arm: 16 (this arm is ignored)]

Inclusion criteria: M or F; 21 to 64 yrs; smoker using non-menthol tobacco cigarettes (at least 10 cpd); not planning to quit

Exclusion criteria: medical conditions; weight of ≤ 110 pounds; planning to quit within 30 days

EC use at baseline: no

Motivated to quit: no

Interventions

EC: Vuse Solo Original ENDS product referred to as Vuse Solo (G2) or Vuse Solo. Pod. Rechargeable Vuse Solo power unit (battery capacity: ≥ 270 mAh; wattage: 3.00 W) and a closed cartridge containing 0.5 mL of original (tobacco-flavoured) e-liquid, a mix of propylene glycol (PG), glycerin (PG:glycerin ratio of 21:79), water, and flavouring ingredients. The e-liquid included nicotine at 4.8% nicotine by weight (57.4 mg/mL) and contained nicotine salts.

EC: Vuse ciro 1.5% nicotine EC. pre-filled, closed ENDS products (RJR Vapor Company, Winston-Salem, NC, USA. Original, tobacco-flavored, nicotine containing e-liquids. The Vuse Ciro product was originally marketed under the brand name “Vuse Solo+”. The product was subsequently renamed to “Vuse Ciro”. Tobacco flavour.

EC: Vuse vibe, 3% nicotine EC. The Vuse Vibe power unit is powered by a ≥ 550 -mAh rechargeable battery and is paired with a cartridge containing 1.9 mL of e-liquid with 3% nicotine content by weight (36 mg/mL) and a propylene glycol-to-glycerin ratio (PG/VG) of 20/80. The maximum puff duration for Vuse Vibe is 6 s. Tobacco flavour

Outcomes

Day 1, 5, 7 (urine)

AEs, SAEs monitored throughout study from day 1 to day 8 (discharge)

Most outcomes were measured at day 5 and not eligible for extraction.

Study funding

“This study was funded by RAI Services Company.“

Tobacco industry funded. Parent company is Reynolds American. Reynolds American manufacture and market a variety of tobacco products, including cigarettes (Newport, Camel, Pall Mall, Kent, Doral, Misty, Capri, and Natural American Spirit brands), electronic cigarettes (Vuse brand), and moist snuff (Grizzly and Kodiak brands).

Kanobe 2023: This research was funded by RAI Services Company, a wholly owned subsidiary of Reynolds American Inc., which is an indirect, wholly owned subsidiary of British American Tobacco plc.

Author declarations

M.K., P.C., J.D., P.M., E.R., J.W.C., and E.S. are full-time employees of RAI Services Company, and B.G.B., B.A.J., G.L.P., and P.N. are former full-time employees of RAI Services Company. RAI Services Company and R.J. Reynolds Tobacco Company are wholly owned subsidiaries of Reynolds American Inc., which is a wholly owned subsidiary of British American Tobacco plc. G.L.P. is an independent consultant. B.N. is a full-time employee of JTI Leaf Services (US) LLC.

Kanobe 2023: M.N.K., P.M., P.C. and J.W.C. are full-time employees of RAI Services Company, E.K.R. is a full-time employee of BAT (Investments) Limited, and B.G.B., G.L.P. and P.R.N. are former full-time employees of RAI Services Company. G.L.P. works as an independent scientific consultant. RAI Services Company is a wholly owned subsidiary of Reynolds American Inc., which is an indirect, wholly owned subsidiary of British American Tobacco plc

Notes

Participants were compensated for their time and participation. For the purposes of our analyses, this study is treated as a single-arm study and reported narratively.

Random sequence generation (selection bias)

Low risk

A computer software program was used by the statistician at the CRO to generate the randomization sequences.

Allocation concealment (selection bias)

Low risk

A computer software program was used by the statistician at the CRO to generate the randomization sequences.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

“The study was unblinded by necessity due to the very different visual appearances of the study products”

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Relevant outcomes are biomarkers, which are objectively measured

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Vuse solo group 35/35; Vuse Vibe group 33/37; Vuse Ciro group 35/37.

Selective reporting (reporting bias)

High risk

The NCT record stated that some biomarkers would be measured at 5 days. Extra biomarkers have been reported at 7 days follow-up.

Methods

Design: Randomized, cross-over, open-label. Two consecutive randomly ordered 2-week phases

Setting: Greater Burlington, VT, USA. University of Vermont, USA

Participants

N=21

Age 'at least 40 years old’.

Inclusion: smoke (≥5 cigarettes/day for ≥1 year); diagnosed with COPD, chronic bronchitis, emphysema, or asthma-COPD overlap syndrome); no intention to quit smoking within the next month.

Exclusion criteria: patients who are medically unstable (unstable symptoms, changes in medications or hospitalizations within last 3 months); inability to conduct in-home measurements.

Not motivated to quit smoking.

Inclusion based on specific population characteristics: diagnosed with COPD

Interventions

From paper.

Cigarette phase, usual brand CCs

Nicotine-containing EC phase. EC: 3% and/or 5% nicotine tobacco-flavored JUUL available. During the EC phase, participants earned monetary incentives for CO readings ≤6ppm to promote cigarette abstinence.

From NCT record:

EC: JUUL/Vuse Alto and pods

1) Experimental: e-cigarette. Participants in this arm will smoke EC for 2 weeks. EC (either JUUL or Vuse Alto) and pods (JUUL: Virginia tobacco flavour at 3% or 5% nicotine concentration; Vuse Alto: golden tobacco flavour at 1.8%, 2.4%, or 5% nicotine concentration) will be provided. In the EC arm, availability of EC and altering the availability of financial incentives for abstaining from combustible cigarettes will be investigated.

2) No intervention: CC. Participants in this arm will smoke their usual brand of combustible cigarettes for 2 weeks.

Outcomes

Baseline, 2 weeks.

CO

Pulmonary (spirometry, oscillometry, COPD Assessment Test [CAT], Saint George’s Respiratory Questionnaire for COPD [SGRQ-C]) and cardiac (heart rate, blood pressure) assessments were completed at baseline and after each phase.

From NCT record. Baseline, 2 weeks, 4 weeks

Baseline and change from baseline: FEV1/FVC; lung reactance; oxygen saturation (SpO2); exhaled nitric oxide (FeNO); COPD; blood pressure; heart rate; tobacco use; Fagerstrom Test of Nicotine Dependence (FTND); Wisconsin Inventory of Smoking Dependence Motives-Brief (WISDM-Brief); Minnesota Tobacco Withdrawal Scale (MNWS); Questionnaire on Smoking Urges-Brief (QSU-Brief); health changes

Study funding

Tobacco Centers of Regulatory Science (TCORS) Award U54DA036114 from the National Institute on Drug Abuse (NIDA) and Food and Drug Administration (FDA). Content is solely the authors’ responsibility and does not necessarily represent the official views of these institutions

Author declarations

No conflicts for any of the authors (email correspondence).

Notes

Ongoing study moved to included study in 2025 update. Contact information: Brian R Katz, Katz, Brian brkatz@UTMB.EDU Diann Gaalema Diann.Gaalema@uvm.edu.

Random sequence generation (selection bias)

Unclear risk

Conference abstract, minimal detail

Allocation concealment (selection bias)

Unclear risk

Conference abstract, minimal detail

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Conference abstract, minimal detail

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All outcomes measured objectively

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Conference abstract, minimal detail

Selective reporting (reporting bias)

Unclear risk

Only conference abstract published so far

Methods

Design: RCT. Pragmatic, 2-armed, single-centre, randomized controlled pilot study

Recruitment: community. Recruitment from NHSGGC Smokefree Services. GP surgeries. Secondary care QEUH, GRI, New Victoria Hospital and Glasgow Dental School. Advertized on NHSGGC staff payslips, local newspapers, community magazines, and on Gumtree. The British Heart Foundation, University of Glasgow and NHSGGC released a joint press release, which generated media coverage in 4 newspapers. Social media. Public engagement “pop up stands” were held collaboratively with smoke-free services and the VAPOUR study team in the entrance foyer of the QEUH and at the Celtic Football Club Healthy Hoops Event.

Setting: Scotland, UK

Study start date: 1 December 2015. Study end date: 13 July 2018

Participants

Total N: 55

EC arm 28. NRT arm 27

Inclusion criteria:

Aged 18 to 65 yrs; habitual tobacco smokers (smoking on average 1 to 15 tobacco cigarettes pd > 6 months); willing to quit tobacco smoking; with either the use of nicotine replacement patches or an EC with nicotine-containing e-liquid, in addition to engaging with NHSGGC Community Smokefree Service's 12-wk behavioural support programme. No established history of cardiovascular disease

Exclusion criteria:

Pregnant or breastfeeding; had used an EC or nicotine replacement patch in the last 3 months; were allergic to the active substances in either of the nicotine replacement products; history of illicit drug use, major depressive illness or other psychiatric conditions, peripheral arterial occlusive disease (PAOD), COPD, renal impairment (eGFR < 45 mL/min), uncontrolled hypertension (BP ≥ 165/95 mmHg), or CVD.

Female 43.7%; mean age 44.2; mean CPD 15; mean FTND 7

E-cigarette use at baseline: not reported

Motivated to quit: participants were willing to quit

Interventions

EC: Refillable

EC arm

E-cigarette starter pack contained two commercially available second-generation e-cigarette devices with charging devices, 11 replacement atomisers and 12 x 10 bottles of nicotine containing e-liquid, tobacco-flavoured e-liquid, 18 mg/mL nicotine. Each e-cigarette device consisted of a 1300 mAh variable voltage rechargeable battery, a tank and an atomiser, and the charging device comprised of USB e-cigarette charger and USB mains adaptor (SmokeMax; Groove Trading Ltd, 194 Glasgow UK), and written instructions.

At baseline, oral and written information was given on how to operate the e-cigarette, and for the duration of the study, participants were asked only to use the study e-cigarette and e-liquid they were provided with.

NRT arm: NRT nicotine replacement patches, 12-week reducing nicotine regimen (21 mg, 14 mg, 7 mg) of Nicotinell® Patches

Weekly supply of nicotine replacement patches. If required, participants were also permitted to use additional other licensed nicotine replacement products (gum, lozenges, nasal spray, inhalers, and micro-tabs), in combination with the nicotine replacement patches.

Both arms: all participants received 12 weeks of behavioural support provided by NHSGGC Smokefree Community Services. Following the baseline visit, participants were asked to define their “quit date”.

Outcomes

Baseline and 12 weeks

CO confirmed smoking cessation

Secondary outcomes: cardiovascular function (heart rate SBP, DBP), lung function, weight

Study funding

Grant from British Heart Foundation (Centre of Research Excellence Award, reference number RE/13/5/30177)

Author declarations

There were no conflicts of interest with the tobacco industry.

Notes

New to 2022 update

Random sequence generation (selection bias)

Low risk

Quote: "Using a secure website (Sealed Envelope Ltd, 2016), participants were randomised in a 1:1 fashion, to either the e-cigarettes combined with behavioural support or nicotine replacement patch group combined with behavioural support. Using a permuted block design with a computer random number generator, block randomisation with block sizes of 4, 6 and 8 was used to reduce bias and achieve balance in the allocation of participants to treatment arms".

Allocation concealment (selection bias)

Low risk

Quote: “Secure website (Sealed Envelope Ltd, 2016) participants randomised in a 1:1 fashion, ……Using a permuted block design with a computer random number generator, etc.”

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Not blinded, but as both arms contained active interventions, performance bias judged unlikely

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

BP, heart rate, and oxygen saturation measured. Abstinence at 12 weeks, self-report was CO validated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

31/55 (56.3%)

EC arm 18/28; NRT arm 14/27

Selective reporting (reporting bias)

Low risk

Reported outcomes ‘per protocol’

Methods

Design: RCT

Recruitment: participants were screened via phone interviews

Setting: East London, UK

Study start date: participants recruited between December 2015 and December 2016

Participants

Total: N = 50 people who smoked combustible cigarettes and were e-cigarette naive. Initial sample (N = 70) attended first session; all analyses were conducted on the N = 50 who returned for their 2nd and 3rd session.

Cig-a-likes: N = 11

Tank18: N = 20

Tank6: N = 19

Inclusion criteria:

Smoke daily ≥ 5 cigarettes, have smoked for ≥ 1 year, not currently using an EC, willing to abstain 1 hr before the start of the session and willing to make a quit attempt

Exclusion criteria:

< 18 years, not fluent in English, pregnancy or breastfeeding, or a known neurobiological or heart condition

64% women; mean age 29.5 (SD 9.31); mean CPD 13.09 (SD 6.66), mean FTND 4.14 (SD 2.45)

Motivated to quit: "Willing to make a quit attempt"

E-cigarette use at baseline: no

Interventions

EC: cartridge and refillable

Arm 1: cig-a-like (18 mg/mL)

The ‘Blu’ (n = 13) and ‘TECC Go e-cigarette’ models (n = 11) were used for the Cig-a-like condition, due to issues of leakages with the latter. Non-adjustable battery power output and could be recharged, a supply of spare disposable cartridges were provided.

Arm 2: a tank model containing 18 mg/mL (Tank18)

Arm 3: a tank model containing 6 mg/mL (Tank6)

For both conditions, Tank18 and Tank6 the ‘Totally Wicked mini curve’ was mounted with a 2 mL capacity tank which housed a standard atomiser of 1.5 ohm resistance. E-liquid ingredients composition and flavours were kept consistent across all conditions using the same ratio of propylene glycol and vegetable glycerin (PG/VG: 50/50) and tobacco flavour.

Intervention. All 3 group participants vaped 20 min ad libitum in 3 separate sessions (baseline, 1 and 2 weeks post-baseline). Ahead of their baseline session, participants were instructed to abstain from smoking for an hour. Rated their craving and withdrawal symptoms (at the beginning and end of the session), before receiving instructions on how to use their EC and to vape ad libitum for 20 mins

Positive and adverse effects were measured at the end of the last puff. All vaping sessions were video-recorded.

At the end of each session, participants were given the EC and were instructed to keep a record of the number of cigarettes smoked at the end of each day until their next and subsequent sessions. Each participant was provided with a weekly supply of either, 60–80 mL of e-liquid in refill bottles for those in the tank conditions, or 15 cartridges for those in the cig-a-like condition at the end of each testing session. The session was repeated the following week, then one week later. Participants were asked to keep the device and encouraged to try and replace as many tobacco cigarettes as they could with the use of their EC.

Outcomes

Baseline, week 1, week 2

CO was measured at baseline, wk 1 and wk 2. Self-reported CPD. Adverse events. Puff duration, puff number, inter-puff intervals (IPI). Cigarette dependence, craving, withdrawal, and subjective effects

Study funding

This work was funded by the University of East London through a PhD studentship award. The funder had no role in the study design, collection, analysis or interpretation of data, writing the manuscript and the decision to submit the manuscript for publication.

Author declarations

CK and KS have no conflicts of interest to declare. LD has provided consultancy for the pharmaceutical industry relating to the development of smoking cessation products.

Notes

New to 2022 update

Random sequence generation (selection bias)

Low risk

Participants were randomly allocated (using SPSS).

Allocation concealment (selection bias)

Unclear risk

No detail

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention arms received equally intensive interventions.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

CO measured

Incomplete outcome data (attrition bias)
All outcomes

High risk

There was a > 20% difference in FU between arms at 2 weeks. Overall, 50/70 = 71.43%. Cig-a-like 11/24 = 45%. Tank6 19/23 = 82.61%. Tank18 20/23 = 86.96%

Selective reporting (reporting bias)

High risk

Reported on AEs but excluded those who had reported AEs (as they did not complete all sessions (due to AEs)

Methods

Design: RCT. Pragmatic, 3-group, randomized, assessor-blinded, single-centre trial

Setting: Centre for Sport and Exercise Science (CSES) of Sheffield Hallam University, UK

Recruitment: from the community in the wider Sheffield area via: i) low-cost newspaper and post-office advertisement, ii) posters in local pharmacies, libraries, mosques, churches, and clubs, iii) social media or search engine advertisement (Facebook, Google ads) iv) notices in newsletters or participation in outreach events of community organizations (such as Sheffield U3A and AGE UK), iv) a study website, and v) out-reach events in local ethnic community centres or places of worship

Study start April 2017. Study end December 2020

Participants

Actual enrolment: 248 participants

Nicotine EC arm = 84

Non-nicotine arm = EC 82

NRT arm = 82

% female: nicotine EC = 55%; non-nicotine EC = 50%; NRT = 44%

Mean age 44

Mean CPD: nicotine EC = 18 (SD7); non-nicotine EC = 16 (SD7); NRT = 18 (SD7)

Mean FTND: 6 (SD2)

Inclusion criteria: Age > 18 years of either sex; People who smoke (at least 10 cpd for the past year); Willing (by declaration) to attempt to quit smoking by using the NHS services or e-cigarettes.

Exclusion criteria: Inability to walk; Recent (within 6 months) cardiovascular disease event (e.g. stroke, myocardial infarction) or cardiac surgery; Insulin-controlled diabetes mellitus or with co-existing skin conditions, leg ulcers, vasculitis or deep venous occlusion (as these may affect their cardiovascular function); Pregnancy; Requiring major surgery during the course of the study; Contra-indications/unsuitability for NRT; Current daily use of e-cigarettes; Currently undertaking a cessation attempt supported by a smoking cessation clinic.

Motivated to quit: yes

Interventions

• a) Complimentary e-cigarette equipment and refills (Tornado V5, Joyetech, Shenzhen, China, Totally Wicked, Blackburn, UK) at allocation stage, together with instructions on the correct usage of e-cigarettes. They will also receive behavioural support for a 3-month period. The nicotine strength of Group A cartridges will be up to 18 mg/mL nicotine strength. Participants, on average, received 20 bottles of 10 mL during the intervention period. Participants could choose ice menthol or tobacco flavour.
• b) As a), but with nicotine-free liquid
• c) Referral to NHS smoking cessation clinics and will receive NRT in conjunction with behavioural support. Received money or shopping vouchers (depending on personal preference) as reimbursement for NRT prescription charges

All groups received the same level and type of behavioural support as currently offered as standard by stop-smoking services, in the form of regular face-to-face or telephone appointments as per relevant guidelines, e.g. minimum of 6 support sessions within the 3-month period.

Outcomes

Follow-up: within 3 days of “quit date”, 3 and 6 months past quit date

Outcome measures:

• Macrovascular function (FMD assessment)
• Microvascular function
• Smoking status at 3 and 6 months, self-reported and biochemically validated by exhaled air measurement of < 10 ppm CO
• Change in CVD risk using Q-risk assessment
• Health economic effects using EQ-5D-L
• Total cholesterol and high density lipoprotein via fingerprick blood sample
• Participant experiences' assessment

Study funding

The trial was funded by Heart Research UK under a Translational Research Grant (RG2658). The funder had no role in the study’s design, conduct, and reporting.

Author declarations

The authors declare that they have no competing interests.

Notes

New to 2023 (previously ongoing)

Random sequence generation (selection bias)

Low risk

“Randomized remotely into three groups by an independent statistician using a computer-generated (nQuery Advisor 6.0, Statistical Solutions, Ireland) block randomization stratifed by gender and “pack-years” (number of packs (20 cigarettes per pack) per day times number of years smoked)

Unique trial number for each participant for the study duration”

Allocation concealment (selection bias)

Low risk

“Outcome assessors were blinded to group allocation and participants were reminded regularly not to share their group allocation with assessors or those providing behavioural support. The study statistician/health economist was blinded to group allocation.”

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Interventions equally intensive

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors were blinded to group allocation and participants were reminded regularly not to share their group allocation with assessors or those providing behavioural support. The study statistician/health economist was blinded to group allocation. Those delivering the intervention were only blinded in relation to which e-cigarette group the participants belonged to as the NRT group was receiving support through the stop-smoking service.

All measures biochemically validated or measured

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Nic EC 66/84 at 6 months

Non-Nic EC 64/82

NRT 72/82

Selective reporting (reporting bias)

Unclear risk

Not all secondary outcomes reported in this paper, but more publications likely to follow

Methods

RCT

Setting: Spiliopouleio Hospital , Cardiology Department Athens, Greece

Recruitment: Visiting Cardiology Unit Jan 2016 to Nov 2022

Participants

N=57

Aged 41 ± 8years; BMI:33.8±2.4Kg/m2

Inclusion: person with obesity; CC user.

Interventions

Electronic cigarette (EC).

NRT (nicotine patch)

NRT + bupropion (NRT+bupr)

Outcomes

Baseline, 3mths (end of treatment), 6 months

Abstinence at 6 mths. EC use at FU. Blood pressure. Weight.

Study funding

“Funding Acknowledgements: None.”

Author declarations

Not reported.

Notes

New to 2025 update.

Random sequence generation (selection bias)

Unclear risk

‘Randomised’ no detail provided.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Equally intensive

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not reported.

Selective reporting (reporting bias)

Unclear risk

No clinical record or full publication. Numbers at FU not reported.

Methods

Design: prospective randomized clinical trial

Recruitment: all patients admitted to a smoking cessation clinic at the Department of Otorhinolaryngology-Head and Neck Surgery, Okmeydanı Training and Research hospital

Setting: smoking cessation clinic, Turkey

Study start date: March 2013; Study end date: November 2013

Participants

Total N: 98 but analysis excluded 16 from intervention and 10 from control who did not stop smoking; thus 72 analyzed

N per arm: EC: 58 (42 analyzed); non-EC 40 (30 analyzed)

Inclusion criteria:

• Smoked at least 1 pack of cigarettes a day for at least 5 years

Exclusion criteria:

• History of allergic rhinitis, chronic sinusitis, vasomotor rhinitis, asthma, malignancy, or surgery in upper respiratory tract
• Age under 18 years
• Use of psychoactive drugs

Inclusion based on specific population characteristics: no

44% women; mean age 36; mean cpd and mean FTND not specified

Motivated to quit: “All patients were willing to quit smoking”.

E-cigarette use at baseline: not specified

Interventions

EC: Unclear

EC arm: “used EC to quit smoking” – allowed to select brand and flavour, used “medium density” liquid (11 to 12 mg/mL) (no further detail given)

Non-EC arm: received cognitive behavioural therapy (no further detail given)

Outcomes

3 months

Sinonasal outcome test (SNOT-22) via self-administered questionnaire, to evaluate changes in subjective symptoms. Saccharin transit test to evaluate nasal mucociliary clearance (MCC) function, which authors stated is “an important defence mechanism”

Study funding

Not specified

Author declarations

Not specified

Random sequence generation (selection bias)

Unclear risk

Quote: “Patients participating in the study were randomly divided into two groups; EC smokers (group 1) and non-EC smokers (group 2).”

No further detail provided

Allocation concealment (selection bias)

Unclear risk

No information given

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants were not blinded. The trial is described as single-blinded and outcome assessors were blinded. No placebo used

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Self-reported outcome data, participants not blinded and unequal amounts of support between arms

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Dropout rate not clear. Only analyzed people who quit

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Methods

Randomized, parallel-assignment, double-blind pilot trial

Setting: San Francisco Veterans Affairs Medical Center (SFVAMC), USA

Recruitment: veterans awaiting surgery

Recruitment: from VA hospital presenting for surgery

Study start date: August 2015; study end date: May 2016

Participants

Total N: 30

N per arm: NRT: 10; END: 20

Inclusion criteria: presented to the anaesthesia preoperative clinic for elective surgery 3 or more days before surgery; currently smoked ≥ 2 CPD, having smoked at least once in the last 7 days

Exclusion criteria: exclusively used other forms of tobacco or marijuana only; pregnancy/breastfeeding; unstable cardiac condition; currently using smoking cessation pharmacotherapy; already enrolled in a smoking cessation trial; using EC on a daily basis

Inclusion based on specific population characteristics: patients awaiting elective surgery

10% women; mean age 54; mean cpd 14; mean FTND 3.3

Motivated to quit: not specified

E-cigarette use at baseline: not specified but excluded daily users

Interventions

EC: Cig-a-like

Both groups received: i) referral to the California Smokers' Helpline, ii) brief advice lasting less than 2 minutes, iii) a brochure from the ASA about quitting smoking before surgery.

EC arm: 6-week supply of NJOY e-cigarettes (disposable, first generation). Instructed to use Bold (4.5%) ad lib for 3 weeks, then Gold (2.4%) ad lib for 2 weeks and then study (0%) ad lib for final week. Number of ECs issued corresponded to baseline cpd, assuming 1 EC = 10 cigarettes. Asked to refrain from the use of all study products at the end of 6 weeks

NRT arm: 5-week Nicoderm CQ patches, 1 week placebo patches. Dose based on cpd at baseline: ≥ 10 cpd, 21 mg/day for 3 weeks, 14 mg/day for 1 week, 7 mg/day for 1 week, 0 mg/day for 1 week. < 10 cpd at baseline: 14 mg/day for 3 weeks, 7 mg/day for 2 weeks, 0 mg/day for 1 week

Outcomes

30 days (phone), 8 weeks (in person), 6 months (phone)

Cessation: 7-day PP at 30 days (not validated), 8 weeks (CO-validated), 6 months (not validated). Smoking cessation for at least 48 hours on day of surgery (CO-validated)

Adverse events and biomarkers:

• Adverse events, side effects, and surgical complications by self-report at 30 days, 8 weeks
• At 8 weeks exhaled CO, FEV1, and FVC

Other outcomes measured:

• Attitudes and usage
• Salivary cotinine
• Smoking reduction

Study funding

“This work was funded by internal UCSF Department of Anesthesia and Perioperative Care funds (San Francisco, California, United States of America) and the UCSF Resource Allocation Program grant, administered by the Helen Diller Family Comprehensive Cancer Center developmental funds from the National Cancer Institute Cancer Center Support Grant (P30 CA 82103-16). E-cigarettes were purchased from NJOY using these funds. NJOY had no involvement in the design, execution, or analysis of the study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

Author declarations

“The authors declare there are no competing interests”.

Notes

3 NRT participants used EC, 2 EC participants used nicotine patch

Study listed as ongoing study NCT02482233 in the 2016 review update

Random sequence generation (selection bias)

Low risk

Quote: “Randomization was computer-generated, with randomly permuted block sizes of 3 or 6, in a 2:1 ratio using the ralloc program”.

Allocation concealment (selection bias)

Low risk

Quote: “Allocation was concealed by consecutively numbered, sealed, opaque envelopes”.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Not blinded but both interventions active with equal amounts of support so performance bias judged unlikely

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Self-report only at 6 months and participants not blinded to condition, but similar level of support given to both groups so differential misreport judged unlikely

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1 NRT and 1 ENDs loss to follow-up at 6 months

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Methods

Design: randomized controlled trial

Recruitment: recruited from motor company

Setting: motor company, medical office in Korea

Study start date: 5 January 2012; study end date: 31 August 2012

Participants

Total N: 150

N per arm: EC: 75; NRT: 75

Inclusion criteria: Male; At least 10 cpd in previous year; Smoked for at least 3 years; Motivate to stop smoking entirely or reduce consumption.

Exclusion criteria: Past history of serious clinical disease; Attempted to stop smoking in past 12 months by using NRTs.

Inclusion based on specific population characteristics: no

0% women; mean age 42.3; mean cpd: not reported, 1.01 packs per day; mean FTND 4.05

Motivated to quit: yes, or to reduce

E-cigarette use at baseline: not specified

Interventions

EC: Refillable

Both arms received 50 minute education sessions on smoking cessation and the use of smoking-cessation aids, instructed to visit the medical office each month for evaluation and counselling by a health practitioner who was unaffiliated with the study.

Arm 1: Participants supplied with eGo-CTM EC (nicotine 0.01 mg/mL) from Ovale in 12-wk supply

Arm 2: 2 mg nicotine gum in 12-wk supply

Outcomes

12, 24 weeks (in person)

Cessation: continuous abstinence from 9 to 24 weeks, exhaled CO < 10 ppm, negative urine cotinine

Adverse events and biomarkers: yes, but just note ‘adverse events’

Other outcomes measured: 7-day PPA, cigarette reduction

Study funding

“none”

Author declarations

“none declared”

Notes

Study listed as ongoing study KCT0001277 in the 2016 review update

Random sequence generation (selection bias)

Low risk

Quote: “computer-generated randomization sequence with a block size of 2”

Allocation concealment (selection bias)

Low risk

Quote: “The enrolment and assignment of all subjects were performed by a clinical research coordinator not involved in the study”.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Not blinded but both interventions active with equal amounts of support, so performance bias judged unlikely

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Participants not blinded but results biochemically validated

Incomplete outcome data (attrition bias)
All outcomes

Low risk

61/75 NRT and 71/75 EC FU at 24 weeks

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported

Methods

Design: randomized, parallel-assignment, double-blind trial

Recruitment: participants enrolled in lung cancer screening programme

Setting: early lung cancer detection programme (Cosmos II) at European Institute of Oncology, Italy

Study start date: September 2014; study end date: January 2016

Participants

Total N: 210

N per arm: 70 participants per arm

At 12 months: nicotine EC 60; non-nicotine EC 58; support only 60

Inclusion criteria:

• Participants are involved in the COSMOS II study
• Participants are 55 years or more and have smoked at least 10 cigarettes a day for the past 10 years
• Participants wish to reduce tobacco smoking (motivational score higher than 10) who are not treated at a smoking centre
• Signed informed consent

Exclusion criteria:

• Symptomatic cardiovascular disease
• Symptomatic severe respiratory disease
• Regular psychotropic medication use
• Current or past history of alcohol abuse
• Use of smokeless tobacco or NRT
• Participation in another anti-smoking programme in the current year

Inclusion based on specific population characteristics: 55 years of age or older

37% women; mean age 62.8; mean cpd 19.38; mean FTND 4.37

Motivated to quit: yes

E-cigarette use at baseline: excluded people who smoke who had ever regularly used e-cigarettes for more than 1 week alone or in combination with tobacco cigarettes

Interventions

EC: Cig-a-like

Both arms received “low intensity counselling” – phone at week 1, 4, 8, and 12, approx. 10 mins each

Nicotine EC arm: e-cigarette kit and 12 x 10 mL liquid cartridges (8 mg/mL nicotine concentration). During the first week, participants could use the e-cigarette ad libitum. At the end of the first week, asked to use only EC for the next 11 weeks.

Nicotine-free EC (placebo) arm: nicotine-free EC – same as above but with nicotine-free EC

Outcomes

Months 3, 6, and 12

Cessation: continuous abstinence for previous month, CO ≤ 7 ppm

Adverse events and biomarkers: FOR EC ARMS ONLY:

• Exhaled CO
• Leicester Cough Questionnaire (LCQ)
• Respiratory symptoms (self-report)
• Side effects using checklist

Other outcomes measured:

• Motivational questionnaire
• HADS
• EC use

Study funding

This study was supported by a grant from Fondazione Umberto Veronesi (FUV).

Author declarations

The authors declared no conflicts of interest.

Notes

Listed as ongoing study Lucchiari 2016 (NCT02422914) in 2016 review; new for 2020 update, relabelled from Lucchiari 2020 to Lucchiari 2022 at 2023 update.

Random sequence generation (selection bias)

Low risk

Quote: “A randomization list using a permuted block design (40 blocks of 6 subjects randomly assigned to 1 of the 3 treatment arms) had been previously prepared by independent personnel.”

Allocation concealment (selection bias)

Low risk

Double-blind, active and placebo e-cigarettes labelled by independent personnel; researcher and participants blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

“double blind” for nicotine vs no nicotine EC but limited info given; however, as similar levels of support across arms performance bias judged unlikely

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biochemical validation used

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Approx. 73% followed up in each group at 6 months, very little difference between groups

At 12 months > 70% FU

Selective reporting (reporting bias)

High risk

Papers stated CO collected but data not presented

Methods

Design: RCT

Recruitment: participants were recruited throughout the USA through Facebook and multimedia advertisements (newspapers, radio, TV, e-cigarette forums, and so on) for a study measuring attitudes and behaviours about cigarettes and e-cigarettes.

Setting: USA

Study start date: 31 March 2015. Study end date 30 June 2019

Participants

2896 dual users of nicotine EC and combustible tobacco cigarettes

Assessment only n = 575; generic smoking cessation booklets n = 1154; targeted booklets n = 1167

37% female; mean age 29.9

Mean cpd: 1 to 10, 1663 (57%); 11 to 20, 972 (34%); > 20, 259 (9%). Mean FTND 3.6. E-cigarette use at baseline

Inclusion criteria: age 18 years or older, smoked 1 or more CC per week over the preceding year, used EC 1 or more times per week over the preceding month, not currently enrolled in a face-to-face smoking cessation programme, and able to speak and read English. The original inclusion criteria required daily smoking. Many dual users were skipping smoking on some days. Amended the use frequency criteria for smoking and vaping at 1 or more uses per week. The protocol was amended on 25 September 2016. 652 participants had been recruited up to that date.

Participants were not necessarily seeking treatment or motivated to quit smoking or vaping.

Interventions

EC type: n/a

Assessment only (n = 575)

Generic smoking cessation self-help booklets previously shown to be efficacious in smokers (n = 1154) (an introductory Stop smoking for good brochure, 10 x Stop smoking for good didactic booklets, and 9 How I quit smoking pamphlets)

Booklets specifically targetting dual users (n = 1167 (If you vape: a guide to quitting smoking), which included an introductory If you vape brochure, a series of 10 x If you vape: guide to quitting smoking booklets, and 9 x My story pamphlets)

Participants assigned to the GENERIC or eTARGET groups were sent the intervention materials by post, with the option of also receiving them electronically.

Outcomes

Full follow-up assessments: 6, 12, 18, and 24 months. Abbreviated assessments: 3, 9, 15, and 21 months after baseline

7-day PPA at each assessment point. Sustained abstinence: 30-day and 90-day PPA

Breath CO and saliva samples (for cotinine analysis) were collected at the 12- and 24-month follow-up points for participants who reported abstinence and resided within 100 miles of the home institution.

Cut-offs of 8 ppm for CO and 10 ng/mL for cotinine were used to determine abstinence. The disconfirmation rates from this sample were used to estimate adjusted smoking rates for the full sample.

Study funding

This work was supported by the National Institute on Drug Abuse of the NIH (R01DA037961). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

This work has also been supported in part by the Biostatistics and Bioinformatics Shared Resource and the Participant Research, Interventions, and Measures Resource at the H Lee Moffitt Cancer Center and Research Institute, a National Cancer Institute designated Comprehensive Cancer Center (P30CA76292)

Author declarations

Quote: "THB has received research support from the US National Institutes of Health (NIH), the American Cancer Society, the Florida Department of Health, and Pfizer; has collaborated on funded research with Voxiva, Optum, and the University of East Anglia (Norwich, UK); spent sabbatical at the Trimbos Institute and Utrecht University (Utrecht, Netherlands); is on the advisory board of, and holds restricted stock in, Hava Health, which is developing a pharmaceutical grade electronic nicotine delivery system for smoking cessation; participated in a Best Brains Exchange for Health Canada, providing advice on e-cigarette policy; and consulted for the Australian Government Solicitor regarding plain tobacco packaging. UM has received research support from the NIH and the Galician Plan of Research, Innovation, and Growth (Spain); and has received funding from the Barrie Foundation to receive predoctoral training at the University of Newcastle (Callaghan, NSW, Australia). VNS has received research support from the NIH and the Florida Department of Health. SKS has received research support from the NIH, the American Cancer Society, the Florida Department of Health, and Pfizer. DJD has received research support from the NIH, the American Cancer Society, and the Florida Department of Health, and has provided paid expert testimony in litigation against tobacco companies. MMB has received funding from the NIH, the Florida Department of Health, the US Department of Veterans Affairs, the US Centers for Disease Control and Prevention, the National Science Foundation, and the US Department of Housing & Urban Development; and has received research support from Gilead Sciences, Florida Blue Foundation, Bristol Myers Squibb Foundation, Merck Foundation, Maine Cancer Foundation, and Pfizer. PTH has received research support from the NIH, US Food and Drug Administration (FDA), and Virginia Foundation for Healthy Youth. TE conducts research supported by the National Institute on Drug Abuse of the NIH and the Center for Tobacco Products of the FDA; is a paid consultant in litigation against the tobacco industry and the electronic cigarette industry; is named on one patent for a device that measures the puffing behaviour of electronic cigarette users and on another patent for a smartphone app that determines electronic cigarette device and liquid characteristics; owns shares in a variety of mutual funds, the exact stock makeup of which he has no control, and owns shares in three publicly traded companies, none of which are in any way related to the tobacco industry, the electronic cigarette industry, or any other aspect of this work; and has served as a special government employee of the US Government in the context of his service on the FDA’s Tobacco Products Scientific Advisory Committee and the Department of Health and Human Services Secretary’s Advisory Committee on Human Research Protection. CRB has received research support from the New Zealand Ministry of Health, the Health Research Council of New Zealand, CureKids Foundation, Heart Foundation, Health Promotion Agency, and Auckland Council and Sanitarium; collaborates on funded research with Newcastle University (Australia) through a grant from the Australian National Health and Medical Research Council, with Zhejiang University (Hangzhou, China) and Kunming University (Yunnan, China) on an Education New Zealand Tripartite grant, and with the University of Malaya (Kuala Lumpur, Malaysia) on a University of Malaya Grand Challenges grant; received funding from Pfizer Australasia for a survey of the impact of COVID-19 on health workers in low-income and middle-income countries and from Johnson & Johnson Japan for consultancy on smoking cessation medication; and was a consultant to Moffit Cancer Center on this study through an NIH grant. LRM and KOB declare no competing interests. The employees of Moffitt Cancer Center—UM, VNS, SKS, DJD, LRM, KOB, MMB, and THB—are eligible for sharing of any revenue that might be generated by products developed during their employment, including the intervention used in this study."

Notes

Quote: "Participants were compensated US$10–20 for the first eight assessments and $40 for the final one, and they were eligible for $40–60 bonuses for completing at least seven assessments. Participants returning assessments within 1 week were sent inexpensive appreciation gifts."

Appendix: "Participants were not aware in advance of the interview that they would be asked for biosamples, and new informed consent was obtained at that time. Participants received $20 for completing a biochemical verification interview and $15 for providing biosamples."

Random sequence generation (selection bias)

Low risk

Quote: "We used computer generated randomisation with balanced permuted blocks (block size 10, with 2-4-4 ratio) to allocate participants to assessment only (ASSESS group), generic smoking cessation self-help booklets (GENERIC group), or booklets targeting dual users (eTARGET group)."

Allocation concealment (selection bias)

Low risk

Computer-generated (see above)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Tailored versus generic booklet judged low risk as similar intensity; this is the comparison used in the meta-analysis.

Tailored versus no support would be high risk due to differential levels of support provided and no blinding.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

As above, tailored versus generic similar intensity so judged to be low risk of differential misreport (self-reported cessation only)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All > 50% at 24 months

ASSESS: 361/575*100 = 62.8%

GENERIC: 619/1154*100 = 53.6%

eTARGET: 642/1167*100 = 55%

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported in the trial register reported in the publication

Methods

Design: randomized, cross-over trial (e-cig vs placebo)

Recruitment: via local media outlets

Setting: community, USA

Study start date/study end date: not specified

Participants

Total N: 24

Inclusion criteria:

• ≥ 18+ years
• People who smoke daily (≥ 10 cpd)
• Not interested in quitting in the next 30 days
• English-speaking
• Interested in using EC

Exclusion criteria:

• Using cessation meds
• Use of ECs in last 6 m
• Exhaled CO < 6 ppm
• History of CV trauma or uncontrolled hypertension
• Pregnant

Inclusion based on specific population characteristics: no

25% women; mean age 48.5; mean cpd 16.3; FTND not reported

Motivated to quit: no (eligibility criteria was to not want to quit in next 30 days)

E-cigarette use at baseline: 8/24 (33%) had previously tried an EC, average 9.4 months since last use, average length of use 3.6 days

Interventions

EC: Cig-a-like
Smoked “as usual” for 1 week followed by 2 weeks of either placebo or active 1st generation EC BluCig starter kit with up to 7 cartridges (prefilled, with either active 16 mg or 0 mg nicotine solution)

Participants were instructed “this e-cig may or may not contain nicotine; we ask that you try it at least once, but use it however you like; smoke regular cigarettes as you wish.” Shown how to charge the device and sampled the product during the visit. Provided a handout on how to use the product (e.g. switching cartridges) and general information about ECs

Outcomes

1 week in each condition, in person

Adverse events and biomarkers:

• Adverse events, not clear how collected
• Exhaled CO

Other outcomes measured:

• Vaping
• Regular smoking
• Perceived reward from ECs
• Intentions/confidence to quit
• Cotinine
• Withdrawal symptoms

Study funding

“…supported by grants P01 CA138389, P30 CA138313 (Hollings Cancer Center Support Grant) from the National Cancer Institute of the National Institutes of Health and UL1 TR000062 from the National Center for Advancing Translational Science of the National Institutes of Health. BWH was supported by K12DA031794”.

Author declarations

“KMC has received grant funding from Pfizer, Inc., to study the impact of a hospital-based tobacco cessation intervention. He also receives funding as an expert witness in litigation filed against the tobacco industry. We have no other declarations of interests to declare”.

Notes

New for 2020 update

Random sequence generation (selection bias)

Unclear risk

Quote: “Participants were randomized to receive either an active or placebo EC first”; no further information provided

Allocation concealment (selection bias)

Unclear risk

Refer to 'random sequence generation'.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: “Participants and research staff conducting sessions were blinded to dose. All cartridges were pre-loaded by the manufacturer. Labeling was removed by a research team member not involved in participant contact to mask placebo versus active ECs. We restricted flavour options to regular tobacco flavour or menthol to most closely match usual cigarette brand flavour profile and reduce unwanted variance in product”.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: “Participants and research staff conducting sessions were blinded to dose. All cartridges were pre-loaded by the manufacturer. Labeling was removed by a research team member not involved in participant contact to mask placebo versus active ECs. We restricted flavour options to regular tobacco flavour or menthol to most closely match usual cigarette brand flavour profile and reduce unwanted variance in product”.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not specified

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Methods

Design: RCT

Setting: Australia

Recruitment: commercial market research panel and supplemental recruitment by study researchers. An invitation to participate was available to 46 857 I-view panel members, including those with no smoking status recorded. In addition, advertisements to the general public were used to recruit additional participants.

Study start date: 2014

Participants

Total: N 1712 (table 1 full sample 1562)

Arm A [Standard cessation advice & NRT (NRT short-term)] flow diagram 368 (324 received intervention)

Arm B [Quit or substitute advice and NRT: advice to use NRT as a longer-term substitute for smoking if required to maintain smoking cessation] flow diagram 671 (620 received intervention)

Arm C [Quit or substitute advice and NRT and/or e-cigarettes] flow diagram 673 (619 received intervention)

Inclusion criteria:

Current daily smoking (at least 6 cpd). Agree to try samples of nicotine products. 18+ years

Exclusion criteria:

Currently being treated for serious cardiovascular disease, cancer, taking regular medication for mental health condition, uncontrolled high blood pressure, stomach ulcer, kidney or liver disease, overactive thyroid or adrenal gland cancer. Use insulin for diabetes. Asthma or chronic throat disease. Pregnant or planning to become pregnant/breastfeeding

Female 64%; mean age 46.7 (SD 12.3); mean CPD 18.2 (SD8.7)

E-cigarette use at baseline: 28% had previously tried EC

Motivated to quit: yes; 58% want to quit a lot

Interventions

EC type: cartridge

Arm C only: disposable e-cigarette available in two strengths (free-base nicotine 3.0% and 4.5%). A rechargeable version of the same brand with replaceable cartridges (3.0% v/v and 4.5% v/v) was substituted when the disposables were discontinued by the manufacturer (September 2014). The e-cigarettes contained only nicotine, vegetable glycerin, and water, and were unflavoured.

a) Arm A (usual care smoking cessation practice in Australia) comprising quit with NRT. Factsheet explaining the relative harm of NRT compared to smoking, free sample of NRT, participant chooses preferences, has the intervention (or a combination of two products if this is their preference) free for 3 weeks then offered at a subsidized rate for further 6 months. The NRT products included nicotine gum, lozenges, inhalator, and mouth spray. Lozenges and gum were offered at two strengths.

b) Arm B as (a), but with additional information provided: advice to quit or substitute with NRT

c) Arm C as (a), but additional information on electronic cigarettes and emphasis on cessation, and may select electronic cigarettes as well as NRT

Outcomes

Baseline, 7 months and 12 months, self-report

• Continuous abstinence
• Self-reported 7-day point prevalence abstinence
• NRT and EC use
• Interest in quitting smoking and in quitting NRT
• Cigarette consumption
• Product orders and use
• Quit attempts
• AEs

Study funding

Funding was from the National Health and Medical Research Council, Australia (#GNT1020123). The e-cigarettes supplied in this trial were Vype brand, and were purchased from the manufacturer Nicoventures Trading Ltd., a UK-based company that was a division of British American Tobacco. The other nicotine products were purchased in Australia from various distributors. Participant recruitment and survey data collection was managed by I-View Social Research. None of these entities had any role in study design, data collection, data analysis, data interpretation, or writing of this paper.

Author declarations

No authors have received financial support for the submitted work from any companies with a financial interest in the products under investigation. C.B. has undertaken consultancy for J&J Japan, a manufacturer of nicotine replacement therapy. N.W. and C.B. have completed a smoking cessation trial in which cytisine was supplied by Achieve Life Sciences, and a smoking cessation trial in which varenicline and matching placebo were supplied by Pfizer under their investigator-initiated research programme. N.W. and C.B. have previously undertaken two trials of e-cigarettes for smoking cessation (with e-cigarettes purchased from a NZ e-cigarette online retailer [NZVAPOR, https://www.nzvapor.com/], e-liquid for one trial purchased from NicoPharm, Australia and nicotine patches supplied by the NZ government via their contract with Novartis [Sydney, Australia]). Neither NZVAPOR nor NicoPharm have links with the tobacco industry. None of the authors' spouses, partners, or children have financial relationships that may be relevant to the submitted work. All authors have no non-financial interests that may be relevant to the submitted work.

Notes

New to 2022 update

Random sequence generation (selection bias)

Low risk

Quote: "After completing the baseline survey, participants were block randomized in a 1:2:2 ratio to one of the three conditions by a computer generated random number sequence".

Allocation concealment (selection bias)

Low risk

Quote: "Participants and researchers were not blind to the allocated treatment; however, participants were not advised that there were different treatment conditions".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Participants and researchers were not blind to the allocated treatment; however, participants were not advised that there were different treatment conditions".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Self-report

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "72.5% of participants who received the allocated intervention in Condition A completed the 7-month survey, compared with 74.4% of Condition B and 72.9% of Condition C".

At 12 months: arm A 233/324; arm B 457/671; arm C 448/673

Selective reporting (reporting bias)

Low risk

Specified outcomes reported

Methods

Design: RCT, pragmatic, randomized, partial cross-over

Setting: Australia

Recruitment: not stated

Study start date: recruited in 2018-2019

Participants

Total: N 355

Arm A: 181

Arm B: 174

Inclusion criteria:

Diagnosed with/treatment for HIV or hepatitis C (HCV) or receiving opioid substitution therapy (OST). Diagnosed with or receiving treatment for priority health conditions in the past 12 months. Referral to Quitline counselling and smoking cessation support programme (standard care) but has not begun quit attempt. 18+ years; currently smoke 10+ cigarettes per day; willing to make a quit attempt

Exclusion criteria:

Already started quit attempt (i.e. post-quit day) or enrolled in another smoking cessation clinical trial or using varenicline or bupropion or used a nicotine vaporizer product in the last 30 days. Health reason (e.g. CVD, terminal illness, recent hospitalization for mental health reason, pregnancy)

Interventions

EC type: refillable

Arm 1) Referral to Quitline telephone smoking cessation counselling + Nicotine patches (15 mg/16-hr) delivered at baseline + refillable nicotine vaporizer device (2 x kits) + nicotine vaporising liquid (in high and low strength - high strength: nicotine 1.8%; low strength: nicotine 0.6%). 1 patch to be applied daily to skin for up to 84 days. The vaporizer with nicotine liquid is to be used as needed, up to 3.5 mL per day to treat withdrawal symptoms for up to 2 years (concurrently with patches for the first 84 days) to assist smoking cessation and relapse prevention. Participants start on high-strength nicotine liquid and may decrease their dose to low strength to assist with dose reduction prior to stopping use of the vaporizer.

Arm 2) Referral to Quitline telephone smoking cessation counselling + Nicotine patches (15 mg/16-hr) + participant’s choice of either nicotine gum or nicotine lozenges (up to 800 x 4 mg pieces to be used up to 8 per day) delivered at baseline. Between 6 and 9 months post-baseline - participants in Arm 2 who are smoking (either failed to quit or relapsed) will be offered: refillable nicotine vaporizer (2 x kits) + nicotine vaporizing liquid (in high and low strength - high strength: nicotine 1.8%; low strength: nicotine 0.6%) to make a second quit attempt. Participants will have until 2 years from baseline to use the vaporizer for smoking cessation and relapse prevention.

Arm B participants who were smoking at 6 months were offered the NVP intervention (NVPs as second-line therapy). Switched over to EC intervention, called Arm C

Outcomes

Baseline 6 months, 12 months, 24 months

Primary outcomes:

Continuous abstinence from smoking from weeks 12 to 26 assessed at 26 weeks from baseline by self-report (bio-confirmed)

Secondary outcomes:

Continuous abstinence from smoking

AEs at 12 weeks and 26 weeks

Abstinence is assessed through study-specific survey questions in Module CS. Combustible Smoking Questions – urine specimens will be batch-tested for anabasine and cotinine at 6-, 12-, and 21-month time points.

Study funding

National Health and Medical Research Council

Author declarations

Not reported

Notes

Abstract only

New to 2022 update

Random sequence generation (selection bias)

Unclear risk

No detail

Allocation concealment (selection bias)

Unclear risk

No detail

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention arms both received interventions.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Participants that self-report abstinence from smoking will be asked for a urine specimen for bio-confirmation.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No detail in conference abstract

Selective reporting (reporting bias)

Unclear risk

Conference abstract. Outcomes may be reported more fully at a later date.

Methods

Design: RCT

Recruitment: Clients of Queen Mary University of London's community stop-smoking service who did not manage to stop smoking with routine treatment were invited to take part. Also recruited eligible smokers seeking help with quitting via social media.

Setting: Queen Mary University of London, community stop-smoking service

Study start date: April 2017 to August 2018

Participants

Total: N = 135

N per arm: E-cigarette 68; NRT 67

Inclusion criteria:

History of failed quit attempts using stop-smoking medications and/or stop-smoking services. Willing to use their allocated harm-reduction strategy for at least 4 weeks. 18+ years

Exclusion criteria:

Currently using EC or any stop-smoking products. Strong preference to use or not to use NRT or EC. Pregnancy or breastfeeding

Women: 49%; mean age 40; median CPD 15 (IQR 10); median FTND: 5 EC arm, 4 NRT arm; motivated to quit

E-cigarette use at baseline: percentage tried EC earlier: 31% EC arm, 49% NRT arm

Interventions

EC: Refillable

EC Arm. EC starter pack and instructions to purchase further e-liquids of flavour and strength of their choice (voucher for up to £40). Participants paid for further supplies themselves. They were encouraged to try e-liquids of different strengths and flavours if the initial purchase did not meet their needs. Up to 8 weeks supply. Minimal behaviour support

NRT Arm: NRT of choice. The choice of products included nicotine patch, chewing gum, nasal spray, microtab, inhalator, and mouth spray. Up to 8 weeks supply. At the baseline visit, participants selected an NRT product or product combination.

Minimal behavioural support

Both groups: 2 face-to-face sessions (baseline and week 1). Baseline: Participants selected products of their choice and received instructions on how to obtain them. Week 1: Smokers bring allocated product to the session, receive advice on use, test and start product use. Commitment to not using unallocated products for the next 4 weeks. Those wishing to stop smoking altogether were asked to set a target quit date (TQD). Participants received phone calls 1 and 4 weeks later to monitor product use and smoking status and to provide brief support.

Outcomes

Baseline (week 0), week 1, week 4, week 24

Primary outcome measure:

Cigarette consumption per day, assessed by self-report in the follow-up survey created for the purpose of the study at 1, 4, and 24 weeks post-quit date/preparation date. Those who report ≥ 50% smoking reduction will be validated with a CO reading in the clinic.

Secondary outcome measures:

1. Use of allocated harm reduction strategies. 2. Strategy ratings. 3. Changes in smoking behaviour. 4. Proportion of people still using allocated strategy at 6 months. All measured by the follow-up survey created for the purpose of the study at 1, 4, and 24 weeks post-quit date/preparation date. AEs

Study funding

The study was funded by a Tobacco Advisory Group project grant, Cancer Research UK (C6815/A20503).

Author declarations

PH and HM have received research funding from and provided consultancy to Pfizer, a manufacturer of stop-smoking medications. DP has received research funding from Pfizer. All other authors had no conflicts to declare.

Notes

Participants invited for CO readings at 4 weeks and 6 months received £10 in compensation for their time and travel at both visits.

New to 2022 update

Random sequence generation (selection bias)

Low risk

Quote: “Randomisation sequences (1:1 ratio in permuted blocks of 20) were produced by an independent statistician using computer generated randomisation codes.“

Allocation concealment (selection bias)

Low risk

Quote: “Codes were sealed in opaque envelopes and marked with a unique randomisation number. Study staff allocated randomisation numbers sequentially. Staff opened the next envelope and entered the allocation onto the clinical record form (CRF) and randomisation log.”

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: “Data analysis was completed blind by an independent statistician.”

Both arms active intervention

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: “Data analysis was completed blind by an independent statistician.”

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: “Follow-up rates were 85% and 88% at 4 weeks and 88% and 70% at 6 months in the EC and NRT group, respectively.”

Selective reporting (reporting bias)

Low risk

Outcomes registered were all reported.

Methods

Design: RCT

Recruitment: clinics

Setting: SMI clinics, USA

Study start date: October 2016; study end date: August 2017

Participants

Total N: 7

N per arm: NRT: 4; EC + NRT 3

Inclusion criteria: diagnosed with schizophrenia (or other SMI, not clear); be in stable medical condition (DSM-V); report smoking ≥ 10 tobacco cigarettes/day; breath CO ≥ 10 ppm; report wanting to reduce their cigarette smoking; stable living situation

Exclusion criteria: pregnant or breastfeeding; report wanting to quit smoking in the immediate future; test positive for illicit drugs except THC; any illness, medical condition, or use of medications, which in the opinion of the study physicians would preclude safe or successful completion of the study, or both

Inclusion based on specific population characteristics: yes - SMI (schizophrenia and schizoaffective disorder, bipolar disorder, or PTSD)

43% women; mean age 48.3; mean cpd: NR; mean FTND: NR

Motivated to quit: Wanted to quit or reduce their cigarette smoking but did not want to quit in the immediate future (this was an exclusion criterion). NB – trial registry stated wanted to reduce and protocol stated wanted to quit or reduce as inclusion criteria.

E-cigarette use at baseline: not specified

Interventions

EC: Refillable

Both arms received a nicotine patch 21 mg for 4 weeks.

EC + NRT: 4 weeks: 1) a 3.3 V, 1000 mAh battery; and 2) a 1.5 Ohm, dual-coil cartomizer (SmokTech; Shenzhen, China). Nicotine concentrations 36 mg/mL. Verbal and written instructions on how to use and maintain the e-cigarettes at week 1 visit. Nicotine patch (21 mg)

NRT arm: NRT only (nicotine patch, 21 mg)

Outcomes

5 weeks

Cessation: n/a but “change in smoking”

Adverse events and biomarkers:

Breath CO, COPD-related symptoms, EC side effects (e-cig side effects questionnaire), AEs, SAEs

Other outcomes measured:

Urinary cotinine, cpd, tobacco dependence, craving, withdrawal symptoms, desire to quit, confidence to quit, EC dependence, EC use, satisfaction with EC, nicotine dependence, schizophrenia symptoms (brief psychiatric rating scale), cognitive domains associated with schizophrenia (MATRICS consensus cognitive battery), changes in positive symptoms of schizophrenia (scale for the assessment of positive symptoms), changes in negative schizophrenia symptoms (scale for the assessment of negative symptoms), suicide ideation (Columbia Suicide Severity Rating Scale)

Study funding

Sponsors: The University of Texas Health Science Center, Houston

Author declarations

Not reported

Notes

New for 2020 update. Information from clinical.trials.gov registry and unpublished protocol; discrepancies between the two in terms of trial methods. Feasibility for future NIH grant application. Intended to recruit 20 participants, but only 7 started and completed.

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

“double-blind” but “open-label” elsewhere, no further info given

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not reported

Selective reporting (reporting bias)

High risk

Schizophrenia and COPD outcomes not reported

Other bias

Unclear risk

Some discrepancies between clinical trials record and protocol linked to from record, including when NRT started and inclusion criteria (just schizophrenia or all SMI). Target sample size was 20 but only 7 people recruited

Methods

RCT, randomized interventional clinical trial

Setting: Ohio State University Comprehensive Cancer Center, USA

Study start date: June 2017. Study completion: January 2022

Participants

Total N: 372

Usual brand CC = 105; Low wattage EC = 133; High wattage EC = 134

62.6% female; mean age 40.33 (11.04 SD); mean CPD 17.28 (8.93 SD)

Inclusion criteria: no quit attempt in the prior 3 months and no plan to quit in the next 3 months; smoked ≥ 5 cigarettes per day for the past year; minimal interest in switching to an alternative product; never purchased or regularly used a tank system, mechanical mod, or advanced personal vaporizer EC, though previous use of cig-a-like devices will be allowed

Exclusion criteria: unstable or significant medical condition such as respiratory, kidney, or liver disease; unstable or significant psychiatric conditions; history of cardiac event or distress within the past 3 months; and pregnant/breastfeeding; < 18 years.

Motivated to quit: no

EC use at baseline: no

Interventions

1. Low-wattage e-cigarette device, provided for 12 weeks. Instructed to vape ad libitum for 12 weeks. Assessed at 6 months and 12 months for continued use of device.

2. High-wattage e-cigarette device, provided for 12 weeks. Instructed to vape ad libitum for 12 weeks. Assessed at 6 months and 12 months for continued use of device.

3. Usual brand cigarette, provided free for 12 weeks, instructed to smoke ad libitum for the duration of the study.

Outcomes

Baseline, week 1, week 4, week 8, week 12, week 26, and week 52

Complete change from conventional cigarettes.

Exhaled carbon monoxide of ≤ 10 ppm.

AEs, SAEs.

Oral mucosa samples collected 0, 4, and 12 weeks. Damage was quantified by q-PADDA

EC dependence; EC preference; biomarkers of exposure NNAL; NNN; TNE; nicotine metabolite ratio; nickel and other relevant metals; cadmium and other relevant metals; lead and other relevant metals; 8-iso-PGF2a; PGEM; q-PADDA

Study funding

NIH/NCI (R01CA204891, Wagener; R01CA242168, Queimado.

Author declarations

Not reported

Notes

Moved to new study in 2025 update. Added as ongoing study in 2022 update

Random sequence generation (selection bias)

Low risk

“Randomization will occur using a stratified block-randomization procedure with small, random-sized blocks."

Allocation concealment (selection bias)

Unclear risk

No detail

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

2 EC arms equally intensive.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biochemically validated complete switch from CC to EC.

Incomplete outcome data (attrition bias)
All outcomes

High risk

High at 12 months: UC = 78/105 = 74.3%; Low wattage EC = 67/133 =50.4%; High wattage EC = 65/134 = 47.0%. [Low at week 26: CC 77/105 = 73%; Low wattage EC: 69/133 = 52%; High wattage EC: 73/134 = 54.5%.]

Selective reporting (reporting bias)

Unclear risk

Some data available on NCT record / abstract other outcome data may be reported later.

Methods

RCT. Randomized, parallel assignment

Setting: USA

Participants

63 participants randomised at baseline and started their first week of the ecological momentary assessment (EMA). 60 randomised to treatment arm at week 1

Usual SREC pod flavours = 32 (30 at week 1);

Choice of SREC pod flavours = 31 (30 at week 1)

Inclusion criteria: ≥ 21 years; ≥ 7 cpd ≥ 1 yr; breath CO ≥ 10 ppm; interested in reducing combustible cigarette use; willing to try EC; attend in-person assessments for 5 months; English-speaking; women who are of childbearing age cannot be pregnant and must agree to use an approved form of birth control during the study.

Exclusion criteria: current use of any smoking cessation medication or participation in a smoking cessation programme or study; daily EC use; pregnancy; no 2 members of the same household may participate in this study.

Interventions

EC: Standardized Research E-Cigarette (SREC)

Participants will be stratified by sex and randomly assigned with a 1:1 allocation ratio to one of two conditions:

1) to receive SREC pods in their usual flavour either tobacco (regular smokers) or menthol (menthol smokers) (N = 30);

2) to receive SREC pods in their choice of flavour (N = 30). The SREC pods used in this study come in tobacco, menthol, blueberry, and watermelon flavors. No other flavors will be available to use with the SREC.

Counseling at Week 2. Participants in both conditions will receive brief behavioral counseling on reducing their combustible cigarette use by substitution with SREC.

NB Earlier version of this study compared: Nicotine SREC vs Placebo (non-nicotine) SREC

Outcomes

3, 4, 5 to 13, 14, 18 weeks

Combustible cigarette use

Abstinence from combustible cigarettes (defined as no cigarette smoking in the past 7 days)

The total number of cigarettes smoked in the 7 days prior to the last assessment

CO level. BP. Heart rate. Weight. Self-report of respiratory symptoms. Fagerstrom Test for Nicotine Dependence

Study funding

Sponsor: University of Illinois at Chicago.

Collaborators: National Institute on Drug Abuse (NIDA); University of Chicago

Notes

New to 2026 update. Added as ongoing to the 2022 update

Random sequence generation (selection bias)

Unclear risk

"Participants stratified by sex and randomly assigned with a 1:1 allocation ratio to one of two conditions" No more detail provided.

Allocation concealment (selection bias)

Unclear risk

No detail provided. No masking (Open Label).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

No masking (Open Label). Similar intensity.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Measured (CO validated abstinence).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completed to 12 weeks: 19/30 (63%), 22/30 (73%)

Selective reporting (reporting bias)

Low risk

Outcomes reported in NCT record. (However changes to study design - see other RoB)

Other bias

High risk

Study design changed substantially from nicotine SREC vs placebo SREC.

Methods

RCT. Prospective, parallel-group, randomized, double-blind, placebo-controlled study

Setting: Penn State Milton S. Hershey Medical Center, USA

Participants

Enrolment: 105

Inclusion criteria: age 21 to 70 years; smoke regular, filtered cigarettes or machine-rolled cigarettes with a filter ≥ 5 cpd for ≥ 12 months (CO ≥ 6 ppm at baseline visit); no serious quit attempt in prior month; willing to stop cigarette consumption and switch to an EC and to attend regular visits over a 7-week period

Exclusion criteria: unstable or significant medical condition such as COPD, kidney disease, or liver disease in the past 12 months or severe immune system disorders, uncontrolled mental illness or substance abuse or use of illicit drug/prescription, history of a seizure or seizure medication. Use of any non-cigarette nicotine delivery product in the past 7 days (including EC); use of hand-rolled, roll-your-own cigarettes; allergy to propylene glycol or vegetable glycerin; pregnancy or breastfeeding

Interventions

EC: Pod

The electronic cigarette (e-cig) used in this study will be the Standardized Research Electronic Cigarette (SREC). The SREC product is a pod-based device and comprises a replaceable pre-filled liquid reservoir ("pod") and a rechargeable power supply unit.

Arm 1. Experimental: Nicotine-containing electronic cigarette

The experimental group will be provided with and encouraged to use a Standardized Research Electronic Cigarette (SREC) with liquid containing 58 mg/mL nicotine for the duration of 6 weeks.

Arm 2. Placebo comparator: Non-nicotine electronic cigarette

The placebo group will be provided with and encouraged to use a Standardized Research Electronic Cigarette (SREC) with liquid containing 0 mg/mL nicotine for the duration of 6 weeks.

Outcomes

3 weeks, 6 weeks, 10 weeks (phone)

3 weeks and 6 weeks after switching

NNAL, FEV1, CO, plasma cotinine concentration, Fagerstrom Test for Nicotine Dependence mean total score, cpd, abstinence from cigarettes and other tobacco (not including e-cigs) CO < 6 ppm, total score on Minnesota Nicotine Withdrawal Scale, EC use days, self-reported abstinence

Notes

New to 2026 update. Added as ongoing to 2022 update

Random sequence generation (selection bias)

Unclear risk

No detail provided in NCT record "will be randomly allocated to use a SREC containing either 58 or 0 mg/ml nicotine in the liquid".

Allocation concealment (selection bias)

Low risk

Masking: Quadruple (Participant Care Provider Investigator Outcomes Assessor)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Equally intensive intervention. Masking: Quadruple (Participant Care Provider Investigator Outcomes Assessor).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcomes measured.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

NEC 35/52 (67%), NNEC34/52 (65%). > 60% completed to 6 weeks in both arms, < 20% difference between arms.

Selective reporting (reporting bias)

Low risk

Outcomes reported in NCT record.

Methods

RCT

Setting and recruitment: Participants will be adults from the local community with persistent asthma symptoms who are regular combustible cigarette smokers and do not also regularly use ENDS. The study will recruit 30 non-treatment-seeking participants using flyers, advertisements, a website triaging visitors to the Center for Alcohol and Addiction Studies, and through targeted recruitment at community immunology clinic partners at Rhode Island Hospital, USA.

Participants

Actual enrollment: 17. Estimated enrolment: 30

Inclusion criteria: 21 to 65 years; Persistent asthma symptoms (i.e. episodic symptoms of airflow obstruction/airway hyper-responsiveness (AHR) as documented in review of medical history); Currently prescribed SABA medication; Past-year smoking of ≥ 5 cigarettes/day (CO ≥ 6 ppm at baseline); Zero breath alcohol during informed consent for participation

Exclusion criteria: Intention to quit smoking during the next 30 days or current engagement in any smoking cessation treatment; Regular EC/ENDS user or using ENDS > 2 days/week; Medical contraindication to nicotine; Pregnancy (due to toxicity of nicotine and tobacco products); Current alcohol dependence (AUDIT > 15); Urine-screened or past-month self-reported use of illicit substances (amphetamine, cocaine, methamphetamine, opioids, benzodiazepines); Current psychosis, mania, or suicidal ideation.

EC use at baseline: No

Motivated to quit smoking: No

Specific population characteristic: people with asthma

Interventions

EC: 4th generation and disposable cartridges

Arm 1: Electronic cigarette, 12 participants.

Participants in this experimental condition will be provided with a 4th generation EC device and disposable cartridges. Participants will be provided with EC and 5% nicotine e-liquid cartridges for 8 weeks and encouraged at weekly assessments to use the EC any time they would normally smoke. Participants will be able to choose commercially available e-liquid flavours (tobacco) at each weekly assessment.

Arm 2: Smoking-as-usual, 5 participants.

Participants in this assessment-only condition will continue smoking-as-usual.

Outcomes

Baseline, week 8, week 16. Eight weekly visits to complete follow-up assessments

cpd

EC use

Asthma symptoms

Pulmonary functioning, FEV, FVC, FEF25-75, PEF

CO. Level of exhaled CO assessed with Smokerlyzer

NNAL

Cotinine

Interleukin-6 (IL-6)

Tumour necrosis factor alpha (TNF-a)

Chemokine ligand 9 (CXCL9)

Matrix metallopeptidase 9 (MMP9)

Study funding

Sponsor: Brown University

Collaborator: National Institute of General Medical Sciences (NIGMS)

Notes

Moved to new in 2026. Added as ongoing to 2022 update.

Random sequence generation (selection bias)

Unclear risk

No detail.

Allocation concealment (selection bias)

High risk

No masking (Open Label)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No masking (Open Label). Interventions not equally intensive.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Respiratory outcomes are measured (e.g. FEV).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

11/12 completed. 5/5 completed.

Selective reporting (reporting bias)

Unclear risk

Changed outcomes between original and current. CO originally reported as outcome and then removed.

Methods

Design: RCT

Recruitment: The study identified African-American current cigarette smokers using the electronic health record in the University of Minnesota Fairview Health system. The authors sent recruitment letters that provided a brief description of the study and invited recipients who were interested in the study to contact study staff. Participants were also invited to refer contacts outside their family to the study.

Setting: Study visits were conducted in the Delaware Clinical Research Unit (DCRU) through the Clinical and Translational Science Institute (CTSI) at the University of Minnesota, USA.

Study start date: June 2018. Study end date September 2019 (NCT record: Start date: 15 November 2016. End date: 8 March 2019)

Participants

Total N: 234

Nicotine EC arm: 118

Non-nicotine EC arm: 116

Inclusion criteria:

1) Self-identification as African-American or black, 2) smoked ≥ 5 cigarettes daily for the past year, smoking status confirmed by expired CO ≥ 5 ppm or positive NicAlert screen, 3) willingness to use EC, 4) 18 to 79 years

Exclusion criteria:

1) Recent unstable or untreated psychiatric diagnosis including substance abuse (DSM-IV criteria), 2) EC use in the past 30 days, 3) planning to quit smoking in the next 30 days, 4) pregnancy or nursing, 5) CO < 5 ppm and no cotinine detected in the urine

Female: 43.9%; mean age 50.8 (SD 11.2); mean CPD 11.5 (SD 6.0)

Motivated to quit: no

E-cigarette use at baseline: no

Interventions

EC: Refillable

EC with 24 mg of nicotine added. Nicotine EC rechargeable Halo G6 brand 2.4% nicotine (24 mg, equivalent to the nicotine content of combustible cigarettes)

EC - No-nicotine EC rechargeable Halo G6 brand 0% nicotine (0 mg)

For both groups:

A free Halo G6 brand rechargeable EC starter kit with the accessories including the charger, batteries, and a 2-week supply of liquid cartridges. The Halo G6 device was 3.3 to 4.2 (average 3.7) volts. The prefilled cartomizers coil resistance was 2.2 to 2.8 ohms. At the week-2 visit, participants received an additional 4-week supply of cartridges.

Participants were given oral and written instructions about how to use the products.

Ad lib for 6 weeks. All participants were provided with EC by the study; menthol and non-menthol flavoured EC cartridges were available. Participants could purchase their own if needed after 6 weeks.

Participants were compensated for their time and transportation: USD 40 at baseline, USD 40 at week 2, USD 50 at week 6, and USD 20 at week 12, for a maximum of USD 150 over 12 weeks.

Outcomes

Baseline, 2, 6, and 12 weeks (all visits were in-person except week 12, which was a telephone survey)

Biomarkers at baseline and 6 weeks. Urinary biomarkers (NNAL, NNK) and total nicotine equivalents (TNE, total nicotine + total cotinine + total 3-hydroxycotinine + nicotine N-oxide). Expired carbon monoxide (CO)

Combustible cigarettes self-reported number of cigarettes smoked per day (and baseline). EC use (Penn State EC Dependence Index)

EC dependence (10-item Penn State EC Dependence Index)

Nicotine withdrawal symptoms (baseline, week 2, 6, 12) (modified Minnesota Nicotine Withdrawal (MNWS))

Data collection was self-administered and collected on electronic tablets.

Study funding

ClearWay Minnesota Grant Award #RC-2014-0009

Author declarations

The authors declared that they had no competing interests.

Notes

New to 2022 update

Random sequence generation (selection bias)

Unclear risk

Quote: "To ensure balance in the number of intervention assignments between the study groups, randomization was blocked (block size unknown to staff or investigators) by nicotine versus no nicotine e-cigarettes." No other information given

Allocation concealment (selection bias)

Unclear risk

No information given

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Single-blind. Interventions equally intensive

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biomarkers measured

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Nicotine EC arm: 109/118

Non-nicotine EC arm: 106/116

Selective reporting (reporting bias)

Low risk

Reported outcomes in NCT record

Methods

Design: randomized, cross-over study

Recruitment: newspaper advertisements, radio announcements, and from local general medicine practices

Setting: lab-based study, Connecticut, USA

Study start date: October 2012; study end date: June 2015

Participants

Total N: 27

Inclusion criteria: non-treatment-seeking people who smoke who were willing to try EC for 2 weeks and abstain from conventional cigarette smoking; 18 to 55 years of age who smoked at least 10 cpd

Exclusion criteria: pregnant; previous myocardial infarction or stroke; uncontrolled hypertension (blood pressure (BP) > 160/100); insulin-dependent diabetes; COPD or current asthma; known allergy to propylene glycol.

45% women; mean age 42; 70% white; 15% Hispanic, 15% black; mean cpd 16; 45% had tried EC at baseline, 50% smoked menthol cigarettes

Motivated to quit: no

E-cigarette use at baseline: not specified

Interventions

EC: Cig-a-like

Prescribed Joye eGo-C (www.joyetech.com) and e-Juice (18 mg/mL nicotine) procured from American eLiquid (www.americanliquid.com) Cross-over study between menthol-flavoured and non-menthol tobacco-flavoured EC. Requested not to smoke their regular cigarettes during study period, but most (60%) reported intermittently smoking cigarettes during study

Outcomes

Follow-up at 1 week and 2 weeks

BP, heart rate, body plethysmography, static lung volumes and airways resistance (Raw), and specific conductance (sGaw) – taken at lab visits after abstaining from EC for at least 2 hrs, then taken again after inhaling EC and repeated 5 mins later

Adverse events also reported but method for measuring not stated

Also measured nicotine concentrations, rates of cigarette and EC use

Study funding

This project was supported by Academic Enhancement funds from the Department of Medicine at the University of Connecticut Health Center (to CO) and the Clinical Research Center at the University of Connecticut Health Center.

Author declarations

CO is currently receiving study medication (nicotine inhaler and placebo) from Pfizer pharmaceuticals for an NIH-funded nicotine inhaler for smoking cessation during pregnancy.

Random sequence generation (selection bias)

Unclear risk

Method not stated

Quote: "Subjects were then randomly assigned to use the menthol or plain e-cigarette cartridge for one week, switching to the other cartridge for the second week".

Allocation concealment (selection bias)

Unclear risk

No detail given

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

No detail given on blinding but equal levels of support between arms, so performance bias judged unlikely

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Some subjective outcomes but equal levels of support between arms, so differential misreport judged unlikely

Incomplete outcome data (attrition bias)
All outcomes

Low risk

20/27 followed up

Selective reporting (reporting bias)

Unclear risk

Unable to determine prespecified outcomes

Methods

Design: RCT

Recruitment: Cigarette smokers were recruited from the community via fliers, online postings, and word of mouth.

Setting: Morgantown, West Virginia, USA

Study start date: not reported. Study end date: not reported

Participants

Total N: 60; E-cigarette plus own brand = 30. Own brand cigarette (control) = 30

38.3% female; mean age completers 35.1 (SD 11) (N = 34), non-completers 36.8 (SD 12.9) (N = 26); mean cpd completers 16.7 (SD 4.9), non-completers 19.6 (SD 6.1); mean FTND completers 5.3 (SD 1.8), non-completers 5.9 (SD 1.9)

Inclusion criteria: 18 to 60 years; smoking ≥ 10 cigarettes per day for ≥ 1 year; exhaled air carbon monoxide (CO) level of ≥ 10 ppm (Micro+™ basic monitor; CoVita; Haddonfield, NJ); contemplation or Preparation Stage of Change (indicating interest in a quit attempt within the next 1 to 6 months)

Exclusion criteria: reported chronic health or psychiatric conditions; past month use of marijuana ≥ 5 days; past month use of any other illicit drugs, or regular use of ECIGs or other tobacco products (i.e. ≥ 1 day per week); individuals in the Precontemplation (no interest in quitting) or Action (actively trying to quit) Stage of Change; pregnancy/breastfeeding

Interventions

EC: Refillable

E-cigarette (18 mg/mL) plus own brand cigarette. Kanger mini Protank-II, which is a 1.5 mL Pyrex glass tank with a drip tip and atomizer head coils (KangerTech; China), and a 3.3 V constant output, 900 mAh, eGo-T battery (Joyetech; Irvine, CA). The liquid (The Vapor Room, Sky Vapors LLC, Frostburg, MD) was labelled as 70% propylene glycol and 30% vegetable glycerin, with a nicotine concentration requested of 18 mg/mL. Participants could choose tobacco, menthol or wild berry flavour and could switch between sessions. Ad libitum use for 4 weeks

Own brand cigarette ad libitum use for 4 weeks

Outcomes

Assessments days 8, 15, 22, and 29. FU 1 month post intervention.

Daily for salivary cotinine samples. Daily self-monitoring device to log e-cigarette and cigarette use. Collected used cigarette filters

Weekly CO breath test

Attended the laboratory weekly for assessments (days 8, 15, 22, and 29). Then completed a follow-up visit 1-month post-intervention

Self-reported withdrawal symptoms

Reported experience of specific symptoms rated using a visual analogue scale with a range from 0 (not at all) to 100 (extremely). e.g. craving, irritability, dry mouth, throat irritation, and cough

Study funding

Financial support provided to MDB and GAD by WVU Senate Grant for Research, and to GAD, MDB, and NAT by Cooperative Agreement Number 1-U48-DP-005004 from the Centers for Disease Control and Prevention (CDC) to the West Virginia Prevention Research Center. Support provided to NJF and JEOH by the National Institute of General Medical Sciences (NIGMS T32 GM081741). Additional support provided by WV Tobacco Cessation QuitLine

Author declarations

Author SGF has consulted for various pharmaceutical companies on matters relating to smoking cessation. All other authors declared that they had no conflicts of interest.

Random sequence generation (selection bias)

Unclear risk

Quote: "Using a simple randomized design"

Comment: not adequately explained

Allocation concealment (selection bias)

Unclear risk

Not adequately described in the paper

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants and investigators were not blind.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Biochemical validation

Incomplete outcome data (attrition bias)
All outcomes

High risk

40% retention, but no difference between groups

Selective reporting (reporting bias)

Low risk

All outcomes reported

Methods

Design: RCT

Setting: USA. University of Wisconsin Center for Tobacco Research and Intervention

Recruitment: participants from the greater Madison and Milwaukee, Wisconsin areas will be recruited via media recruitment methods (i.e. television, newspaper, and earned media) that have recruited thousands of smokers. Investigators will also use Internet/Facebook advertisements.

Study start date September 2019. Study end date May 2023

Participants

Randomised 209 (160 completed both switch weeks)

Number analyzed:

Juul EC + active and placebo patch 54

VLNC + active and placebo patch 53

No product + active and placebo patch 53

60% female; 21.9% African-American; 51.9 (SD 12.1) age; 16.8 (SD 9.3) CPD

Inclusion criteria: Smoking > 4 cigarettes/day for the previous 6 months, (CO) > 6 ppm; No plans to quit smoking in the next 30 days; Not currently taking smoking cessation medication; Willing and medically able to use nicotine patches;21+ years.

Exclusion criteria: Currently in treatment for psychosis or bipolar disorder; EC use within the last month; Pregnant or breastfeeding.

Motivated to quit: no

Interventions

EC: pod

Juul Electronic cigarette. The Juul e-cigarette pods contain 0.7 mL nicotine by volume/5% nicotine by weight. Tobacco or menthol flavour

Very Low Nicotine Cigarettes: These very low nicotine cigarettes (VLNCs) consist of reduced nicotine cigarettes containing 0.03 mg of nicotine; these VLNCs were obtained from the National Institute on Drug Abuse (NIDA's) Drug Supply Program (NOT-DA-14-004).

Active nicotine patches, with dosing based on the package insert (> 10 cigs/day = 21 mg patch and < 11 cigs/day = 14 mg patches)

Placebo patch containing no nicotine

Arm 1: Active comparator: Juul + active patch in wk 1 and placebo patch in wk 2

Participants will be given Juul e-cigarettes for 4 weeks; in switch week 1, participants will also use active nicotine patches; in switch week 2, participants will use placebo patches.

Arm 2: Active comparator: Juul + placebo patch in wk 1 and active patch in wk 2

Participants will be given Juul e-cigarettes for 4 weeks; in switch week 1, participants will also use placebo patches; in switch week 2, participants will use active nicotine patches.

Arm 3: Active comparator: VLNC + active patch in wk 1 and placebo patch in wk 2

Participants will be given very low nicotine cigarettes (VLNCs) for 4 weeks; in switch week 1, participants will also use active nicotine patches; in switch week 2, participants will use placebo patches.

Arm 4: Active comparator: VLNC + placebo patch in wk 1 and active patch in wk 2

Participants will be given very low nicotine cigarettes (VLNCs) for 4 weeks; in switch week 1, participants will also use placebo patches; in switch week 2, participants will use active nicotine patches.

Arm 5: No product + active patch in wk 1 and placebo patch in wk 2

Participants will be given no alternative nicotine delivery products, but in switch week 1, participants will use active nicotine patches; in switch week 2, participants will use placebo patches.

Arm 6: No product + placebo patch in wk 1 and active patch in wk 2

Participants will be given no alternative nicotine delivery products for 2 weeks, but in switch week 1, participants will use placebo patches; in switch week 2, participants will use active nicotine patches.

Outcomes

Weeks 1 to 4

Weeks 1 through 4, participants will use a smartphone to record, in the moment, each time they use their own cigarettes or any alternative product.

Primary outcome: number of conventional cigarettes smoked during each switch week

Secondary outcome: number of VLNCs or Juul pods used during each switch week

SAE, AE

Study funding

Sponsors and Collaborators University of Wisconsin, Madison

National Cancer Institute (NCI)

Author declarations

Not available; abstract and trial registry only

Notes

New to 2023 (previously ongoing) as adverse event data now included in trial registry. However, distribution of AEs across randomised groups is unclear and so data is thus far only included in narrative synthesis and Supplementary Materials. When further information is available, these will be moved to meta-analyses where appropriate.

Random sequence generation (selection bias)

Low risk

Electronic randomization using trial database

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo e-cigarette

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Different intensities of interventions. AEs self-reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

160/209, 76.5%

Selective reporting (reporting bias)

Low risk

Results posted on NCT record

Methods

RCT

Two-arm pragmatic, multicentre, parallel-group, individually randomised controlled trial carried out at 6 UK NHS Emergency Departments

Study start date January 2022

Participants

People attending the Emergency Department who smoke

Total N: 972.

Intervention: 484; control: 488

Female 38%; mean age 40.5 (SD 13.65); median CPD 15 (IQR 10 to 20). Mean FTND 4.89 (SD 2.31). Motivation to quit score, mean 4.13 (SD 1.60).

Inclusion: adults (aged 18 years or older) who reported smoking tobacco daily, attending the ED for medical treatment.

Exclusion: expired carbon monoxide (CO) of < 8 per million (ppm), required immediate medical treatment, were in police custody, had a known allergy to nicotine, were current dual users (defined as daily e-cigarette use).

Interventions

EC intervention:

1) EC starter kit (DotPro, manufactured by Liberty Flights, an independent e-cigarette manufacturer not funded by the tobacco industry) ‘pod’ device. The kit included 11 pods (3 tobacco flavoured, 4 berry flavoured and 4 menthol flavoured) of 20mg/mL nicotine strength. Training in use of EC.

2) Brief smoking cessation advice.

3) Referral to stop smoking services. FU consisted of telephone call offering support &, if taken up, offer of free NRT.

Control:

Treatment-as-usual. Signposting to NHS smoking cessation services through provision of written information about local services.

Outcomes

Baseline, 1, 3, and 6 months

Continuous smoking abstinence, 6 months after randomization, CO confirmed

Smoking status 1, 3, and 6 months after randomization. Abstinence prevalence, CO validated (≥ 8 ppm)

Number of cpd; number of times using an EC per day; self-reported dry cough; mouth or throat irritation; use of GP services; use of smoking cessation services. Quality of Life questionnaire. Adverse events (6 months).

Study funding

National Institute of Health Research, Health Technology Assessment (129438)

Author declarations

None declared

Notes

Data new to 2024 update

Random sequence generation (selection bias)

Low risk

Computer-generated randomization employed varying block sizes and stratified by the recruitment sites, which allowed for concealment of allocation

Allocation concealment (selection bias)

Low risk

Computer-generated randomization allowed for concealment of allocation

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the participatory nature of the intervention, it was not feasible to blind participants or those delivering the intervention to group allocation

Interventions not equally intensive

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

CO measured

Incomplete outcome data (attrition bias)
All outcomes

Low risk

EC 351/484 = 72.5%

Control 317/488 = 65%

Selective reporting (reporting bias)

Low risk

Reported as pre-specified. Cessation and AEs

Methods

Design: RCT

Recruitment: clinician referrals, posters/brochures and mailings. After eligibility confirmation, potential participants were invited for an informational meeting, and interested individuals returned to review the consent form and provide written informed consent.

Setting: 2 urban mental health agencies (Kentucky and Massachusetts) serving primarily Medicaid beneficiaries with SMI; USA

Study start date: 1 March 2017. Study end date: 31 January 2021

Participants

Total: N = 240

EC = 120; Assessment only = 120

Inclusion criteria:1) Diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder, 2) enrolled in services at the research site for a minimum of 3 months, 3) regular smoker (approx. 10 cigarettes for the past 5 years) with a history of at least 1 quit attempt, 4) 18+ years

Exclusion criteria:1) Regular use of EC in the past month, 2) current interest/plan to quit smoking, 3) regular use of NRT or bupropion or varenicline to quit smoking, 4) use of emergency room or hospitalization for psychiatric reasons in the past 30 days, 5) pregnancy, 6) psychiatric instability (hospitalization in the past month), 7) active substance use disorder

Female 47.9%; mean age 45.9 (SD 11.9); mean CPD 18.7; mean FTND 6.9 (SD 1.5)

E-cigarette use at baseline: no

Motivated to quit: no

Inclusion based on specific population characteristics: people living with SMI

Interventions

EC: Cartridge

Arm 1: EC

The Study Coordinator provided participants with a 2-week supply of e-cigarettes (EC) and instructions on their safe use. Per product packaging, each disposable EC provided up to 300 puffs, roughly the equivalent of 20 cigarettes. Participants were given the opportunity to practice using EC before leaving the appointment to ensure proper use. The Study Co-ordinator also provided brief information on safety (e.g. keeping EC out of the reach of children) and they gave participants additional 2-week supplies at 2, 4, and 6 weeks.

The EC arm was provided with 8 weeks of free ECs based on self-report of regular tobacco use. Participants assigned in this arm were asked to switch combustible tobacco with ECs. The appeal of EC and health impacts were measured, but the authors were not targeting quitting combustible tobacco or reducing craving.

Arm 2: Assessment only (no intervention)

EC was given at final FU visit. Following randomization, Study Co-ordinators provided participants with appointments for follow-up study visits, asked them to refrain from using ECs, and reminded participants that they would receive a 4-week supply of ECs at the final follow-up visit.

Outcomes

Baseline, 2, 4, 6, 8, 13, and 26 weeks

Breath CO was measured by the blinded Research Interviewers at each visit using the Smokerlyzer Breath Carbon Monoxide Monitor (Bedfont Scientific) as a biologic measure of toxin exposure.

CO, CPD, nicotine dependence, EC use (EC count), NNAL

AEs: Cough, itchy throat, bad throat

Stated that the following would be collected in the NCT record, but not yet reported: change in cancer-related toxin, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (time frame: baseline, 4 weeks, 8 weeks, 13 weeks, 26 weeks)

Study funding

The study was funded by the National Institute on Drug Abuse (NIDA, 1R01DA041416) in the United States.

Author declarations

None declared

Notes

New to 2022 update

Random sequence generation (selection bias)

Low risk

Quote: “Unblinded Study Coordinator randomly assigned participants within site using an automated program that stratified by diagnosis (schizophrenia vs. bipolar disorder) and amount of daily smoking (> 20 vs. ≤ 20 cigarettes), in blocks of four to assure balance between arms (1:1 ratio).”

Allocation concealment (selection bias)

Low risk

As above, automated programme

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Interventions of different intensity. EC vs assessment only (control)

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Blinded Research Interviewers”

Incomplete outcome data (attrition bias)
All outcomes

Low risk

240 randomized participants. Amongst those participants, 210 (87.5%) were assessed at 8 weeks, and 214 (89.2%) were assessed at 26 weeks.

Selective reporting (reporting bias)

Unclear risk

Some outcomes not reported here

Methods

Design: RCT, unblinded, 2:1 ratio

Recruitment: Participants were recruited from the San Diego, California, and Kansas City, Missouri and Kansas, metropolitan areas.

Setting: USA

Study start date: May 2018. Study end date: May 2019

Participants

Total N = 186; Electronic cigarettes = 125. Own brand cigarette = 61

40.3% female; mean age 43.3 (SD 12.5); mean cpd 12.1 (SD 7.2). E-cigarettes use at baseline: 0.05 (0.3%)

Inclusion criteria: > 21 years of age; smoked cigarettes on > 25 of past 30 days; smoked > 5 cpd on days smoked; smoked cigarettes > 6 months; carbon monoxide > 5 PPM at baseline; systolic BP of < 160 mmHg and diastolic BP of < 105 mmHg at baseline; Hispanic/Latino or African-American/black; fluent in English or Spanish; willing to switch from smoking cigarettes to ECs for 6 weeks; regular access to telephone; transportation to attend appointments (KC Only).

Exclusion criteria: primary use of other tobacco products or equal use of cigarettes and other tobacco products; EC use on > 4 of the past 30 days; currently in a smoking cessation programme or another clinical trial; use of NRT or medication which aids smoking cessation in the past 30 days; hospitalization for a psychiatric issue in the past 30 days; heart-related event in the past 30 days (e.g. heart attack, stroke, severe angina (i.e. chest pain), ischaemic heart disease, and vascular disease); uncontrolled blood pressure; planning to move out of study centres (San Diego or Kansas City) in the next 6 weeks; another person in the household enrolled in the study; pregnancy/breastfeeding; unstable mental status or health status

Interventions

EC: pod

Electronic-cigarettes: JUUL (5% nicotine); choice of flavours (Menthol, Mango, Cool Mint, Virginia Tobacco); given 1 pod per pack of cigarettes; given a 2-week supply at baseline and then a further 4-week supply at week-2 visit. At each follow-up appointment (week 1, telephone call; week 2, in-person visit; and week 4, telephone call), barriers and benefits of switching to e-cigarettes were discussed and action planning for exclusive switching was revisited. Compensated on a schedule of USD 20 at baseline, USD 40 at week 2 and USD 60 at week 6

Own brand cigarettes: compensated on a schedule of USD 20 at baseline, USD 40 at week 2, and USD 60 at week 6

Outcomes

Baseline, week 2 and week 6. Telephone survey at 6 months

Change in past 7-day combustible cigarette use measured by 7-day timeline follow-back interview

30-day point prevalence at 6 months (EC group only)

• Reduction in toxicant exposure, as measured by NNAL excretion
• Cotinine
• CO

Lung function; pulmonary function test of small airway disease that is most sensitive to the effects of cigarette smoking; mean mid-expiratory phase of forced expiratory (FEF 25% to 75%); respiratory symptoms as measured with the American Thoracic Society Questionnaire (scores range from 0 to 32, with higher scores indicating greater respiratory symptoms)

Blood pressure

Adverse events: respiratory symptoms

Study funding

Drs Pulvers and Nollen and Ms Rice were supported by grant No. 5SC3GM122628 from the National Institutes of Health (NIH). Drs Schmid and Ahluwalia were supported in part by grant No. P20GM130414, from the NIH-funded Center of Biomedical Research Excellence (COBRE). Dr Schmid was partially supported by Institutional Development Award No. U54GM115677 from the National Institute of General Medical Sciences of the NIH, which funds Advance Clinical and Translational Research (Advance-CTR).

Author declarations

Dr Schmid reported serving as a consultant for legal firms representing Eli Lilly, Boehringer-Ingelheim, and Gilead outside the submitted work. Dr Benowitz reported receiving personal fees from Pfizer and Achieve Life Sciences and serving as a consultant to pharmaceutical companies that market smoking cessation medications and as an expert witness in litigation against tobacco companies outside the submitted work. Dr Ahluwalia reported receiving personal fees from Lucy Goods outside the submitted work. No other disclosures were reported.

Notes

Additional data provided by the authors

Random sequence generation (selection bias)

Low risk

Randomization sequence was generated with an Excel (Microsoft) random number formula applied to each site (2:1 ratio).

Allocation concealment (selection bias)

Low risk

Allocation was placed into sealed individual envelopes labelled with participant identification numbers for each site, retrieved from a locked cabinet monitored by the project manager, and opened individually following consent of each participant.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Could not be blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Carbon monoxide validation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

E-cig: 115/126

Own brand: 54/61

Selective reporting (reporting bias)

Low risk

Per-protocol reporting

Methods

RCT. Randomized crossover. Double blind (participant and outcome assessor).

Setting: Texas, USA

Fully remote trial.

Participants

169 adults.

Inclusion criteria: 21 or older who reported daily or non-daily smoking (any self-reported smoking in the past 30 days) (range: 2 to 58 cigarettes per day [CPD]) and were uninterested in quitting smoking.

Exclusion criteria: reported depressive symptoms in the moderately severe or severe range (scores of 15 or above) or current suicidal ideation on the Patient Health Questionnaire-9 (PHQ-9); reported uncontrolled or unstable medical condition (e.g., uncontrolled hypertension, angina, diabetes); demonstrated cognitive deficits or instability that would preclude reliable study participation; pregnant/breastfeeding.

Interventions

E-Cig placebo dose followed by E-Cig nicotine dose

E-Cig nicotine dose followed by E-Cig placebo dose

SREC-NIC (5%; ~59 mg/ml nicotine). Tobacco flavour only.

SREC-PLA (0% nicotine)

Participants received 2 SREC devices with non-removable rechargeable batteries (3.3 v, 1000 mAh battery), 1 USB recharger, a 2-week supply of sealed SREC pods, a user manual, and a carrying pouch. Participants recieved guided training over a Zoom video call (Zoom Communications, Inc., San Jose, CA, USA) from a study staff member on using the SREC product, along with an illustrated step-by-step guide.

During weeks 1–2 (Phase 1), participants used their usual brand cigarettes (UBCs). During weeks 3–4 (Phase 2) and weeks 5–6 (Phase 3), they were instructed to use the tobacco-flavored SREC (either nicotine [SREC-NIC] or placebo [SREC-PLA]) in a counter-balanced order between subjects, whenever they had the urge to smoke. Exclusive use of the SREC during Phases 2 and 3 was instructed but was not incentivized. Participants virtually attended 5 sessions over 10 weeks.

Enrolled participants could earn a maximum of $522 for attending all remote visits, completing all assessments, and returning all used and unused study products.

Outcomes

Baseline and after each 2 week phase (3 phases). AE, and SAE assessed weeks 7-10.

Adverse events were assessed at each session, including the 30-day follow-up, using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (US Department of Health).

Respiratory symptoms were assessed at the end of each phase using the 8-item American Thoracic Society questionnaire (ATSQ). Range 8 to 40, with higher numbers indicating more respiratory symptoms.

Other outcomes. Nicotine -related biomarker (mailed urine specimin kits). Participants completed assessments of product use, product acceptability, product reinforcement, and nicotine dependence symptoms. During all phases, participants completed daily text message-prompted smartphone assessments of product use (CC and EC use) and nicotine dependence symptoms (withdrawal, craving, and affect) for the previous day.

Study funding

This research was funded by U.S. National Institute on Drug Abuse grant U01DA047875 and supported by MD Anderson’s Cancer Center Support Grant (P30CA016672).

Author declarations

None of the authors declare a conflict of interest.

Random sequence generation (selection bias)

Unclear risk

No detail, 'all-remote randomized double-blind crossover trial'.

Allocation concealment (selection bias)

Low risk

Double blind. Placebo intervention. Staff blinded to nicotine concentration. No other detail provided.

Blinding of participants and personnel (performance bias)
All outcomes