Stein 2013

Methods	Country: USA Setting: 9 methadone‐maintained treatment centres in New England Aim: "[to] test varenicline versus placebo, and include a comparison condition of combination nicotine replacement therapy" Study Design: Randomised 3‐armed double‐blind controlled trial Dates conducted: December 2008 ‐ January 2012 Analysis: Sample sizes of 132 (varenicline) and 44 (placebo) estimated to give 80% power to detect quit rates of 20% and 2.5% respectively; the study was not powered to detect differences between varenicline and combination NRT
Participants	315 adult methadone‐maintained smokers, smoking 10+ CPD, willing to set a quit date within the 1st wk Allocated 3:1:3 to varenicline (137): placebo (45): combination NRT (133). Mean age 39.9, 47.6% women, 78.5% white, mean CPD 20, mean FTND 5.7
Interventions	All participants received a standardised 15‐min session of advice to quit (5As model), and were asked to set a TQD for 8 days time. All made monthly visits for support and top‐up medication 1. Varenicline: 24‐wk course of varenicline tablets, 1st wk titrated 2. Placebo: 24‐wk course of identical tablets and regimen 3. Combination NRT: 24‐wk course of NRT patch (42 mg for > 30 CPD, 21 mg if < 30 CPD), + ad lib nicotine gum (4 mg) as needed Participants were paid USD 30 for the baseline assessment and USD 40 for the 6m assessment
Outcomes	Primary: 7‐day PPA at 6m Secondary: CA from wk 2 to 6m; for non‐quitters: CPD reduction in the 28 days prior to 6m assessment Validation: CO < 8 ppm; urinary cotinine in varenicline and placebo participants claiming abstinence
Treatment type	Medication: VARENICLINE / NRT
Notes	Funding: NCI grant RO1 CA129226; MDS supported by a NIDA mid‐career investigator award K24 DA000512 New for 2016 update
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Participants were randomized to treatment after completing the baseline assessment". No further information
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	"double‐blind"; research assistants were "blind to participant group assignment"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Losses to treatment and follow‐up reported; ITT analyses conducted
Selective reporting (reporting bias)	Low risk	None noted
Other bias	Low risk	None noted