Tønnesen 2013

Methods	Country: Denmark Setting: 1 hospital‐based smoking cessation specialist clinic Aim: "to evaluate whether varenicline used for 12 weeks would be more effective than placebo to get long‐term NRT users to stop using NRT" Study Design: Randomised placebo‐controlled quadruple‐blind trial Dates conducted: Not given Analysis: Sample sizes of 66 in each group, estimated to give 80% power to detect quit rates of 50% and 25% respectively at 12 weeks in active and placebo groups
Participants	139 adult ex‐smokers, aged 18+, reporting long‐term (> 11m) abstinence, using flexible‐dose NRT (i.e. > 4 pieces of nicotine gum/sublingual tablets or lozenges per day, or > 3 inhaler cartridges per day, or > 10 puffs of nasal spray per day), wishing and willing to try to stop using NRT; allocated to varenicline (70) or placebo (69) Participants used gums (2 mg 68.3%; 4 mg 11.5%), inhalers (5.8%), sublingual tablets (7.2%), lozenge (9.4%); mean daily NRT unit intake was 16 (SD 8.1), and mean NRT usage had lasted 6 years. Mean age 54.6, 54% women, mean CPD when smoking 23.5, mean FTND (recalled) 6.5
Interventions	All participants attended clinic visits at wks 0, 2, 4, 6, 9, 12, 52, + 2 phone calls at wks 26 and 38. Each visit included assessments, < 5 mins counselling from SC nurses. All participants advised to gradually reduce NRT and to stop completely by TQD at 1 ‐ 2 wks 1. Varenicline: standard 12‐wk regimen, titrated 1st wk 2. Placebo: identical tablets, same regimen
Outcomes	7‐day PPA at 12 weeks, not smoking or on NRT; also no NRT (7‐day PPA) + abstinence at 52 wks. CAR from wk 2 to wk 52, proven abstinent at all clinic visits Validation: expired CO < 7 ppm and plasma cotinine < 15 ng/ml
Treatment type	Medication: VARENICLINE
Notes	Not included in the main analysis, as smoking cessation was not the aim Funding was from an Independent Investigator Grant from Pfizer A/S, Denmark and Pfizer, Europe New for 2016 update
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Subjects were randomized to active or placebo using a computer‐generated list with random numbers"
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Described as a "double‐blind" trial. No additional information
Incomplete outcome data (attrition bias) All outcomes	Low risk	By 52 wks, 9 had dropped out of the varenicline group and 15 out of the placebo group (PRISMA flow diagram says 15, text says 14). ITT analyses conducted
Selective reporting (reporting bias)	Low risk	None noted
Other bias	Low risk	None noted