Ebbert 2015

Methods	Country: 65 centres in 10 countries: USA (14), Australia (4), Canada (6), Czech Republic (7), Egypt (3), Germany (7), Japan (6), Mexico (4), Taiwan (7), UK (7) Setting: Clinics, hospitals, academic research centres Aim: To determine the efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction Study Design: Double‐blind placebo‐controlled multinational RCT Study name: Reduce to Quit Dates conducted: July 2011 ‐ July 2013 Analysis: "A sample size of 1404 randomized participants in a 1:1 ratio (702 in each group) was estimated to provide 90% or more power to detect a difference between varenicline and placebo of 10.3% in the primary end point of CAR during weeks 15 through 24, assuming a CAR of 17.2% for varenicline and 6.9% for placebo using a 2‐group, continuity–corrected, 2‐sided χ² test. A P value of .05 or less was considered significant"
Participants	1510 adult smokers, unwilling to quit abruptly (within the next month), aged 18+, smoking mean 10+ CPD, interested in trying to quit within 3 months. Mean age 44.5, 43.7% women, mean CPD 20.7, mean FTND 5.5. Allocated to varenicline (760) or placebo (750) Exclusions: suicidal behaviour in previous 2 years or history of suicide attempts; major depression, anxiety; diagnosis of psychosis, panic disorder, PTSD, schizophrenia
Interventions	1. Varenicline 24 wks, titrated 1st wk (12 wks to quit + 12 wks post‐quit) 2. Placebo 24 wks, titrated 1st wk (12 wks to quit + 12 wks post‐quit) All participants asked to reduce their smoking rate by 50% by wk 4, by 75%+ by wk 8, and 100% by wk 12. Individual 10‐minute counselling at each visit (18 face‐to‐face and 10 phone calls), + a copy of Clearing the air: quit smoking today.
Outcomes	Primary: CAR at wks 15 ‐ 24 Secondary: CAR at wks 21 ‐ 24, 15 ‐ 52, 21 ‐ 52; 7‐day PPA at wks 24, 52 Validation: CO < 10 ppm
Treatment type	Medication: VARENICLINE
Notes	New for 2016 update Funding: Pfizer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Participants were randomized to receive varenicline or placebo for 24 weeks of treatment in a 1:1 ratio using a computer generated block randomization schedule within site"
Allocation concealment (selection bias)	Low risk	"Investigators obtained participant identification numbers and treatment group assignments through a web‐based or telephone call‐in drug management system"
Blinding (performance bias and detection bias) All outcomes	Low risk	"Participants, investigators, and research personnel were blinded to randomization until after the database was locked"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Losses fully reported. ITT analyses conducted for efficacy (760 varenicline, 750 placebo), and treated denominators for safety outcomes (751 varenicline, 742 placebo)
Selective reporting (reporting bias)	Low risk	None noted
Other bias	Low risk	None noted