Nakamura 2007.

Study characteristics
Methods	Country: Japan Setting: 19 study sites Aim: to test efficacy, safety and tolerability of 3 doses of varenicline over 12 weeks Dates conducted: not stated Study design: double‐blind, placebo‐controlled, parallel‐group RCT
Participants	619 healthy Japanese adult volunteers, aged 20‐75, smoking ≥ 10 CPD. Allocated to varenicline 0.25 mg x 2/day (153), 0.5 mg x 2/day (156), 1.0 mg x 2/day (156) or placebo x 2/day (154). 1 participant withdrew before treatment, and is excluded from ITT denominator. 1 road traffic accident death removed from varenicline group at 52 weeks Participants stratified by level of nicotine dependence, measured by Tobacco Dependence Screener scale (≥ 5) and by FTND. 515 (83.3%) classified as nicotine‐dependent Demographic data only supplied for nicotine‐dependent group (515/618): 75% men, mean age 39.8, mean CPD 24, mean FTND score 5.6 Exclusion criteria: standard pharmacotherapy trial criteria, + use of NRT within last 30 days, use of pipe tobacco, snuff, chewing tobacco, cigars within last 30 days and throughout trial
Interventions	Varenicline 0.25 mg x 2/day Varenicline 0.50 mg x 2/day Varenicline 1.00 mg x 2/day Placebo tablet x 2/day Treatment period 12 weeks, 1st week titrated dosage. All participants received a SC booklet Clearing the Air at baseline, + brief counselling (≤ 10 min) at each clinic visit. Weekly visits throughout treatment phase, plus a 5‐min phone call at TQD and +3 days post‐TQD In follow‐up phase, clinic visits at weeks 13, 16, 24, 36, 44 and 52, plus brief phone calls at weeks 20, 28, 32, 40 and 48
Outcomes	Primary outcome: CO‐validated CAR at 9‐12 weeks Secondary outcomes: CO‐validated CAR at 9‐24 weeks and 9‐52 weeks; 7‐day PPA at weeks 2, 12, 24 and 52 Validation was by expired CO ≤ 10 ppm Other outcomes: withdrawal symptoms (using MNWS, QSU‐brief and mCEQ), AEs Dropouts and losses to follow‐up were included in the analyses as continuing smokers (ITT analysis) Attrition in treatment phase was 6.4%, losses to follow‐up 11.4% of treatment completers (excluding 1 death)
Notes	Trial was funded by Pfizer Inc New for 2008 update Author declaration of interests: "Dr. Nakamura has received research contracts from Pfizer Japan Inc. (Tokyo, Japan), Novartis Pharma K.K. (Tokyo, Japan), and Sanofi‐Aventis K.K. (Tokyo, Japan), and a research grant from Pfizer Research Foundation (Tokyo, Japan). Dr. Oshima has received research contracts from Pfizer Japan Inc"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐generated list of random numbers"
Allocation concealment (selection bias)	Low risk	"randomized to 1 of the 4 treatment groups in a 1:1:1:1 ratio using a central procedure"
Blinding (performance bias and detection bias) All outcomes	Low risk	"double‐blinding of subjects and investigators was maintained throughout the study".
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No comment on level or handling of missing data
Selective reporting (reporting bias)	High risk	CA rates for all participants reported, but demographics, withdrawal and craving measures, and PPA for nicotine‐dependent group only