Niaura 2008

Methods	Country: USA Setting: 5 research centres Aim: To test the efficacy and safety of varenicline in smokers allowed to modify their own dosage regimen. Dates conducted: December 2001 ‐ June 2003 Study Design: Double‐blind placebo‐controlled RCT Analysis: Power calculation (90%, alpha = 0.05); ITT denominators and logistic regression analysis (step‐down procedure)
Participants	320 healthy adult volunteers, aged 18 ‐ 65, smoking ≥ 10 CPD. Allocated to varenicline (160), or placebo (160) 52% men, 91% white, mean age 42, mean CPD 22, mean FTND score 5.4 Exclusion criteria: Standard pharmacotherapy trial criteria, + use of NRT within last 3m
Interventions	1. 0.5 mg varenicline ad lib, from 1 to 4 per day as wished 2. Placebo tablets ad lib, from 1 to 4 per day as wished Treatment period 12 wks, 1st wk titrated dosage up to 0.5 mg x 2/day. All participants received a smoking cessation booklet Clearing the Air at baseline, + brief counselling (≤ 10 mins) at each clinic visit. Weekly visits throughout treatment phase In follow‐up phase, clinic visits at wks 13, 24, and 52 wks, plus monthly phone calls between visits
Outcomes	Primary outcome: CAR at 4 ‐ 7, 9 ‐ 12 and 9 ‐ 52 wks Validation was by expired CO ≤ 10 ppm Secondary outcomes: CO‐confirmed CAR at 9 ‐ 24 wks; CO‐confirmed 7‐day PPA Other outcomes: Mean modal dosage; withdrawal symptoms (using MNWS, QSU‐brief and mCEQ), adverse events Dropouts and losses to follow‐up were included in the analyses as continuing smokers (ITT analysis) Attrition in treatment phase was 22% in varenicline group and 29% in placebo group; losses to follow‐up by wk 52 were 36% from varenicline group and 43% from placebo group
Treatment type	Medication: VARENICLINE
Notes	The trial was funded by Pfizer Inc New for 2010 update.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomly permuted blocks and a pseudo‐random number generator"
Allocation concealment (selection bias)	Low risk	"participants were assigned in a 1:1 ratio to varenicline treatment or placebo in the numerical order that they were accepted to the study"
Blinding (performance bias and detection bias) All outcomes	Unclear risk	"double‐blind" but no further information
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing data imputed if prior and subsequent abstinence confirmed, otherwise assumed still smoking
Selective reporting (reporting bias)	Low risk	All expected and predicted outcomes covered
Other bias	Unclear risk	None noted