Nides 2006

Methods	Country: USA Setting: 7 research centres Aim: To test efficacy, tolerability and safety of 3 doses of varenicline over 6 wks Dates conducted: February 2000 ‐ January 2003 Study Design: Phase 2 double‐blind placebo‐controlled RCT Analysis: Power calculation (80%, 2‐tailed, alpha = 0.05); Dunnett adjustment for multiple comparisons used for primary endpoint (CQR within treatment phase). ORs and CIs least squares mean estimates. Not powered for varenicline/bupropion comparison
Participants	638 healthy volunteer smokers, aged 18 ‐ 65, smoking at least 10 CPD on average. 48% men, 87% white, av age 42, av CPD 20, mean FTND 5.5. Allocated to varenicline group 1 (128), group 2 (128), group 3 (127), bupropion (128), placebo≤ (127) Exclusion criteria: Standard pharmacotherapy trial criteria, + use of bupropion within previous 12m, use of NRT within past 3m
Interventions	1. varenicline tartrate 0.3 mg x 1/day for 6wks, + 1 wk placebo 2. varenicline tartrate 1.0 mg x 1/day for 6 wks, + 1 wk placebo 3. varenicline tartrate 1.0 mg x 2/day for 6 wks, + 1 wk placebo 4. bupropion 150 mg x 2/day (titrated in wk 1) for 7 wks 5. placebo tablets x 2/day for 7 wks All groups received self‐help booklet Clearing the Air at baseline, + brief (≤ 10 mins) counselling at weekly clinic visits throughout treatment phase. At each visit smoking status reported and verified; lab samples taken at screening, baseline and wks 1, 2, 4, 6 and 7 Follow‐up phase (optional): Clinic visits at wks 12, 24, 52 for brief counselling, smoking status and vital signs. Phone calls every 4 wks from wk 16
Outcomes	Primary outcome: Continuous verified 4‐wk abstinence for any part of treatment period Secondary outcomes: CQR wks 4 ‐ 7; CQR from wk 4 to wks 12, 24, and 52 Other outcomes: Weight change; reduction of craving and withdrawal using MNWS, QSU‐brief and mCEQ; adverse events Validation was by expired CO ≤ 10 ppm Trial report ITT analysis based on numbers treated (N = 626); for consistency our MA used numbers randomised (N = 638). Attrition was 30% during treatment period, 25% of follow‐up consenters lost during follow‐up phase
Treatment type	Medication: VARENICLINE / BUPROPION
Notes	Previous users of bupropion > 12m before were not excluded, unlike Gonzalez and Jorenby trials; prior use ranged from 13% to 20.6% across groups Denominator in trial report is all treated; we have used all randomised in our MA The trial was funded by Pfizer Inc
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐generated using a method of randomly permuted blocks and a pseudo‐random number generator"
Allocation concealment (selection bias)	Low risk	"assigned ... medication to subjects in numerical order of acceptance into the study"
Blinding (performance bias and detection bias) All outcomes	Unclear risk	"double‐blind", "to preserve treatment blinding"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No information
Selective reporting (reporting bias)	Low risk	All expected and predicted outcomes covered
Other bias	Unclear risk	None noted