Rose 2013

Methods	Country: USA Setting: Duke University Medical Center, Durham, NC Aim: "Given the safety and tolerability profile of nicotine replacement therapy, our rationale in this study was to use nicotine replacement therapy as an initial line of treatment, and then identify early on which smokers are unlikely to benefit from nicotine alone" Study Design: Randomised double‐blind parallel‐arm adaptive treatment trial in 2 phases Dates conducted: Not stated Analysis: Logistic regression
Participants	606 adult smokers, motivated to quit, aged 18 ‐ 65, mean CPD 10+ for 3 yrs, expired CO level 10+ ppm. 46% women, 63% white, mean CPD 21.7, mean FTND 5.8. Participants could receive up to USD 320 for study participation
Interventions	Two phase study: All participants seen weekly for 2 wks before TQD, and attended 4 ‐ 6 sessions after the TQD. At each session, participant received brief (< 15 mins) support, + clinical trial materials. Smoking diaries, expired CO, withdrawal symptoms and reports of adverse events were collected each time. Participants were recontacted at 6m, and those reporting abstinence were invited to return to give a CO sample All participants were given open‐label active NRT patch, either 42 mg/day (baseline CO > 30 ppm) or 21 mg/day (baseline CO < 30 ppm) for 2 wks; dose reductions allowed if side effects dictated. At 1 wk, participants were classified as 'responders' (reduced ad lib smoking by > 50%, CO‐verified) or 'non‐responders' (< 50%) Phase 1 (12 weeks): Non‐responders only (N = 371 ‐ 36 who withdrew, = 335) allocated to: 1. Double‐blind varenicline, stopping NRT (N = 112) 2. Double‐blind augmentation of NRT with bupropion (N = 109) 3. Continuation on open‐label NRT alone (N = 114) All participants received dummy (placebo) versions of the other 2 treatments as well as their own active treatment. Phase 2: 235 responders after wk 1 assessed at 1st wk after TQD (wk 3). Lapsers (N = 105) were assigned a 2nd TQD 1 wk later, and were allocated to the same 3 double‐blind treatment conditions as Phase 1 non‐responders. 1. Double‐blind varenicline, stopping NRT (N = 36) 2. Double‐blind augmentation of NRT with bupropion (N = 34) 3. Continuation on open‐label NRT alone (N = 35) Non‐lapsers (N = 130) remained on open‐label NRT throughout study duration All participants received dummy (placebo) versions of the other 2 treatments as well as their own active treatment. 47 participants were excluded from the analysis (27 Phase 1, 20 Phase 2) because of using contra‐indicated medications during the study or failing to meet other entry requirements. 1 individual died before end of treatment, and 1 was excluded for extreme CO change from the mean sample range
Outcomes	Primary: CAR at wks 8 ‐ 11 Secondary: CA from TQD for 11 wks (EoT); 7‐day PPA at 6m: CA from TQD to 6m Validation: CO ≤ 10 ppm AEs and SAEs (reported, but not by treatment group)
Treatment type	Medication: VARENICLINE, BUPROPION, NRT
Notes	Funding by a grant from Philip Morris USA, with NRT supplied free by GSK Phase 1 and Phase 2 groups combined for varenicline vs NRT analysis New for 2016 update
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly assigned"
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No information
Incomplete outcome data (attrition bias) All outcomes	Low risk	Losses fully reported; exclusions for protocol violations or contra‐indicated medicines. 1 death and 1 'rogue' CO reading excluded
Selective reporting (reporting bias)	Low risk	None noted
Other bias	Unclear risk	Unexplained disparity between CONSORT (N = 103) and Results table (N = 108) denominators for rescue varenicline group