EAGLES 2016

Methods	Countries: Argentina, Australia, Brazil, Bulgaria, Canada, Chile, Denmark, Finland, Germany, Mexico, New Zealand, Russian Federation, Slovakiam South Africa, Spain, USA Setting: multiple research centres Aim: To evaluate the efficacy of varenicline, bupropion SR, nicotine patch and placebo for smoking cessation, and to assess how far this is moderated by the presence of psychiatric disorders Dates conducted: November 2011 ‐ January 2015 Study Design: Phase 4 triple‐dummy, double‐blind placebo‐controlled parallel‐group RCT Study name: EAGLES (Evaluating Global Events in a Global Smoking Cessation Study)
Participants	Treatment‐seeking adult smokers, aged 18 ‐ 75, smoking at least 10 CPD, with exhaled CO > 10 ppm at screening. Participants in the psychiatric disorder cohort had to have a current or lifetime stable psychiatric diagnosis, confirmed by Structured Clinical Interview for DSM IV disorders (SCID), i.e. no acute exacerbation in the previous 6 months, no changes to treatment for 3 months, not imminently likely to change treatment, and not at risk of self harm. Allocation for the pyshiatric cohort was balanced across four diagnostic group disorders, i.e. mood, anxiety, psychotic, personality 44% men, mean age 46, mean CPD 20.7, mean FTND 5.8 Exclusions: Past or current diagnosis of schizophreniform or delusional disorders, all delirium, dementia, and other cognitive disorders, and all substance‐induced disorders (other than nicotine) In the psychiatric disorders group, 70% had primary affective disorders, 19% anxiety disorders, 9.5% psychotic disorders, 0.6% personality disorders, and at least ⅓ were taking psychotropic medications Participants were grouped by the presence (4116) or absence (4028) of a history of psychiatric disorders Psychiatric disorders: varenicline 1032; bupropion 1033, NRT patch 1025, placebo 1026 No psychiatric disorders: varenicline 1005; bupropion 1001, NRT patch 1013, placebo 1009 Safety analyses were conducted in cohorts of 4074 (psychiatric) and 3984 (non‐psychiatric)
Interventions	1. Varenicline, 1 mg x 2/day (1 wk titrated, then 11 weeks full dose) 2. Bupropion SR, 150 mg x 2/day (titrated for 3 days, then full dose for 11 weeks) 3. Nicotine patch, 21 mg x 7 weeks, 14 mg x 2 wks, 7 mg x 2 weeks (11 weeks) 4. Triple‐dummy placebo for each arm of the trial (12 weeks) All participants received counselling (up to 10 mins) at all contacts, and were encouraged to complete all visits even if treatment was discontinued Participants were monitored at weeks 1 ‐ 6, 8, 12, 13, 16, 20, 24; contacts were up to 15 face‐to‐face visits and 11 telephone visits
Outcomes	At least 1 SAE of anxiety depression, feeling abnormal, or hostility, and/or moderate or severe AE of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic paranoia, psychosis, suicidal ideation/behaviour/completed 4‐week abstinence confirmed by CO < 10 ppm at wks 9 ‐ 12, and 15‐wk abstinence at weeks 9 ‐ 24 In the non‐psychiatric cohort, 78.9% completed treatment, and 78.4% completed the study In the psychiatric cohort, 74.2% completed treatment, and 77.8% completed the study
Treatment type	VARENICLINE / BUPROPION / NRT
Notes	Trial was funded by Pfizer and GlaxoSmithKline
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐generated randomisation schedule ... using a block size of 8 (1:1:1:1 ratio) for each of the 20 diagnosis by region combinations"
Allocation concealment (selection bias)	Low risk	"Investigators obtained participant identification numbers via a web‐based or telephone call‐in drug management system"
Blinding (performance bias and detection bias) All outcomes	Low risk	"Study product kit codes did not allow deciphering of randomised treatment or block size. As such, participants, investigators, and research personnel were masked to treatment assignment" "The triple dummy design feature required participants to take study medication as masked tablets dispensed in separate varenicline and bupropion pill bottles each with matching placebo along with with either applying active or placebo patches on a daily basis"
Incomplete outcome data (attrition bias) All outcomes	Low risk	All losses fully accounted for; ITT analysis conducted throughout
Selective reporting (reporting bias)	Low risk	All protocol‐reported outcomes were addressed
Other bias	Low risk	None noted