Anthenelli 2013

Methods	Country: USA (9 centres) and international (24 centres, across Bosnia & Herzogovina, Croatia, Germany, Hungary, Romania, Russian Federation, Spain) Setting: Academic clinical trial centres and smoking cessation clinics Aim: To assess the efficacy and safety of 12 weeks of varenicline treatment or placebo for smoking cessation, with 40 weeks of non‐treatment follow‐up, in adults with current or past depression (MDD) Study Design: Double‐blind placebo‐controlled RCT Dates conducted: March 2010 ‐ June 2012 Analysis: Power calculation of 250 in each arm (80%, alpha = 0.05) to detect an OR of 2.35, assuming a placebo efficacy rate of 7%
Participants	525 adult smokers, aged 18 ‐ 75, smoking at least 10 CPD, motivated to quit, diagnosed with unipolar MDD without psychotic features. 37% male, mean age 46, av CPD at baseline 22, mean FTND 5.9. Allocated to varenicline (256) or placebo (269) Exclusion criteria: Current or past diagnosis of dementia, schizophrenia, schizoaffective disorder, or other psychotic disorder, bipolar I disorder, bipolar II disorder. People with antisocial, schizotypal, or any other personality disorder severe enough to compromise their ability to comply with the study requirements Current use of either bupropion or nortryptiline
Interventions	1. Varenicline 1 mg x 2/day, titrated for first wk 2. Placebo inactive tablets, same regimen All participants received manual‐guided SC support, telephone support and one‐to‐one 10‐minute counselling by the same person where possible. Participants in both groups could reduce the dosage if they wished TQD was set for wk 1 visit Treatment period was 12 wks. Visits at screening, baseline, weekly for wks 1 ‐ 12, and then at wks 13, 16, 24, 32, 40, 52 (or early termination); phone calls at wks 14, 20, 28, 36, 44 and 48. Weekly pill counts to assess adherence Safety data were reviewed regularly by an external independent data safety monitoring committee
Outcomes	Primary: CO‐confirmed CAR for wks 9 ‐ 12 Secondary: CO‐confirmed CAR for wks 9 ‐ 24, 9 ‐ 52; 7‐day PPA at wks 12, 24, 52; AEs and SAEs Verification: CO < 10 ppm
Treatment type	Medication: VARENICLINE
Notes	New for 2016 update Funding by Pfizer; Dept of VA merit review award; NIAAA grant
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Eligible participants were randomly assigned to varenicline or placebo in a 1:1 ratio by using a computer generated, 4‐block randomization scheme at each site."
Allocation concealment (selection bias)	Low risk	"Randomization was stratified by antidepressant medication use at baseline (any vs. none) and baseline Montgomery–Åsberg Depression Rating Scale (MADRS) score (11 vs. 11) (32). Investigators obtained participant identification numbers and randomized study drug assignments by using a Web‐based or telephone call‐in computerized drug management system."
Blinding (performance bias and detection bias) All outcomes	Low risk	"The study drug was supplied in blinded bottles by the sponsor to the study sites, where they were dispensed according to computerized instructions."
Incomplete outcome data (attrition bias) All outcomes	Low risk	68.4% of varenicline group completed study (lost 15.6% in treatment and 16% in follow‐up); 66.6% of placebo group completed study (lost 21.9% in treatment and 11.5% in follow‐up)
Selective reporting (reporting bias)	Low risk	None noted
Other bias	Low risk	None noted