title: Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial.
abstract: BACKGROUND
  Substantial variability exists in therapeutic response and adverse effects with pharmacotherapies for tobacco dependence. Biomarkers to optimise treatment choice for individual smokers might improve treatment outcomes. We tested whether a genetically informed biomarker of nicotine clearance, the nicotine metabolite ratio (NMR; 3'-hydroxycotinine:cotinine), predicts response to nicotine patch or varenicline for smoking cessation.
  
  
  METHODS
  We undertook NMR-stratified multicentre, randomised, placebo-controlled clinical trial from Nov 16, 2010, to Sept 12, 2014, at four sites. Smokers seeking treatment were randomly assigned by baseline NMR status and study site, in blocks of 12 patients (1:1:1 ratio), to 11 weeks of placebo (placebo pill plus placebo patch), nicotine patch (active patch plus placebo pill), or varenicline (active pill plus placebo patch), plus behavioural counselling. Participants and investigators were masked to group allocation and NMR status. An intention-to-treat analysis was done. Participants were followed up for 12 months after the target quit date. The primary endpoint was biochemically verified 7 day point prevalence abstinence at the end of treatment to estimate the pharmacological effect of treatment by NMR. The trial is registered at ClinicalTrials.gov, number NCT01314001.
  
  
  RESULTS
  1246 participants (662 slow metabolisers of nicotine, 584 normal metabolisers of nicotine) were enrolled and randomly assigned to the three interventions (408 placebo, 418 nicotine patch, 420 varenicline). At end of treatment, varenicline was more efficacious than nicotine patch in normal metabolisers (OR 2·17, 95% CI 1·38-3·42; p=0·001), but not in slow metabolisers (OR 1·13, 0·74-1·71; p=0·56). In the longitudinal model including all timepoints, the NMR-by-treatment interaction was significant (ratio of odds ratios [ORR] 1·96, 95% CI 1·11-3·46; p=0·02). An NMR-by-treatment interaction showed that slow (vs normal) metabolisers reported greater overall side-effect severity with varenicline versus placebo (β=-1·06, 95% CI -2·08 to -0·03; p=0·044).
  
  
  CONCLUSIONS
  Treating normal metabolisers with varenicline and slow metabolisers with nicotine patch could optimise quit rates while minimising side-effects.
  
  
  BACKGROUND
  National Institutes of Health, Canadian Institutes of Health Research, Abramson Cancer Center, Centre for Addiction and Mental Health Foundation, and Pennsylvania Department of Health.
authors.affiliation: Department of Psychiatry, Annenberg School for Communication, and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: clerman@upenn.edu.
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
authors.affiliation: Department of Psychiatry and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Schnoll
authors.affiliation: Department of Psychology, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Hawk
authors.affiliation: Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Cinciripini
authors.affiliation: Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tony P
authors.initials: TP
authors.lastname: George
authors.affiliation: Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: E Paul
authors.initials: EP
authors.lastname: Wileyto
authors.affiliation: Department of Medicine, Stanford University, Palo Alto, CA, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.affiliation: Departments of Medicine, and Bioengineering & Therapeutic Sciences, University of California, San Francisco, CA, USA.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.affiliation: Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.affiliation: Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D003367:Cotinine / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D016540:Smoking Cessation / Q000379:methods*; D061485:Tobacco Use Cessation Devices; D016896:Treatment Outcome; D000068580:Varenicline / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D018722:Nicotinic Agonists; C001381:hydroxycotinine; D009538:Nicotine; D003367:Cotinine; D000068580:Varenicline