title: Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial.
abstract: BACKGROUND
  The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.
  
  
  METHODS
  We did this multicentre, parallel-group, randomised, placebo-controlled trial between Oct 1, 2010, and Dec 20, 2013, at 21 primary care sites and 41 secondary care sites in England and Scotland. Children aged 10 months to 5 years with two or more wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) via a permuted block schedule (size ten), to receive intermittent montelukast or placebo given by parents at each wheeze episode over a 12 month period. Clinical investigators and parents were masked to treatment group and genotype strata. The primary outcome was number of unscheduled medical attendances for wheezing episodes. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01142505.
  
  
  RESULTS
  We randomly assigned 1358 children to receive montelukast (n=669) or placebo (n=677). Consent was withdrawn for 12 (1%) children. Primary outcome data were available for 1308 (96%) children. There was no difference in unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 [SD 2·6] vs 2·3 [2·7]; incidence rate ratio [IRR] 0·88, 95% CI: 0·77-1·01; p=0·06). Compared with placebo, unscheduled medical attendances for wheezing episodes were reduced in children given montelukast in the 5/5 stratum (2·0 [2·7] vs 2·4 [3·0]; IRR 0·80, 95% CI 0·68-0·95; p=0·01), but not in those in the 5/x+x/x stratum (2·0 [2·5] vs 2·0 [2·3]; 1·03, 0·83-1·29; p=0·79, pinteraction=0·08). We recorded one serious adverse event, which was a skin reaction in a child allocated to placebo.
  
  
  CONCLUSIONS
  Our findings show no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5 ALOX5 promoter genotype might identify a montelukast-responsive subgroup.
  
  
  BACKGROUND
  Medical Research Council (UK) and National Institute for Health Research.
authors.affiliation: Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
authors.forename: Chinedu
authors.initials: C
authors.lastname: Nwokoro
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Pandya
authors.affiliation: Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Turner
authors.affiliation: Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Eldridge
authors.affiliation: Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Griffiths
authors.affiliation: Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.affiliation: Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Price
authors.affiliation: Department of Medicine, Jagiellonian University Medical School, Krakow, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Sanak
authors.affiliation: Human Development and Health, University of Southampton, Southampton General Hospital, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.affiliation: Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
authors.forename: Rossa
authors.initials: R
authors.lastname: Brugha
authors.affiliation: Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Koh
authors.affiliation: Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Dickson
authors.affiliation: Centre for Primary Care and Public Health, Blizard Institute, Queen Mary University of London, London, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Rutterford
authors.affiliation: Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK. Electronic address: j.grigg@qmul.ac.uk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Grigg
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000627:therapeutic use*; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001071:Appointments and Schedules; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects; D001249:Asthma / Q000188:drug therapy*; D002675:Child, Preschool; D003521:Cyclopropanes; D003545:Cysteine / Q000652:urine; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D015289:Leukotrienes / Q000652:urine; D008297:Male; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D012135:Respiratory Sounds / Q000187:drug effects*; D013440:Sulfides; D016896:Treatment Outcome
chemical_list: D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D015289:Leukotrienes; D011804:Quinolines; D013440:Sulfides; C112381:cysteinyl-leukotriene; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human; D003545:Cysteine; C093875:montelukast