BackgroundThe clinical effectiveness of intermittent montelukast for wheeze in young children is unclear. Previous work has been equivocal. Variation in copy numbers of the specificity protein 1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter; where the wild type has five copies per allele, denoted here as 5/5, but variant genotypes may have 1–8 copies on each allele, denoted as x/x or 5/x, influences montelukast efficacy in asthmatic adults. This polymorphism may identify a responsive subgroup within this population.ObjectivesTo assess the clinical effectiveness of montelukast in preschool wheezing children. To explore the effect of theALOX5promoter genotype on this effect.DesignA multicentre, parallel-group, double-blind, randomised, placebo-controlled trial.SettingTwenty-one primary care sites and 41 secondary care sites in England and Scotland.ParticipantsChildren aged 10 months to 5 years with two or more wheeze episodes, one within the last 3 months, stratified byALOX5promoter genotype, either 5/5 or [5/x + x/x]. Children with other respiratory vulnerabilities were excluded.InterventionParent-initiated 4 mg oral granules of montelukast or identical placebo administered once daily for 10 days from the onset of every cold or wheeze episode over 12 months.Main outcome measureNeed for unscheduled medical attendance for wheezing.RandomisationChildren were stratified byALOX5promoter genotype, either 5/5 or [5/x + x/x], where x ≠ 5. Children in each stratum were independently randomised to receive montelukast or placebo in a 1 : 1 ratio via a permuted block schedule (size 10). Clinical investigators and parents were blinded to treatment group and genotype stratum.MethodsGenotype was identified by analysis of salivary deoxyribonucleic acid. Analysis was by intention to treat. Primary outcome data came from treatment diaries, scheduled telephone calls and caregiver records.ResultsA total of 1358 children were randomised 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 Consent was withdrawn for 12 (1%) children.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 [standard deviation (SD) 2.6] vs. mean 2.3 (SD 2.7) unscheduled medical attendances; incidence rate ratio (IRR) 0.88, 95% confidence interval (CI) 0.77 to 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 [mean 2.0 (SD 2.7) vs. mean 2.4 (SD 3.0) unscheduled medical attendances; IRR 0.80, 95% CI 0.68 to 0.95;p = 0.01], but not in those in the [5/x + x/x] stratum [mean 2.0 (SD 2.5) vs. mean 2.0 (SD 2.3) unscheduled medical attendances; IRR 1.03, 95% CI 0.83 to 1.29;p = 0.79,p-interaction = 0.08]. We recorded one serious adverse event: a skin reaction in a child allocated to placebo.InterpretationThere is no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5ALOX5promoter genotype might identify a montelukast-responsive subgroup.LimitationsThe study lacks power to confirm the validity of the suggested genotype stratum effect. Additionally, the effect is contrary to that hypothesised and is not supported by urinary data. We could not robustly measure treatment compliance.Future workFuture work should test the stratum effect with a repeat trial in the apparently more responsive (5/5) stratum only.Study registrationClinicalTrials.gov NCT01142505.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.