Weiss 2010.

Methods	Study design: randomised, double‐blind, placebo‐controlled, multicentre study Aim: to determine the effectiveness of montelukast therapy in reducing asthma burden in children when initiated prophylactically on school return. Study centres and method of recruitment: 165 allergy and clinical paediatric practices in the United States and Canada. Hospital‐led recruitment. No recruitment information given. Dates of study: 28 June 2006 to 20 November 2006. Run‐in period: 2‐ to 12‐week screening. Duration of participation: 10 weeks. Consent: approved by local institutional review boards or ethical review committees with informed consent obtained from participants and parents or guardians. Power: assuming a treatment difference of 5% and a standard deviation of 24%, 495 evaluable participants in each treatment group was estimated to provide 90% power (2‐sided alpha 0.05) to demonstrate the superiority of montelukast. Imputation of missing data, i.e. assumptions made for ITT analysis: efficacy analysis was based on the analysis set population, which included all children who had received at least 1 dose of study medication and had a valid measurement of the percentage of days with worsening asthma during the study period (derived from at least 7 days of diary data). All randomised children who had received at least 1 dose of study drug were included in the safety analysis.
Participants	Age (mean, range): 9.9 years, 6 to 14 years. Gender: 61.2% male montelukast group, 59.5% male placebo group. Asthma severity: 30% prescribed inhaled corticosteroids at randomisation (likely low/moderate). Diagnostic criteria: history of chronic asthma. Number recruited: 1162 Number randomised (intervention, control): 580, 582 Number completed (intervention, control): 536, 545 Number analysed (intervention, control): efficacy analysis 499, 499; safety analysis 566, 566. Withdrawals: 44 montelukast group: 5 clinical adverse events, 4 protocol deviation, 1 laboratory adverse event, 1 lack of efficacy, 12 lost to follow‐up, 1 moved, 15 withdrew consent, 5 other 37 control group: 5 clinical adverse events, 4 protocol deviation, 5 lack of efficacy, 7 lost to follow‐up, 2 moved, 7 withdrew consent, 7 other Inclusion criteria: age 6 to 14 years history of chronic asthma for at least 1 year, in association with the need for treatment and asthma medication 6 months preceding screening history of at least 1 asthma exacerbation in the previous year, in conjunction with a cold alteration in environment differing from their typical school or education environment throughout August/September Exclusion criteria: FEV1 < 60% corticosteroid use other than ICS within 4 weeks of randomisation LABA or LTRA use within 10 days of randomisation hospitalisation within 4 weeks or more than 3 times in the previous year moving to a different area for greater than 7 days after school start
Interventions	Intervention: montelukast 5 mg from the night before the first day of school for 8 weeks Comparison: matching placebo Concomitant medication: usual medications Excluded medication: none reported beyond exclusion criteria
Outcomes	Primary outcome: percentage of days with worsening asthma symptoms, defined as 1 or more of: increased beta‐agonist use > 70% from baseline and a minimum increase of 2 puffs; increased daytime symptoms score > 50% from baseline; awake 'all night'; increased ICS use ≥ 100% from baseline or OCS rescue for worsening asthma; unanticipated visits to a doctor, emergency department, or hospital for asthma. Secondary outcomes: individual components of the primary composite endpoint occurrence of any adverse event any serious adverse event any drug‐related adverse event discontinuation due to adverse events Time points measured: 4, 8, and 10 weeks. Primary outcome result: percentage of days with worsening asthma symptoms: montelukast 24.3% vs placebo 27.2%; least squares means difference 3.0, 95% CI 6.21 to 0.29; P = 0.07 (OR for use of OCS obtained from authors and unpublished: OR 0.79, 95% CI 0.59 to 1.06). Secondary outcome results: no significant changes in components of primary outcome, safety outcomes, or interaction terms for subgroup analyses. Adverse events: 4 SAEs in the intervention group, 1 SAE in the placebo group. No SAE thought to be treatment related. The most common AEs were upper respiratory tract infections.
Notes	Funding: Merck & Co. Subgroups: intervention better than control in boys and children 10 to 14 years, but interaction terms for age and gender non‐significant. No difference between groups according to inhaled corticosteroid use at entry, presence of cold symptoms, or according to individual components of the primary outcome. age group: percentage days worsening symptoms intervention vs control 10 to 14 years: 21.4% vs 26.4%; 6 to 9 years: 27.4% vs 27.7% gender: percentage days worsening symptoms intervention vs control boys: 23.7% vs 28.9%; girls: 25.3% vs 25.0% Additional post hoc subgroup analyses suggested an increased percentage of days with asthma symptoms in the placebo compared to the intervention group at 3 to 4 weeks after school return and near‐significant superiority of intervention if school return is later than 15 August.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, randomisation schedule generated by study statistician.
Allocation concealment (selection bias)	Unclear risk	No description of schedule. Numbered containers, not specified whether identical.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Identical placebo used. Study double‐blinded including laboratory technicians, monitors, and study site personnel.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Assessors blinded, outcome systematic but largely subjective participant‐reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Primary analysis based on a modified intention‐to‐treat design, including all children who had received at least 1 dose of study medication and had a valid measurement of the percentage of days with worsening asthma during the study period (derived from at least 7 days of diary data). There was no imputation of missing data, but similar dropout rates and reasons between groups.
Selective reporting (reporting bias)	Low risk	All outcomes reported.
Other bias	Low risk	Generally balanced groups at baseline except inhaled corticosteroids last year intervention 54.1% vs placebo 48.7%.

AE: adverse event
 BMI: body mass index
 CI: confidence interval
 CPRD: Clinical Practice Research Datalink
 EPR‐3: Expert Panel Report 3
 GP: general practitioner
 ICS: inhaled corticosteroids
 IgE: immunoglobulin E
 IFNα: interferon alpha
 ITT: intention‐to‐treat
 FeNO: fractional exhaled nitric oxide
 FEV₁: forced expiratory volume in the first second of expiration
 LABA: long‐acting beta‐agonist
 LTRA: leukotriene receptor antagonist
 mITT: modified intention‐to‐treat
 NHS: National Health Service
 OCS: oral corticosteroid
 OR: odds ratio
 PBMCs: peripheral blood mononuclear cells
 PP: per protocol
 SAE: serious adverse event
 QALY: quality‐adjusted life year