Parent-determined oral montelukast therapy for preschool wheeze with stratification for arachidonate-5-lipoxygenase

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Scientific Abstract Design. An independent, 12 month, multicentre, parallel group, double-blind, randomised placebo-controlled trial. Settings. Recruitment will be based in at 40 GP practices in the East London GP Academic Network, at 60 practices in the Norwich Academic Primary Care Network, the Accident and Emergency Department and paediatric wards of the Barts and the London Children's Hospital, and the A&E and paediatric wards of the University Hospitals of Leicester NHS Trust Children's Hospital. Intervention being evaluated. The trial will test the hypothesis that intermittent treatment with montelukast is efficacious in preschool wheeze, and that there is a highly responsive subgroup of children defined by a variant number [x/x or 5/x (where x is not equal to 5)] of SP1 repeats of the membrane-bound arachidonate-5-lipoxygenase gene (ALOX5). Children 10 to 60 months of age with preschool wheeze will be stratified as either; 5/5, or [5/x and x/x] genotypes of membrane-bound arachidonate-5-lipoxygenase polymorphism (ALOX5), and then randomised to receive either oral montelukast 4 mg granules or oral placebo granules. The trial medication is to be given by parents at the onset of every viral upper respiratory tract infection and continued for a minimum of 7 days or until symptoms have resolved for 48 hours, and for every episode of wheeze not triggered by a viral cold, and stopped when symptoms have resolved. Randomisation, manufacture of placebos, and packaging of trial medication is done by Nova labs.|Measurement of outcomes and duration of follow up. The primary clinical outcome is the number of attacks of wheeze over the 12 month trial period requiring an unscheduled medical opinion. An attack is defined as clinician-diagnosed attack of wheeze, requiring an unscheduled attendance to either a general practitioner, or to an accident and emergency department. We chose this outcome since it is less subject to parental bias than a symptom diary/number of puffs of salbutamol, it is the best marker of a clinically significant attack, and it can be readily verified. The secondary outcomes are; i) number of days of wheeze over the 12 month trial period, ii) number of admissions to hospital > 4 hrs duration, iii) time to first attack of wheeze, iv) parent assessment of efficacy of trial medication, v) need for additional asthma therapy (regular inhaled steroids, and long acting beta 2 agonists), and vi) change in weight of salbutamol metered dose inhaler canister. In addition to assessing the effect of ALOX5 status on the primary outcome, children will be genotyped for 150 single nucleotide polymorphisms (SNPs) associated with the leukotriene (LT) pathway, and will have baseline and exacerbation urinary cysteinyl leukotrienes assessed. Children will be followed up for 12 months. Parents views on the intervention will be assessed in a qualitative study. Sample size To detect a 33% drop in attack rate requiring medical attention, with a power of 90% and at a significance level of 5%, and a 6% loss to follow up, we require 1,050 children in total. A 33% drop in attack rates equates to an attack rate of 0.51 for the treatment group. The clinical significance of these changes is that approximately four children will need to be treated to prevent one clinically severe attack. A sample size of 1200 gives just over 80% power at the 5% significance level to detect an interaction between treatment and genotype if the effect is a 60% reduction in the [5/x plus x/x] and a 20% reduction in the [5/5] stratum. Assuming a 6% dropout, 1,300 children will need to be recruited. The 6% drop out rate is based on our data from a RCT of 12 month intermittent montelukast in a mixed age group and our community-based study of parent initiated steroids in the preschool age group. For the clinical primary outcome a 15% drop out will result in sufficient power to assess the primary clinical outcome (which requires 1,050 subjects). Increased drop out wil