Title: Parent-determined oral montelukast therapy for preschool wheeze
Funder: Department of Health (England)

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 Childrens Hospital and the A&E and paediatric wards of the University Hospitals of Leicester NHS Trust Childrens 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 1050 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 1300 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 1050 subjects). Increased drop out will affect the power to detect an interaction between treatment of genotype (below). However it is likely that ALOX5 promoter genotyping would be clinically applicable if the reduction attacks with montelukast in the less responsive genetic strata is very low. Thus a 15% drop out will have sufficient power to inform whether pharmacogenetic testing of ALOX5 is clinically applicable.Planned analyses. We will use poisson regression with a random effect representing individuals to account for overdispersion. The primary analyses will be performed on an intention to treat basis. Fixed effects will represent the stratification factor (ALOX5 promoter) and treatment centre. The incident rate ratio (relative risk) and 95% confidence interval will be calculated Analysis will be conducted in Stata version 10. The primary analyses will be performed on an intention to treat basis. To assess the difference in responsiveness to montelukast in the two strata (the primary mechanisms question) we will fit an interaction term to test for the interaction between montelukast and stratum in our main model or each treatment limb. We will report the associations between clinical phenotype genotype urinary LT and will determine the economic benefit of as required oral montelukast and the cost/benefit of ALOX5 genotyping.Expertise of team. For this trial we have assembled a multidisciplinary team that combines individuals with an international track record of delivering high quality studies in both primary and secondary care with scientists with cutting-edge knowledge of molecular biology and the genetic determinants of response to anti-asthma therapies. Prof. Grigg (principal applicant) is an international expert in the diagnosis and treatment of preschool wheeze. He has recently published 2 major randomised controlled trials in this condition; the most recent is in press in the New England Journal of Medicine. Dr Vulliamy has an international profile in molecular genetics in children. Prof. Griffiths is an international expert on the association between vitamin D and respiratory disease and has extensive experience of performing trials of respiratory interventions in primary care in the East End of London. Prof Eldridge has extensive experience in the design and analysis of clinical trials and is Director of the Barts and the London Clinical Trials Unit. Prof. Price has extensive experience in performing clinical trials in asthma in primary care including studies of montelukast in children. Dr Pandya has a detailed understanding of the clinical-scientific interface in Leicester. Dr Holloway is an international expert in genetic polymorphisms in asthma especially those relating to the leukotriene pathway. Prof Seale has extensive experience of performing qualitative studies.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: RESPIRATORY