Wheeze and Intermittent Treatment

Study Overview
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Brief Summary
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The clinical aim of this trial is to assess whether intermittent montelukast is an effective treatment strategy in preschool wheeze. The mechanisms aim of the trial is to determine whether there is a genetically highly-responsive subgroup of children. In designing this trial the investigators have incorporated several novel aspects. First, parents will be able to adjust the use of oral montelukast to their child's symptoms. This allows the investigators to recruit both episodic and multi trigger patterns of preschool wheeze - and control for any change in wheeze pattern during the trial. Second, before the investigators issue the trial medication, the investigators will assess children's leukotriene genes, focusing primarily on a gene called ALOX5. This ALOX5 stratification step will ensure that an equal number of potentially treatment-responsive children receive the active drug (montelukast) and the dummy medicine - and the equal numbers will help the investigators to assess the role of ALOX5. For the trial, the investigators will first recruit 1,300 children with a history of preschool wheeze, then divide them into the group with responsive and less responsive genes by their ALOX5 status. The investigators will then issue parents with the trial medication; 50% will be given montelukast and 50% will be given dummy medication. Parents will start the trial medication whenever their child develops a cold, and stop the medication when wheeze resolve. Parents will also be able to give the trial medication for wheeze between colds. Over the 12 month trial period, the investigators will assess the number of unscheduled attendances to a medical practitioner for wheeze for each child. At the end of the trial, the investigators will determine whether montelukast is effective then whether there is a difference in response to montelukast between the 2 ALOX5 gene groups. At the same time, the investigators will measure many other genes that may influence response to montelukast, as well as the amount of leukotrienes that are excreted in the urine before and during attacks. Using these results, the investigators will be able to both inform national treatment policy, and develop new concepts on the mechanism of preschool wheeze that will inform the development of new therapies. Since children will continue to receive normal inhaled therapy, there are no ethical issues in giving a dummy medicine to half of the 1300 children to be recruited. The study will be the largest trial in wheezy preschool children to date, and may open up genetic testing in preschool wheeze.

Detailed Description
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Background A quarter of all UK children will have at least one attack of wheeze during the preschool period (1 to 5 years of age). Severe attacks of wheeze in these young children are usually triggered by viral-colds. The majority of affected children will only wheeze with colds, although these attacks may be severe and repeated resulting in GP attendances and hospital admissions. This pattern of wheeze is called episodic preschool wheeze. A minority of preschool children wheeze both with and between colds - a pattern that is called multi-trigger preschool wheeze. In real life this distinction is blurred, with preschool children changing their pattern of wheeze over time. What is clear is that asthma therapies that are effective in older children with classical allergic asthma may not necessarily be effective in preschool wheeze. For example, although a short-course of oral steroids is very effective in treating attacks of wheeze in school age children with allergic asthma, the investigators have shown in 2 major trials that a short course of oral steroids does not reduce the severity of attacks of preschool wheeze. Recently, montelukast, an oral medicine that blocks a substance (leukotriene) that narrows the breathing tubes, has shown promise in preschool wheeze. However, to date, only modest benefits have been reported when large groups of children have been studied. One explanation for this, is that a significant proportion of preschool children do not respond to montelukast, but there is a subgroup who are genetically programmed to respond very well. Recent analysis of trials of montelukast suggests that this responsive subgroup may be defined by variations in leukotriene-producing genes. Thus an understanding of the role of leukotriene genes and leukotriene production in preschool wheeze may better target montelukast treatment in this age group, and inform the development of new therapies. Trial Description The clinical aim of this trial is to assess whether intermittent montelukast is an effective treatment strategy in preschool wheeze. The mechanisms aim of the trial is to determine whether there is a genetically highly-responsive subgroup of children. In designing this trial the investigators have incorporated several novel aspects. First, parents will be able to adjust the use of oral montelukast to their child's symptoms. This allows us to recruit both episodic and multi trigger patterns of preschool wheeze - and control for any change in wheeze pattern during the trial. Second, before the investigators issue the trial medication, the investigators will assess children's leukotriene genes, focusing primarily on a gene called ALOX5. This ALOX5 stratification step will ensure that an equal number of potentially treatment-responsive children receive the active drug (montelukast) and the dummy medicine - and the equal numbers will help us to assess the role of ALOX5. For the trial, the investigators will first recruit 1,300 children with a history of preschool wheeze, then divide them into the group with responsive and less responsive genes by their ALOX5 status. The investigators will then issue parents with the trial medication; 50% will be given montelukast and 50% will be given dummy medication. Parents will start the trial medication whenever their child develops a cold, and stop the medication when wheeze resolve. Parents will also be able to give the trial medication for wheeze between colds. Over the 12 month trial period, the investigators will assess the number of unscheduled attendances to a medical practitioner for wheeze for each child. At the end of the trial, the investigators will determine whether montelukast is effective then whether there is a difference in response to montelukast between the 2 ALOX5 gene groups. At the same time, the investigators will measure many other genes that may influence response to montelukast, as well as the amount of leukotrienes that are excreted in the urine before and during attacks. Using these results, the investigators will be able to both inform national treatment policy, and develop new concepts on the mechanism of preschool wheeze that will inform the development of new therapies. Since children will continue to receive normal inhaled therapy, there are no ethical issues in giving a dummy medicine to half of the 1300 children to be recruited. The study will be the largest trial in wheezy preschool children to date, and may open up genetic testing in preschool wheeze.

Official Title
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Parent-determined Oral Montelukast Therapy for Preschool Wheeze With Stratification for Arachidonate-5-Lipoxygenase (ALOX5) Promoter Genotype

Conditions
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Wheezing

Intervention / Treatment
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* Drug: Mannitol
* Drug: Montelukast


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age ≥ 10 months and ≤ 5 years old on the day of the first dose of Investigational Medicinal Product two or more attacks of parent-reported wheeze at least one attack with wheeze validated by a clinician the most recent attack within the last 3 months contactable by telephone and able to attend one face-to-face review for issue of Investigational Medicinal Product parent or guardian able to give written informed consent for their child to participate in the study Exclusion Criteria: any other chronic respiratory condition diagnosed by a clinician including structural airway abnormality (e.g. floppy larynx) and cystic fibrosis any chronic condition that increases vulnerability to respiratory tract infection such as severe developmental delay with feeding difficulty history of neonatal chronic lung disease current continuous oral montelukast therapy in a trial using an Investigational Medicinal Product in the previous 3 months prior to recruitment

Ages Eligible for Study
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Minimum Age: 10 Months
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Patients in the placebo arm will be given an inactive version of the investigational medical product formed of the excipient mannitol (which is coated with the active drug montelukast in the active comparator arm) | Drug: Mannitol<br>* 4mg once daily granules for 10 days, given orally alone or with cold or warm food from the onset of a cold or wheezing attack.<br>* Other names: Pearlitol SD 200;|
| Active Comparator: Montelukast<br>Patients in the active arm will be given an active version of the investigational medical product formed of the inactive excipient mannitol with a coating of active drug montelukast. | Drug: Montelukast<br>* 4mg once daily granules for 10 days, given orally alone or with cold or warm food from the onset of a cold or wheezing attack<br>* Other names: Singulair;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for unscheduled medical attention | Number of times a child attends for an unscheduled medical opinion with respiratory problems over a 12 month period, as confirmed from medical records. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of admissions to hospital |  | 12 months | 
| Duration of admissions to hospital |  | 12 months | 
| Number of unscheduled GP consultations for wheeze | The number of times a child is brought to his primary care/family doctor with wheeze | 12 months | 
| Duration of wheezy episodes | The duration of wheezy episodes as recorded by parents on their diary cards. | 12 months | 
| Severity of episodes by diary card | The severity of wheeze episodes as recorded in parent diary cards | 12 months | 
| Parent's overall impression of efficacy of Investigational Medicinal Product | Parent's overall impression of efficacy of Investigational Medicinal Product as recorded in diary cards. | 12 months | 
| Time to first attack of wheeze | Time to first attack of wheeze as recorded in parent diary card and researcher phonecalls. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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wheeze, preschool, leukotriene, montelukast, 5-lipoxygenase