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Wheeze and Intermittent Treatment

2014-08-27 03:12:57 | BioPortfolio

Summary

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 13,000 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.

Description

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, we 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 we 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 we issue the trial medication, we 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, we 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. We 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, we will assess the number of unscheduled attendances to a medical practitioner for wheeze for each child. At the end of the trial, we 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, we 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, we 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 13,000 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.

Study Design

Allocation: Randomized, Control: Active Control, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Conditions

Preschool Wheeze

Intervention

Mannitol, Montelukast

Location

Barts and the London NHS Trust
London
United Kingdom
E1 1BB

Status

Not yet recruiting

Source

Queen Mary University of London

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:12:57-0400

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Preschool wheeze, genes and treatment.

Preschool wheeze is a common but poorly understood cause of respiratory morbidity that is both distinct from and overlaps with infantile bronchiolitis and school age asthma. Attempts at classification...

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Medical and Biotech [MESH] Definitions

Phosphoric acid esters of mannitol.

Sugar alcohol dehydrogenases that have specificity for MANNITOL. Enzymes in this category are generally classified according to their preference for a specific reducing cofactor.

A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate. Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity.

A child between the ages of 2 and 5.

A person 6 to 12 years of age. An individual 2 to 5 years old is CHILD, PRESCHOOL.

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