Wheeze and Intermittent Treatment
Condition: Wheezing
MeSH terms: Respiratory Sounds
Study type: Interventional
Phase: Phase 3

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 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: 
      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.
    

Intervention name(s): Mannitol; Montelukast
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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
Other intervention name(s): Pearlitol SD 200; Singulair
Intervention MeSH terms: Mannitol; Montelukast
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: wheeze; preschool; leukotriene; montelukast; 5-lipoxygenase