Prescribing Asthma Controller Medication According to Gene Status to Improve Quality of Life in Young People With Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional

Summary: 
      One in every 11 children in the United Kingdom (UK) has asthma. Children with asthma cough,
      wheeze and have difficulty breathing. The symptoms which children experience can mean they
      miss school and makes it difficult for children to take part in playground games and sports.
      Some have to be admitted to hospital. In fact, in the UK a child is admitted to hospital
      every 18 minutes because of their asthma.

      Effective medicines are available, but a child's response to these medicines is currently
      unpredictable. This project focuses on an asthma controller medicine called salmeterol.
      According to reports, tens of thousands of children may be taking this medicine in the UK,
      but evidence suggests it might not work for around one in seven of them. The study team are
      investigating whether a new approach to treatment, where prescribing is personalised
      according to a child's genetic make-up, improves the child's quality of life and provides
      better control of their asthma. Treatment that is tailored in this way to a person's genetic
      features is often called 'personalised medicine'.

      At the moment, doctors commonly prescribe salmeterol to relieve asthma symptoms if children
      do not benefit enough from other medicines. But evidence suggests salmeterol may not work
      properly in children with a certain genetic makeup.

      The study team are investigating whether it helps to take children and young people's genetic
      makeup into account when deciding whether to give them salmeterol or an alternative medicine
      called montelukast. A simple and inexpensive saliva test can provide the information needed
      to guide decision making.
    

Detailed description: 
      Asthma is a common chronic illness in children and young people. It affects, for example, an
      average of two children in every UK classroom. Initial treatment usually consists of
      salbutamol used on demand at step 1 of British Thoracic Society (BTS) guidelines. At step 2,
      regular anti-inflammatory 'controller' therapy starts with the regular use of inhaled
      corticosteroids such as beclomethasone. Therapeutic efficacy with inhaled steroids usually
      peaks around 400 micrograms per day of beclomethasone (or equivalent). With inadequate asthma
      control at step 2, inhaled long-acting β2 agonists (LABA) such as salmeterol, or leukotriene
      receptor antagonists (LTRA) such as montelukast are added; this represents BTS step 3 for
      asthma management.

      The improvement of asthma-related quality-of-life represents an important goal for the
      overall pharmacological management of asthma. Juniper has developed and validated
      questionnaires for the measurement of asthma-related quality-of-life and asthma control in
      both children and adults. Furthermore, Juniper has defined the minimum improvement in
      asthma-related quality-of-life that is clinically relevant for participants with this
      disease. In addition, Juniper has recently validated on-line versions of the asthma-related
      quality-of-life and asthma control questionnaires in children aged 12 and above. This could
      provide an opportunity for more long-term and cost-effective comparisons of different asthma
      treatments through the use of tools that measure asthma control without the need for clinic
      visits and the completion of paper-based forms.

      Overall, in children with asthma managed on step 3, salmeterol appears to provide better
      asthma control than montelukast in the setting of a randomized controlled trial. However, in
      real life, the efficacy of salmeterol at step 3 for improving asthma control in individual
      children appears rather variable, and some children continue to experience day-to-day
      symptoms and exacerbations.

      The investigators showed in a earlier study of 1182 UK children and young adults (4-22
      years), 50% of those on regular salmeterol experienced asthma exacerbations over a 6-month
      period, and 18% required inhaled salbutamol at least daily for symptom relief. A step-wise
      increase was reported in the risk of asthma attacks related to each copy of the Arg16 allele
      on the β2 receptor gene (1.7-fold) in asthmatic children and young adults exposed to regular
      salmeterol in conjunction with inhaled corticosteroids. This led the investigators to
      hypothesize that, contrary to the observations on the overall population of children and
      young adults where salmeterol is superior in efficacy to montelukast at step 3, those
      possessing susceptible Arg16 β2 receptor genotype may experience better asthma control with
      the addition of montelukast rather than salmeterol as second-line controller medication, in
      addition to inhaled corticosteroids. As such the investigators elected to identify from their
      database those children with two copies of the Arg16 polymorphism [i.e. homozygous Arg
      genotype (∼15% of overall population) who would potentially be at greatest risk]. The
      mechanism for worse control with regular salmeterol involves a greater susceptibility to
      agonist-induced down-regulation and uncoupling of airway β2 receptors and associated
      sub-sensitivity of response in the Arg16 genotype.

      The investigators therefore performed a proof-of-concept randomized controlled trial to
      determine whether genetically susceptible children with homozygous Arg16 genotype experience
      superior long-term asthma control with montelukast compared with salmeterol when used as
      tailored second-line controller therapy as add-on to the inhaled steroid fluticasone. The
      purpose of this preliminary study was to provide evidence to support the potential for
      personalised medicine based on the individual genotype to improve asthma-related
      quality-of-life and control. This study was published in 2013, and represents the first
      prospective randomized controlled study in children with asthma that addresses personalised
      medicine based on genotype. The results of this study showed that in children expressing the
      homozygous Arg 16 genotype, in comparison with salmeterol, adding montelukast to inhaled
      fluticasone significantly improved asthma-related quality-of-life and clinical symptoms,
      while reducing school absences and inhaled reliever use. The relative benefits of montelukast
      in comparison with salmeterol became evident within the first 3 months and persisted
      throughout the whole year.

      Subsequently, the investigators systematically searched for other randomised controlled
      trials comparing the effects of salmeterol (or other long-acting beta2 agonist) with
      montelukast (or other leukotriene antagonist) within the context of Arg/Gly variation, in
      children with asthma. No studies could be identified. In particular, there were no trials in
      either adults or children that have studied quality-of-life, which is a key outcome of
      interest in the context of asthma-related disability, and which is often unrelated to
      outcomes such as lung function. The absence of other randomised trials, together with the
      strength of the investigators proof-of-concept evidence, underscores the need for this
      powered study.

      Rationale:

      Children with asthma inadequately controlled on inhaled steroids as 'controller' medication
      experience greater benefit in asthma-related quality-of-life from allocation of further drug
      therapy on the basis of their genetic status, in comparison to allocation on the basis of
      current method of doctor or nurse choice informed by the BTS guidelines.

      Primary Objective:

      Does the prescribing of asthma controller medication according to beta2 receptor gene status
      improve quality of life as determined by validated questionnaire (Juniper) in 12-18 year olds
      with asthma?

      Secondary Objectives:

      Asthma control, as determined by validated questionnaire 3, 6, 9 and 12 months and an
      evaluation of how many visits participants report to have attended their General Practitioner
      (GP) or asthma nurse (non- routine asthma review), A&E or been hospitalised as a result of
      their asthma . Courses of oral steroids and any other medication taken will also be recorded.
    

Intervention name(s): Personalised medicine (Salmeterol); Personalised medicine (Montelukast); Standard care
Intervention type(s): Genetic; Genetic; Other
Intervention description(s): If participants require add-on medication and have the Gly/Gly variant on the ADRB2, salmeterol will be prescribed.; If participants require add-on medication and have the Arg/Arg or Arg/Gly variant on the ADRB2, montelukast will be prescribed.; If participants require add-on medication in the arm, they will be prescribed either salmeterol or montelukast according to health professional's choice based on current guidelines.
Other intervention name(s): Salmeterol; Montelukast; Salmeterol or montelukast
Intervention MeSH terms: Salmeterol Xinafoate; Montelukast
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment