Pharmacogenetics Use For Further Treatment Improvement in childreN
Condition: Asthma in Children
Study type: Interventional

Summary: 
      There is large heterogeneity in treatment response to asthma medication and a one-size fits
      all approach based on current guidelines might not fit all children with asthma. It is
      expected that children with one or more variant alleles (Arg16Arg and Arg16Gly) within the
      beta2 adrenergic receptor (ADRB2) gene coding for the beta2-receptor have a higher risk to
      poorly respond to long-acting beta2-agonists (LABA) comparing to the Gly16Gly wildtype.

      Aims To study whether ADRB2 genotype-guided treatment will lead to improvement in asthma
      control in children with uncontrolled asthma on inhaled corticosteroids compared with usual
      care.

      Design A multicentre, double-blind, precision medicine, randomized trial will be carried out
      within 20 Dutch hospitals. 310 asthmatic children (6-17 years of age) not well controlled on
      a low dose of inhaled corticosteroids (ICS) will be included and randomized over a
      genotype-guided and a non-genotype-guided(control) arm. In the genotype-guided arm children
      with Arg16Arg and Arg16Gly will be treated with double dosages of ICS and with the Gly16Gly
      wildtype with add on LABA. In the control arm children will be randomized over both treatment
      options. Lung function measurements, questionnaires focussing on asthma control (ACT/c-ACT)
      and quality of life, will be obtained in three visits within 6 months. The primary outcome
      will be improvement in asthma control based on repeated measurement analysis of c-ACT or ACT
      scores in the first three months of the trial. Additional cost effectiveness studies will be
      performed.

      Conclusion Currently, pharmacogenetics is not used in paediatric asthmas. This trial may pave
      the way to implement promising results for genotype-guided treatment in paediatric asthma in
      clinical practice.
    

Detailed description: 
      Study design: national, multi-centre, double-blind randomized controlled trial

      Duration: 6 months, with 3 visits in the hospitals (at t=0, t=3 months and t=6 months)

      Setting: Patients are recruited at out-patient asthma clinics in secondary and tertiary care
      hospitals in the Netherlands.

      Description: Three hundred ten children (6 to 17 years of age) with a doctor's diagnosis of
      asthma and uncontrolled asthma symptoms despite adherent and adequate use of ICS for at least
      three months (step 2 asthma treatment) will be recruited by secondary and tertiary care
      centers in the Netherlands. All participants are eligible for step-up asthma treatment (from
      step 2 to step 3) as assessed by the treating paediatrician/paediatric pulmonologist.
      Participants will be randomized to a genotype-guided treatment arm (n=155) or to a usual
      care, non-genotype guided arm (n=155) and followed for 6 months.

      Genotyping before start treatment During the baseline visit in the hospital, clinical data
      and biological samples (including a DNA sample) will be collected. Upon this visit, the DNA
      sample will be send to the Clinical Chemistry department of the Erasmus MC (Head: Prof. R.
      van Schaik) to perform genotyping of the ADRB2 gene within one week. The treating physician
      will adapt the treatment regime of the participant based on the treatment advice of the study
      coordinator (Table 1). For the children in the genotype-arm, this will be based on the
      genotype. The treating physician will not know (be blinded) whether the treatment advice was
      based on the genotype (intervention arm) or based on randomization (control arm). The
      participant will be followed for 6 months. If the participant is still uncontrolled at t=3
      months, treatment will be adapted. All children will be genotyped, in order to assess the
      influence of the genotype on treatment outcome in the usual arm group retrospectively. The
      children should use the same inhalation device during the study to avoid confusion on how
      they should inhale their medication.

      Furthermore, to test the hypothesis it is necessary to include enough children in the control
      group with Arg16Arg or Arg16Gly to be treated with LABA. The amount of children treated with
      LABA and ICS should be equal in the control group. Therefore children are randomized in the
      control group over doubling ICS (n=77) and adding LABA (n=77). This will lead to an estimated
      number of children with Arg16Arg or Arg16Gly of 51 who will get LABA add on. In this way the
      power is high enough to determine the effectivity of both treatment options in the three
      genotypes. The investigators find it important to define effectivity next to the question
      whether genotyping benefits children with asthma. In the control group DNA samples will be
      obtained for retrospective analysis.

      It is safe to randomise the children again who are randomised within the control arm, because
      treatment with a double dose of ICS and adding a LABA are both standard of care. A Cochrane
      review from 2009 has shown that both treatments have proven to be equally effective in both
      children and adults Randomisation in the control arm is important because it would be futile
      if the children in this arm would be treated with the same therapy by accident. Randomisation
      is necessary to make the trial as small and effective as possible. At this moment physicians
      do not have the tools to determine which therapy is the best for every child. This is why the
      investigators think it is correct to randomise in the control arm.
    

Intervention name(s): ADRB2-genotype guided treatment; Randomisation
Intervention type(s): Genetic; Other
Intervention description(s): This intervention assesses whether ADRB2 genotype-guided treatment leads to better asthma control after 3 months compared to usual care in children who are uncontrolled despite adherent and adequate use of ICS.; In the control arm, children will be randomised over double dose ICS or ICS+LABA instead of treatment according to their genotype.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: multicentre, double-blind, precision medicine, randomized trial
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: long-acting beta2-agonist; pharmacogenetics