<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03269318</url>
  </required_header>
  <id_info>
    <org_study_id>183898</org_study_id>
    <nct_id>NCT03269318</nct_id>
  </id_info>
  <brief_title>PRISTINE - Personalised Approach to Improve aSThma prescrIbing iN childrEn</brief_title>
  <acronym>PRISTINE</acronym>
  <official_title>Feasibility of a Personalised Medicine Clinic for Children With Asthma Aged 5-11 Years</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Brighton and Sussex University Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Brighton and Sussex University Hospitals NHS Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Asthma is one of the most common chronic diseases affecting children in the UK. Poorly&#xD;
      controlled asthma manifests with chronic cough, wheeze and shortness of breath which in-turn&#xD;
      has a significant negative impact on a child's quality of life, interfering with sleep,&#xD;
      impairing exercise ability and resulting in frequent school absences and hospital admissions.&#xD;
&#xD;
      Management of paediatric asthma in the UK is directed by the British Thoracic Society (BTS)&#xD;
      Guidelines, which recommend a stepwise (one to five) treatment plan. Step three of the&#xD;
      management guideline for children aged 5-12 years of age recommends the addition of the&#xD;
      preventer inhaled medication, including long-acting β2 agonists such as salmeterol. However,&#xD;
      there is a wide variation in response to this medication with approximately one in seven&#xD;
      people, with a specific genetic change, found to have an increase in asthma symptoms in&#xD;
      association with the use of thisiss medication. A related medicine, formoterol, is used less&#xD;
      commonly in children with asthma.&#xD;
&#xD;
      In this study, the investigators will aim to identify children with asthma whose symptoms are&#xD;
      poorly controlled on inhaled long-acting beta2 agonists. Via a simple saliva test, the&#xD;
      investigators will identify the presence or absence of the specific genetic change potentally&#xD;
      influencing the effectiveness of treatment with salmeterol or related longacting beta2&#xD;
      agonists thus enabling the investigators to recommend either salmeterol or an alternative&#xD;
      medication for the treatment plan such as montelukast. The investigators will randomise the&#xD;
      patients into two groups; to receive &quot;personalised care&quot; where the choice of controller&#xD;
      medication would be based on the child's gene test results and predicted response to&#xD;
      long-acting beta2 agonists, or &quot;standard care&quot; following the BTS guidelines at the&#xD;
      clinician's discretion without knowledge of the gene test results. The investigators aim to&#xD;
      measure whether this individualized approach to asthma prescribing results in improved&#xD;
      control of asthma symptoms and overall quality of life. Targeting treatment to a child's&#xD;
      specific genetic make-up is a concept known as &quot;personalised medicine&quot;.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Asthma is a common chronic illness in children and young people. It affects, for example, an&#xD;
      average of two children in every UK classroom. Initial treatment usually consists of&#xD;
      salbutamol used on demand at step 1 of British Thoracic Society (BTS) guidelines. At step 2,&#xD;
      regular anti-inflammatory 'controller' therapy starts with the regular use of inhaled&#xD;
      corticosteroids such as beclomethasone. Therapeutic efficacy with inhaled steroids usually&#xD;
      peaks around 400 micrograms per day of beclomethasone (or equivalent). With inadequate asthma&#xD;
      control at step 2, inhaled long-acting β2 agonists (LABA) such as salmeterol, or leukotriene&#xD;
      receptor antagonists (LTRA) such as montelukast are added or inhaled corticosteroids are&#xD;
      increased; this represents BTS step 3 for asthma management.&#xD;
&#xD;
      Overall, in children with asthma managed on step 3, salmeterol appears to provide better&#xD;
      asthma control than montelukast in the setting of a randomized controlled trial. However, in&#xD;
      real life, the efficacy of salmeterol at step 3 for improving asthma control in individual&#xD;
      children appears rather variable, and some children continue to experience day-to-day&#xD;
      symptoms and exacerbations.&#xD;
&#xD;
      In this study of 1182 UK children and young adults (4-22 years), 50% of those on regular&#xD;
      salmeterol experienced asthma exacerbations over a 6-month period, and 18% required inhaled&#xD;
      salbutamol at least daily for symptom relief. Indeed, the investigators reported a step-wise&#xD;
      increase in the risk of asthma attacks related to each copy of the Arg16 allele on the β2&#xD;
      receptor gene (1.7-fold) in asthmatic children and young adults exposed to regular salmeterol&#xD;
      in conjunction with inhaled corticosteroids. This led the investigators to hypothesize that,&#xD;
      contrary to the observations on the overall population of children and young adults where&#xD;
      salmeterol is superior in efficacy to montelukast at step 3, those possessing susceptible&#xD;
      Arg16 β2 receptor genotype may experience better asthma control with the addition of&#xD;
      montelukast rather than salmeterol as second-line controller medication, in addition to&#xD;
      inhaled corticosteroids. As such the investigators elected to identify from the database&#xD;
      those children with two copies of the Arg16 polymorphism [i.e. homozygous Arg genotype (∼15%&#xD;
      of overall population) who would potentially be at greatest risk]. The mechanism for worse&#xD;
      control with regular salmeterol involves a greater susceptibility to agonist-induced&#xD;
      down-regulation and uncoupling of airway β2 receptors and associated sub-sensitivity of&#xD;
      response in the Arg16 genotype.&#xD;
&#xD;
      The investigators therefore performed a proof-of-concept randomized controlled trial to&#xD;
      determine whether genetically susceptible children with homozygous Arg16 genotype experience&#xD;
      superior long-term asthma control with montelukast compared with salmeterol when used as&#xD;
      tailored second-line controller therapy as add-on to the inhaled steroid fluticasone. The&#xD;
      purpose of this preliminary study was to provide evidence to support the potential for&#xD;
      personalised medicine based on the individual genotype to improve asthma-related&#xD;
      quality-of-life and control. This study was published in 2013, and represents the first&#xD;
      prospective randomized controlled study in children with asthma that addresses personalised&#xD;
      medicine based on genotype. The results of this study showed that in children expressing the&#xD;
      homozygous Arg 16 genotype, in comparison with salmeterol, adding montelukast to inhaled&#xD;
      fluticasone significantly improved asthma-related quality-of-life and clinical symptoms,&#xD;
      while reducing school absences and inhaled reliever use. The relative benefits of montelukast&#xD;
      in comparison with salmeterol became evident within the first 3 months and persisted&#xD;
      throughout the whole year.&#xD;
&#xD;
      Subsequently, the investigators used Pubmed to search the Medline database for other&#xD;
      randomised controlled trials comparing the effects of salmeterol (or other long-acting beta2&#xD;
      agonist) with montelukast (or other leukotriene antagonist) within the context of Arg/Gly&#xD;
      variation, in children with asthma. No studies could be identified. In particular, there are&#xD;
      no trials in either adults or children that have studied quality-of-life, which is a key&#xD;
      outcome of interest in the context of asthma-related disability, and which is often unrelated&#xD;
      to outcomes such as lung function. This led to the development of the Personalised Medicine&#xD;
      for Asthma Control (PACT)-study, a randomised controlled trial to determine if personalised&#xD;
      medicine improves quality of life and asthma control in 12-18 years olds. Results of this&#xD;
      trial when published, will provide more conclusive evidence as to the effectiveness of&#xD;
      personalised medicine in this age group. However, there is an absence of trials in a younger&#xD;
      age group of children with asthma (5-11 years) and no evidence to determine if a personalised&#xD;
      medicine clinic is feasible within a hospital setting, which underscores the need for this&#xD;
      study.&#xD;
&#xD;
      There is an absence of trials in a younger age group of children with asthma (5-11 years) and&#xD;
      no evidence to determine if a personalised medicine clinic is feasible within a hospital&#xD;
      setting and this underscores the need for this study.&#xD;
&#xD;
      This research proposes two stages of work and has two main objectives:&#xD;
&#xD;
        1. Feasibility study: Conduct a feasibility study to determine important parameters&#xD;
           (standard deviation of outcomes, recruitment and retention) to inform the design of a&#xD;
           definitive randomised controlled trial&#xD;
&#xD;
           Research questions:&#xD;
&#xD;
             1. Are children with asthma and their parents willing to be recruited and randomised&#xD;
                to a trial of genotyping and personalised management for asthma?&#xD;
&#xD;
             2. Are there retention issues? If yes, at what stages did these occur? What were the&#xD;
                reasons?&#xD;
&#xD;
             3. Are follow-up data complete?&#xD;
&#xD;
             4. Can the intervention (genotyping plus medication) be delivered with sufficient&#xD;
                fidelity?&#xD;
&#xD;
             5. Is there sufficient evidence for scaling up to a definitive randomised controlled&#xD;
                trial?&#xD;
&#xD;
             6. What sample size is needed to power a full scale randomised controlled trial?&#xD;
&#xD;
             7. Are there any safety issues or adverse events?&#xD;
&#xD;
             8. What are the associated costs of running a personalised asthma clinic and is it&#xD;
                cost effective?&#xD;
&#xD;
        2. Qualitative aspect: Assess the acceptability of a personalised asthma clinic for&#xD;
           children with asthma&#xD;
&#xD;
      Research questions:&#xD;
&#xD;
        1. How acceptable do children with asthma and their parents find genotyping and the&#xD;
           personalised approach? How does this compare with their views on acceptability of&#xD;
           conventional clinics?&#xD;
&#xD;
        2. Was there any aspect of genotyping and personalised medicine clinic which children with&#xD;
           asthma and their parents thought was particularly good or worked well?&#xD;
&#xD;
        3. Was there any aspect of genotyping and personalised medicine clinic which children with&#xD;
           asthma and their parents thought was particularly bad or difficult?&#xD;
&#xD;
        4. How satisfied were children with asthma and their parents with the genotyping and&#xD;
           personalised medicine clinic?&#xD;
&#xD;
        5. How did the genotyping and personalised medicine clinic differ from usual care?&#xD;
&#xD;
        6. What would encourage other children with asthma and their parents to participate in a&#xD;
           genotyping and personalised medicine clinic?&#xD;
&#xD;
        7. What would participants change about the personalised clinic?&#xD;
&#xD;
        8. How has the genotyping and personalised medicine clinic impacted on the child and their&#xD;
           parent?&#xD;
&#xD;
        9. Were there any outcomes which weren't measured which should have been?&#xD;
&#xD;
       10. What did the health professionals involved think about the clinic? (in primary and&#xD;
           secondary care)&#xD;
&#xD;
      Two arm, randomised controlled feasibility trial of genotyping and personalised medicine&#xD;
      versus usual care with qualitative aspect to assess acceptability and impact.&#xD;
&#xD;
      The genotyping and personalised medicine clinic is based in the Royal Alexandra Children's&#xD;
      Hospital in Brighton, England. Participants are referred to the research team by their health&#xD;
      care professional (primary and secondary care).&#xD;
&#xD;
      The intervention and follow up period will last 4 months per participant. Outcomes will be&#xD;
      measured at baseline and 3-months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Change to Primary Endpoint resulted in development of new protocol&#xD;
  </why_stopped>
  <start_date type="Actual">July 1, 2017</start_date>
  <completion_date type="Actual">August 30, 2019</completion_date>
  <primary_completion_date type="Actual">August 30, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Participants will be allocated to one of two groups as per block randomisation, with no stratification or minimisation to Group 1; Personalised Medicine who will be prescribed controller medication based on genetic test, Arg/Arg or Arg/Gly - montelukast (LTRA) or Gly/Gly -salmeterol (LABA). While Group 2, Standard Care will be prescribed controller medication based on guidelines.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Are children with asthma and their parents willing to be recruited and randomised to a trial of genotyping and personalised management for asthma? Qualitative interview</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>Recruitment rates will be measured as rate of invited participants who are eligible and consenting and will be reported in a Consolidated Standards of Reporting Trials (CONSORT) participant flowchart.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Are there retention issues? If yes, at what stages did these occur? What were the reasons? Qualitative interview</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>Acceptability of allocation procedures will be assessed by examining reasons for dropout in discontinuing participants and comparing attrition rates between the two study groups and between participants who did and did not receive their preferred allocation. Attrition rates will be established as discontinuation of intervention and loss to follow-up measurement for both groups</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Are follow-up data complete?</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>Suitability of outcome measures will be evaluated based on completion rates and rates of missing data</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Acceptability of personalised approach</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>All participants and their parents/guardians will be invited to have a semi-structured interview with a member of the research team in order to discuss their experiences of living with and managing their asthma. To enhance communication and ensure the child's perspective is captured, children will be invited to make a drawing of what it is like to have asthma and what it feels like when they take their asthma medication. The research team interviewing will then discuss the drawings (as a visual cue) in simple language with each child to understand what the child means.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Childhood Asthma Control Test</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>The Childhood Asthma Control Test (C-ACT) [10], a 7-item validated questionnaire capturing the frequency of asthma symptoms and their effect on daily function in children 4 to 11 years of age. It uses a 4-point Likert scale with higher scores indicating better control. The C-ACTuses a single cut point of a score of ≤19 to identify children whose asthma is not well controlled.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lung Function</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>Lung function will be measured by a nurse trained in collecting spirometry data in the Royal Alexandra Children's Hospital. Measure of PEF (litres/second), FEV1 (litres) and FVC (litres)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days unable to complete usual activities</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>Participants and parents will be asked to report how many days in the last month they have been unable to complete usual activities as a result of their asthma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Use of medication</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>Number of courses of oral corticosteroids for asthma and any other medication use will be recorded.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Use of health services</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>Participants and parents will be asked to report how many times they have had to see their GP or asthma nurse (outside of routine asthma review), been to A&amp;E or been admitted to hospital as a result of their asthma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Beliefs about medicine questionnaire</measure>
    <time_frame>Baseline to 3 months</time_frame>
    <description>The Beliefs About Medicine Questionnaire (BMQ) [11] is an 18-item validated questionnaire which will capture parental beliefs about asthma, asthma medication and how these may have affected their child's life. Respondents indicate their degree of agreement with each individual statement about medicines on a 5-point Likert scale, (1=strongly disagree to 5=strongly agree). Scores obtained are summed to give a scale score with higher scores indicating stronger beliefs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Experience of service</measure>
    <time_frame>3 month visit</time_frame>
    <description>At the final follow up, participants and parents will be asked to comment on their experience of the service received in the personalised medicine clinic. The validated Commission for Health Improvement Experience of Service Questionnaire will be used as the outcome measure [12]. The ESQ consists of 12 items rated on a 3-point Likert scale (3=Certainly True to 1=Not true) and three free-text sections looking at what the respondent liked about the clinic, what they felt needed improving, and any other comments. Higher scores indicate more positive experiences.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Asthma</condition>
  <arm_group>
    <arm_group_label>Personalised Medicine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Personalised Medicine who will be prescribed controller medication based on genetic test, Arg/Arg or Arg/Gly - montelukast (LTRA) or Gly/Gly -salmeterol (LABA).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard Care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard of care (Standard Care will be prescribed controller medication based on guidelines)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Montelukast or Salmeterol or Theophylline or Steroid</intervention_name>
    <description>Medication will be patient specific according to their current medication, clinical symptoms and genotype. It will be from a choice of; leukotriene receptor antagonist (montelukast), long-acting beta2 agonist (salmeterol), theophylline or increase dose of inhaled steroid.</description>
    <arm_group_label>Personalised Medicine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Parent/Guardian/Participant is willing and able to give informed consent/assent&#xD;
&#xD;
          -  Physician-diagnosed asthma that is inadequately controlled as per view of doctor (for&#xD;
             example, history of at least two emergency visits to GP or hospital over the previous&#xD;
             year, frequent use of blue inhaler (three times or more per week))&#xD;
&#xD;
          -  Aged 5-11 years (inclusive)&#xD;
&#xD;
          -  Children who are already on at least 400 micrograms per day inhaled beclomethasone or&#xD;
             equivalent and hence ready to be prescribed inhaled long-acting beta2 agonists and/or&#xD;
             other add-on medication or are already on inhaled long-acting beta2 agonists and/or&#xD;
             other add-on medication&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Parent/Guardian/Participant is unwilling or unable to give informed consent/assent&#xD;
&#xD;
          -  Known contraindication to montelukast or salmeterol&#xD;
&#xD;
          -  Other known significant airway or lung disease (e.g. chronic lung disease of&#xD;
             prematurity, cystic fibrosis or congenital airway abnormalities) or other co-existing&#xD;
             serious disease such as congenital cardiac disease&#xD;
&#xD;
          -  Poor inhaler technique and/or history of poor adherence on checking following standard&#xD;
             procedure at the clinic&#xD;
&#xD;
          -  Participating in another clinical trial (other than observational trials and&#xD;
             registries) concurrently or within 30 days prior to screening for entry into this&#xD;
             study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>11 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Somnath Prof Mukhopadhyay</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brighton and Sussex University Hospital NHS Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>BrightonNHS</name>
      <address>
        <city>Brighton</city>
        <state>East Sussex</state>
        <zip>BN2 5BE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>December 2019</verification_date>
  <study_first_submitted>July 11, 2017</study_first_submitted>
  <study_first_submitted_qc>August 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 31, 2017</study_first_posted>
  <last_update_submitted>December 17, 2019</last_update_submitted>
  <last_update_submitted_qc>December 17, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Theophylline</mesh_term>
    <mesh_term>Salmeterol Xinafoate</mesh_term>
    <mesh_term>Montelukast</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03269318
org study id: 183898
nct id: NCT03269318
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Asthma is one of the most common chronic diseases affecting children in the UK. Poorly
      controlled asthma manifests with chronic cough, wheeze and shortness of breath which in-turn
      has a significant negative impact on a child's quality of life, interfering with sleep,
      impairing exercise ability and resulting in frequent school absences and hospital admissions.

      Management of paediatric asthma in the UK is directed by the British Thoracic Society (BTS)
      Guidelines, which recommend a stepwise (one to five) treatment plan. Step three of the
      management guideline for children aged 5-12 years of age recommends the addition of the
      preventer inhaled medication, including long-acting β2 agonists such as salmeterol. However,
      there is a wide variation in response to this medication with approximately one in seven
      people, with a specific genetic change, found to have an increase in asthma symptoms in
      association with the use of thisiss medication. A related medicine, formoterol, is used less
      commonly in children with asthma.

      In this study, the investigators will aim to identify children with asthma whose symptoms are
      poorly controlled on inhaled long-acting beta2 agonists. Via a simple saliva test, the
      investigators will identify the presence or absence of the specific genetic change potentally
      influencing the effectiveness of treatment with salmeterol or related longacting beta2
      agonists thus enabling the investigators to recommend either salmeterol or an alternative
      medication for the treatment plan such as montelukast. The investigators will randomise the
      patients into two groups; to receive "personalised care" where the choice of controller
      medication would be based on the child's gene test results and predicted response to
      long-acting beta2 agonists, or "standard care" following the BTS guidelines at the
      clinician's discretion without knowledge of the gene test results. The investigators aim to
      measure whether this individualized approach to asthma prescribing results in improved
      control of asthma symptoms and overall quality of life. Targeting treatment to a child's
      specific genetic make-up is a concept known as "personalised medicine".
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 or inhaled corticosteroids are
      increased; this represents BTS step 3 for asthma management.

      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.

      In this 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. Indeed, the investigators reported a step-wise
      increase 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 the 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 used Pubmed to search the Medline database 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 are
      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. This led to the development of the Personalised Medicine
      for Asthma Control (PACT)-study, a randomised controlled trial to determine if personalised
      medicine improves quality of life and asthma control in 12-18 years olds. Results of this
      trial when published, will provide more conclusive evidence as to the effectiveness of
      personalised medicine in this age group. However, there is an absence of trials in a younger
      age group of children with asthma (5-11 years) and no evidence to determine if a personalised
      medicine clinic is feasible within a hospital setting, which underscores the need for this
      study.

      There is an absence of trials in a younger age group of children with asthma (5-11 years) and
      no evidence to determine if a personalised medicine clinic is feasible within a hospital
      setting and this underscores the need for this study.

      This research proposes two stages of work and has two main objectives:

        1. Feasibility study: Conduct a feasibility study to determine important parameters
           (standard deviation of outcomes, recruitment and retention) to inform the design of a
           definitive randomised controlled trial

           Research questions:

             1. Are children with asthma and their parents willing to be recruited and randomised
                to a trial of genotyping and personalised management for asthma?

             2. Are there retention issues? If yes, at what stages did these occur? What were the
                reasons?

             3. Are follow-up data complete?

             4. Can the intervention (genotyping plus medication) be delivered with sufficient
                fidelity?

             5. Is there sufficient evidence for scaling up to a definitive randomised controlled
                trial?

             6. What sample size is needed to power a full scale randomised controlled trial?

             7. Are there any safety issues or adverse events?

             8. What are the associated costs of running a personalised asthma clinic and is it
                cost effective?

        2. Qualitative aspect: Assess the acceptability of a personalised asthma clinic for
           children with asthma

      Research questions:

        1. How acceptable do children with asthma and their parents find genotyping and the
           personalised approach? How does this compare with their views on acceptability of
           conventional clinics?

        2. Was there any aspect of genotyping and personalised medicine clinic which children with
           asthma and their parents thought was particularly good or worked well?

        3. Was there any aspect of genotyping and personalised medicine clinic which children with
           asthma and their parents thought was particularly bad or difficult?

        4. How satisfied were children with asthma and their parents with the genotyping and
           personalised medicine clinic?

        5. How did the genotyping and personalised medicine clinic differ from usual care?

        6. What would encourage other children with asthma and their parents to participate in a
           genotyping and personalised medicine clinic?

        7. What would participants change about the personalised clinic?

        8. How has the genotyping and personalised medicine clinic impacted on the child and their
           parent?

        9. Were there any outcomes which weren't measured which should have been?

       10. What did the health professionals involved think about the clinic? (in primary and
           secondary care)

      Two arm, randomised controlled feasibility trial of genotyping and personalised medicine
      versus usual care with qualitative aspect to assess acceptability and impact.

      The genotyping and personalised medicine clinic is based in the Royal Alexandra Children's
      Hospital in Brighton, England. Participants are referred to the research team by their health
      care professional (primary and secondary care).

      The intervention and follow up period will last 4 months per participant. Outcomes will be
      measured at baseline and 3-months.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Participants will be allocated to one of two groups as per block randomisation, with no stratification or minimisation to Group 1; Personalised Medicine who will be prescribed controller medication based on genetic test, Arg/Arg or Arg/Gly - montelukast (LTRA) or Gly/Gly -salmeterol (LABA). While Group 2, Standard Care will be prescribed controller medication based on guidelines.
primary purpose: Treatment
masking: None (Open Label)
measure: Are children with asthma and their parents willing to be recruited and randomised to a trial of genotyping and personalised management for asthma? Qualitative interview
time frame: Baseline to 3 months
description: Recruitment rates will be measured as rate of invited participants who are eligible and consenting and will be reported in a Consolidated Standards of Reporting Trials (CONSORT) participant flowchart.
measure: Are there retention issues? If yes, at what stages did these occur? What were the reasons? Qualitative interview
time frame: Baseline to 3 months
description: Acceptability of allocation procedures will be assessed by examining reasons for dropout in discontinuing participants and comparing attrition rates between the two study groups and between participants who did and did not receive their preferred allocation. Attrition rates will be established as discontinuation of intervention and loss to follow-up measurement for both groups
measure: Are follow-up data complete?
time frame: Baseline to 3 months
description: Suitability of outcome measures will be evaluated based on completion rates and rates of missing data
measure: Acceptability of personalised approach
time frame: Baseline to 3 months
description: All participants and their parents/guardians will be invited to have a semi-structured interview with a member of the research team in order to discuss their experiences of living with and managing their asthma. To enhance communication and ensure the child's perspective is captured, children will be invited to make a drawing of what it is like to have asthma and what it feels like when they take their asthma medication. The research team interviewing will then discuss the drawings (as a visual cue) in simple language with each child to understand what the child means.
measure: Childhood Asthma Control Test
time frame: Baseline to 3 months
description: The Childhood Asthma Control Test (C-ACT) [10], a 7-item validated questionnaire capturing the frequency of asthma symptoms and their effect on daily function in children 4 to 11 years of age. It uses a 4-point Likert scale with higher scores indicating better control. The C-ACTuses a single cut point of a score of ≤19 to identify children whose asthma is not well controlled.
measure: Lung Function
time frame: Baseline to 3 months
description: Lung function will be measured by a nurse trained in collecting spirometry data in the Royal Alexandra Children's Hospital. Measure of PEF (litres/second), FEV1 (litres) and FVC (litres)
measure: Days unable to complete usual activities
time frame: Baseline to 3 months
description: Participants and parents will be asked to report how many days in the last month they have been unable to complete usual activities as a result of their asthma.
measure: Use of medication
time frame: Baseline to 3 months
description: Number of courses of oral corticosteroids for asthma and any other medication use will be recorded.
measure: Use of health services
time frame: Baseline to 3 months
description: Participants and parents will be asked to report how many times they have had to see their GP or asthma nurse (outside of routine asthma review), been to A&E or been admitted to hospital as a result of their asthma.
measure: Beliefs about medicine questionnaire
time frame: Baseline to 3 months
description: The Beliefs About Medicine Questionnaire (BMQ) [11] is an 18-item validated questionnaire which will capture parental beliefs about asthma, asthma medication and how these may have affected their child's life. Respondents indicate their degree of agreement with each individual statement about medicines on a 5-point Likert scale, (1=strongly disagree to 5=strongly agree). Scores obtained are summed to give a scale score with higher scores indicating stronger beliefs.
measure: Experience of service
time frame: 3 month visit
description: At the final follow up, participants and parents will be asked to comment on their experience of the service received in the personalised medicine clinic. The validated Commission for Health Improvement Experience of Service Questionnaire will be used as the outcome measure [12]. The ESQ consists of 12 items rated on a 3-point Likert scale (3=Certainly True to 1=Not true) and three free-text sections looking at what the respondent liked about the clinic, what they felt needed improving, and any other comments. Higher scores indicate more positive experiences.
arm group label: Personalised Medicine
arm group type: Experimental
description: Personalised Medicine who will be prescribed controller medication based on genetic test, Arg/Arg or Arg/Gly - montelukast (LTRA) or Gly/Gly -salmeterol (LABA).
arm group label: Standard Care
arm group type: No Intervention
description: Standard of care (Standard Care will be prescribed controller medication based on guidelines)
intervention type: Drug
intervention name: Montelukast or Salmeterol or Theophylline or Steroid
description: Medication will be patient specific according to their current medication, clinical symptoms and genotype. It will be from a choice of; leukotriene receptor antagonist (montelukast), long-acting beta2 agonist (salmeterol), theophylline or increase dose of inhaled steroid.
arm group label: Personalised Medicine
criteria: 
gender: All
minimum age: 5 Years
maximum age: 11 Years
healthy volunteers: No
last name: Somnath Prof Mukhopadhyay
role: Principal Investigator
affiliation: Brighton and Sussex University Hospital NHS Trust
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Asthma
mesh term: Theophylline
mesh term: Salmeterol Xinafoate
mesh term: Montelukast
sharing ipd: Undecided