PRISTINE - Personalised Approach to Improve aSThma prescrIbing iN childrEn
PRISTINE - Personalised Approach to Improve aSThma prescrIbing iN childrEn
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.
Inclusion Criteria:

 -  Parent/Guardian/Participant is willing and able to give informed consent/assent

 -  Physician-diagnosed asthma that is inadequately controlled as per view of doctor (for
 example, history of at least two emergency visits to GP or hospital over the previous
 year, frequent use of blue inhaler (three times or more per week))

 -  Aged 5-11 years (inclusive)

 -  Children who are already on at least 400 micrograms per day inhaled beclomethasone or
 equivalent and hence ready to be prescribed inhaled long-acting beta2 agonists and/or
 other add-on medication or are already on inhaled long-acting beta2 agonists and/or
 other add-on medication

 Exclusion Criteria:

 -  Parent/Guardian/Participant is unwilling or unable to give informed consent/assent

 -  Known contraindication to montelukast or salmeterol

 -  Other known significant airway or lung disease (e.g. chronic lung disease of
 prematurity, cystic fibrosis or congenital airway abnormalities) or other co-existing
 serious disease such as congenital cardiac disease

 -  Poor inhaler technique and/or history of poor adherence on checking following standard
 procedure at the clinic

 -  Participating in another clinical trial (other than observational trials and
 registries) concurrently or within 30 days prior to screening for entry into this
 study