PRISTINE - Personalised Approach to Improve aSThma prescrIbing iN childrEn (PRISTINE)
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|ClinicalTrials.gov Identifier: NCT03269318|
Recruitment Status : Terminated (Change to Primary Endpoint resulted in development of new protocol)
First Posted : August 31, 2017
Last Update Posted : December 18, 2019
|First Submitted Date ICMJE||July 11, 2017|
|First Posted Date ICMJE||August 31, 2017|
|Last Update Posted Date||December 18, 2019|
|Actual Study Start Date ICMJE||July 1, 2017|
|Actual Primary Completion Date||August 30, 2019 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||PRISTINE - Personalised Approach to Improve aSThma prescrIbing iN childrEn|
|Official Title ICMJE||Feasibility of a Personalised Medicine Clinic for Children With Asthma Aged 5-11 Years|
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:
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.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 4|
|Study Design ICMJE||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.Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Drug: Montelukast or Salmeterol or Theophylline or Steroid
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.
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Terminated|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||August 30, 2019|
|Actual Primary Completion Date||August 30, 2019 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||5 Years to 11 Years (Child)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United Kingdom|
|Removed Location Countries|
|NCT Number ICMJE||NCT03269318|
|Other Study ID Numbers ICMJE||183898|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Brighton and Sussex University Hospitals NHS Trust|
|Study Sponsor ICMJE||Brighton and Sussex University Hospitals NHS Trust|
|Collaborators ICMJE||Not Provided|
|PRS Account||Brighton and Sussex University Hospitals NHS Trust|
|Verification Date||December 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP