Prescribing Asthma Controller Medication According to Gene Status to Improve Quality of Life in Young People With Asthma

Study Overview
=================
Brief 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.

Official Title
-----------------
Prescribing Asthma Controller Medication According to Gene Status to Improve Quality of Life in Young People With Asthma

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Genetic: Personalised medicine (Salmeterol)
* Genetic: Personalised medicine (Montelukast)
* Other: Standard care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Parent/Guardian/Participant is willing and able to provide informed consent/assent Physician-diagnosed asthma Aged 12-18 years Taking inhaled corticosteroids (ICS) with/without second line controller (i.e. LABA/LTRA) Exclusion Criteria: Parent/Guardian/Participant is unwilling or unable to give informed consent/assent Known contraindication to montelukast or salmeterol Other major airway or lung disease, e.g. chronic lung disease of prematurity, cystic fibrosis, and abnormal airway anatomy Pregnant or lactating females (if participants become pregnant during the course of the study they will be asked to inform the research team and be withdrawn from the study) Participating in another clinical trial (other than observational trials and registries) concurrently or within 30 days prior to screening for entry into this study On step 4 asthma control medication e.g. taking Theophylline, Slo-phylin, Uniphyllin Unable to provide saliva/buccal cells for genotyping

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Personalised Medicine<br>If an add-on controller is required, young people in this arm will be prescribed personalised medicine by results of the genotyping for the adrenergic beta2-receptor gene (ADRB2). Health professional's will be advised to prescribe inhaled salmeterol as 'add-on' controller if trial participants have the Gly/Gly variant on ADRB2, and montelukast if they have Arg/Arg or Arg/Gly variant on ADRB2. | Genetic: Personalised medicine (Salmeterol)<br>* If participants require add-on medication and have the Gly/Gly variant on the ADRB2, salmeterol will be prescribed.<br>* Other names: Salmeterol;Genetic: Personalised medicine (Montelukast)<br>* If participants require add-on medication and have the Arg/Arg or Arg/Gly variant on the ADRB2, montelukast will be prescribed.<br>* Other names: Montelukast;|
| Active Comparator: Standard care<br>If an add-on controller is required, young people will be prescribed medication as per the choice of the primary or secondary care physician, without knowledge of genotypic status. | Other: Standard care<br>* 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.<br>* Other names: Salmeterol or montelukast;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma Quality of Life Questionnaires with Standardised Activities (AQLQ(S)) | A disease-specific health-related quality of life instrument that taps both physical and emotional impact of disease. Participants are asked to think about how they have been during the previous 2 weeks and to respond to each of the 32 questions on a 7-point scale (7 = not bothered at all - 1 = extremely bothered). | Past two weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma Control Questionnaire (ACQ) | The ACQ has 6 questions (the top scoring 5 symptoms, and daily rescue bronchodilator use). Patients are asked to recall how their asthma has been during the previous week and to respond to the symptom and bronchodilator use questions on a 7-point scale (0=no impairment, 6= maximum impairment). | Past week | 
| Health care utilisation | Participants will be asked to record how many times they have had to visit their GP or asthma nurse (outside of routine asthma review), A&E or hospital as a result of their asthma over the previous 3 months. Total scores for health care utilisation will be summed over the 12-month study period to create a total score for health care utilisation for each participant. Participants will be asked to enter this data via on the online questionnaire at each 3-month follow up. | 3 months | 
| Medication use | Participants will be asked to record any courses of oral corticosteroids for asthma and any other medication use over the last 3 months. Medication use (scored by each type of medicinal product) will be summed across the 12 month study period to create total number of additional medicinal product use for each participant. Participants will be asked to enter this data via on the online questionnaire at each 3-month follow up. | 3 months |