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.

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

Asthma

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.

Personalised medicine (Salmeterol)

Personalised medicine (Montelukast)

Standard care

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).

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).

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.

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.

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.

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.

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

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Not accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Locations

Location

Status