Management of Asthma in School-age Children on Therapy
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 4

Summary: 
      Asthma affects 1 in 8 children in the UK. Up to half of these are treated with preventative
      medicine in the form of low-dose steroids using an inhaler. The National Asthma Treatment
      Guidelines recommend when this treatment is not working other treatments are started. Studies
      to support this have taken place in adults but not with children. If patients are instructed
      how to use inhalers and are given information about asthma, they can control their disease
      much better. The first part of this study, lasting 4 weeks, will make sure the children and
      their families understand how to use their inhaler. All children will be given the same
      steroid inhaler to use and after 4 weeks those still with symptoms will enter the study
      proper which lasts for 48 weeks. During this part of the study the children will be given one
      of three treatments. These are:- a steroid inhaler + a dummy tablet, an inhaler containing a
      steroid and a long-acting reliever + a dummy tablet or a steroid inhaler + an active tablet.
      In this way the patient, the family and the researchers will not know which of the three
      treatments the child is taking until the code is broken at the end of the study.

      What matters to children is how they feel, are they able to run around and play with friends
      and are they well enough to go to school. The investigators will assess which of the above
      treatments best allow these to happen by asking the parents and children to fill in
      questionnaires on 4 occasions during the study. The investigators will also see which
      treatment best prevents the need for short courses of steroids tablets during the study.
      These are commonly given when asthma symptoms worsen.

      Most children will be started in the study through their general practitioner clinic. It will
      take one year to enroll all 900 children. Once enrolled the children will be followed-up in
      hospital centres. Much of the funding will be required to recruit and follow-up the children,
      train everyone to the same standard and develop and administer the questionnaires and health
      economic assessments. Asthma care is an expensive. The investigators will look at the costs
      and assess which treatment offers most benefit. The team has experience and ability in this
      field and will ensure the results are well publicised. Any child can withdraw from the study
      at any time.
    

Detailed description: 
      Asthma remains the most common medical condition seen in children in primary care and the
      most frequent cause for medical paediatric hospital admission. It affects 1 in 8 children
      nationwide, approximately 50% of whom are prescribed low-dose inhaled corticosteroids (ICS).
      When treatment with low-dose ICS fails to control asthma symptoms, the National Guidelines
      suggest ensuring compliance, maximising inhaler technique and giving appropriate information
      about the disease to children and their families. Once these measures have been established
      and if asthma symptoms persist, the Guidelines recommend changing the treatment (Step 3 of
      the National Guidelines). The evidence at this step of the Guidelines is much weaker in
      children than it is in adults. The reasons for this are that few studies have been undertaken
      in children and most that have taken place have used adult-based outcomes such as lung
      function measurements. This is unsatisfactory because we know that as a chronic disease
      entity asthma in children is much more variable than in adults and between periods of
      symptoms, lung function is often normal. Pharmaceutical company studies have really only been
      conducted as part of their requirements to obtain a license to market their product. These
      studies have generally been of short-term duration. They have not added to clinicians'
      understanding of how and where to use the medications. They have not necessarily selected a
      representative population due to their entry criteria and their intensive study requirements.
      Such requirements mean that "real-life" compliance does not occur. In the independent
      National Dutch Study which attempted to enter patients uncontrolled on low-dose ICS, three
      treatment groups were employed: inhaled corticosteroids alone, inhaled corticosteroids in
      double the dose and inhaled corticosteroids + a long-acting beta2 agonist. There was
      essentially no difference in outcome measures between the three treatment groups as once
      again the primary outcome measure was that of lung function (FEV1). Comparing this study with
      a similar adult study6 both of which used lung function as the primary outcome measure, the
      mean FEV1 on entry into the paediatric study was approximately 89% expected for the
      children"s heights. In the adult study the mean FEV1 on entry into the study was 74%
      expected. It is therefore not surprising that the paediatric study was unable to show any
      differences between the treatment groups.

      We do not have the scientific information about how to treat children with asthma who are not
      well controlled on low-dose ICS therapy. It used to be recommended that when low-dose ICS
      were not effective their dose should be doubled. Studies in children, however, have
      investigated this statement and the results are not impressive7 . There is no scientific
      evidence that when control is poor in children with asthma, the dose of the inhaled steroid
      should be increased. We have therefore decided not to introduce into this study a treatment
      limb with a higher ICS dosage. There is anecdotal information, however, from many studies
      undertaken within the pharmaceutical industry that when children enter a study which is
      controlled and double-blind in nature, up to 30% of them improve, their symptoms reduce and
      their lung function increases8. It is therefore surprising that approximately one third of
      children receiving ICS are prescribed high-dose inhaled steroid therapy (≥ 800micrograms and
      unlicensed beclometasone dipropionate or equivalent) or they are commenced on "add-on"
      therapies such as long-acting beta2 agonists (LABA) or leukotriene receptor antagonists
      (LTRA) in addition to low-dose ICS. Concerns about the safety of high-dose ICS have been
      raised in relation to growth impairment9, hypoglycaemia10 and suppression of the adrenal
      cortex11 resulting in warnings on prescribing from the Medicines & Healthcare Products
      Regulatory Agency (MHRA) in the UK12 and from the Food and Drug Administration (FDA) in the
      USA. It is therefore unacceptable that approximately one third of children with asthma are
      being treated with the above regimes. Asthma is a very common condition and the worth of
      these regimes has not been proven by appropriately devised paediatric studies. The National
      Guidelines have been developed in a "stepwise" manner, the amount of medication increasing at
      each step if symptoms are not controlled.

      However, as stated above, it may be that childhood asthma differs from that in adults. It
      seems that relatively poorly controlled asthma in children who exhibit frequent symptoms do
      not necessarily show abnormal lung function between their periods of symptoms. It is for this
      reason that in our study we will be concentrating on outcome measures such as exacerbations
      and quality of life although we will have the opportunity to measure spirometric values at
      the first (T0) and last (T48) visits in the randomised part of the study. It could be that an
      increase in medication may only be needed for a short time in children with asthma and there
      have been suggestions that once control is achieved children should have their add-on therapy
      reviewed. To incorporate such a step within the present study would make it excessively
      complicated and would have major implications on the number of patients included. The
      inclusion of such a step would make the study impractical within the UK. A study is needed
      which is simple, pragmatic (but placebo-controlled and double-blinded), has outcomes which
      will be of practical benefit to children and will provide evidence for the use of add-on
      medications in the most cost effective and efficient way. Children dislike exacerbations.
      School attendance, daily activity and general well-being increase when asthma is well
      controlled. Once families understand sufficiently about asthma, inhaler technique has been
      evaluated and optimised, and compliance issues addressed, one of the reasons why a specific
      medication may be less effective could be related to the genetic make-up of the patient. In
      this study we will have the opportunity, through a separate consent process, to collect and
      store DNA specimens from saliva for later analysis of specific genetic polymorphisms in
      relation to asthma severity and outcome. This aspect will bring added value to the study.
    

Intervention name(s): inhaled fluticasone propionate; salmeterol; Montelukast
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 100 micrograms; 50 m; Double blind double dummy
Intervention MeSH terms: Fluticasone; Xhance; Salmeterol Xinafoate; Montelukast
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Asthma; Children; Therapy; Fluticasone; Salmeterol; Montelukast