Background

Respiratory disease has recently been declared a target for improved management by the Department of Health. Although a major focus of this initiative is adult chest disease, especially chronic obstructive pulmonary disease, it has been recognised that asthma is an important unresolved burden, especially in childhood where much asthma originates. The longitudinal studies from Aberdeen¹ have shown that 60% of adults with asthma suffered their first symptoms in early childhood, continuing with these through later childhood and into adult life.

Rationale

Asthma remains a common medical condition seen in children in primary care and a frequent cause of medical paediatric hospital admission. It affects one in eight children nationwide, of whom many are prescribed low-dose inhaled corticosteroids (ICSs).¹ When treatment with low-dose ICSs fails to control asthma symptoms or adequately prevent exacerbations, national guidelines² suggest ensuring compliance, including giving appropriate information about the disease to children and their families, maximising inhaler technique and treating comorbidities such as rhinitis. Once these measures have been established and if asthma remains uncontrolled, step 3 of the national guidelines recommends increasing the treatment. The evidence base at this step of the guidelines is much more limited 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 inappropriate adult-based outcomes such as lung function measurements, which suffer from assay insensitivity and fail to capture the episodic nature of much of childhood asthma. Pharmaceutical company studies have generally been conducted only as part of their requirements to obtain a licence to market their product. These studies have generally been of short duration and have not added to clinicians' understanding of how and where to use the medications.^3,4 In addition, they have not necessarily selected a representative population because of their tight entry criteria and their intensive study requirements. Such requirements mean that ‘real-life’ compliance and hence outcomes do not occur. In the independent national Dutch study,⁵ which enrolled patients uncontrolled on low-dose ICSs, three treatment groups were employed: ICSs alone, ICSs in double the dose and ICSs plus a long-acting beta2-agonist. There was essentially no difference in outcome measures between the three treatment groups, probably because the primary outcome measure was lung function (forced expiratory volume in 1 second or FEV₁). Comparing this study with a similar adult study,⁶ which also used lung function as the primary outcome measure, the mean FEV₁ on entry into the Dutch paediatric study was approximately 89% of that expected for the children's heights and the mean FEV₁ on entry into the adult study was 74% of that expected. It is therefore not surprising that the paediatric study was unable to show any differences between the treatment groups.

There is little scientific evidence on how to treat children with asthma who are not well controlled on low-dose ICS therapy, apart from the limited value of increasing the ICS dose.⁷ There is no clinical study evidence showing that, when control is poor in children with asthma, the dose of the inhaled steroid should be increased. We 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 that is controlled and double blind in nature, up to 30% of them improve, their symptoms reduce and their lung function increases (Bisgaard H, Professor of Respiratory Paediatrics at the University Hospital in Copenhagen, personal correspondence – during development of paediatric asthma studies). It is therefore surprising that approximately one-third of children receiving ICSs are prescribed high-dose inhaled steroid therapy (≥ 800 μg beclometasone dipropionate or equivalent) or are commenced on ‘add-on’ therapies such as long-acting beta-2 agonists or leukotriene receptor antagonists in addition to low-dose ICSs. Concerns about the safety of high-dose ICSs have been raised in relation to growth impairment,⁸ hypoglycaemia⁹ and suppression of the adrenal cortex,¹⁰ resulting in warnings on prescribing from the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK.¹¹ Asthma is a very common condition and the worth of these regimens has not been proven by appropriately devised paediatric studies. The UK guidelines on asthma management² 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 children with relatively poorly controlled asthma who exhibit frequent symptoms do not necessarily show abnormal lung function between their periods of symptoms. It is for this reason that our study focused on outcome measures such as exacerbations and quality of life, although spirometric values at the first (T0) and last (T48) visits were measured and recorded.

A study is needed that is simple, is pragmatic (but placebo controlled and double blind), has outcomes that 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. Since the MASCOT study was commenced the Best Add-on Therapy Giving Effective Response (BADGER) trial has been completed and reported.¹² This study, however, required reversibility or hyper-responsiveness as an entry criterion, which excluded many patients, was short term in nature and focused primarily on symptomatic control as measured by the Childhood Asthma Control Test as opposed to exacerbations.

Potential risks and benefits

The medications used in this study are subject to marketing authorisations and prescribed in accordance with their licensed indications. The management of any symptoms or exacerbations was in accordance with usual clinical practice, and a research worker, either the local principal investigator or research nurse, was available throughout the study to discuss specific issues with individuals concerned. Patients were free to withdraw from the study at any time with no detriment to their future care. All ethical aspects of the study were discussed when informed written consent was obtained. Appropriate patient and family information leaflets (Appendix 1) were developed and were discussed at the screening consultation. Patients and their families were provided with copies of the information sheets and their signed consent/assent forms.

All of the medications have been shown to be efficacious for children with chronic asthma when used appropriately as preventative therapy. The ultimate aims of preventative asthma treatment are the prevention of chronic symptoms and the maintenance of near-normal lung function and normal activity levels with prevention of recurrent acute episodes in order to maximise quality of life. The potential benefit for participants of taking these medications as part of the trial is that they will improve control of their asthma, reducing symptoms and exacerbations and meeting the goals above.

Objective