InternationaL cross-sectIonAl and longItudinal assessment on aSthma cONtrol in European adult patients : the LIAISON study protocol

The study is funded by Chiesi Farmaceutici S.p.A., Parma, ItalyPeer reviewedPublisher PD

FourFold Asthma Study (FAST): a study protocol for a randomised controlled trial evaluating the clinical cost-effectiveness of temporarily quadrupling the dose of inhaled steroid to prevent asthma exacerbations

BACKGROUND: Asthma is one of the commonest chronic diseases in the UK. Acute exacerbations of asthma are unpredictable, disruptive and frightening. They cause considerable morbidity and account for a large component of the health service costs of asthma. The widespread use of an asthma self-management plan, designed to encourage disease monitoring and timely intervention, can reduce exacerbations and is, therefore, recommended for all patients with asthma. Unfortunately, the majority of patients are not provided with such a plan. There are a variety of reasons for this but uncertainty about what to include in the plan when asthma control is deteriorating, but before the need for orally administered corticosteroids, is a contributing factor. The aim of this trial is to determine whether an asthma self-management plan, which includes a temporary quadrupling of the dose of inhaled corticosteroid when asthma control starts to deteriorate, reduces asthma exacerbations requiring orally administered corticosteroids or unscheduled health care consultation for asthma. METHODS: A multicentre, pragmatic, randomised trial in adults aged over 16 years with a clinical diagnosis of asthma, treated with a licensed dose of inhaled corticosteroid and at least one exacerbation in the previous 12 months requiring treatment with systemic corticosteroids. Participants will be randomised to either a self-management plan, which includes a temporary (maximum of 14 days) fourfold increase in inhaled corticosteroid or the same plan without an increase in inhaled corticosteroid. Participants will be followed up at 6 and 12 months and will attend the clinic for an additional visit if their asthma control deteriorates. The primary outcome is time to first asthma exacerbation, defined as the need for systemic corticosteroids and/or unscheduled health care consultation for asthma. The estimated sample size is 1800 participants. DISCUSSION: The FAST trial is an independent study that has been prioritised and commissioned by the National Institute for Health Research (NIHR) in the United Kingdom. It will provide high-quality evidence to inform clinical decision-making on the role of an asthma self-management plan, which includes a temporary fourfold increase of inhaled corticosteroid, when asthma control starts to deteriorate. The first participant was randomised on 17th May 2013 and recruitment will close on 31 January 2016 with the last patient last visit taking place in January 2017. TRIAL REGISTRATION: ISRCTN: 15441965, registered on 25 April 2013

Characterisation of a murine model of the late asthmatic response

Background: The incidence of asthma is increasing at an alarming rate. While the current available therapies are effective, there are associated side effects and they fail to adequately control symptoms in all patient subsets. In the search to understand disease pathogenesis and find effective therapies hypotheses are often tested in animal models before progressing into clinical studies. However, current dogma is that animal model data is often not predictive of clinical outcome. One possible reason for this is the end points measured such as antigen-challenge induced late asthmatic response (LAR) is often used in early clinical development, but seldom in animal model systems. As the mouse is typically selected as preferred species for pre-clinical models, we wanted to characterise and probe the validity of a murine model exhibiting an allergen induced LAR. Methods: C57BL/6 mice were sensitised with antigen and subsequently topically challenged with the same antigen. The role of AlumTM adjuvant, glucocorticoid, long acting muscarinic receptor antagonist (LAMA), TRPA1, CD4+ and CD8+ T cells, B cells, Mast cells and IgE were determined in the LAR using genetically modified mice and a range of pharmacological tools. Results: Our data showed that unlike other features of asthma (e.g. cellular inflammation, elevated IgE levels and airway hyper-reactivity (AHR) the LAR required AlumTMadjuvant. Furthermore, the LAR appeared to be sensitive to glucocorticoid and required CD4+ T cells. Unlike in other species studied, the LAR was not sensitive to LAMA treatment nor required the TRPA1 ion channel, suggesting that airway sensory nerves are not involved in the LAR in this species. Furthermore, the data suggested that CD8+ T cells and the mast cell—B-cell - IgE axis appear to be protective in this murine model. Conclusion: Together we can conclude that this model does feature steroid sensitive, CD4+ T cell dependent, allergen induced LAR. However, collectively our data questions the validity of using the murine pre-clinical model of LAR in the assessment of future asthma therapies