A randomised trial of aminophylline, magnesium sulfate or salbutamol intravenous therapy for acute severe asthma in children and young people.

RESEARCH QUESTION: What is the clinical effectiveness and cost-effectiveness of intravenous (IV) bronchodilators in children and young people (CYP) with severe acute asthma unresponsive to maximal inhaled therapy?

BACKGROUND: Asthma exacerbations are a common presentation to emergency departments. They are currently treated with one of three IV bronchodilators. There are minimal comparative effectiveness data for these. A randomised controlled trial is needed to determine which therapy is most effective and cost-effective.

AIMS AND OBJECTIVES: The aim of this proposal is to determine which IV bronchodilator should be used in CYP with severe acute asthma.

Primary objective: To determine whether IV aminophylline, magnesium sulfate or salbutamol (interventions and comparators) is most effective as determined by paediatric asthma severity score at 2 hours (outcome) in CYP aged 2-18-years with severe acute asthma unresponsive to maximal inhaled therapy (population).

Primary economic objective: To determine which IV bronchodilator is most cost-effective.

Secondary objectives: Key secondary objective is (a) to determine which IV bronchodilator has the shortest time to discharge from hospital. Others include (b) which is most acceptable to patients, parents/carers and healthcare professionals and (c) whether response to each varies by patient factors.

METHODS: We propose an open-label, three arm, individually-randomised, parallel group trial. CYP aged 2-18-years with a severe exacerbation of asthma, not responding to maximal inhaled therapy, will be recruited from UK hospitals. A total of 357 will be randomised (1:1:1) between IV aminophylline infusion, magnesium sulfate bolus and salbutamol infusion.

Deferred consent will be obtained for using participants’ data in the trial. The primary outcome will be the validated asthma severity score after two hours. Key secondary outcome will be length of hospital stay.

Within-trial cost-effectiveness will be evaluated and acceptability assessed with interviews and a follow up questionnaire. The analysis is described in an estimands (treatment policy framework). TIMELINES FOR DELIVERY: Months -3 to 0: Pre-award: draft protocol, draft key contracts; engage sites. Months 1-6: Finalise protocol, ethics, HRA & MHRA submission, design data collection tools, site set up and training.

Months 7-31: Recruitment (including internal pilot) and follow up: 357 participants across 20 NHS hospitals. Months 8-31: Process evaluation interviews.

Months 30-36: Analysis and write up: analysis, discussion of results with PPI panel, trial steering and data monitoring committees plus drafting trial report and manuscripts. Dissemination and implementation.

ANTICIPATED IMPACT AND DISSEMINATION: This trial will inform future evidence-based clinical guidelines. In doing so, the evidence we produce will minimise inter-centre variation in management maximising the likelihood that patients rapidly respond to therapy. This will reduce admission time, lessen impact on quality of life and reduce NHS costs.

We will work with key patient groups (e.g. Asthma+Lung UK), healthcare professional (e.g. Royal College of Paediatrics & Child Health) and healthcare delivery (e.g.

Integrated Care Boards) stakeholders to develop an implementation plan. The trial findings will be published in a peer reviewed medical journal, presented at relevant conferences and disseminated via social media and third-sector groups supported by our PPI panel.