EstablishINg the best STEp-up treatments for children with uncontrolled asthma despite INhaled corticosteroids (EINSTEIN): protocol for a systematic review, network meta-analysis and cost-effectiveness analysis using individual participant data (IPD).

INTRODUCTION Asthma affects millions of children worldwide-1.1 million children in the UK. Asthma symptoms cannot be cured but can be controlled with low-dose inhaled corticosteroids (ICSs) in the majority of individuals. Treatment with a low-dose ICS, however, fails to control asthma symptoms in around 10%-15% of children and this places the individual at increased risk for an asthma attack. At present, there is no clear preferred treatment option for a child whose asthma is not controlled by low-dose ICS and international guidelines currently recommend at least three treatment options. Herein, we propose a systematic review and individual participant data network meta-analysis (IPD-NMA) aiming to synthesise all available published and unpublished evidence from randomised controlled trials (RCTs) to establish the clinical effectiveness of pharmacological treatments in children and adolescents with uncontrolled asthma on ICS and help to make evidence-informed treatment choices. This will be used to parameterise a Markov-based economic model to assess the cost-effectiveness of alternative treatment options in order to inform decisions in the context of drug formularies and clinical guidelines. METHODS AND ANALYSIS We will search in MEDLINE, the Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, NICE Technology Appraisals and the National Institute for Health Research (NIHR) Health Technology Assessment series for RCTs of interventions in patients with uncontrolled asthma on ICS. All studies where children and adolescents were eligible for inclusion will be considered, and authors or sponsors will be contacted to request IPD on patients aged <18. The reference lists of existing clinical guidelines, along with included studies and relevant reviews, will be checked to identify further relevant studies. Unpublished studies will be located by searching across a range of clinical trial registries, including internal trial registers for pharmaceutical companies. All studies will be appraised for inclusion against predefined inclusion and exclusion criteria by two independent reviewers with disagreements resolved through discussion with a third reviewer. We will perform an IPD-NMA-eventually supplemented with aggregate data for the RCTs without IPD-to establish both the probability that a treatment is best and the probability that a particular treatment is most likely to be effective for a specific profile of the patient. The IPD-NMA will be performed for each outcome variable within a Bayesian framework, using the WinBUGS software. Also, potential patient-level characteristics that may modify treatment effects will be explored, which represents one of the strengths of this study. ETHICS AND DISSEMINATION The Committee on Research Ethics, University of Liverpool, has confirmed that ethics review is not required. The dissemination plan consists of publishing the results in an open-access medical journal, a plain-language summary available for parents and children, dissemination via local, national and international meetings and conferences and the press offices of our Higher Education Institutions (HEIs). A synopsis of results will be disseminated to NICE and British Thoracic Society/Scottish Intercollegiate Guidelines Network (SIGN) as highly relevant to future clinical guideline updates. PROSPERO REGISTRATION NUMBER CRD42019127599.