TY - JOUR

T1 - 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)

AU - Cividini, Sofia

AU - Sinha, Ian

AU - Donegan, Sarah

AU - Maden, Michelle

AU - Culeddu, Giovanna

AU - Rose, Katie

AU - Fulton, Olive

AU - Hughes, Dyfrig

AU - Turner, Stephan

AU - Smith, Catrin Tudur

N1 - NIHR Health Technology Assessment Programme (project number 16/110/16)

PY - 2021/2/5

Y1 - 2021/2/5

N2 - Asthma affects millions of children worldwide – 1.1 million children in the UK. Asthma symptoms cannot be cured but can be palliated with low dose inhaled corticosteroids (ICS) 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review and individual participant data network meta-analysis (IPD-NMA) aiming to synthesise all available published and unpublished evidence from randomised controlled trials (RCTs) to establish the clinical effectiveness of pharmacological treatments in children and adolescents with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 NIHR HTA 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 Unpublished studies will be located by searching across a range of clinical trial registries, including internal trial registers for pharmaceutical companies.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 University of Liverpool committee on Research Ethics 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 HEIs. A synopsis of results will be disseminated to NICE and BTS/SIGN as highly relevant to future clinical guideline updates.

AB - Asthma affects millions of children worldwide – 1.1 million children in the UK. Asthma symptoms cannot be cured but can be palliated with low dose inhaled corticosteroids (ICS) 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 NIHR HTA 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 University of Liverpool committee on Research Ethics 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 HEIs. A synopsis of results will be disseminated to NICE and BTS/SIGN as highly relevant to future clinical guideline updates.

KW - inhaled corticosteroids

KW - long-acting β2-agonists

KW - leukotriene receptor antagonist

KW - theophylline

KW - exacerbation

KW - asthma control

KW - hospital admissions

KW - adolescents

U2 - 10.1136/bmjopen-2020-04052

DO - 10.1136/bmjopen-2020-04052

M3 - Article

VL - 11

JO - BMJ Open

JF - BMJ Open

SN - 2044-6055

M1 - e040528

ER -