EstablishINg the best STEp-up treatments for children with uncontrolled asthma despite Inhaled corticosteroids (EINSTEIN): A systematic review, network meta-analysis and cost effectiveness analysis

EstablishINg the best STEp-up treatments for children with uncontrolled asthma despite Inhaled corticosteroids (EINSTEIN): A systematic review, network meta-analysis and cost effectiveness analysis

We have applied for funding from NIHR HTA to conduct the EINSTEIN study. The funding has been provisionally approved subject to sufficient IPD being pledged.

In the UK over a million children have asthma, which causes symptoms of cough, noisy breathing and shortness of breath which can get suddenly worse during an asthma attack. Symptoms and asthma attacks can affect a child's overall wellbeing and quality of life, including their ability to attend school and play sports.The first line of treatment is to give a child an inhaled steroid. If a child's asthma is still troublesome, various other medications can be used to help control the symptoms and prevent attacks. These will already have been tested in clinical trials (a type of research study) before being given to children by doctors. The summary results from clinical trials should be published in medical journals, and are used to compare risks and benefits of treatments. However, many clinical trials have been conducted in children with asthma and these results are published in many medical journals. Some clinical trials might not agree with other clinical trials, they may be of better quality than others, or they may not give very accurate results by themselves. It can therefore be very difficult for doctors, parents and children to make sense of this information and consider the best evidence to help them make important decisions.In the EINSTEIN study we will bring together all of the available clinical trials and provide doctors and patients with a high quality summary of all available information. We will use a process called a systematic review to identify all the relevant trials, assess their quality, and extract and summarise their results. We will then use a technique called network meta-analysis to join the results of different studies together to make is easier to understand and to find out which of the treatments is best.In this project we will also collect the individual participant data from each clinical trial rather than rely on the summary information that has been published in journal articles. This is very important as the summary results published in journals are known to be incomplete, sometimes inaccurate, and even presented in a biased or confusing way which can mean that standard network meta-analyses using those data may be unreliable. Individual participant data will also help us to ask even more complexquestions and look at whether features of a patient, such as the child's age, gender, or asthma severity, could be used to tell how well they might respond to different treatments. Having this information would help inform choices about which medicine might be better for some patients andwhich should be avoided for others. This question can only be answered using the individual participant data.Throughout this project we will work with children with asthma and their parents to ensure that we are asking relevant questions in the right way, and to help us learn how we can make our findings accessible and understandable.

[{ "PostingID": 47, "Title": "GSK-SFA106484", "Description": "A randomized, double-blind, parallel group study evaluating the safety of fluticasone propionate/salmeterol 100/50mcg HFA (2 inhalations of 50/25mcg) twice daily compared with fluticasone propionate 100mcg HFA (2 inhalations of 50mcg) twice daily in subjects 4-11 years of age with persistent asthma" },{ "PostingID": 379, "Title": "GSK-FFA109685", "Description": "A Randomized Double-Blind, Double Dummy, Placebo-Controlled, Parallel-Group, Multicenter Dose Ranging Study to Evaluate the Efficacy and Safety of GW685698X Inhalation Powder Once Daily and Fluticasone Propionate Inhalation Powder 250mcg Twice Daily compared with Placebo for 8 Weeks in Adolescent and Adult Subjects with Persistent Asthma Symptomatic on Low-Dose ICS Therapy" },{ "PostingID": 389, "Title": "GSK-HZA106829", "Description": "HZA106829: A randomised, double-blind, parallel group, multicentre study of Fluticasone Furoate/GW642444 Inhalation Powder, Fluticasone Furoate Inhalation Powder alone, and Fluticasone Propionate alone in the treatment of persistent asthma in adults and adolescents" },{ "PostingID": 392, "Title": "GSK-HZA113091", "Description": "A randomised, double-blind, double-dummy, parallel-group multicentre study to assess efficacy and safety of Fluticasone Furoate/GW642444 Inhalation Powder and Fluticasone Propionate/Salmeterol Inhalation Powder in the treatment of persistent asthma in adults and adolescents" },{ "PostingID": 404, "Title": "GSK-SAM40100", "Description": "Randomised, double-blind parallel group study to assess the bronchodilative and bronchoprotective properties of SERETIDE DISKUS ® inhlaer 50/100mcg twice daily vs. FLIXOTIDE® inhaler 200mcg twice daily." },{ "PostingID": 422, "Title": "GSK-SFA100314", "Description": "A Stratified, Multicenter, Randomized, Double-Blind, Parallel Group, 4-Week Comparison of Fluticasone Propionate/Salmeterol DISKUS® inhaler Combination Product 100/50mcg Twice Daily versus Fluticasone Propionate DISKUS® inhaler 100mcg Twice Daily in Pediatric and Adolescent Subjects with Activity-Induced Bronchospasm" },{ "PostingID": 423, "Title": "GSK-SFA100316", "Description": "A Stratified, Multicenter, Randomized, Double-Blind, Parallel Group, 4-Week Comparison of Fluticasone Propionate/Salmeterol DISKUS® inhaler Combination Product 100/50mcg Twice Daily versus Fluticasone Propionate DISKUS® inhaler 100mcg Twice Daily in Pediatric and Adolescent Subjects with Activity-Induced Bronchospasm" },{ "PostingID": 1440, "Title": "GSK-LPA112186", "Description": "A Randomised Double-Blind, Double-Dummy, Placebo-Controlled, Stratified, Parallel-Group, Multicentre, Dose Ranging Study to Evaluate the Efficacy and Safety of GSK2190915 Tablets Administered Once Daily, Fluticasone Propionate Inhalation Powder 100mcg Twice Daily and Montelukast 10mg Once Daily compared with Placebo for 8 Weeks in Adolescent and Adult Subjects with Persistent Asthma while Treated with Short Acting Beta2-agonist." },{ "PostingID": 1487, "Title": "GSK-SAS30031", "Description": "A Randomized, Double-Blind, 12-Week Trial Evaluating the Safety of the Fluticasone Propionate/Salmeterol DISKUS Combination Product 100/50mcg twice daily Versus Fluticasone Propionate DISKUS 100mcg twice daily in Symptomatic Pediatric Subjects (4-11 Years) With Asthma" },{ "PostingID": 1712, "Title": "GSK-FFA112059", "Description": "A randomised, double-blind, double-dummy, placebo controlled (with rescue medication), multicenter study to evaluate the efficacy and safety of Fluticasone Furoate inhalation powder in the treatment of persistent asthma in adults and adolescents." },{ "PostingID": 1722, "Title": "GSK-FFA114496", "Description": "A randomised, double-blind, multi-centre study to evaluate the efficacy and safety of inhaled fluticasone furoate in the treatment of persistent asthma in adults and adolescents currently receiving mid to high strength inhaled corticosteroids." },{ "PostingID": 1737, "Title": "GSK-HZA106837", "Description": "A Long-Term, Randomized, Double-Blind, Parallel Group Study of Fluticasone Furoate/GW642444 Inhalation Powder Once-Daily and Fluticasone Furoate Inhalation Powder Once-Daily in Subjects with Asthma" },{ "PostingID": 1738, "Title": "GSK-HZA106827", "Description": "HZA106827: A randomised, double-blind, placebo-controlled (with rescue medication), parallel group multicentre study of Fluticasone Furoate/GW642444 Inhalation Powder and Fluticasone Furoate Inhalation Powder alone in the treatment of persistent asthma in adults and adolescents" },{ "PostingID": 2462, "Title": "GSK-B2C112060", "Description": "A randomized, double-blind, double-dummy, parallel-group, placebo controlled (on inhaled corticosteroid medication), multicenter study to evaluate the efficacy and safety of vilanterol inhalation powder (GW642444) and salmeterol, compared with placebo in the treatment of persistent asthma in adults and adolescents uncontrolled on inhaled corticosteroids" },{ "PostingID": 2995, "Title": "GSK-SMS30077", "Description": "Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Parallel Group, Multi-Center Clinical Trial of Four Weeks Treatment with SEREVENT™ Inhalation Aerosol, 25mcg BID, 50mcg BID and Placebo Administered Via a Valved-Holding Chamber with Facemask in Subjects with Symptoms of Asthma or Reactive Airways Disease Age 6 to 23 months" },{ "PostingID": 2999, "Title": "GSK-SMS20011", "Description": "A Five-Week, Randomized, Double-Blind, Double-Dummy, Two-Period, Four-Treatment Crossover, Placebo-Controlled, Balanced, Incomplete Block Design, Multi-Center Study of Salmeterol Inhalation Aerosol 25mcg BID, 25mcg TID, 50mcg BID and Placebo Administered via a Holding Chamber with Facemask in Subjects with Asthma Aged 6 to 23 Months" },{ "PostingID": 3000, "Title": "GSK-SMS30076", "Description": "A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Parallel-Group Clinical Trial of 4 Weeks Treatment With SEREVENT Inhalation Aerosol, 25mcg BID, 50mcg BID, and Placebo Administered via a Valved Holding Chamber With Facemask in Subjects With Asthma Aged 24 to 47 Months" },{ "PostingID": 3411, "Title": "GSK-FFA115283", "Description": "A randomised, double-blind, placebo-controlled (with rescue medication), multi-centre study to evaluate the efficacy and safety of inhaled fluticasone furoate in the treatment of persistent asthma in adults and adolescents not currently receiving inhaled corticosteroids" },{ "PostingID": 3412, "Title": "GSK-FFA115285", "Description": "A randomised, double-blind, double-dummy, placebo controlled multi-centre study to evaluate the efficacy and safety of fluticasone furoate inhalation powder and fluticasone propionate inhalation powder in the treatment of asthma in adults and adolescents not currently treated with inhaled corticosteroids" },{ "PostingID": 3424, "Title": "GSK-HZA113714", "Description": "A randomised, double-blind, double-dummy, parallel group study to evaluate the efficacy and safety of fluticasone furoate/vilanterol trifenatate (FF/VI) inhalation powder delivered once daily compared to fluticasone propionate delivered twice daily in the treatment of asthma in adolescent and adult subjects of Asian ancestry currently treated with high-strength inhaled corticosteroids or mid-strength ICS/LABA combination therapy." },{ "PostingID": 3780, "Title": "GSK-HZA116863", "Description": "A Randomized, Double-Blind, Parallel Group, Multicenter Study of Fluticasone Furoate/Vilanterol 200/25 mcg Inhalation Powder, Fluticasone Furoate/Vilanterol 100/25 mcg Inhalation Powder, and Fluticasone Furoate 100 mcg Inhalation Powder in the Treatment of Persistent Asthma in Adults and Adolescents" },{ "PostingID": 4018, "Title": "GSK-HZA106853", "Description": "A dose-ranging study of vilanterol (VI) inhalation powder in children aged 5-11 years with asthma on a background of inhaled corticosteroid therapy" },{ "PostingID": 4296, "Title": "GSK-HZA113719", "Description": "A randomised, double-blind, placebo-controlled, parallel group, multicentre study to evaluate the efficacy and safety of fluticasone furoate/vilanterol trifenatate (FF/VI) inhalation powder delivered once daily for 12 weeks in the treatment of asthma in adolescent and adult subjects of Asian ancestry currently treated with low to mid-strength inhaled corticosteroid or low-strength combination therapy." },{ "PostingID": 4298, "Title": "GSK-SAS115359", "Description": "SAS115359, a Safety and Efficacy Study of Inhaled Fluticasone Propionate/Salmeterol Combination versus Inhaled Fluticasone Propionate in the Treatment of Adolescent and Adult Subjects with Asthma" },{ "PostingID": 4497, "Title": "GSK-SAS115358", "Description": "A 6-month safety and benefit study of inhaled fluticasone propionate/ salmeterol combination versus inhaled fluticasone propionate in the treatment of 6,200 pediatric subjects 4-11 years old with persistent asthma" },{ "PostingID": 4575, "Title": "GSK-HZA106855", "Description": "A dose-ranging study of fluticasone furoate (FF) inhalation powder in children aged 5-11 years with asthma" },{ "PostingID": 4913, "Title": "GSK-SAM104926", "Description": "A multicenter, randomised, double-blind, double dummy, parallel group study to compare the salmeterol/fluticasone propionate combination (SeretideTM) at a dose of 50/100µg twice daily and fluticasone propionate (FlixotideTM) at a dose of 200µg twice daily, both delivered via a dry powder inhaler (DiskusTM) for 12 weeks in asthma in children aged 4-11 years not controlled by inhaled corticosteroids alone at medium dose" },{ "PostingID": 4955, "Title": "GSK-HZA107112", "Description": "A randomised, double-blind, two-way crossover study to investigate the effect of inhaled fluticasone furoate on short-term growth in paediatric subjects with asthma" },{ "PostingID": 4957, "Title": "GSK-SAM102318", "Description": "Steroid-sparing management of the salmeterol/fluticasone 50/100µg b.i.d. combination compared to fluticasone 200µg b.i.d. in children and adolescents with moderate asthma" },{ "PostingID": 4999, "Title": "GSK-SMS40065 (521/120 [SLPT10])", "Description": "Efficacy and safety of long-term inhaled salmeterol and beclomethasone dipropionate in corticosteroid-naïve children with mild to moderate, chronic, stable asthma." },{ "PostingID": 14491, "Title": "GSK-SAM101667", "Description": "A multicentre, randomised, double-blind, parallel group study to compare the efficacy and safety of Salmeterol/Fluticasone propionate combination product (Seretide®) 50/100 mcg with Fluticasone propionate (Flixotide® ) 200 mcg, both delivered twice daily via the DISKUS inhaler, in the treatment of children aged 6-12 years with symptomatic asthma" },{ "PostingID": 19762, "Title": "GSK-200860", "Description": "Clinical assessment of fluticasone propionate/ salmeterol xinafoate HFA MDI in 6-month to 4-year-old Japanese patients with bronchial asthma" },{ "PostingID": 19881, "Title": "GSK-201832", "Description": "201832: A Randomised, Double-Blind, Double-Dummy, Crossover Comparison of Fluticasone Furoate/Vilanterol 100/25 mcg Once Daily Versus Fluticasone Propionate 250 mcg Twice Daily in Adolescent and Adult Subjects with Asthma and Exercise-Induced Bronchoconstriction" }]

Best step-up treatments for children with uncontrolled asthma: a systematic review and network meta-analysis of individual participant data Sofia Cividini, Ian Sinha, Sarah Donegan, Michelle Maden, Katie Rose, Olivia Fulton, Giovanna Culeddu, Dyfrig A. Hughes, Stephen Turner, Catrin Tudur Smith on behalf of the EINSTEIN Collaborative Group European Respiratory Journal 2023 62: 2301011
DOI: 10.1183/13993003.01011-2023