Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA)

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) working group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies.METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult, and paediatric clinicians, pharmaceutical representatives and health regulators from across Europe. Evidence included a systematic review of development, validity, and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria.RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire, and Asthma Control Test (ACT) or Childhood-ACT while the adult COM includes the Severe Asthma Questionnaire and the Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately).CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.</p

Definitions of non-response and response to biological therapy for severe asthma: a systematic review

Background: Biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined and evaluated definitions of non-response and response to biologics for severe asthma. Methods: We searched four bibliographic databases from inception to 15 March 2021. Two reviewers screened references, extracted data, and assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). A modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and narrative synthesis were undertaken. Results: 13 studies reported three composite outcome measures, three asthma symptoms measures, one asthma control measure and one quality of life measure. Only four measures were developed with patient input; none were composite measures. Studies utilised 17 definitions of response: 10 out of 17 (58.8%) were based on minimal clinically important difference (MCID) or minimal important difference (MID) and 16 out of 17 (94.1%) had high-quality evidence. Results were limited by poor methodology for the development process and incomplete reporting of psychometric properties. Most measures rated “very low” to “low” for quality of measurement properties and none met all quality standards. Conclusions: This is the first review to synthesise evidence about definitions of response to biologics for severe asthma. While high-quality definitions are available, most are MCIDs or MIDs, which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics

Outcome measures and predictors of response to biological treatments for severe asthma

Severe asthma affects 5-10% of the total asthma population but imposes a disproportionate burden on both healthcare systems and individual patients. The emergence of novel therapies, particularly biologics, promises an era of personalised medicine for improved management of severe asthma. However, achieving this requires optimal outcome measures and predictors of treatment response. Therefore, this thesis aimed to: i) identify ‘priority’ outcome measures, ii) develop a paediatric quality of life (QoL) measure, and iii) identify predictors of biologic response, for use in severe asthma research and practice. Chapter 2 reports a systematic review of outcome measures considered to be a ‘priority’ for severe asthma. Following a multi-step process, 24 ‘priority’ measures were selected by key stakeholders, including patients. An assessment of the methodological quality of studies reporting on these measures revealed that existing paediatric QoL tools were not developed with input from Children and Young People (CYP) with severe asthma, and thus fail to capture the deficits experienced by this group. Chapter 3 reports the development of a QoL tool for paediatric severe asthma. Qualitative interviews with CYP with severe asthma, parents, and healthcare professionals (n=46) revealed that the adult Severe Asthma Questionnaire (SAQ) is mostly relevant for the paediatric population subject to removal of adult-related examples and rewording to enhance comprehensibility. The findings informed the development of the prototype PSAQ. Preliminary field testing of the PSAQ amongst CYP and parents (n=40) found that 9 of 15 items were deemed as most important for inclusion in the questionnaire. The survey is ongoing, following which the prototype PSAQ will be finalised. Chapter 4 reports a systematic review and meta-analysis of response predictors for anti-IL-5, anti-IL-4Ra, and anti-IL-13 therapies. From a total of 4704 records, 29 studies were included in the analysis. There was consistent evidence for the ability of high blood eosinophil counts and FeNO levels to predict response to anti-IL-4Ra therapy, but inconclusive evidence for other variables investigated such as lung function parameters, clinical and sociodemographic characteristics. This thesis makes several contributions to the field of severe asthma. The systematic review of ‘priority’ outcome measures informed the development of a core outcome measurement set for severe asthma. The PSAQ, once validated, will be an invaluable tool for assessing treatment response in clinical trials and practice. Lastly, the systematic review of biologic response predictors provides evidence to inform clinical decision making about optimal biologic selection. Taken together, this work is a step towards achieving personalised medicine for severe asthma

Real-world efficacy of treatment with Benralizumab, Dupilumab, Mepolizumab and Reslizumab for severe asthma: A systematic review and meta-analysis

Background: severe asthma is a major cause of morbidity. Some patients may benefit from biological therapies. Most evaluations of these treatments are derived from randomized controlled trials (RCTs), but few patients are eligible for these trials. Studies involving more diverse groups of participants exist, but there is a lack of precise pooled estimates. Objective: this systematic review aims to evaluate the real-world efficacy of recently and nearly licensed biological therapies for severe asthma to assess the generalizability of the RCT data. Methods: Clinical outcomes including exacerbation rate, oral corticosteroid usage, forced expiratory volume in 1 second (FEV 1) and fractional exhaled nitric oxide (FeNO) were examined. Studies were assessed for risk of bias using the Critical Appraisal Skills Programme checklist tool. The certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). Results: a total of 21 studies examining biologicals in real-world settings were identified; they mostly focused on benralizumab and mepolizumab. The introduction of biologicals reduced the annualzsed exacerbation rate significantly by −3.79 (95% confidence interval [CI] −4.53, −3.04), −3.17 (95% CI −3.74, −2.59) and −6.72 (95% CI −8.47, −4.97) with benralizumab, mepolizumab and reslizumab, respectively. Likewise, improvements were observed in FEV 1 (0.17 L 95% CI 0.11, 0.24) and FeNO (−14.23 ppb 95% CI −19.71, −8.75) following the treatment with mepolizumab. After treatment with benralizumab, there was an increase in FEV 1 (0.21 L 95% CI 0.08, 0.34). Conclusions: these data demonstrate that anti-IL5 biologicals may improve the clinical outcomes of patients with severe asthma in a clinic environment with similar effect sizes to RCTs. The data were mainly retrospective and unadjusted, so estimated effect sizes may not be reliable. More data are needed to acquire accurate effect estimates in different subpopulations of patients. </p

Narrative review to capture patients' perceptions and opinions about non-response and response to biological therapy for severe asthma

Background: There are now many biological therapies to treat severe asthma. To assess which work best for which patient, we need to develop definitions of response. This narrative review aims to capture severe asthma patients' perceptions about non-response and response to biological therapy. Methods Four bibliographic databases were searched from inception to September 2021. Grey literature was searched with the involvement of patient representatives. A thematic approach was used for synthesis. No qualitative studies specifically explore patients' perspectives on response to biological therapy for severe asthma. Three papers and one published asthma patient interview were included. Relevant grey literature was included from online discussion forums, blogs and social media websites. Results Adult patients framed positive response to biological therapy in terms of reduced burden of disease and treatment. Both were multifaceted. Some patients experienced reduced benefit from biological therapy over time. There was a group of patients who described a limited response or non-response to biological therapy. This was framed within the context of continuing hospitalisation and oral corticosteroid treatment. The speed of onset of benefit was felt to be important by some. Conclusions Definitions of non-response and response need to be patient-centred, yet there is a complete lack of qualitative research focused on this topic. By combining relevant published and grey literature we have provided a description of adult patients' perceptions of response to biological therapy in severe asthma. We now need to understand the views of children and adolescents with severe asthma and their carers, and diverse patient experiences in real-world settings

Identifying and appraising outcome measures for severe asthma:a systematic review

Background Valid outcome measures are imperative to evaluate treatment response, yet the suitability of existing end-points for severe asthma is unclear. This review aimed to identify outcome measures for severe asthma and appraise the quality of their measurement properties. Methods A literature search was performed to identify “candidate” outcome measures published between 2018 and 2020. A modified Delphi exercise was conducted to select “key” outcome measures within healthcare professional, patient, pharmaceutical and regulatory stakeholder groups. Initial validation studies for “key” measures were rated against modified quality criteria from COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). The evidence was discussed at multi-stakeholder meetings to ratify “priority” outcome measures. Subsequently, four bibliographic databases were searched from inception to 20 July 2020 to identify development and validation studies for these end-points. Two reviewers screened records, extracted data, assessed their methodological quality and graded the evidence according to COSMIN. Results 96 outcome measures were identified as “candidates”, 55 as “key” and 24 as “priority” for severe asthma, including clinical, healthcare utilisation, quality of life, asthma control and composite. 32 studies reported measurement properties of 17 “priority” end-points from the latter three domains. Only the Severe Asthma Questionnaire and Childhood Asthma Control Test were developed with input from severe asthma patients. The certainty of evidence was “low” to “very low” for most “priority” end-points across all measurement properties and none fulfilled all quality standards. Conclusions Only two outcome measures had robust developmental data for severe asthma. This review informed development of core outcome measures sets for severe asthma.</p

Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2 to 4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly implicated in IPF disease initiation, but the factors that determine whether fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that zinc finger E-box-binding homeobox 1-mediated epithelial-mesenchymal transition in human alveolar epithelial type II (ATII) cells augments transforming growth factor-\u3b2-induced profibrogenic responses in underlying lung fibroblasts via paracrine signaling. Here, we investigated bidirectional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA-Seq of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced epithelial-mesenchymal transition identified many differentially expressed genes including those involved in cell migration and extracellular matrix regulation. We confirmed that paracrine signaling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a zinc finger E-box-binding homeobox 1-tissue plasminogen activator axis. In a reciprocal fashion, paracrine signaling from transforming growth factor-\u3b2-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein acidic and rich in cysteine, which may signal via the epithelial growth factor receptor via epithelial growth factor-like repeats. Together, these data identify that aberrant bidirectional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining profibrotic signals

Identifying and appraising outcome measures for severe asthma: a systematic review

Background: Valid outcome measures are imperative to evaluate treatment response, yet the suitability of existing endpoints for severe asthma is unclear. This review aimed to identify outcome measures for severe asthma and appraise the quality of their measurement properties.Methods: A literature search was performed to identify ‘candidate’ outcome measures published between 2018 – 2020 (PROSPERO, CRD42020204437). A modified Delphi exercise was conducted to select ‘key’ outcome measures within healthcare professional, patient, pharmaceutical, and regulatory stakeholder groups. Initial validation studies for ‘key’ measures were rated against modified quality criteria from COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN). The evidence was discussed at multi-stakeholder meetings to ratify ‘priority’ outcome measures. Subsequently, four bibliographic databases were searched from inception to identify development and validation studies for these endpoints. Two reviewers screened records, extracted data, assessed their methodological quality, and graded the evidence according to COSMIN.  Results: 96 outcome measures were identified as ‘candidates’, 55 as ‘key’, and 24 as ‘priority’ for severe asthma; including clinical, healthcare utilisation, quality of life, asthma control, and composite. 32 studies reported measurement properties of 17 ‘priority’ endpoints from the latter three domains. Only SAQ and C-ACT were developed with input from severe asthma patients. The certainty of evidence was ‘low’ to ‘very low’ for most ‘priority’ endpoints across all measurement properties, and none fulfilled all quality standards.  Conclusion: Only two outcome measures had robust developmental data for severe asthma. This review informed development of core outcome measures sets for severe asthma. <br/

Definitions of non-response and response to biological therapy for severe asthma: a systematic review

Background: biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined and evaluated definitions of non-response and response to biologics for severe asthma.Methods: we searched four bibliographic databases from inception to 15 March 2021. Two reviewers screened references, extracted data, and assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). A modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and narrative synthesis were undertaken.Results: 13 studies reported three composite outcome measures, three asthma symptoms measures, one asthma control measure and one quality of life measure. Only four measures were developed with patient input; none were composite measures. Studies utilised 17 definitions of response: 10 out of 17 (58.8%) were based on minimal clinically important difference (MCID) or minimal important difference (MID) and 16 out of 17 (94.1%) had high-quality evidence. Results were limited by poor methodology for the development process and incomplete reporting of psychometric properties. Most measures rated "very low" to "low" for quality of measurement properties and none met all quality standards.Conclusions: this is the first review to synthesise evidence about definitions of response to biologics for severe asthma. While high-quality definitions are available, most are MCIDs or MIDs, which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics.</p