Evaluation of real-world mepolizumab use in severe asthma across Europe: the SHARP experience with privacy-preserving federated analysis.

Background: An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns. Methods: In this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11-18 months) period in frequent (two or more) exacerbations, maintenance OCS use and dose were analysed in a privacy-preserving manner using meta-analysis of generalised estimating equation parameters. Periods before and during the coronavirus disease 2019 pandemic were analysed separately. Results: In 912 patients who fulfilled selection criteria, mepolizumab significantly reduced frequent exacerbations (OR 0.18, 95% CI 0.13-0.25), maintenance OCS use (OR 0.75, 95% CI 0.61-0.92) and dose (mean -3.93 mg·day-1, 95% CI -5.24-2.62 mg·day-1) in the pre-pandemic group, with similar trends in the pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns. Conclusions: By harmonising patient-level registry data and applying federated analysis, SHARP demonstrated the real-world effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner.

"Life-changing": the experience of super-responders to biologics in severe asthma.

BACKGROUND: There is limited information on the patient's perspective of how biologic treatments impact their lives. We conducted a qualitative study to explore the patient's experience of being considered a super-responder from a quality of life perspective. METHODS: Patients with severe asthma identified as super-responders were invited to semi-structured interviews conducted online. Participants could bring a family member/friend to the interview. The interviews explored experiences of biologic treatment, were transcribed and underwent thematic analysis. RESULTS: Twenty-five participants took part in this study. Themes emerged on the impact of biologic treatment for participants and for their friends/family: (i) Words used to describe their often life-changing experiences and (ii) the positive changes noted. Biologic treatment stopped the disruption of family life and social life caused by exacerbations. Improvements in mental health were also noted. Marked individual variations in the way it affected their lives were noted. Most participants noticed improvements 2-3 months after starting their biologic, but some noticed improvement within a few days and others after 6 months. CONCLUSIONS: Super-responders reported profound but heterogeneous improvements following biologic treatment beyond asthma symptoms and exacerbations including important benefits to social and family life. Improvements may be underestimated as social and family benefits are not reliably measured in current studies with implications for health economic evaluations. Not all patients are super-responders, and excellent responses may be lost in group mean data in trials. Individual time course and response patterns need further elucidation to identify who will respond best to biologics.

Preliminary development of a questionnaire to measure the extra-pulmonary symptoms of severe asthma.

BACKGROUND: Research into the effects of asthma treatments on the extra-pulmonary symptoms of severe asthma is limited by the absence of a suitable questionnaire. The aim was to create a questionnaire suitable for intervention studies by selecting symptoms that are statistically associated with asthma pathology and therefore may improve when pathology is reduced. METHODS: Patients attending a specialist asthma clinic completed the 65-item General Symptom Questionnaire (GSQ-65), a questionnaire validated for assessing symptoms of people with multiple medically unexplained symptoms. Lung function (FEV1%) and cumulative oral corticosteroids (OCS) calculated from maintenance dose plus exacerbations were obtained from clinic records. Pathology was represented by the two components of a principal component analysis (PCA) of FEV1% and OCS. LASSO regression was used to select symptoms that had high coefficients with these two principal components and occurred frequently in severe asthma. RESULTS: 100 patients provided data. PCA revealed two components, one where FEV1% and OCS were inversely related and another where they were directly related. LASSO regression revealed 39 symptoms with non-zero coefficients on one or more of the two principal components from which 16 symptoms were selected for the GSQ-A on the basis of magnitude of coefficient and frequency. Asthma symptoms measured by asthma control questionnaires were excluded. The GSQ-A correlated 0.33 and - 0.34 (p = 0.001) with the two principal components. CONCLUSION: The GSQ-A assesses the frequency of 16 heterogenous non-respiratory symptoms that are associated with asthma severity using the statistical combination of FEV1% and OCS.

Comparison of the sensitivity of patient-reported outcomes for detecting the benefit of biologics in severe asthma.

BackgroundThe sensitivity of patient-reported outcomes (PROs) to detect the effects of treatment change depends on the match between the change in items of the PRO and the change that takes place in a sample of people. The aim of this study is to compare the sensitivity of different PROs in detecting changes following the initiation of biologic treatment in asthma. Methods: Patients starting a biologic treatment as part of clinical care completed the Asthma Control Questionnaire (ACQ-6), the Severe Asthma Questionnaire (SAQ and SAQ-global scores) and the EQ5D (EQ-5D-5L and EQ5D-VAS) at baseline. They completed the ACQ-6, SAQ, SAQ-global and a retrospective global rating of change (GRoC) scale at weeks 4, 8 and 16 and completed the EQ-5D-5L and EQ5D-VAS at week 16. The SAQ-global and EQ5D-VAS differ but both are single item 100-point questions. Sensitivity was measured by Cohen's D effect size at each of the three time points. Results: 110 patients were recruited. Depending on the time of assessment, effect size varied between 0.45 and 0.64 for the SAQ, between 0.50 and 0.77 for the SAQ-global; between 0.45 and 0.69 for ACQ-6; between 0.91 and 1.22 for GRoC; 0.32 for EQ-5D-5L and 0.49 for EQ5D-VAS. Conclusion: The sensitivity to change of a questionnaire varies with the time of measurement. The three asthma-specific prospective measures (SAQ, SAQ-global and ACQ-6) have similar sensitivity to change. The single-item EQ5D-VAS was less sensitive than the asthma specific measures and less sensitive than the single-item SAQ-global. The EQ-5D-5L was least sensitive.

Defining a Severe Asthma Super-Responder: Findings from a Delphi Process.

BACKGROUND: Clinicians are increasingly recognizing severe asthma patients in whom biologics and other add-on therapies lead to dramatic improvement. Currently, there is no agreed-upon super-responder (SR) definition. OBJECTIVE: To survey severe asthma experts using a modified Delphi process, to develop an international consensus-based definition of a severe asthma SR. METHODS: The Delphi panel was composed of 81 participants (94% specialist pulmonologists or allergists) from 24 countries and consisted of three iterative online voting rounds. Consensus on individual items, whether acceptance or rejection, required at least 70% agreement by panel members. RESULTS: Consensus was achieved that the SR definition should be based on improvement across three or more domains assessed over 12 months. Major SR criteria included exacerbation elimination, a large improvement in asthma control (two or more times the minimal clinically important difference), and cessation of maintenance of oral steroids (or weaning to adrenal insufficiency). Minor SR criteria were composed of a 75% exacerbation reduction, having well-controlled asthma, and 500 mL or greater improvement in FEV1. The SR definition requires improvement in at least two major criteria. In the future, the SR definition should be expanded to incorporate quality of life measures, although current tools can be difficult to implement in a clinical setting and further research is needed. CONCLUSIONS: This international consensus-based definition of severe asthma SRs is an important prerequisite for better understanding SR prevalence, predictive factors, and the mechanisms involved. Further research is needed to understand the patient's perspective and to measure quality of life more precisely in SRs.

Validation of subscales of the Severe Asthma Questionnaire (SAQ) using exploratory factor analysis (EFA).

BACKGROUND: The Severe Asthma Questionnaire (SAQ) is a health related quality of life (HRQoL) questionnaire validated for use in severe asthma. It is scored using the mean value of 16 items (SAQ score) in addition to a single item global rating of HRQoL (SAQ-global). The aim was to validate clinically relevant subscales using exploratory factor analysis (EFA). METHODS: The SAQ was completed, along with measures of asthma control and EQ5D-5L by patients attending six UK severe asthma centres. Clinical data were included in the analysis. EFA using principal axis factoring and oblimin rotation was used to achieve simple structure of data. RESULTS: 460 patients with severe asthma participated, 65% women, mean age 51 (16-83) years. A three factor solution achieved best fit and showed that the SAQ items formed three distinct but inter-correlated groups of items where items were grouped in a way that was consistent with item content. The three subscales were differentially associated with clinically relevant variables (lung function and mood). Males and females interpreted the question of night disturbance in different ways. CONCLUSIONS: This paper provides a template for best practice in the use of EFA when validating HRQoL subscales. The SAQ can be scored as three subscales with content reflecting three different constructs people with severe asthma use when making judgements about their lives. The subscale 'My Life' assesses the impact of severe asthma on different life activities, 'My Mind' assesses the perceived emotional impact and 'My Body' the impact of extra-pulmonary symptoms and side effects.

Comparison of the effects of pulmonary and extra-pulmonary symptoms on health-related quality of life in patients with severe asthma.

OBJECTIVES: To survey the frequency of extra-pulmonary symptoms reported by a sample of patients with severe asthma, their contribution to quality of life and relationship to treatment pathways. METHODS: Consenting patients (N = 100) attending a severe asthma clinic completed questionnaire measures of extra-pulmonary symptoms (the General symptom Questionnaire, GSQ), pulmonary symptoms (Asthma Control Test, ACT), quality of life (the Severe Asthma Questionnaire, SAQ) and health status (EQ-5D-5L). RESULTS: A median of 21 extra-pulmonary symptoms were reported per week. GSQ correlated -0.65 with the ACT and 0.69 with the SAQ. Linear regression showed that both the ACT and GSQ were significant predictors of SAQ mean score, p < 0.001. In patients not receiving biologics, those with high cumulative OCS exposure (≥1120 mg per year) had significantly worse scores (p < 0.05) on all questionnaires except the ACT and GSQ compared to those with low cumulative OCS exposure. DISCUSSION: Extra-pulmonary symptoms were common in this sample of people with severe asthma. Extra-pulmonary and pulmonary symptoms contribute equal variance to the score of HRQoL, showing that they are equally important contributors to patients' experience of severe asthma. Extra-pulmonary symptoms are often overlooked in clinical medicine and in measures of quality of life. Participants receiving biologic treatments had lower extra-pulmonary symptoms possibly indicating that biologics reduce systemic symptoms more effectively than other treatments.

Evidence for similarity in symptoms and mechanism: The extra-pulmonary symptoms of severe asthma and the polysymptomatic presentation of fibromyalgia.

BACKGROUND: Asthma is a disease of the lung and a systemic disease. Functional disorders are associated with multiple systemic abnormalities that have been explained by complexity models. The aim was to test the similarity in type and aetiology between the extra-pulmonary symptoms of severe asthma and the symptoms of fibromyalgia. METHODS: One Hundred patients recruited from a specialist severe asthma clinic and 1751 people reporting different functional disorder diagnoses recruited via the internet completed the same 60-item questionnaire. Symptom patterns were compared between groups using a new measure, the symptom pattern similarity index where 0 = no relationship, 1 = identical patterns between groups. RESULTS: Severe asthma patients report numerous extra-pulmonary symptoms. The similarity index between the symptom pattern of the asthma patients with other groups was irritable bowel syndrome = 0.54, chronic fatigue syndrome = 0.69, and fibromyalgia = 0.75. The index between fibromyalgia and asthma patients with the most and least frequent extra-pulmonary symptoms was 0.81 and 0.55 respectively. CONCLUSIONS: Patients with severe asthma have numerous extra-pulmonary symptoms similar in type and pattern to the symptoms of fibromyalgia. The similarity of the symptom pattern between asthma and fibromyalgia increases as the number of extra-pulmonary symptoms increases as predicted by network theory and previously shown to be the case with other functional disorders. These findings support the hypothesis that functional disorders and extra-pulmonary asthma symptoms have a common complexity or network aetiology. Evidence based behavioural interventions for fibromyalgia may be helpful for patients with severe asthma reporting extra-pulmonary symptoms.

Long-term Safety and Clinical Benefit of Mepolizumab in Patients With the Most Severe Eosinophilic Asthma: The COSMEX Study.

PURPOSE: The goal of this study was to assess the long-term safety and efficacy of mepolizumab in patients with the most severe eosinophilic asthma. METHODS: This multicenter, open-label, long-term, Phase IIIb study (COSMEX [COSMOS Extension]; 201312/NCT02135692) enrolled patients from the 52-week, open-label extension study COSMOS (A Study to Determine Long-term Safety of Mepolizumab in Asthmatic Subjects) that previously enrolled patients from the double-blinded, placebo-controlled Phase III studies MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) and SIRIUS (Steroid Reduction with Mepolizumab Study). To enter COSMEX, patients had to have life-threatening/seriously debilitating asthma before entering MENSA or SIRIUS and to have completed these previous studies with demonstrated improvement while receiving mepolizumab. In COSMEX, patients received mepolizumab 100 mg subcutaneously every 4 weeks as add-on therapy for up to 172 weeks. Primary endpoints were adverse event frequency and exacerbation rate per year; also assessed were forced expiratory volume in 1 s, Asthma Control Questionnaire-5 score, and daily oral corticosteroid (OCS) use. FINDINGS: Of the 340 patients enrolled, 339 received mepolizumab; median treatment duration within this extension study was 2.2 years, equating to 718 patient-years of additional exposure. No new safety signals were identified. Patients receiving mepolizumab throughout this study and previous studies had lasting reductions in exacerbation rate and daily OCS use and improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire-5 score. In COSMEX, the on-treatment exacerbation rate (95% CI) was 0.93 (0.81-1.06) event/year for clinically significant exacerbations, 0.13 (0.10-0.18) event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 (0.05-0.10) event/year for exacerbations requiring hospitalization. In patients requiring systemic/oral corticosteroids with ≥128 weeks of continuous enrollment across SIRIUS, COSMOS, and COSMEX, mepolizumab maintained the median daily OCS dose at 1.3-2.8 mg during COSMEX, with additional patients no longer requiring OCS after extended mepolizumab treatment. IMPLICATIONS: This study indicates that long-term mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT02135692.

The construction and validation of the Severe Asthma Questionnaire.

The US Food and Drug Administration's procedure for scale validation requires a documented stepwise process of qualitative and quantitative data. The aim of this paper is to provide final quantitative validating data for the Severe Asthma Questionnaire (SAQ).The SAQ, Asthma Control Test, Mini Asthma Quality of Life Questionnaire and EQ-5D-5L were completed by 160 patients attending a severe asthma clinic; 51 patients completed the SAQ on two occasions for test-retest reliability analysis. The SAQ produces two scores, a SAQ score based on the average of 16 items and a SAQ-global score from a single 100-point global quality of life scale.Construct validity was demonstrated by factor analysis of the 16 items, convergent validity by correlations of >0.6 between the SAQ, SAQ-global and other questionnaires, and discriminant validity by the ability of the SAQ and SAQ-global to distinguish between different treatment levels. Test-retest reliability (intra-class correlation) was 0.93 for the SAQ and 0.93 for the SAQ-global, and the alpha coefficient for the SAQ was 0.93.The SAQ was developed using recommended qualitative and quantitative procedures for scale development, and can be used to gain insight into patients' perceptions of how severe asthma and its treatment affects their lives.

How patient participation was used to develop a questionnaire that is fit for purpose for assessing quality of life in severe asthma.

BACKGROUND: Previous research shows that existing asthma quality of life questionnaires fail to measure the burden of oral corticosteroids that can be used to treat severe asthma, and are therefore not fit for purpose for severe asthma according to the USA's Federal Drug Authority's (FDA) criteria for content validity. Patient input and documentation of that input is key to achieving content validity according to FDA guidelines. This paper describes the process of constructing a new questionnaire to measure the burden of asthma symptoms and burden of treatment in severe asthma, using criteria specified by the FDA. METHODS: A draft severe asthma questionnaire (SAQ) was constructed using qualitative input from severe asthma patients who took part in an earlier study. The aim of this study was to improve that draft questionnaire using a further group of patients. In four iterative focus groups, 16 people with severe asthma completed the draft questionnaire, discussed the wording and structure and suggested changes that were incorporated into the final version. RESULTS: The original intention to ask patients to identify whether problems were caused by asthma symptoms or side effects of medication was abandoned as the attribution of cause was found to be difficult and inconsistent. The recall period of 2 weeks was acceptable but fails to reflect the patients' desire to express the variability of severe asthma. Patients suggested improvements to the wording of the draft questionnaire, including splitting some items in two, combining two items in one, and changes to some of the words in individual items and the response scale. CONCLUSIONS: The final version of the questionnaire was substantially different from one constructed using only qualitative reports from patients about the quality of life deficits of severe asthma. Patients make a valuable contribution to the questionnaire if they are asked to comment and improve an initial draft and where patients are treated as partners in the process of questionnaire construction, rather than only as a source of information to experts who construct the questionnaire.

Impact of omalizumab on treatment of severe allergic asthma in UK clinical practice: a UK multicentre observational study (the APEX II study).

OBJECTIVE: To describe the impact of omalizumab on asthma management in patients treated as part of normal clinical practice in the UK National Health Service (NHS). DESIGN: A non-interventional, mixed methodology study, combining retrospective and prospective data collection for 12 months pre-omalizumab and post-omalizumab initiation, respectively. SETTING: Data were collected in 22 UK NHS centres, including specialist centres and district general hospitals in the UK. PARTICIPANTS: 258 adult patients (aged ≥16 years; 65% women) with severe persistent allergic asthma treated with omalizumab were recruited, of whom 218 (84.5%) completed the study. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was change in mean daily dose of oral corticosteroids (OCS) between the 12-month pre-omalizumab and post-omalizumab initiation periods. A priori secondary outcome measures included response to treatment, changes in OCS dosing, asthma exacerbations, lung function, employment/education, patient-reported outcomes and hospital resource utilisation. RESULTS: The response rate to omalizumab at 16 weeks was 82.4%. Comparing pre-omalizumab and post-omalizumab periods, the mean (95% CIs) daily dose of OCS decreased by 1.61 (-2.41 to -0.80) mg/patient/day (p<0.001) and hospital exacerbations decreased by 0.97 (-1.19 to -0.75) exacerbations/patient (p<0.001). Compared with baseline, lung function, assessed by percentage of forced expiratory volume in 1 s, improved by 4.5 (2.7 to 6.3)% at 16 weeks (p<0.001; maintained at 12 months) and patient quality of life (Asthma Quality of Life Questionnaire) improved by 1.38 (1.18 to 1.58) points at 16 weeks (p<0.001, maintained at 12 months). 21/162 patients with complete employment data gained employment and 6 patients lost employment in the 12-month post-omalizumab period. The mean number of A&E visits, inpatient hospitalisations, outpatient visits (excluding for omalizumab) and number of bed days/patient decreased significantly (p<0.001) in the 12-month post-omalizumab period. CONCLUSIONS: These data support the beneficial effects of omalizumab on asthma-related outcomes, quality of life and resource utilisation in unselected patients treated in 'real-world' clinical practice.

A qualitative study of the impact of severe asthma and its treatment showing that treatment burden is neglected in existing asthma assessment scales.

BACKGROUND: People with severe asthma experience significant respiratory symptoms and suffer adverse effects of oral corticosteroids (OCS), including disturbed mood and physical symptoms. OCS impacts on health-related quality of life (HRQoL) have not been quantified. Asthma HRQoL scales are valid as outcome measures for patients requiring OCS only if they assess the deficits imposed by OCS. AIMS: The aim of this study was to compare the burden of disease and treatment in patients with severe asthma with items in eight asthma-specific HRQoL scales. METHODS: Twenty-three patients with severe asthma recruited from a severe asthma clinic were interviewed about the impact of their respiratory symptoms and the burden of their treatment. The domains from a thematic analysis of these interviews were compared with the items of eight asthma-specific HRQoL scales. RESULTS: In addition to the burden caused by symptoms, ten domains of OCS impact on HRQoL were identified: depression, irritability, sleep, hunger, weight, skin, gastric, pain, disease anxiety, and medication anxiety. Some patients experienced substantial HRQoL deficits attributed to OCS. Although all HRQoL scales include some OCS-relevant items, all eight scales fail to adequately assess the several types of burden experienced by some patients while on OCS. CONCLUSION: The burden of OCS in severe asthma is neglected in policy and practice because it is not assessed in outcome studies. Existing asthma HRQoL scales provide an overly positive estimation of HRQoL in patients with frequent exposure to OCS and underestimate the benefit of interventions that reduce OCS exposure. Changes to existing measurement procedures are needed.

The 24 h duration of bronchodilator action of the budesonide/formoterol combination inhaler.

INTRODUCTION: The duration of bronchodilator action of the long-acting beta-agonist formoterol when administered in the evening has not been investigated. In this study we have investigated whether a single evening dose of formoterol, administered from the combination budesonide/formoterol (BUD/F) Turbuhaler significantly attenuates the circadian rhythm in airway tone over 24 h. METHODS: Twenty subjects with mild to moderate asthma (mean FEV1 84% predicted) participated in a double-blind, placebo-controlled, cross-over study. Subjects inhaled, in random order, placebo or BUD/F (2x100/6 microg) administered in the evening (2000 h) on two separate occasions. Lung function measurements including FEV1, specific airways conductance (sGaw) and maximum expiratory flow at 25-75% of vital capacity (MEF(25-75%)) were assessed at baseline, at 1 h and subsequently every 4 h post-dose for 24 h. RESULTS: Compared with placebo, BUD/F significantly improved the three measures of airways function throughout the 24 h period, with a difference in FEV1 at 24 h of 0.20L (0.04-0.35L). BUD/F attenuated the biphasic pattern of the circadian rhythm in airway tone. CONCLUSION: The single evening administration of formoterol from the combination BUD/F inhaler resulted in a duration of bronchodilation of at least 24 h.