A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial

Background: Patients with difficult-to-control asthma consume 50–60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called ‘T2-low asthma’ and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy.Methods/design: Patients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers.Discussion: Multi-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct.Trial registration: ClinicalTrials.gov, NCT02717689. Registered on 16 March 2016

From DREAM to REALITI-A and beyond: Mepolizumab for the treatment of eosinophil-driven diseases

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation

Background: In T2-mediated severe asthma, biologic therapies, such as mepolizumab, are increasingly used to control disease. Current biomarkers can indicate adequate suppression of T2 inflammation, but it is unclear whether they provide information about airway microbial composition. We investigated the relationships between current T2 biomarkers and microbial profiles, characteristics associated with a ProteobacteriaHIGH microbial profile and the effects of mepolizumab on airway ecology. Methods: Microbiota sequencing was performed on sputum samples obtained at stable and exacerbation state from 140 subjects with severe asthma participating in two clinical trials. Inflammatory subgroups were compared on the basis of biomarkers, including FeNO and sputum and blood eosinophils. ProteobacteriaHIGH subjects were identified by Proteobacteria to Firmicutes ratio ≥0.485. Where paired sputum from stable visits was available, we compared microbial composition at baseline and following ≥12 weeks of mepolizumab. Results: Microbial composition was not related to inflammatory subgroup based on sputum or blood eosinophils. FeNO ≥50 ppb when stable and at exacerbation indicated a group with less dispersed microbial profiles characterised by high alpha-diversity and low Proteobacteria. ProteobacteriaHIGH subjects were neutrophilic and had a longer time from asthma diagnosis than ProteobacteriaLOW subjects. In those studied, mepolizumab did not alter airway bacterial load or lead to increased Proteobacteria. Conclusion: High FeNO could indicate a subgroup of severe asthma less likely to benefit from antimicrobial strategies at exacerbation or in the context of poor control. Where FeNO is <50 ppb, biomarkers of microbial composition are required to identify those likely to respond to microbiome-directed strategies. We found no evidence that mepolizumab alters airway microbial composition

Exacerbation Profile and Risk Factors in a T2-Low Severe Asthma Population

Although present in a minority of severe asthmatics, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. METHODS Exacerbation assessment was a pre-specified secondary analysis of data from a RCT comparing the use of biomarkers & symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort. Participants were phenotyped as T2LOW(fractional exhaled nitric oxide [FeNO] ≤20 ppb & blood eosinophil count [PBE] ≤150 cells/µL) or T2HIGH ( FeNO>20 or PBE>150) at study enrolment & at each exacerbation. We report comparison of exacerbators & non-exacerbators, physiological changes at exacerbation in T2LOW & T2HIGH ,& stability of inflammatory phenotypes. RESULTS 60.8% (183/301) ≥1 self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher BMI & more exacerbations requiring oral corticosteroid (OCS) & unscheduled primary care attendances for exacerbations. At enrolment, 23.6% (71/301) were T2LOW, & 76.4% (230/301) T2HIGH. The T2LOW group had more asthma primary care attendances, were more likely to have a previous admission to HDU/ICU & to be receiving maintenance OCS. At exacerbation the T2LOW events were indistinguishable from T2HIGH exacerbations in terms of lung function & symptom increase, with no increase in T2 biomarkers from stable to exacerbation state in the T2LOW exacerbations. CONCLUSION Asthma exacerbations demonstrating a T2LOW phenotype were physiologically & symptomatically similar to T2HIGHexacerbations. The clinically significant T2LOW exacerbations highlights the unmet & pressing need to further understand the mechanisms at play in non-T2 asthma

Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK)

The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies

Factors affecting adherence with treatment advice in a clinical trial of patients with severe asthma.

BACKGROUND Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management. METHODS We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma. RESULTS Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68-5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51-5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32-0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07-53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice. CONCLUSIONS Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies

Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation

Background: In T2-mediated severe asthma, biologic therapies, such as mepolizumab, are increasingly used to control disease. Current biomarkers can indicate adequate suppression of T2 inflammation, but it is unclear whether they provide information about airway microbial composition. We investigated the relationships between current T2 biomarkers and microbial profiles, characteristics associated with a ProteobacteriaHIGH microbial profile and the effects of mepolizumab on airway ecology. Methods: Microbiota sequencing was performed on sputum samples obtained at stable and exacerbation state from 140 subjects with severe asthma participating in two clinical trials. Inflammatory subgroups were compared on the basis of biomarkers, including FeNO and sputum and blood eosinophils. ProteobacteriaHIGH subjects were identified by Proteobacteria to Firmicutes ratio ≥0.485. Where paired sputum from stable visits was available, we compared microbial composition at baseline and following ≥12 weeks of mepolizumab. Results: Microbial composition was not related to inflammatory subgroup based on sputum or blood eosinophils. FeNO ≥50 ppb when stable and at exacerbation indicated a group with less dispersed microbial profiles characterised by high alpha-diversity and low Proteobacteria. ProteobacteriaHIGH subjects were neutrophilic and had a longer time from asthma diagnosis than ProteobacteriaLOW subjects. In those studied, mepolizumab did not alter airway bacterial load or lead to increased Proteobacteria. Conclusion: High FeNO could indicate a subgroup of severe asthma less likely to benefit from antimicrobial strategies at exacerbation or in the context of poor control. Where FeNO is <50 ppb, biomarkers of microbial composition are required to identify those likely to respond to microbiome-directed strategies. We found no evidence that mepolizumab alters airway microbial composition

Exacerbation Profile and Risk Factors in a T2-Low Severe Asthma Population.

Although present in a minority of severe asthmatics, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. METHODS: Exacerbation assessment was a pre-specified secondary analysis of data from a RCT comparing the use of biomarkers & symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort. Participants were phenotyped as T2LOW(fractional exhaled nitric oxide [FeNO] ≤20 ppb & blood eosinophil count [PBE] ≤150 cells/µL) or T2HIGH ( FeNO>20 or PBE>150) at study enrolment & at each exacerbation. We report comparison of exacerbators & non-exacerbators, physiological changes at exacerbation in T2LOW & T2HIGH ,& stability of inflammatory phenotypes. RESULTS: 60.8% (183/301) ≥1 self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher BMI & more exacerbations requiring oral corticosteroid (OCS) & unscheduled primary care attendances for exacerbations. At enrolment, 23.6% (71/301) were T2LOW, & 76.4% (230/301) T2HIGH. The T2LOW group had more asthma primary care attendances, were more likely to have a previous admission to HDU/ICU & to be receiving maintenance OCS. At exacerbation the T2LOW events were indistinguishable from T2HIGH exacerbations in terms of lung function & symptom increase, with no increase in T2 biomarkers from stable to exacerbation state in the T2LOW exacerbations. CONCLUSION: Asthma exacerbations demonstrating a T2LOW phenotype were physiologically & symptomatically similar to T2HIGHexacerbations. The clinically significant T2LOW exacerbations highlights the unmet & pressing need to further understand the mechanisms at play in non-T2 asthma.</p