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A multi-center randomized, controlled, open-label trial evaluating the effects of eosinophil-guided corticosteroid-sparing therapy in hospitalised patients with COPD exacerbations - The CORTICO steroid reduction in COPD (CORTICO-COP) study protocol.

ABSTRACT: The most commonly applied treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a 5-day course of high-dose systemic corticosteroids. However, this treatment has not been shown to reduce mortality and can potentially have serious side effects. Recent research has shown that, presumably, only a subgroup of COPD patients identifieable by blood eosinophil count benefit from a rescue course of prednisolone. By applying a biomarker-guided strategy, the aim of this study is to determine whether it is possible to reduce the use of systemic corticosteroids in AECOPD without influencing the outcome.This is an ongoing prospective multicenter randomized controlled open label trial comprising 320 patients with AECOPD recruited from four hospitals in Denmark. The patients are randomized 1:1 to either standard care or eosinophil-guided corticosteroid-sparing therapy where prednisolone is not administered if the daily blood sampling reveals an eosinophil level below 0.3 × 109 cells/L. The primary endpoint is length of hospital stay within 14 days after recruitment. The secondary endpoints are treatment failure, 30-day mortality rate, COPD related re-admission rate, change in FEV1, and a number of adverse effect measures obtained within 3 months after the index hospitalisation date related to corticosteroid usage.This will be a very large RCT providing knowledge about the effectiveness of individualized biomarker-guided corticosteroid therapy in hospitalised patients with AECOPD.Clinicaltrials.gov, NCT02857842 , 02-august-2016. Clinicaltrialregister.eu: Classification Code: 10,010,953, 02-marts-2016.

SUBMITTER: Sivapalan P

PROVIDER: S-EPMC5558695 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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A multi-center randomized, controlled, open-label trial evaluating the effects of eosinophil-guided corticosteroid-sparing therapy in hospitalised patients with COPD exacerbations - The CORTICO steroid reduction in COPD (CORTICO-COP) study protocol.

Sivapalan Pradeesh P Moberg Mia M Eklöf Josefin J Janner Julie J Vestbo Jørgen J Laub Rasmus Rude RR Browatzki Andrea A Armbruster Karin K Wilcke Jon Torgny JT Seersholm Niels N Weinreich Ulla Møller UM Titlestad Ingrid Louise IL Andreassen Helle Frost HF Ulrik Charlotte Suppli CS Bødtger Uffe U Nielsen Thyge Lynghøj TL Hansen Ejvind Frausing EF Jensen Jens Ulrik Stæhr JUS

BMC pulmonary medicine 20170815 1

<h4>Background</h4>The most commonly applied treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a 5-day course of high-dose systemic corticosteroids. However, this treatment has not been shown to reduce mortality and can potentially have serious side effects. Recent research has shown that, presumably, only a subgroup of COPD patients identifieable by blood eosinophil count benefit from a rescue course of prednisolone. By applying a biomarker-guided strategy, ...[more]

PMID: 28810909

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Project description:BackgroundSystemic corticosteroid administration for severe acute exacerbations of COPD (AECOPD) reduces the duration of hospital stays. Corticosteroid-sparing regimens have showed non-inferiority to higher accumulated dose regimens regarding re-exacerbation risk in patients with AECOPD. However, it remains unclear whether 14-day or 2-5-day regimens would result in shorter admission durations and changes in mortality risk. We explored this by analysing the number of days alive and out of hospital based on two randomised controlled trials with different corticosteroid regimens.MethodsWe pooled individual patient data from the two available multicentre randomised trials on corticosteroid-sparing regimens for AECOPD: the REDUCE (n = 314) and CORTICO-COP (n = 318) trials. In the 14-day regimen group, patients were older, fewer patients received pre-treatment with antibiotics and more patients received pre-treatment with systemic corticosteroids. Patients randomly allocated to the 14-day and 2-5-day regimens were compared, with adjustment for baseline differences.ResultsThe number of days alive and out of hospital within 14 days from recruitment was higher for the 2-5 day regimen group (mean 8.4 days; 95% confidence interval [CI] 8.0-8.8) than the 14-day regimen patient group (4.2 days; 95% CI3.4-4.9; p < 0.001). The 14-day AECOPD group had longer hospital stays (mean difference, 5.4 days [standard error ± 0.6]; p < 0.0001) and decreased likelihood of discharge within 30 days (hazard ratio [HR] 0.5; 95% CI 0.4-0.6; p < 0.0001). Comparing the 14-day regimen and the 2-5 day regimen group showed no differences in the composite endpoint 'death or ICU admission' (odds ratio [OR] 1.4; 95% CI 0.8-2.3; p = 0.15), new or aggravated hypertension (OR 1.5; 95% CI 0.9-2.7; p = 0.15), or mortality risk (HR 0.8; 95% CI 0.4-1.5; p = 0.45) during the 6-month follow-up period.Conclusion14-day corticosteroid regimens were associated with longer hospital stays and fewer days alive and out of hospital within 14 days, with no apparent 6-month benefit regarding death or admission to ICU in COPD patients. Our results favour 2-5 day regimens for treating COPD exacerbations. However, prospective studies are needed to validate these findings.

Project description:OBJECTIVES:Presently, those outcomes that should be prioritised for chronic obstructive pulmonary disease (COPD) exacerbation studies remain unclear. In order to coordinate multicentre studies on eosinophilia-driven corticosteroid therapy for patients hospitalised for acute exacerbation of COPD (AECOPD), we aimed to find consensus among experts in the domain regarding the prioritisation of outcomes. DESIGN:A modified Delphi study was proposed to recognised COPD experts. Two brainstorming questionnaires were used to collect potential outcomes. Four subsequent rounds of questionnaires were used to rank items according to a six-point Likert scale for their importance in the protocol, as well as for being the primary outcome. Priority outcome criteria were predefined as those for which ?70% of experts indicated that the outcome was essential for interpreting study results. SETTING:COPD exacerbation management in France. PARTICIPANTS:34 experts recommended by the French Language Pulmonology Society were invited to participate. Of the latter, 21 experts participated in brainstorming, and 19 participated in all four ranking rounds. RESULTS:105 outcomes were ranked. Two achieved consensus as candidate primary outcomes: (1) treatment failure defined as death from any cause or the need for intubation and mechanical ventilation, readmission because of COPD or intensification of pharmacologic therapy, and (2) the time required to meet predefined discharge criteria. The 10 secondary priority outcomes included survival, time with no sign of improvement, episodes of hospitalisation, exacerbation, pneumonia, mechanical or non-invasive ventilation and oxygen use, as well as comorbidities during the initial hospitalisation. CONCLUSIONS:This Delphi consensus project generated and prioritised a great many outcomes, documenting current expert views concerning a diversity of COPD endpoints. Among the latter, 12 reached consensus as priority outcomes for evaluating the efficacy of eosinophil-driven corticosteroid therapy in AECOPD inpatients. STUDY REGISTRATION:The eo-Delphi project/protocol was registered on 23 January 2018 at https://osf.io/4ahqw/.

Project description:BackgroundBlood eosinophil count has been proposed as a predictor of response to inhaled corticosteroid (ICS) in the prevention of acute exacerbations of COPD. An optimal threshold of blood eosinophil count for prescribing ICS has not been agreed. Doubt has been cast on the role by observational studies. The role of inhaled corticosteroids in this relationship, independent of long-acting bronchodilators, has not been examined.MethodsWe conducted a systematic review of post-hoc analyses of randomised controlled trials (RCTs) and observational studies examining three blood eosinophil thresholds and the independent role of ICS. Included studies were categorised by the form (relative or absolute count) and cut point of eosinophil threshold used. Thresholds assessed were relative eosinophil count of 2%, and absolute counts of 150 cells/μL and 300 cells/μL. Three meta-analyses of the effect of ICS use in post-hoc analyses of RCTs based on these counts were carried out. Initial analysis included all studies of ICS vs. any non-ICS regimen. Further analysis examined the effect of ICS, independent of the effect of long-acting bronchodilators.ResultsSixteen studies examined the association between blood eosinophil count and response of exacerbation risk to ICS, in COPD patients. Eleven studies (25,881 patients) were post-hoc analyses of RCTs. Five studies (109,704 patients) were retrospective observational studies. The independent effect of ICS on the reduction of exacerbation risk was 20% at ≥2% blood eosinophil threshold (RR, 0.80; 95% CI, 0.74-0.85), 35% at ≥150 cells/μL blood eosinophil threshold (RR, 0.65; 0.52-0.79), and 39% at ≥300 cells/μL blood eosinophil threshold (RR, 0.61; 0.44-0.78). No association was found in four out of five observational studies.ConclusionThis is the first systematic review to assess, in post-hoc analyses of RCTs, the independent effect of ICS in reducing the risk of COPD exacerbation across a range of blood eosinophil thresholds. Association between ICS prescription and reduced exacerbation risk at these thresholds was confirmed. The lack of association found in the observational studies questions the relevance of these observations to a "real world" COPD population. To clarify the clinical utility of this biomarker, the association should be tested in prospective effectiveness studies.

Project description:PurposeCurrent understanding of the relationship between COPD phenotype and health care resource utilization (HCRU) is limited. This real-world study evaluated disease burden and HCRU for COPD subgroups prone to exacerbation as defined by blood eosinophil (EOS) count and multiple inhaler triple therapy (MITT) use.MethodsThis was a large-scale, retrospective, longitudinal, observational cohort study using data from the US IBM Watson Explorys real-world database (GSK Study HO-17-18395). The population of interest comprised patients with COPD ≥40 years of age with ≥2 moderate or ≥1 severe exacerbations (prior year) while on inhaled maintenance therapy, with ≥1 blood EOS count. Data were analyzed during the year prior to index date (last COPD encounter between January 1, 2011 and December 31, 2016). Four subgroups were analyzed based on a combination of EOS counts (<150 and ≥150 cells/μL) and MITT use (receiving or not receiving). Among these groups, clinical characteristics, exacerbations, and HCRU were described. A sensitivity analysis that further stratified EOS into four categories (<150, ≥150-<300, ≥300-<500, and ≥500 cells/μL) was also performed.ResultsThe COPD population of interest comprised 34,268 patients. Subgroups with EOS ≥150 cells/μL vs <150 cells/μL had more comorbidities and experienced significantly higher mean numbers of moderate exacerbations (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 1.93 vs 1.82, P<0.0001; receiving MITT 2.26 vs 2.16, P=0.0062) and COPD-related emergency visits (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 3.0 vs 2.5, P<0.001; receiving MITT 3.4 vs 3.1, P=0.0011). Increasing EOS category was associated with higher HCRU.ConclusionBlood EOS ≥150/μL cells were associated with increased HCRU and higher exacerbation rates compared with EOS <150 cells/μL, irrespective of MITT use. COPD phenotyping using blood EOS could help identify candidates for additional therapies that target eosinophilic inflammatory pathways.

Dataset Information

A multi-center randomized, controlled, open-label trial evaluating the effects of eosinophil-guided corticosteroid-sparing therapy in hospitalised patients with COPD exacerbations - The CORTICO steroid reduction in COPD (CORTICO-COP) study protocol.

Publications

A multi-center randomized, controlled, open-label trial evaluating the effects of eosinophil-guided corticosteroid-sparing therapy in hospitalised patients with COPD exacerbations - The CORTICO steroid reduction in COPD (CORTICO-COP) study protocol.

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