학술논문
Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial.
Document Type
Academic Journal
Author
Keir HR; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Long MB; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Abo-Leyah H; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Giam YH; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Vadiveloo T; Health Services Research Unit, University of Aberdeen, Aberdeen, UK.; Pembridge T; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Hull RC; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.; Delgado L; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Band M; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; McLaren-Neil F; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Adamson S; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Lahnsteiner E; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Gilmour A; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Hughes C; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; New BJ; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Connell D; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Dowey R; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.; Turton H; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.; Richardson H; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Cassidy D; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Cooper J; NHS Grampian, Aberdeen, UK.; Suntharalingam J; Royal United Hospitals, Bath, UK.; Diwakar L; University Hospital North Midlands, Stoke-on-Trent, UK.; Russell P; Princess Alexandria Hospital, Harlow, UK.; Underwood J; Cardiff & Vale University Health Board, Cardiff, UK.; Hicks A; Portsmouth Hospitals NHS Trust, Portsmouth, UK.; Dosanjh DP; University Hospitals Birmingham, Birmingham, UK.; Sage B; NHS Highland, Inverness, UK.; Dhasmana D; NHS Fife, Kirkcaldy, UK.; Spears M; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Thompson AR; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.; Brightling C; Department of Respiratory Sciences, University of Leicester, Leicester, UK.; Smith A; NHS Lanarkshire, Wishaw, UK.; Patel M; NHS Lanarkshire, Wishaw, UK.; George J; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; Condliffe AM; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.; Shoemark A; Molecular and Clinical Medicine, University of Dundee, Dundee, UK.; MacLennan G; Health Services Research Unit, University of Aberdeen, Aberdeen, UK.; Chalmers JD; Molecular and Clinical Medicine, University of Dundee, Dundee, UK. Electronic address: jchalmers@dundee.ac.uk.
Source
Publisher: Elsevier Country of Publication: England NLM ID: 101605555 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2619 (Electronic) Linking ISSN: 22132600 NLM ISO Abbreviation: Lancet Respir Med Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19.
Methods: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012.
Findings: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug.
Interpretation: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19.
Funding: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.
Competing Interests: Declaration of interests JDC reports grants and personal fees from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Gilead Sciences, Grifols, Insmed, Janssen, Novartis, and Zambon. CB reports grants from the UK National Institute for Health and Care Research Biomedical Research Centre during the conduct of the study; grants and personal fees from GSK, AstraZeneca, Chiesi, Boehringer-Ingelheim, Genentech, Roche, Sanofi, Regeneron, Merck, TEVA, Mologic, 4DPharma, and Novartis. AART reports grants and personal fees from British Heart Foundation and Actelion Pharmaceuticals. JU reports personal fees from Gilead Sciences and ViiV Healthcare and from Celltrion; and is supported by the UK Medical Research Council (MR/T023791/1). DPSD reports grants and personal fees from GSK, Vir Biotechnology, AstraZeneca, and Boehringer-Ingelheim. ASm has received non-financial support for clinical trial work from AstraZeneca, GSK, Chiesi, and Oncimmune; and has done consultancy work with AstraZeneca and GSK. MP reports non-financial support for clinical trial work from AstraZeneca, GSK, Chiesi, and Oncimmune and consultancy work with AstraZeneca and GSK. All other authors report no competing interests.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Methods: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012.
Findings: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug.
Interpretation: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19.
Funding: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.
Competing Interests: Declaration of interests JDC reports grants and personal fees from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Gilead Sciences, Grifols, Insmed, Janssen, Novartis, and Zambon. CB reports grants from the UK National Institute for Health and Care Research Biomedical Research Centre during the conduct of the study; grants and personal fees from GSK, AstraZeneca, Chiesi, Boehringer-Ingelheim, Genentech, Roche, Sanofi, Regeneron, Merck, TEVA, Mologic, 4DPharma, and Novartis. AART reports grants and personal fees from British Heart Foundation and Actelion Pharmaceuticals. JU reports personal fees from Gilead Sciences and ViiV Healthcare and from Celltrion; and is supported by the UK Medical Research Council (MR/T023791/1). DPSD reports grants and personal fees from GSK, Vir Biotechnology, AstraZeneca, and Boehringer-Ingelheim. ASm has received non-financial support for clinical trial work from AstraZeneca, GSK, Chiesi, and Oncimmune; and has done consultancy work with AstraZeneca and GSK. MP reports non-financial support for clinical trial work from AstraZeneca, GSK, Chiesi, and Oncimmune and consultancy work with AstraZeneca and GSK. All other authors report no competing interests.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)