A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome
Abstract Background Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzym...
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doaj-4b40439005934e0f95c189083cecdc5c2020-11-24T22:24:47ZengBMCCritical Care1364-85352017-09-012111910.1186/s13054-017-1823-xA pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndromeAkram Khan0Cody Benthin1Brian Zeno2Timothy E. Albertson3John Boyd4Jason D. Christie5Richard Hall6Germain Poirier7Juan J. Ronco8Mark Tidswell9Kelly Hardes10William M. Powley11Tracey J. Wright12Sarah K. Siederer13David A. Fairman14David A. Lipson15Andrew I. Bayliffe16Aili L. Lazaar17Div. of Pulmonary & Critical Care Medicine, Department of Medicine, Oregon Health & Science UniversityDiv. of Pulmonary & Critical Care Medicine, Department of Medicine, Oregon Health & Science UniversityRiverside Methodist HospitalSchool of Medicine, University of CaliforniaSt. Paul’s HospitalDivision of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania School of MedicineNova Scotia Health Authority and Dalhousie UniversityCharles LeMoyne Hospital, Sherbrooke UniversityCritical Care Medicine, Vancouver General Hospital, University of British ColumbiaDivision of Pulmonary and Critical Care, Department of Medicine, Baystate Medical CenterGlaxoSmithKline R&DGlaxoSmithKline R&DGlaxoSmithKline R&DGlaxoSmithKline R&DGlaxoSmithKline R&DDivision of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania School of MedicineGlaxoSmithKline R&DDivision of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania School of MedicineAbstract Background Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. Methods We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. Results Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1–7) and angiotensin-(1–5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. Conclusions GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. Trial registration ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.http://link.springer.com/article/10.1186/s13054-017-1823-xAngiotensin-converting enzyme 2Acute lung injuryRespiratory distress syndromeAdultAcute respiratory failureRenin-angiotensin system |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Akram Khan Cody Benthin Brian Zeno Timothy E. Albertson John Boyd Jason D. Christie Richard Hall Germain Poirier Juan J. Ronco Mark Tidswell Kelly Hardes William M. Powley Tracey J. Wright Sarah K. Siederer David A. Fairman David A. Lipson Andrew I. Bayliffe Aili L. Lazaar |
spellingShingle |
Akram Khan Cody Benthin Brian Zeno Timothy E. Albertson John Boyd Jason D. Christie Richard Hall Germain Poirier Juan J. Ronco Mark Tidswell Kelly Hardes William M. Powley Tracey J. Wright Sarah K. Siederer David A. Fairman David A. Lipson Andrew I. Bayliffe Aili L. Lazaar A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome Critical Care Angiotensin-converting enzyme 2 Acute lung injury Respiratory distress syndrome Adult Acute respiratory failure Renin-angiotensin system |
author_facet |
Akram Khan Cody Benthin Brian Zeno Timothy E. Albertson John Boyd Jason D. Christie Richard Hall Germain Poirier Juan J. Ronco Mark Tidswell Kelly Hardes William M. Powley Tracey J. Wright Sarah K. Siederer David A. Fairman David A. Lipson Andrew I. Bayliffe Aili L. Lazaar |
author_sort |
Akram Khan |
title |
A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome |
title_short |
A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome |
title_full |
A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome |
title_fullStr |
A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome |
title_full_unstemmed |
A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome |
title_sort |
pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome |
publisher |
BMC |
series |
Critical Care |
issn |
1364-8535 |
publishDate |
2017-09-01 |
description |
Abstract Background Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. Methods We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. Results Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1–7) and angiotensin-(1–5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. Conclusions GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. Trial registration ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012. |
topic |
Angiotensin-converting enzyme 2 Acute lung injury Respiratory distress syndrome Adult Acute respiratory failure Renin-angiotensin system |
url |
http://link.springer.com/article/10.1186/s13054-017-1823-x |
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