A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 80years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72h. In part A, open-label GSK2586881 was administered at doses from 0.1mg/kg to 0.8mg/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 (0.4mg/kg) for 3days 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 48h. 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.

Original languageEnglish (US)
Article number234
JournalCritical Care
Volume21
Issue number1
DOIs
StatePublished - Sep 7 2017

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Adult Respiratory Distress Syndrome
Clinical Trials
Placebos
Renin-Angiotensin System
Pulmonary Surfactant-Associated Protein D
Organ Dysfunction Scores
Medical Futility
Oxygen
Acute Lung Injury
Partial Pressure
Angiotensins
North America
Angiotensin II
Intensive Care Units
Interleukin-6
Pharmacokinetics
Biomarkers
Hemodynamics
Safety
Peptides

Keywords

  • Acute lung injury
  • Acute respiratory failure
  • Adult
  • Angiotensin-converting enzyme 2
  • Humans
  • Interleukin-6
  • Renin-angiotensin system
  • Respiratory distress syndrome

ASJC Scopus subject areas

  • Medicine(all)
  • Dentistry(all)

Cite this

A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. / Khan, Akram; Benthin, Cody; Zeno, Brian; Albertson, Timothy E.; Boyd, John; Christie, Jason D.; Hall, Richard; Poirier, Germain; Ronco, Juan J.; Tidswell, Mark; Hardes, Kelly; Powley, William M.; Wright, Tracey J.; Siederer, Sarah K.; Fairman, David A.; Lipson, David A.; Bayliffe, Andrew I.; Lazaar, Aili L.

In: Critical Care, Vol. 21, No. 1, 234, 07.09.2017.

Research output: Contribution to journalArticle

Khan, A, Benthin, C, Zeno, B, Albertson, TE, Boyd, J, Christie, JD, Hall, R, Poirier, G, Ronco, JJ, Tidswell, M, Hardes, K, Powley, WM, Wright, TJ, Siederer, SK, Fairman, DA, Lipson, DA, Bayliffe, AI & Lazaar, AL 2017, 'A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome', Critical Care, vol. 21, no. 1, 234. https://doi.org/10.1186/s13054-017-1823-x
Khan, Akram ; Benthin, Cody ; Zeno, Brian ; Albertson, Timothy E. ; Boyd, John ; Christie, Jason D. ; Hall, Richard ; Poirier, Germain ; Ronco, Juan J. ; Tidswell, Mark ; Hardes, Kelly ; Powley, William M. ; Wright, Tracey J. ; Siederer, Sarah K. ; Fairman, David A. ; Lipson, David A. ; Bayliffe, Andrew I. ; Lazaar, Aili L. / A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. In: Critical Care. 2017 ; Vol. 21, No. 1.
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AU - Khan, Akram

AU - Benthin, Cody

AU - Zeno, Brian

AU - Albertson, Timothy E.

AU - Boyd, John

AU - Christie, Jason D.

AU - Hall, Richard

AU - Poirier, Germain

AU - Ronco, Juan J.

AU - Tidswell, Mark

AU - Hardes, Kelly

AU - Powley, William M.

AU - Wright, Tracey J.

AU - Siederer, Sarah K.

AU - Fairman, David A.

AU - Lipson, David A.

AU - Bayliffe, Andrew I.

AU - Lazaar, Aili L.

PY - 2017/9/7

Y1 - 2017/9/7

N2 - 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 80years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72h. In part A, open-label GSK2586881 was administered at doses from 0.1mg/kg to 0.8mg/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 (0.4mg/kg) for 3days 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 48h. 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.

AB - 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 80years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72h. In part A, open-label GSK2586881 was administered at doses from 0.1mg/kg to 0.8mg/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 (0.4mg/kg) for 3days 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 48h. 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.

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KW - Acute respiratory failure

KW - Adult

KW - Angiotensin-converting enzyme 2

KW - Humans

KW - Interleukin-6

KW - Renin-angiotensin system

KW - Respiratory distress syndrome

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