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Critical Care
Published in: Critical Care 1/2017

Open Access 01-12-2017 | Research

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

Authors: 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

Published in: Critical Care | Issue 1/2017

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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.
Appendix
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Literature
1.
Ito M, Oliverio MI, Mannon PJ, Best CF, Maeda N, Smithies O, Coffman TM. Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci U S A. 1995;92(8):3521–5.CrossRefPubMedPubMedCentral
2.
Krege JH, John SW, Langenbach LL, Hodgin JB, Hagaman JR, Bachman ES, Jennette JC, O’Brien DA, Smithies O. Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature. 1995;375(6527):146–8.CrossRefPubMed
3.
Oudit GY, Crackower MA, Backx PH, Penninger JM. The role of ACE2 in cardiovascular physiology. Trends Cardiovasc Med. 2003;13(3):93–101.CrossRefPubMed
4.
Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev. 2006;86(3):747–803.CrossRefPubMed
5.
Bernstein KE, Berk BC. The biology of angiotensin II receptors. Am J Kidney Dis. 1993;22(5):745–54.CrossRefPubMed
6.
Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and renal fibrosis. Hypertension. 2001;38:635–8.CrossRefPubMed
7.
Herr D, Rodewald M, Fraser HM, Hack G, Konrad R, Kreienberg R, Wulff C. Potential role of renin-angiotensin-system for tumor angiogenesis in receptor negative breast cancer. Gynecol Oncol. 2008;109(3):418–25.CrossRefPubMed
8.
Oudit GY, Kassiri Z, Patel MP, Chappell M, Butany J, Backx PH, Tsushima RG, Scholey JW, Khokha R, Penninger JM. Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovasc Res. 2007;75(1):29–39.CrossRefPubMed
9.
Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002;277(17):14838–43.CrossRefPubMed
10.
Trask AJ, Averill DB, Ganten D, Chappell MC, Ferrario CM. Primary role of angiotensin-converting enzyme-2 in cardiac production of angiotensin-(1-7) in transgenic Ren-2 hypertensive rats. Am J Physiol Heart Circ Physiol. 2007;292(6):H3019–24.CrossRefPubMed
11.
Chappell MC. Emerging evidence for a functional angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS receptor axis: more than regulation of blood pressure? Hypertension. 2007;50(4):596–9.CrossRefPubMed
12.
Santos RA, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. J Endocrinol. 2013;216(2):R1–17.CrossRefPubMed
13.
Gu H, Xie Z, Li T, Zhang S, Lai C, Zhu P, Wang K, Han L, Duan Y, Zhao Z, et al. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci Rep. 2016;6:19840.CrossRefPubMedPubMedCentral
14.
Zou Z, Yan Y, Shu Y, Gao R, Sun Y, Li X, Ju X, Liang Z, Liu Q, Zhao Y, et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun. 2014;5:3594.PubMed
15.
Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112–6.CrossRefPubMed
16.
Wenz M, Hoffmann B, Bohlender J, Kaczmarczyk G. Angiotensin II formation and endothelin clearance in ARDS patients in supine and prone positions. Intensive Care Med. 2000;26(3):292–8.CrossRefPubMed
17.
Doerschug KC, Delsing AS, Schmidt GA, Ashare A. Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis. Crit Care. 2010;14(1):R24.CrossRefPubMedPubMedCentral
18.
Wenz M, Steinau R, Gerlach H, Lange M, Kaczmarczyk G. Inhaled nitric oxide does not change transpulmonary angiotensin II formation in patients with acute respiratory distress syndrome. Chest. 1997;112(2):478–83.CrossRefPubMed
19.
Shen L, Mo H, Cai L, Kong T, Zheng W, Ye J, Qi J, Xiao Z. Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor κB and mitogen-activated protein kinases. Shock. 2009;31(5):500–6.CrossRefPubMed
20.
Marshall RP, Webb S, Bellingan GJ, Montgomery HE, Chaudhari B, McAnulty RJ, Humphries SE, Hill MR, Laurent GJ. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;166(5):646–50.CrossRefPubMed
21.
Adamzik M, Frey U, Sixt S, Knemeyer L, Beiderlinden M, Peters J, Siffert W. ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS. Eur Respir J. 2007;29(3):482–8.CrossRefPubMed
22.
Jerng JS, Yu CJ, Wang HC, Chen KY, Cheng SL, Yang PC. Polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome. Crit Care Med. 2006;34(4):1001–6.CrossRefPubMed
23.
Tsantes AE, Kopterides P, Bonovas S, Bagos P, Antonakos G, Nikolopoulos GK, Gialeraki A, Kapsimali V, Kyriakou E, Kokori S, et al. The effect of angiotensin converting enzyme gene I/D polymorphism and its expression on clinical outcome in acute respiratory distress syndrome. Minerva Anestesiol. 2013;79(8):861–70.PubMed
24.
Treml B, Neu N, Kleinsasser A, Gritsch C, Finsterwalder T, Geiger R, Schuster M, Janzek E, Loibner H, Penninger J, et al. Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets. Crit Care Med. 2010;38(2):596–601.CrossRefPubMed
25.
Haschke M, Schuster M, Poglitsch M, Loibner H, Salzberg M, Bruggisser M, Penninger J, Krahenbuhl S. Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet. 2013;52(9):783–92.CrossRefPubMed
26.
World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191–4.CrossRef
27.
Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149(3 Pt 1):818–24.CrossRefPubMed
28.
Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian approaches to clinical trials and health-care evaluation. Chichester, UK: John Wiley & Sons; 2004.
29.
30.
Parish RC, Miller LJ. Adverse effects of angiotensin converting enzyme (ACE) inhibitors: an update. Drug Saf. 1992;7(1):14–31.CrossRefPubMed
31.
de Man FS, Tu L, Handoko ML, Rain S, Ruiter G, Francois C, Schalij I, Dorfmuller P, Simonneau G, Fadel E, et al. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(8):780–9.CrossRefPubMedPubMedCentral
32.
Zhang W, Chen X, Huang L, Lu N, Zhou L, Wu G, Chen Y. Severe sepsis: low expression of the renin-angiotensin system is associated with poor prognosis. Exp Ther Med. 2014;7(5):1342–8.PubMedPubMedCentral
33.
Hartl D, Griese M. Surfactant protein D in human lung diseases. Eur J Clin Invest. 2006;36(6):423–35.CrossRefPubMed
34.
Jain D, Atochina-Vasserman EN, Tomer Y, Kadire H, Beers MF. Surfactant protein D protects against acute hyperoxic lung injury. Am J Respir Crit Care Med. 2008;178(8):805–13.CrossRefPubMedPubMedCentral
35.
Douda DN, Jackson R, Grasemann H, Palaniyar N. Innate immune collectin surfactant protein D simultaneously binds both neutrophil extracellular traps and carbohydrate ligands and promotes bacterial trapping. J Immunol. 2011;187(4):1856–65.CrossRefPubMed
36.
Hamilton DJ, Zhang A, Li S, Cao TN, Smith JA, Vedula I, Cordero-Reyes AM, Youker KA, Torre-Amione G, Gupte AA. Combination of angiotensin II and l-N G-nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure. Am J Physiol Heart Circ Physiol. 2016;310(6):H667–80.CrossRefPubMed
37.
Ismael-Badarneh R, Guetta J, Klorin G, Berger G, Abu-Saleh N, Abassi Z, Azzam ZS. The role of angiotensin II and cyclic AMP in alveolar active sodium transport. PLoS One. 2015;10(7), e0134175.CrossRefPubMedPubMedCentral
38.
Kleinsasser A, Pircher I, Treml B, Schwienbacher M, Schuster M, Janzek E, Loibner H, Penninger JM, Loeckinger A. Recombinant angiotensin-converting enzyme 2 suppresses pulmonary vasoconstriction in acute hypoxia. Wilderness Environ Med. 2012;23(1):24–30.CrossRefPubMed
Metadata
Title
A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome
Authors
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
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2017
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-017-1823-x

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