Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial

Katharina Krenn, Rudolf Lucas, Adrien Croizé, Stefan Boehme, Klaus Ulrich Klein, Robert Hermann, Klaus Markstaller, Roman Ullrich, Katharina Krenn, Rudolf Lucas, Adrien Croizé, Stefan Boehme, Klaus Ulrich Klein, Robert Hermann, Klaus Markstaller, Roman Ullrich

Abstract

Background: High-permeability pulmonary edema is a hallmark of acute respiratory distress syndrome (ARDS) and is frequently accompanied by impaired alveolar fluid clearance (AFC). AP301 enhances AFC by activating epithelial sodium channels (ENaCs) on alveolar epithelial cells, and we investigated its effect on extravascular lung water index (EVLWI) in mechanically ventilated patients with ARDS.

Methods: Forty adult mechanically ventilated patients with ARDS were included in a randomized, double-blind, placebo-controlled trial for proof of concept. Patients were treated with inhaled AP301 (n = 20) or placebo (0.9% NaCl; n = 20) twice daily for 7 days. EVLWI was measured by thermodilution (PiCCO®), and treatment groups were compared using the nonparametric Mann-Whitney U test.

Results: AP301 inhalation was well tolerated. No differences in mean baseline-adjusted change in EVLWI from screening to day 7 were found between the AP301 and placebo group (p = 0.196). There was no difference in the PaO2/FiO2 ratio, ventilation pressures, Murray lung injury score, or 28-day mortality between the treatment groups. An exploratory subgroup analysis according to severity of illness showed reductions in EVLWI (p = 0.04) and ventilation pressures (p < 0.05) over 7 days in patients with initial sequential organ failure assessment (SOFA) scores ≥11 inhaling AP301 versus placebo, but not in patients with SOFA scores ≤10.

Conclusions: There was no difference in mean baseline-adjusted EVLWI between the AP301 and placebo group. An exploratory post-hoc subgroup analysis indicated reduced EVLWI in patients with SOFA scores ≥11 receiving AP301. These results suggest further confirmation in future clinical trials of inhaled AP301 for treatment of pulmonary edema in patients with ARDS.

Trial registration: The study was prospectively registered at clinicaltrials.gov, NCT01627613 . Registered 20 June 2012.

Keywords: Acute respiratory distress syndrome; Alveolar fluid clearance; Clinical trial; ENaC; Pulmonary edema.

Conflict of interest statement

Ethics approval and consent to participate

The study (Ethics Committee No. 1424/2012) was approved by the ethics committee of the Medical University of Vienna, Vienna, Austria (Chairperson: Prof. E. Singer) on June 12 2012. Informed consent was obtained from all study participants according to the Austrian legislation that regulates the consent of nonconscious subjects included in clinical trials.

Competing interests

KK, AC, SB, KUK, KM, and RU report a grant by Apeptico GmbH (Vienna, Austria) to their institution during the conduct of the study and outside the submitted work. RH reports personal fees from Apeptico GmbH during the conduct of the study. RU reports personal fees from Biotest and personal fees and grants from Pfizer outside the submitted work, and a pending patent (EP15189777.4 “Blood purification device”). RL declares that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Consort flow chart showing study progress from enrollment to analysis. EVLWI extravascular lung water index, PBW predicted body weight
Fig. 2
Fig. 2
Baseline-adjusted differences in extravascular lung water index (EVLWI) over 7 days. Comparison of 7-day (d0–d7) treatment with inhaled AP301 (dashed line) or placebo (dotted line). Data are given as mean and patient count per day. A positive ΔEVLWI indicates a decrease from baseline value at screening. a AP301 versus placebo. b AP301 versus placebo in stratum A (SOFA score ≤10). c AP301 versus placebo in stratum B (SOFA score ≥11). *p = 0.04. ns not significant, PBW predicted body weight

References

    1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49. doi: 10.1056/NEJM200005043421806.
    1. Caser EB, Zandonade E, Pereira E, Gama AM, Barbas CS. Impact of distinct definitions of acute lung injury on its incidence and outcomes in Brazilian ICUs: prospective evaluation of 7,133 patients. Crit Care Med. 2014;42:574–82. doi: 10.1097/01.ccm.0000435676.68435.56.
    1. Darmon M, Clec’h C, Adrie C, et al. Acute respiratory distress syndrome and risk of AKI among critically ill patients. Clin J Am Soc Nephrol. 2014;9:1347–53. doi: 10.2215/CJN.08300813.
    1. Dizier S, Forel JM, Ayzac L, Richard JC, Hraiech S, Lehingue S, et al. Early hepatic dysfunction is associated with a worse outcome in patients presenting with acute respiratory distress syndrome: a post-hoc analysis of the ACURASYS and PROSEVA studies. PLoS One. 2015;10:e0144278. doi: 10.1371/journal.pone.0144278.
    1. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526–33.
    1. Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;163:1376–83. doi: 10.1164/ajrccm.163.6.2004035.
    1. Matthay MA, Idell S. Update on acute lung injury and critical care medicine 2009. Am J Respir Crit Care Med. 2010;181:1027–32. doi: 10.1164/rccm.201001-0074UP.
    1. Guerin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368:2159–68. doi: 10.1056/NEJMoa1214103.
    1. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012;122:2731–40. doi: 10.1172/JCI60331.
    1. Matthay MA, Robriquet L, Fang X. Alveolar epithelium: role in lung fluid balance and acute lung injury. Proc Am Thorac Soc. 2005;2:206–13. doi: 10.1513/pats.200501-009AC.
    1. Zemans RL, Matthay MA. Bench-to-bedside review: the role of the alveolar epithelium in the resolution of pulmonary edema in acute lung injury. Crit Care. 2004;8:469–77. doi: 10.1186/cc2906.
    1. Hazemi P, Tzotzos SJ, Fischer B, Andavan GS, Fischer H, Pietschmann H, et al. Essential structural features of TNF-alpha lectin-like domain derived peptides for activation of amiloride-sensitive sodium current in A549 cells. J Med Chem. 2010;53:8021–9. doi: 10.1021/jm100767p.
    1. Hribar M, Bloc A, van der Goot FG, Fransen L, De Baetselier P, Grau GE, et al. The lectin-like domain of tumor necrosis factor-alpha increases membrane conductance in microvascular endothelial cells and peritoneal macrophages. Eur J Immunology. 1999;29:3105–11. doi: 10.1002/(SICI)1521-4141(199910)29:10<3105::AID-IMMU3105>;2-A.
    1. Shabbir W, Scherbaum-Hazemi P, Tzotzos S, Fischer B, Fischer H, Pietschmann H, et al. Mechanism of action of novel lung edema therapeutic AP301 by activation of the epithelial sodium channel. Mol Pharmacol. 2013;84:899–910. doi: 10.1124/mol.113.089409.
    1. Czikora I, Alli A, Bao HF, Kaftan D, Sridhar S, Apell HJ, et al. A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation. Am J Respir Crit Care Med. 2014;190:522–32. doi: 10.1164/rccm.201405-0833OC.
    1. Braun C, Hamacher J, Morel DR, Wendel A, Lucas R. Dichotomal role of TNF in experimental pulmonary edema reabsorption. J Immunol. 2005;175:3402–8. doi: 10.4049/jimmunol.175.5.3402.
    1. Elia N, Tapponnier M, Matthay MA, Hamacher J, Pache JC, Brundler MA, et al. Functional identification of the alveolar edema reabsorption activity of murine tumor necrosis factor-alpha. Am J Respir Crit Care Med. 2003;168:1043–50. doi: 10.1164/rccm.200206-618OC.
    1. Vadasz I, Schermuly RT, Ghofrani HA, Rummel S, Wehner S, Muhldorfer I, et al. The lectin-like domain of tumor necrosis factor-alpha improves alveolar fluid balance in injured isolated rabbit lungs. Crit Care Med. 2008;36:1543–50. doi: 10.1097/CCM.0b013e31816f485e.
    1. Hamacher J, Stammberger U, Roux J, Kumar S, Yang G, Xiong C, et al. The lectin-like domain of tumor necrosis factor improves lung function after rat lung transplantation—potential role for a reduction in reactive oxygen species generation. Crit Care Med. 2010;38:871–8. doi: 10.1097/CCM.0b013e3181cdf725.
    1. Lucas R, Yang G, Gorshkov BA, Zemskov EA, Sridhar S, Umapathy NS, et al. Protein kinase C-alpha and arginase I mediate pneumolysin-induced pulmonary endothelial hyperpermeability. Am J Respir Cell Mol Biol. 2012;47:445–53. doi: 10.1165/rcmb.2011-0332OC.
    1. Hartmann EK, Boehme S, Duenges B, Bentley A, Klein KU, Kwiecien R, et al. An inhaled tumor necrosis factor-alpha-derived TIP peptide improves the pulmonary function in experimental lung injury. Acta Anaesthesiol Scand. 2013;57:334–41. doi: 10.1111/aas.12034.
    1. Hartmann EK, Thomas R, Liu T, Stefaniak J, Ziebart A, Duenges B, et al. TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants. BMC Anesthesiol. 2014;14:42. doi: 10.1186/1471-2253-14-42.
    1. Lucas R, Yue Q, Alli A, Duke BJ, Thai TL, Hamacher J, et al. The lectin-like domain of TNF increases ENaC open probability through a novel site at the interface between the second transmembrane and C-terminal domains of the alpha-subunit. J Biol Chem. 2016;291:23440–51. doi: 10.1074/jbc.M116.718163.
    1. Schwameis R, Eder S, Pietschmann H, Fischer B, Mascher H, Tzotzos S, et al. A FIM study to assess safety and exposure of inhaled single doses of AP301-A specific ENaC channel activator for the treatment of acute lung injury. J Clin Pharmacol. 2014;54:341–50. doi: 10.1002/jcph.203.
    1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J Crit Care. 1994;9:72–81. doi: 10.1016/0883-9441(94)90033-7.
    1. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–10. doi: 10.1007/BF01709751.
    1. Saha C, Jones MP. Bias in the last observation carried forward method under informative dropout. J Statist Plan Interfer. 2009;139:246–55. doi: 10.1016/j.jspi.2008.04.017.
    1. Overall JE, Tonidandel S, Starbuck RR. Last-observation-carried-forward (LOCF) and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts. Soc Science Res. 2009;38:492–503. doi: 10.1016/j.ssresearch.2009.01.004.
    1. Little RJA, Rubin DB. Statistical analysis with missing data. 2. New York: Wiley; 1987.
    1. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720–3. doi: 10.1164/ajrccm/138.3.720.
    1. Artigas A, Bernard GR, Carlet J, Dreyfuss D, Gattinoni L, Hudson L, et al. The American-European Consensus Conference on ARDS, part 2: ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome. Am J Respir Crit Care Med. 1998;157:1332–47. doi: 10.1164/ajrccm.157.4.ats2-98.
    1. Kiss T, Guldner A, Bluth T, Uhlig C, Spieth PM, Markstaller K, et al. Rationale and study design of ViPS—variable pressure support for weaning from mechanical ventilation: study protocol for an international multicenter randomized controlled open trial. Trials. 2013;14:363. doi: 10.1186/1745-6215-14-363.
    1. Vincent JL, de Mendonça A, Cantraine F, Moreno R, Takala J, Suter PM, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med. 1998;26:1793–800. doi: 10.1097/00003246-199811000-00016.
    1. Jones AE, Trzeciak S, Kline JA. The Sequential Organ Failure Assessment score for predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department presentation. Crit Care Med. 2009;37:1649–54. doi: 10.1097/CCM.0b013e31819def97.
    1. Berthiaume Y, Matthay MA. Alveolar edema fluid clearance and acute lung injury. Respir Physiol Neurobiol. 2007;159:350–9. doi: 10.1016/j.resp.2007.05.010.
    1. Vadasz I, Raviv S, Sznajder JI. Alveolar epithelium and Na, K-ATPase in acute lung injury. Intensive Care Med. 2007;33:1243–51. doi: 10.1007/s00134-007-0661-8.
    1. Matthay MA. Resolution of pulmonary edema. Thirty years of progress. Am J Resp Crit Care Med. 2014;189:1301–8. doi: 10.1164/rccm.201403-0535OE.
    1. Tzotzos S, Fischer B, Fischer H, Pietschmann H, Lucas R, Dupre G, et al. AP301, a synthetic peptide mimicking the lectin-like domain of TNF, enhances amiloride-sensitive Na(+) current in primary dog, pig and rat alveolar type II cells. Pulm Pharmacol Ther. 2013;26:356–63. doi: 10.1016/j.pupt.2012.12.011.
    1. Xiong C, Yang G, Kumar S, Aggarwal S, Leustik M, Snead C, et al. The lectin-like domain of TNF protects from listeriolysin-induced hyperpermeability in human pulmonary microvascular endothelial cells—a crucial role for protein kinase C-alpha inhibition. Vascul Pharmacol. 2010;52:207–13. doi: 10.1016/j.vph.2009.12.010.
    1. Lucas R, Sridhar S, Rick FG, Gorshkov B, Umapathy NS, Yang G, et al. Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema. Proc Natl Acad Sci U S A. 2012;109:2084–9. doi: 10.1073/pnas.1121075109.
    1. Queiroz LF, Anami EH, Zampar EF, Tanita MT, Cardoso LT, Grion CM. Epidemiology and outcome analysis of burn patients admitted to an intensive care unit in a university hospital. Burns. 2016;42:655–62. doi: 10.1016/j.burns.2015.08.002.
    1. Jeschke MG, Pinto R, Kraft R, Nathens AB, Finnerty CC, Gamelli RL, et al. Morbidity and survival probability in burn patients in modern burn care. Crit Care Med. 2015;43:808–15. doi: 10.1097/CCM.0000000000000790.
    1. Mehter HM, Wiener RS, Walkey AJ. “Do not resuscitate” decisions in acute respiratory distress syndrome. A secondary analysis of clinical trial data. Ann Am Thorac Soc. 2014;11:1592–6. doi: 10.1513/AnnalsATS.201406-244BC.

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