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Clinical Trial
. 2017 Jul 27;21(1):194.
doi: 10.1186/s13054-017-1795-x.

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  1 , Rudolf Lucas  2 , Adrien Croizé  1 , Stefan Boehme  1 , Klaus Ulrich Klein  1 , Robert Hermann  3 , Klaus Markstaller  1 , Roman Ullrich  4
Affiliations
Clinical Trial

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 et al. Crit Care. .

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.

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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
See this image and copyright information in PMC

References

    1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49. doi: 10.1056/NEJM200005043421806. - DOI - PubMed
    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. - DOI - PubMed
    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. - DOI - PMC - PubMed
    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. - DOI - PMC - PubMed
    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. - PubMed

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