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

• Published in: Critical care (London, England) Vol. 21; no. 1; pp. 194 - 11
• Main Authors: Krenn, Katharina, Lucas, Rudolf, Croizé, Adrien, Boehme, Stefan, Klein, Klaus Ulrich, Hermann, Robert, Markstaller, Klaus, Ullrich, Roman
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.07.2017; BioMed Central; BMC
• Subjects: Acute respiratory distress syndrome; Administration, Inhalation; Adult; Aged; Alveolar fluid clearance; Artificial respiration; Care and treatment; Catheters; Clinical trial; Clinical trials; Critical care; Data collection; Double-Blind Method; Edema; ENaC; Evidence-based medicine; Female; Health aspects; Humans; Intensive care; Kinases; Lectins; Lung - drug effects; Male; Middle Aged; Organ Dysfunction Scores; Patients; Peptides; Peptides, Cyclic - pharmacology; Peptides, Cyclic - therapeutic use; Permeability; Pulmonary edema; Pulmonary Edema - drug therapy; Pulmonary Edema - etiology; Respiration, Artificial - methods; Respiratory distress syndrome; Respiratory Distress Syndrome, Adult - complications; Respiratory therapy; Rodents; Sepsis; Stratigraphy; Streptococcus infections; Tumor necrosis factor-TNF; Austria; Acute respiratory distress syndrome; Clinical trial; ENaC; Pulmonary edema; Alveolar fluid clearance
• ISSN: 1364-8535; 1466-609X; 1364-8535; 1366-609X
• DOI: 10.1186/s13054-017-1795-x

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. 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. 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 PaO /FiO 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. 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. The study was prospectively registered at clinicaltrials.gov, NCT01627613 . Registered 20 June 2012.