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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number194
JournalCritical Care
Volume21
Issue number1
DOIs
StatePublished - Jul 27 2017

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Extravascular Lung Water
Adult Respiratory Distress Syndrome
Pulmonary Edema
Randomized Controlled Trials
Placebos
Organ Dysfunction Scores
Inhalation
Therapeutics
Ventilation
Epithelial Sodium Channels
Alveolar Epithelial Cells
Pressure
Thermodilution
Lung Injury
Nonparametric Statistics
Permeability
Clinical Trials
Mortality

Keywords

  • Acute respiratory distress syndrome
  • Alveolar fluid clearance
  • Clinical trial
  • ENaC
  • Pulmonary edema

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome : A phase IIa randomized placebo-controlled trial. / Krenn, Katharina; Lucas, Rudolf; Croizé, Adrien; Boehme, Stefan; Klein, Klaus Ulrich; Hermann, Robert; Markstaller, Klaus; Ullrich, Roman.

In: Critical Care, Vol. 21, No. 1, 194, 27.07.2017.

Research output: Contribution to journalArticle

Krenn, Katharina ; Lucas, Rudolf ; Croizé, Adrien ; Boehme, Stefan ; Klein, Klaus Ulrich ; Hermann, Robert ; Markstaller, Klaus ; Ullrich, Roman. / Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome : A phase IIa randomized placebo-controlled trial. In: Critical Care. 2017 ; Vol. 21, No. 1.
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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{\circledR}), 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.",
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AU - Croizé, Adrien

AU - Boehme, Stefan

AU - Klein, Klaus Ulrich

AU - Hermann, Robert

AU - Markstaller, Klaus

AU - Ullrich, Roman

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AB - 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.

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KW - Clinical trial

KW - ENaC

KW - Pulmonary edema

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