Safety and efficacy of inhaled PEG-ADM in ARDS patients: a randomised controlled trial

Karagiannidis et al. Critical Care (2025) 29:448 https://doi.org/10.1186/s13054-025-05617-y Critical Care Open Access RESEARCH Safety and efficacy of inhaled PEG-ADM in ARDS patients: a randomised controlled trial Christian Karagiannidis1* , Danny F. McAuley2 , B. Taylor Thompson3 , Thomas Reimer4, Kaweh Shakery4, Sebastian Schmitz4, Manuel Núñez Cortés4, Roman Ullrich5 , Ferhat Meziani6 , Alain Mercat7, Davide Chiumello8,9,10, Frantisek Duska11 , Alain Combes12,13 and for the SEAL Trial Investigators Abstract Background This study aimed to evaluate the safety and efficacy of inhaled pegylated adrenomedullin (PEG-ADM) for the management of acute respiratory distress syndrome in critically ill patients on mechanical ventilation. Methods A Phase 2a/b randomised, double-blind, placebo-controlled multicentre trial was conducted. Patients with acute respiratory distress syndrome were assigned to receive PEG-ADM 960 μg or 1920 μg, or placebo. The primary endpoints were safety, efficacy, and ventilator-free survival at Day 28. Efficacy was assessed using ventilator-free survival and the clinical utility index, a composite endpoint that includes extravascular lung water index, oxygenation index, non-pulmonary Sequential Organ Failure Assessment score. Results Ninety patients were randomised (PEG-ADM 960 μg: n = 29; PEG-ADM 1920 μg: n = 30; placebo: n = 31). Both dosages of PEG-ADM were well tolerated, with adverse event profiles similar to placebo. However, no significant efficacy was observed on the clinical utility index. Ventilator-free survival at Day 28 was lower in the PEG-ADM 960 μg group (52%) compared with the PEG-ADM 1920 μg (67%) and placebo (65%) groups. No significant differences were noted in overall mortality or the need for continued ventilation at Days 28 and 60. Conclusion Inhaled PEG-ADM was well tolerated in patients with acute respiratory distress syndrome, but it did not improve clinical outcomes, which led to the early discontinuation after the first part of the trial for futility. Trial registration ClinicalTrials.gov: NCT04417036 (date of registration: 4 June 2020). Key message What is already known on this topic - summarise the state of scientific knowledge on this subject before you did your study and why this study needed to be done Acute respiratory distress syndrome (ARDS) is known to have a high 28-day mortality rate with no effective specific pharmacologic interventions currently available. PEGylated adrenomedullin (PEG-ADM) was hypothesised to reduce A full list of SEAL Trial investigators is provided in the online supplement. *Correspondence: Christian Karagiannidis Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Karagiannidis et al. Critical Care (2025) 29:448 Page 2 of 9 vascular permeability of lung endothelial cells and, therefore, improve pulmonary function and patient outcomes. An inhaled formulation was further developed to increase lung selectivity and reduce hypotensive systemic effects. What this study adds - summarise what we now know as a result of this study that we did not know before This Phase 2 randomised controlled trial investigated the safety and efficacy of inhaled PEG-ADM in ARDS patients on mechanical ventilation. Main efficacy outcomes included 28-day ventilator-free survival and the clinical utility index, which comprised the extravascular lung water index, change in oxygenation index, and change in nonpulmonary Sequential Organ Failure Assessment score. While PEG-ADM was well tolerated with a safety profile comparable to placebo, no meaningful clinical benefits were observed in both efficacy outcomes at either of the two investigated doses. How this study might affect research, practice or policy - summarise the implications of this study Further Phase IIB/IIA studies with inhaled ADM-PEG in ARDS are not warranted. Introduction While there has been significant progress in recent years, 28-day mortality in acute respiratory distress syndrome (ARDS) remains high (~ 30 to 45%) [1]. Treatment is largely supportive, with no effective specific pharmacological intervention currently available [2, 3]. Early resolution of lung oedema is associated with improved outcomes [4, 5], and reduction of fluid extravasation maybe a target to reduce extravasation of fluid and therefore progression of ARDS. Adrenomedullin (ADM) is an endogenous peptide hormone associated with enhanced barrier function and reduced hyperpermeability of endothelial cells [6], with receptors highly expressed in lung endothelium [7, 8]. Wild-type ADM has a short half-life, so a PEGylated form (PEG-ADM; BAY 1097761) was developed in which ADM is bound to a 40 kDa polyethylene glycol polymer. Data from Phase 1 studies of PEG-ADM confirmed its prolonged half-life but revealed blood pressure-lowering effects after intravenous (IV) administration (Bayer AG, data on file). An inhaled formulation was, therefore, developed to increase lung selectivity and reduce the potential for hypotensive systemic effects. Here we presented data from a Phase 2 trial investigating the safety and efficacy of inhaled PEG-ADM in patients with ARDS. Methods Study design This was a randomised, double-blind, placebo-controlled, multicentre Phase 2a/b clinical trial conducted in Austria, Czechia, France, Germany, Italy, Spain, and the United Kingdom (ClinicalTrials.gov: NCT04417036). Patients in Part A were randomised 1:1:1 to PEG-ADM 960 μg, PEGADM 1920 μg, or placebo (Supplementary Fig. 1). The study was initiated with the placebo and 960 μg arms, and safety was assessed by an unblinded independent data monitoring committee (DMC) after four patients were exposed to PEG-ADM 960 μg and again after 10 patients. The 1920 μg arm was opened when safety was confirmed by the DMC. The next 15 participants were recruited for the 1920 μg and placebo arms to assess the safety of the higher dose and, on confirmation of safety by the DMC, the 960 μg arm was reopened to allow parallel recruitment into all three study arms. Details of randomisation and blinding are presented in the Supplementary Methods. All s (...truncated)