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

## TL;DR

This study tested inhaled PEG-ADM for treating ARDS but found it safe but ineffective, leading to early trial discontinuation.

## Contribution

The study is the first to evaluate inhaled PEG-ADM in ARDS patients in a randomized controlled trial.

## Key findings

- PEG-ADM was well tolerated but did not improve clinical outcomes in ARDS patients.
- No significant differences in mortality or ventilator use were observed between PEG-ADM and placebo groups.
- The trial was discontinued early due to lack of efficacy.

## Abstract

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.

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.

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.

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.

ClinicalTrials.gov: NCT04417036 (date of registration: 4 June 2020).

The online version contains supplementary material available at 10.1186/s13054-025-05617-y.

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 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 non-pulmonary 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.

The online version contains supplementary material available at 10.1186/s13054-025-05617-y.