This Study Collects Information on the Safety of Inhaled Pegylated Adrenomedullin (PEG-ADM), How the Drug is Tolerated and How it Affects Patients Suffering From a Type of Lung Failure That Cause Fluid to Build up in the Lungs Making Breathing Difficult (ARDS)

Study Overview
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Brief Summary
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The study is composed of two parts. In part A of the study two active doses of inhaled pegylated adrenomedullin (PEG-ADM) will be compared regarding safety and efficacy to a substance that has no therapeutic effect (placebo) in order to find an optimal and safe of the study drug. In part B of the study the highest dose that is considered safe and has demonstrated efficacy will be taken forward to collect information how well patients suffering from Acute Respiratory Distress Syndrome (ARDS) respond to treatment with inhaled pegylated adrenomedullin (PEG-ADM) compared to treatment with placebo. ARDS is a type of lung failure that cause fluid to build up in the lungs making breathing difficult or impossible.

Official Title
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Safety and Efficacy of Inhaled Pegylated Adrenomedullin (PEG-ADM) in Patients Suffering From Acute Respiratory Distress Syndrome (ARDS): a Double-blind, Randomized, Placebo-controlled, Multicenter Phase 2a/b Clinical Trial

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: BAY1097761 Active Dose 1
* Other: Placebo to BAY1097761
* Drug: BAY1097761 Active Dose 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age at the time of inclusion into study. Invasively mechanically ventilated acute respiratory distress syndrome [ARDS] patients (diagnosed according to Berlin definition of ARDS, including positive end-expiratory pressure [PEEP] of ≥5 cm H2O, X-ray (or CT scan) indicative of ARDS: bilateral opacities not fully explained by cardiac failure, fluid overload, lobar/lung collapse, effusions or nodules). Initial diagnosis of mild, moderate or severe ARDS prior to study inclusion, with acute onset of ARDS within 1 week after suspected trigger factor of Pneumonia Aspiration Sepsis Pancreatitis Prior to randomization, hypoxemia with PaO2:FiO2 ≤300 mmHg continuously observed for a period of ≥4 hours (with values of ≥2 arterial blood gas [ABG] analyses during that time, with the last value obtained timely (generally ≤3 hours) prior to randomization), under ventilation with minimum PEEP ≥8 cm H2O. Time from first meeting the last diagnostic ARDS criterion (Berlin criteria) to randomization must be ≤48 hours. For Study Part A: ARDS patients for whom measurements of extra-vascular lung water are regarded as medically indicated by the treating physician, and these measurements are planned as part of their clinical care, from Study Day 1 up to Study Day 7 (if then still intubated). Exclusion Criteria: Any value of a PaO2:FiO2 ratio >300 mmHg within a time interval of 4 hours before randomization Rescue therapy (e.g. inhalation of nitric oxide gas and/or inhalation of prostacyclin analogues, or extra corporeal membrane oxygenation [ECMO] / extra corporeal CO2 removal [ECCO2R]) already initiated at screening and/or Study Day 1 (prior to first dose of the study intervention) Moribund participants not expected to survive 24 hours (clinical decision) Expected duration of invasive mechanical ventilation less than 48 hours (clinical decision) History of co-morbidities requiring long-term/home oxygen use (e.g. severe chronic obstructive pulmonary disease [COPD], pulmonary fibrosis) or non-invasive ventilation (except for sleep apnea management), or making weaning per se improbable (e.g. ALS, muscular dystrophy) Smoke inhalation injury, extensive burns or trauma/head injury as concomitant condition History of pneumectomy, lung lobectomy or lung transplant Diffuse alveolar hemorrhage from vasculitis Current lung malignancy (incl. lung metastasis), or other malignancy requiring chemotherapy or radiation within the last month Chronic kidney disease with a history of renal replacement therapy (e.g. dialysis) Chronic liver disease Child-Pugh Class C Chronic heart failure NYHA IV Known hypersensitivity to polyethyleneglycol (PEG, Macrogol) Participation in other interventional studies involving pharmacological interventions, or biological or cell therapy interventions Diagnosis of COVID-19 pneumonia within 6 weeks prior to study inclusion. History of SARS-CoV-2 infection (positive test based on nucleic acid amplification technology or positive antigen test) without COVID-19 pneumonia does not exclude patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - Active Drug Dose 1<br>Participants will receive Active Drug Dose 1 for a maximum of 14 days in study phase Part A | Drug: BAY1097761 Active Dose 1<br>* Participants will receive a lower dose ADM by inhalation<br>|
| Experimental: Part A - Active Drug Dose 2<br>Participants will receive Active Drug Dose 2 for a maximum of 14 days in study phase Part A | Drug: BAY1097761 Active Dose 2<br>* Participants will receive a higher dose ADM by inhalation<br>|
| Placebo Comparator: Part A - Placebo<br>Participants will receive Placebo for a maximum of 14 days in study phase Part A | Other: Placebo to BAY1097761<br>* Participants will receive Placebo to BAY1097761 by inhalation<br>|
| Experimental: Part B - Active Drug Dose<br>Participants will receive Active Drug 1 or 2 for a maximum of 14 days in study phase Part B | Drug: BAY1097761 Active Dose 1<br>* Participants will receive a lower dose ADM by inhalation<br>Drug: BAY1097761 Active Dose 2<br>* Participants will receive a higher dose ADM by inhalation<br>|
| Placebo Comparator: Part B - Placebo<br>Participants will receive Placebo for a maximum of 14 days in study phase Part B | Other: Placebo to BAY1097761<br>* Participants will receive Placebo to BAY1097761 by inhalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VFS in Part B participants | Ventilator-free survival (VFS, participants alive and not on invasive mechanical ventilation) | At Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CUI in Part A participants | Clinical Utility Index (CUI) is a summary measure used to compare different treatments, the index score will range between 0 and 1. | Up to 7 days | 
| VFS in Part A participants | Ventilator-free survival (VFS, participants alive and not on invasive mechanical ventilation) | At Day 28 | 
| All-cause mortality in Part A and Part B participants |  | At Day 28, Day 60 and Day 90 | 
| Proportion of participants who still require invasive mechanical ventilation support in Part A and Part B participants |  | At Day 28 and Day 60 | 
| Ventilator-free days (VFDs) in Part A and Part B participants |  | Within Day 28 and Day 60 | 
| VFS in Part A and Part B participants | Ventilator-free survival (VFS, participants alive and not on invasive mechanical ventilation) | At Day 60 | 
| Integrated analysis on VFS invoving all participants from Part A and Part B | Ventilator-free survival (VFS, participants alive and not on invasive mechanical ventilation) | At Day 28 and Day 60 |