EndotyPIng PreHospitAl de Novo Acute hYpoxemic Respiratory Failure (EPIPHANY)

August 4, 2025 updated by: Ilias Siempos, Evangelismos Hospital
We attempt to perform dynamic endotyping of critically ill patients presenting in the emergency department with de novo acute hypoxemic respiratory failure (AHRF). We also attempt to identify what clinical, radiological, physiological and biological variables collected early in the course of AHRF correlate with subsequent mortality and/or persistent severe hypoxemia.

Study Overview

Status

Recruiting

Conditions

Detailed Description

Rationale:

Even before the pandemic of the new coronavirus disease (COVID-19), acute respiratory distress syndrome (ARDS), the most severe form of acute hypoxemic respiratory failure (AHRF), constituted a public health challenge. Despite the intense research on identifying targeted pharmacological therapies for ARDS, there is no available treatment for the syndrome.

The failure of clinical trials exploring pharmacological therapies for ARDS has been attributed to incomplete understanding of the pathogenesis and heterogeneity of the syndrome. As examples of the heterogeneity of ARDS, our recent work has identified differential outcomes of patients with ARDS depending on whether hypoxemia is rapidly improving or persistent severe or associated with non-identifiable risk factors or associated with neutropenia. It is advocated that the heterogeneity of ARDS can be tangled by a precision approach, which identifies endotypes of ARDS; i.e., subtypes characterized by a distinct biological profile that might share mortality risk, clinical course, or treatment responsiveness.

Notwithstanding their contributions, current research efforts on endotyping ARDS might be limited by the fact that they are based on the current conceptual framework of the syndrome, which has been widely questioned. Indeed, for reasons such as high interobserver variability of radiological criteria of ARDS and exclusion of patients requiring high-flow nasal oxygen, influential experts have even suggested to completely abandon the term.

Objective:

Accordingly, in the current study, we attempt to perform endotyping of critically ill patients presenting in the emergency department with de novo AHRF, which is a simpler and more reliable phenotype than ARDS. The approach for endotyping will be dynamic rather than static; i.e, two blood samples with a 24-hour interval will be used for endotyping to trace trajectories of biomarkers (over 1500 unique human proteins). In addition, we attempt to identify what clinical, radiological, physiological and biological variables collected early in the course of AHRF correlate with subsequent mortality and/or persistent severe hypoxemia.

Thus, the research protocol is organized as 3 aims.

Aim#1 will organize a registry and biobank of critically ill patients presenting in the emergency department with de novo AHRF.

Aim#2 will build a predictive model to identify what variables among those collected in Aim#1 are associated with subsequent mortality and/or persistent severe hypoxemia.

Aim#3 will use an agnostic discovery approach to explore novel proteomic biomarkers-based dynamic endotypes in critically ill patients presenting in the emergency department with de novo AHRF. Also, Aim#3 will create a multiprotein model of biomarkers associated with subsequent mortality and/or persistent severe hypoxemia and will determine whether inclusion of this multiprotein panel in the predictive score developed in Aim#2 improves risk prediction.

Study Type

Observational

Enrollment (Estimated)

250

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Greece
    • Attiki
      • Athens, Attiki, Greece, 10676
        • Recruiting
        • Evangelismos Hospital
        • Contact:
          • Eleni Papoutsi, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

Patients presenting in the emergency department with de novo acute hypoxemic respiratory failure

Description

Inclusion Criteria:

  • Adult patients (aged >18 years) presenting in the emergency department
  • De novo acute hypoxemic respiratory failure (requiring oxygen flow rate of 5 liters per minute or more to maintain SpO2 of 90% or more)

Exclusion Criteria:

  • Age <18 years
  • Not admitted to the hospital
  • Postoperative acute respiratory failure (within one week from surgery)
  • Chronic hypoxemic respiratory failure (requiring long term oxygen therapy at home)
  • Hypercapnic respiratory failure
  • Transferred from another hospital or facility
  • Pregnant women
  • Admitted to the hospital purely to facilitate comfort care
  • Lack of informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Patients with de novo acute hypoxemic respiratory failure
We will consider for inclusion patients presenting in the emergency department with de novo acute hypoxemic respiratory failure (AHRF). De novo AHRF is defined as the requirement of oxygen flow rate of 5 liters per minute or more to maintain SpO2 of 90% or more in a patient who does not receive long term oxygen therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Identification of dynamic endotypes of acute hypoxemic respiratory failure
Time Frame: Until death or hospital discharge, assessed up to 28 days following presentation to the emergency department
Mutually exclusive subgroups of patients (clusters) characterized by a distinct biological profile that might share mortality risk, clinical course, and/or treatment responsiveness.
Until death or hospital discharge, assessed up to 28 days following presentation to the emergency department

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All-cause mortality
Time Frame: Until death or hospital discharge, assessed up to 28 days following presentation to the emergency department
To determine what variables among those collected, including protein biomarkers, are associated with subsequent all-cause mortality.
Until death or hospital discharge, assessed up to 28 days following presentation to the emergency department
Persistent severe hypoxemia
Time Frame: Until 28 days following presentation to emergency department
To determine what variables among those collected, including protein biomarkers, are associated with persistent severe hypoxemia. We will consider that persistent severe hypoxemia is present in endotracheally intubated individuals receiving positive pressure ventilation and having a PaO2:FiO2 ratio of equal to or less than 100 mmHg at 48 hours following intubation.
Until 28 days following presentation to emergency department
Intensive care unit-free days
Time Frame: Until 28 days following presentation to emergency department
Intensive care unit-free days are calculated by the number of days in the first 28 days following presentation in the emergency department that a patient is alive and not in the intensive care unit.
Until 28 days following presentation to emergency department
Vasopressor-free days
Time Frame: Until 28 days following presentation to emergency department
Vasopressor-free days are calculated by the number of days in the first 28 days following presentation in the emergency department that a patient is alive and not receiving vasopressors.
Until 28 days following presentation to emergency department
Ventilator-free days
Time Frame: Until 28 days following presentation to emergency department
Ventilator-free days are calculated by the number of days in the first 28 days following presentation in the emergency department that a patient is alive and not on a ventilator.
Until 28 days following presentation to emergency department
Continuous renal replacement therapy-free days
Time Frame: Until 28 days following presentation to emergency department
Continuous renal replacement therapy-free days are calculated by the number of days in the first 28 days following presentation in the emergency department that a patient is alive and not receiving continuous renal replacement therapy.
Until 28 days following presentation to emergency department
Bacteremia
Time Frame: Until 28 days following presentation to emergency department
Bacteremia is determined by a positive blood culture.
Until 28 days following presentation to emergency department

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Evangelismos Hospital

Investigators

  • Principal Investigator: Ilias I. Siempos, MD, DSc, Evangelismos Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 10, 2021

Primary Completion (Estimated)

March 25, 2026

Study Completion (Estimated)

April 30, 2026

Study Registration Dates

First Submitted

November 22, 2021

First Submitted That Met QC Criteria

December 3, 2021

First Posted (Actual)

December 9, 2021

Study Record Updates

Last Update Posted (Actual)

August 7, 2025

Last Update Submitted That Met QC Criteria

August 4, 2025

Last Verified

August 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 80-1/15.10.2020

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Sharing Time Frame

Within 3 months from publication

IPD Sharing Access Criteria

For research use

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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