ErythroPOietin Alfa to Prevent Mortality and Reduce Severe Disability in Critically Ill TRAUMA Patients (EPO-TRAUMA)

A Randomised, Double-blind, Placebo-controlled Trial of Erythropoietin Alfa Versus Placebo in Mechanically Ventilated Critically Ill Patients Following Traumatic Injury

The EPO-TRAUMA study is a prospective, multi-centre, double-blind, phase III, randomised controlled trial evaluating the efficacy of epoetin alfa compared to placebo in reducing mortality and severe disability at six months in critically ill trauma patients.

2500 mechanically ventilated ICU patients admitted with a primary trauma diagnosis presenting to the ICU will be recruited into the study from participating study centres in Australia, New Zealand, Europe, and Saudi Arabia.

Study Overview

• Status: Recruiting
• Conditions: Wounds and Injuries; Trauma; Traumatic Brain Injury; Multiple Trauma; Major Trauma; Traumatic Injury; Penetrating Injury; Blunt Injury
• Intervention / Treatment: Drug: Epoetin Alfa 40000 UNT/ML; Drug: Sodium Chloride 0.9%

Detailed Description

Trauma can cause many injuries, some of which are life-threatening and require treatment in an intensive care unit (ICU). Despite best available treatment and therapies, people who sustain a critical traumatic injury are at greater risk of death or long-term disability. From 2010 to 2015, approximately 9% of people admitted to an ICU in Australia and New Zealand for treatment of their injuries, did not survive. In Victoria, 6-months post injury, approximately 31% of people who were critically injured developed severe disabilities or died.

Following a traumatic injury, a number of complex pathways are activated by the body. These pathways can occur over hours or weeks and may lead to damage of cells, tissues or blood vessels and may destroy other healthy tissue. The treatment of traumatic injury focuses on trying to minimise further damage that can occur after the initial injury.

Erythropoietin is a glycoprotein hormone essential for erythropoiesis and was first purified in 1977. Its human recombinant analogues known as erythropoiesis stimulating agents (ESAs) are approved for human therapeutic use. However, erythropoietin is also a pleiotropic cytokine with effects beyond just erythropoiesis. Studies in animals have demonstrated the potential protective effects of erythropoietin to organs including the brain, kidney, liver and heart, and anti-inflammatory properties.

Previous research suggests the use of the ESA called epoetin alfa, increases the number of patients surviving severe trauma and reduces the risk of disability in those who survive.

The primary aim of the study is to determine the efficacy of epoetin alfa compared to placebo in reducing mortality and severe disability at six months in critically ill trauma patients.

2500 mechanically ventilated ICU patients admitted with a primary trauma diagnosis presenting to the ICU will be recruited into the study from participating study centres in Australia, New Zealand, Europe, and Saudi Arabia.

• Study Type: Interventional
• Enrollment (Estimated): 2500
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Vicki Papanikolaou; Phone Number: +61 409 142 695; Email: vicki.papanikolaou@monash.edu

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • Royal Prince Alfred Hospital
      • Principal Investigator: David Gattas
    • Darlinghurst, New South Wales, Australia, 2010
      • Recruiting
      • St Vincent's Hospital Sydney
      • Principal Investigator: David Lowe
    • Kogarah, New South Wales, Australia, 2217
      • Recruiting
      • St George Hospital
      • Principal Investigator: Kush Deshpande
    • Liverpool, New South Wales, Australia, 2170
      • Recruiting
      • Liverpool Hospital
      • Principal Investigator: Victor Tam
    • New Lambton Heights, New South Wales, Australia, 2305
      • Recruiting
      • John Hunter Hospital
      • Principal Investigator: Zsolt Balogh
    • Saint Leonards, New South Wales, Australia, 2065
      • Recruiting
      • Royal North Shore Hospital
      • Principal Investigator: Chris Andersen
    • Westmead, New South Wales, Australia, 2145
      • Recruiting
      • Westmead Hospital
      • Principal Investigator: Vineet Nayyar
  • Northern Territory
    • Tiwi, Northern Territory, Australia, 0810
      • Not yet recruiting
      • Royal Darwin Hospital
      • Principal Investigator: Lewis Campbell
  • Queensland
    • Cairns, Queensland, Australia, 4870
      • Withdrawn
      • Cairns Hospital
    • Herston, Queensland, Australia, 4029
      • Recruiting
      • Royal Brisbane and Women'S Hospital
      • Principal Investigator: Michael Reade
    • Southport, Queensland, Australia, 4215
      • Recruiting
      • Gold Coast University Hospital
      • Principal Investigator: Don Campbell
    • Woolloongabba, Queensland, Australia, 4102
      • Recruiting
      • Princess Alexandra Hospital
      • Principal Investigator: Adam Suliman
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • Royal Adelaide Hospital
      • Principal Investigator: Mark Plummer
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • The Alfred Hospital
      • Principal Investigator: Dashiell Gantner
    • Melbourne, Victoria, Australia, 3050
      • Recruiting
      • Royal Melbourne Hospital
      • Principal Investigator: Yasmine Ali Abdelhamid
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Recruiting
      • Royal Perth Hospital
      • Principal Investigator: Robert McNamara
• Finland
  • Helsinki, Finland
    • Recruiting
    • Helsinki University Hospital (HUS)
    • Principal Investigator: Markus Skrifvars
  • Kuopio, Finland
    • Recruiting
    • Kuopio University Hospital
    • Principal Investigator: Stepani Bendel
  • Turku, Finland
    • Recruiting
    • Turku University Hospital
    • Principal Investigator: Timo Laitio
• Germany
  • Münster, Germany
    • Not yet recruiting
    • University Hospital Münster
    • Principal Investigator: Alexander Zarbock
• Ireland
  • Beaumont, Ireland
    • Recruiting
    • Beaumont Hospital
    • Principal Investigator: Gerard Curley
  • Cork, Ireland
    • Recruiting
    • Cork University Hospital
    • Principal Investigator: Patrick Seigne
  • Dublin, Ireland
    • Recruiting
    • St Vincent's University Hospital
• New Zealand
  • Christchurch, New Zealand, 8011
    • Recruiting
    • Christchurch Hospital
    • Principal Investigator: Brandon Burke
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Recruiting
      • Auckland City Hospital
      • Principal Investigator: Colin McArthur
  • Otahuhu
    • Auckland, Otahuhu, New Zealand, 1640
      • Recruiting
      • Middlemore Hospital
      • Principal Investigator: Tony Williams
  • Waikato
    • Hamilton, Waikato, New Zealand, 3204
      • Recruiting
      • Waikato Hospital
      • Principal Investigator: Robert Martynoga
  • Wellington
    • Newtown, Wellington, New Zealand, 6021
      • Recruiting
      • Wellington Hospital
      • Principal Investigator: James Moore
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • Recruiting
    • King Abdulaziz Medical City
    • Principal Investigator: Hassan Alhabeeb
• Slovenia
  • Ljubljana, Slovenia
    • Recruiting
    • University Medical Centre Ljubljana
    • Principal Investigator: Anja Kramaric
    • Principal Investigator: Primoz Gradisek
  • Maribor, Slovenia
    • Recruiting
    • University Medical Centre Maribor
    • Principal Investigator: Andreja M Petrun
• Switzerland
  • Bern, Switzerland
    • Recruiting
    • University Hospital Bern
    • Principal Investigator: Matthias Hänggi
  • Lucerne, Switzerland
    • Not yet recruiting
    • Lucerne Cantonal Hospital
    • Principal Investigator: Andreas Bloch
  • Saint Gallen, Switzerland
    • Recruiting
    • St. Gallen Cantonal Hospital
    • Principal Investigator: Urs Pietsch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria: Patients with trauma admitted to the ICU who:

• Are ≥ 18 to ≤ 75 years of age
• Are < 24 hours since primary traumatic injury
• Are invasively mechanically ventilated
• Are expected to stay in the ICU ≥ 48 hours
• Have a haemoglobin not exceeding the upper limit of the applicable normal (ULN) reference range in clinical use at the treating institution
• Have informed consent from a legal surrogate according to local law

Exclusion Criteria: Patients will be excluded from the study if any of the following criteria apply:

• GCS = 3 and fixed dilated pupils
• Recent history of DVT, PE or other thromboembolic event (within previous 12 months or receiving concomitant anticoagulant treatment for this indication)
• A chronic hypercoagulable disorder, including known malignancy
• Treatment with EPO in the last 30 days
• First dose of study drug unable to be given within 24 hours of primary injury
• Pregnancy or lactation or 3 months postpartum
• Expected to die imminently (< 24 hours)
• Known sensitivity to mammalian cell derived products
• Known contraindication to epoetin alfa
• End stage renal failure (receives chronic dialysis)
• Severe pre-existing physical or mental disability or severe co-morbidity that may interfere with the assessment of outcome
• The treating physician believes it is not in the best interest of the patient to be randomised to this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Erythropoietin (EPO); Epoetin alfa 40,000 IU (1mL pre-filled syringe) will be given by subcutaneous injection to eligible patients on Study Days 1 and 8 during the intensive care unit stay.	Drug: Epoetin Alfa 40000 UNT/ML; Epoetin alfa 40,000IU 1mL pre-filled syringe given as subcutaneous injection.; Other Names: Eprex; Binocrit
Placebo Comparator: Placebo; Sodium Chloride 0.9% (1mL in volume) will be given by subcutaneous injection to eligible patients allocated to the placebo arm on Study Days 1 and 8 during the intensive care unit stay.	Drug: Sodium Chloride 0.9%; Sodium Chloride 0.9% 1mL in volume given as subcutaneous injection.; Other Names: Saline; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Combined proportion of participants who have died or have severe disability (WHODAS 2.0 > 25)	6-months

Secondary Outcome Measures

Outcome Measure	Time Frame
Mortality at day 28	28 days
Mortality at 6-months	6 months
Mortality at ICU discharge	6-months
Mortality at Hospital discharge	6-months
Proportion of participants with a favourable Glasgow Outcome Score Extended (GOSE) (GOSE 5-8) compared to those have have died (GOSE 1), or have severe disability (GOSE 2-4).	6-months
Proportion of participants with composite thrombotic vascular events (deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (PI), cardiac arrest and cerebrovascular events) at 6 months.	6-months

Collaborators and Investigators

• Sponsor: Australian and New Zealand Intensive Care Research Centre
• Collaborators: Monash University; University College Dublin; Health Research Board, Ireland; Health Research Council, New Zealand; Medical Research Future Fund; Medical Research Institute of New Zealand; ANZICS Clinical Trials Group; Irish Critical Care Clinical Trials Network
• Investigators: Study Chair: A/Professor Craig French, Western Health; ANZIC Research Centre; Study Chair: Professor Alistair Nichol, University College Dublin; ANZIC Research Centre

Publications and helpful links

General Publications

• Nichol A, French C, Little L, Haddad S, Presneill J, Arabi Y, Bailey M, Cooper DJ, Duranteau J, Huet O, Mak A, McArthur C, Pettila V, Skrifvars M, Vallance S, Varma D, Wills J, Bellomo R; EPO-TBI Investigators; ANZICS Clinical Trials Group. Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial. Lancet. 2015 Dec 19;386(10012):2499-506. doi: 10.1016/S0140-6736(15)00386-4. Epub 2015 Oct 6.

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2020
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: October 1, 2020
• First Submitted That Met QC Criteria: October 8, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Actual): October 3, 2023
• Last Update Submitted That Met QC Criteria: October 1, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Erythropoietin; Intensive Care Unit; Epoetin alfa; Trauma; EPO; Major trauma; Traumatic injury
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Multiple Trauma; Wounds, Penetrating; Wounds, Nonpenetrating; Hematinics; Epoetin Alfa
• Other Study ID Numbers: ANZIC-RC/CF001; U1111-1242-3694 (Registry Identifier: Australian New Zealand Clinical Trials Registry (ANZCTR)); 2020-003388-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: At the conclusion of the study, the study management committee will consider requests from researchers who provide a methodically sound scientific proposal as per the Data Sharing Policy set out in the ANZIC-RC Terms of Reference.
• IPD Sharing Time Frame: As per the ANZIC Research Centre Data Sharing Policy
• IPD Sharing Access Criteria: As per the ANZIC Research Centre Data Sharing Policy

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