Clinical trial NCT04588311: ErythroPOietin Alfa to Prevent Mortality and Reduce Severe Disability in Critically Ill TRAUMA Patients
Official title: A Randomised, Double-blind, Placebo-controlled Trial of Erythropoietin Alfa Versus Placebo in Mechanically Ventilated Critically Ill Patients Following Traumatic Injury
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Trauma
Traumatic Injury
Traumatic Brain Injury
Wounds and Injuries
Penetrating Injury
Blunt Injury
Major Trauma
Multiple Trauma
Keywords: Intensive Care Unit
Trauma
Major trauma
Traumatic injury
EPO
Erythropoietin
Epoetin alfa
Lead sponsor: Australian and New Zealand Intensive Care Research Centre
Sponsor class: OTHER
Collaborators: name: University College Dublin
name: Medical Research Institute of New Zealand
name: Medical Research Future Fund
name: Health Research Board, Ireland
name: Health Research Council, New Zealand
name: Irish Critical Care Clinical Trials Network
name: ANZICS Clinical Trials Group
name: Monash University
First posted: 2020-10-19
Enrollment: 2500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Combined proportion of participants who have died or have severe disability (WHODAS 2.0 > 25)
timeFrame: 6-months
Secondary outcomes:
measure: Mortality at 6-months
timeFrame: 6 months
measure: Mortality at ICU discharge
timeFrame: 6-months
measure: Mortality at Hospital discharge
timeFrame: 6-months
measure: Mortality at day 28
timeFrame: 28 days
measure: 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).
timeFrame: 6-months
measure: 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.
timeFrame: 6-months
Other outcomes:
Locations:
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Tiwi
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Cairns
country: Australia
facility: Cairns Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Helsinki
country: Finland
facility: Helsinki University Hospital (HUS)
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Turku
country: Finland
facility: Turku University Hospital
city: Münster
country: Germany
facility: University Hospital Münster
city: Beaumont
country: Ireland
facility: Beaumont Hospital
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: Grafton
country: New Zealand
facility: Auckland City Hospital
state: Auckland
city: Auckland
country: New Zealand
facility: Middlemore Hospital
state: Otahuhu
city: Hamilton
country: New Zealand
facility: Waikato Hospital
state: Waikato
city: Newtown
country: New Zealand
facility: Wellington Hospital
state: Wellington
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana
city: Maribor
country: Slovenia
facility: University Medical Centre Maribor
city: Bern
country: Switzerland
facility: University Hospital Bern
city: Lucerne
country: Switzerland
facility: Lucerne Cantonal Hospital
city: Saint Gallen
country: Switzerland
facility: St. Gallen Cantonal Hospital
Study officials:
affiliation: Western Health; ANZIC Research Centre
name: A/Professor Craig French
role: STUDY_CHAIR
affiliation: University College Dublin; ANZIC Research Centre
name: Professor Alistair Nichol
role: STUDY_CHAIR
References:
citation: 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.