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

Overview

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.

Interventions

• Drug Epoetin Alfa 40000 UNT/ML
  Epoetin alfa 40,000IU 1mL pre-filled syringe given as subcutaneous injection.
• Drug Sodium Chloride 0.9%
  Sodium Chloride 0.9% 1mL in volume given as subcutaneous injection.

Primary outcome measures

• Combined proportion of participants who have died or have severe disability (WHODAS 2.0 > 25) [Time frame: 6-months]

Secondary outcome measures (6)

• Mortality at 6-months [Time frame: 6 months]
• Mortality at ICU discharge [Time frame: 6-months]
• Mortality at Hospital discharge [Time frame: 6-months]
• Mortality at day 28 [Time frame: 28 days]
• 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). [Time frame: 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. [Time frame: 6-months]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Australia · 17 centers

• Royal Prince Alfred Hospital — Camperdown
• St Vincent's Hospital Sydney — Darlinghurst
• St George Hospital — Kogarah
• Liverpool Hospital — Liverpool
• John Hunter Hospital — New Lambton Heights
• Royal North Shore Hospital — Saint Leonards
• Westmead Hospital — Westmead
• Royal Darwin Hospital — Tiwi
• … and 9 more centers

Belgium · 6 centers

• Cliniques Universitaires Saint-Luc — Brussels
• HUB Hopital Erasme — Brussels
• CHU-Charleroi Chimay — Charleroi
• Ziekenhuis Oost-Limburg — Genk
• Ghent University Hospital — Ghent
• CHR de la Citadelle de LIEGE — Liège

New Zealand · 5 centers

• Auckland City Hospital — Grafton
• Christchurch Hospital — Christchurch
• Middlemore Hospital — Auckland
• Waikato Hospital — Hamilton
• Wellington Hospital — Newtown

Finland · 3 centers

• Helsinki University Hospital (HUS) — Helsinki
• Kuopio University Hospital — Kuopio
• Turku University Hospital — Turku

Ireland · 3 centers

• Beaumont Hospital — Beaumont
• Cork University Hospital — Cork
• St Vincent's University Hospital — Dublin

Switzerland · 3 centers

• University Hospital Bern — Bern
• Lucerne Cantonal Hospital — Lucerne
• St. Gallen Cantonal Hospital — Sankt Gallen

Slovenia · 2 centers

• University Medical Centre Ljubljana — Ljubljana
• University Medical Centre Maribor — Maribor

Germany · 1 center

• University Hospital Münster — Münster

Saudi Arabia · 1 center

• King Abdulaziz Medical City — Riyadh

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/S0140-673 PMID 26452709

Identifiers

NCT: NCT04588311 · ANZIC-RC/CF001 · U1111-1242-3694 · 2020-003388-24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗