ErythroPOietin Alfa to Prevent Mortality and Reduce Severe Disability in Critically Ill TRAUMA Patients

Study Overview
=================
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.

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

Conditions
-----------------
Trauma, Traumatic Injury, Traumatic Brain Injury, Wounds and Injuries, Penetrating Injury, Blunt Injury, Major Trauma, Multiple Trauma

Intervention / Treatment
-----------------
* Drug: Epoetin Alfa 40000 UNT/ML
* Drug: Sodium Chloride 0.9%


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Erythropoietin (EPO)<br>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<br>* Epoetin alfa 40,000IU 1mL pre-filled syringe given as subcutaneous injection.<br>* Other names: Binocrit;|
| Placebo Comparator: Placebo<br>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%<br>* Sodium Chloride 0.9% 1mL in volume given as subcutaneous injection.<br>* Other names: Saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality at 6-months |  | 6 months | 
| Mortality at ICU discharge |  | 6-months | 
| Mortality at Hospital discharge |  | 6-months | 
| Mortality at day 28 |  | 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). |  | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
EPO, Intensive Care Unit, Trauma, Major trauma, Traumatic injury, Erythropoietin, Epoetin alfa