Erythropoietin in Traumatic Brain Injury (EPO-TBI)

Study Overview
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Brief Summary
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This study seeks to determine if erythropoietin alpha (EPO) administered to adult critical care patients with moderate or severe traumatic brain injury improves neurological function assessed at six months after injury.

Detailed Description
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Many people who have a traumatic brain injury (TBI) - usually from a blow to the head such as in a vehicle collision or in a fall do not survive or, if they do, suffer from long-term disability. Previous studies have shown that about 1,000 people in Australia and New Zealand suffer a moderate or severe TBI every year. With current best available treatment and therapies many of these patients sustain loss of brain function and long term disability in varying degrees. When a patient sustains a traumatic brain injury there are two phases to the injury. First, the head-impact causes immediate damage to the brain. The secondary injury, which can evolve over hours or weeks, is a very complicated process. It involves many, linked, changes to the cells, brain chemistry, tissues or blood vessels that can destroy brain tissue. The treatment of brain injury focuses on trying to minimize the secondary injury and there is much research being done to try to find treatments that will prevent it. Erythropoietin (EPO) has recently emerged as a drug that may help reduce secondary injury and improve brain function. It has been found to offer some protection to the brain when brain cells are deprived of their normal oxygen supply causing cells to die or be impaired. The aim of this study is to determine if EPO reduces secondary brain injury and helps patients make a better recovery after traumatic brain injury. The investigators also plan to monitor the effect of EPO on the rate of deep vein thrombosis (DVT - blood clots in the large veins in lower extremity) in patients with moderate or severe TBI in the intensive care unit (ICU). Study Hypothesis: In patients with moderate (GCS 9-12) or severe (3-8) TBI, EPO therapy improves long-term neurological function assessed 6 months after injury.

Official Title
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A Randomised, Placebo-controlled Trial of Erythropoietin in ICU Patients With Traumatic Brain Injury

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: Epoetin Alfa
* Drug: Sodium Chloride 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are ≥ 15 to ≤ 65 years of age Are < 24 hours since primary traumatic injury Are expected to stay ≥ 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 written informed consent from legal surrogate Exclusion Criteria: GCS = 3 and fixed dilated pupils History of DVT, PE or other thromboembolic event 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 post partum Uncontrolled hypertension (systolic blood pressure of >200 mm Hg or diastolic blood pressure of >110 mm Hg) Acute myocardial infarct Expected to die imminently (< 24 hours) Inability to perform lower limb ultrasounds Known sensitivity to mammalian cell derived products Hypersensitivity to the active substance or to any of the additives Pure red cell aplasia (PRCA) 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 Spinal cord injury Treatment with any investigational drug within 30 days before enrolment The treating physician believes it is not in the best interest of the patient to be randomised to this trial

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Erythropoietin<br>Epoetin alfa 40,000 international units will be given by subcutaneous injection to eligible patients, allocated to the treatment arm, on Study Days 1; 8 and15 during the intensive care unit stay. | Drug: Epoetin Alfa<br>* 40,000 IU given as subcutaneous injection weekly up to 3 doses<br>* Other names: Eprex;|
| Placebo Comparator: Placebo<br>Sodium Chloride 0.9% in m/L will be given by subcutaneous injection to eligible patients, allocated to the placebo arm, on Study Days 1; 8 and15 during the intensive care unit stay. | Drug: Sodium Chloride 0.9%<br>* 1 m/L given as subcutaneous injection weekly up to 3 doses<br>* Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined proportion of unfavourable neurological outcomes at 6 months: severe disability (defined as GOSE scores 2-4) or death (GOSE score 1). |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of an equal or greater Glasgow Coma Scale Extended (GOSE) level at 6 months compared to the probability of a lesser GOSE level, using a proportional odds model |  | 6 months | 
| Proportion of surviving patients with unfavourable neurological outcome (GOSE 2-4) at 6 months |  | 6 months | 
| Quality of life assessment (SF-12 and EQ-5D) at 6 months |  | 6 months | 
| Mortality at 6 months |  | 6 months | 
| Rate of proximal deep venous thrombosis detected during screening by compression Doppler ultrasound |  | 21 days | 
| Proportion of patients with composite thrombotic vascular events (DVT, pulmonary embolus, myocardial infarction, cardiac arrest and cerebrovascular events) at 6 months |  | 6 months | 
| Cost effectiveness analysis at 6 months (based on EQ-5D) |  | 6 months |