Erythropoietin in Traumatic Brain Injury (EPO-TBI) (EPO-TBI)

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

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.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Epoetin Alfa; Drug: Sodium Chloride 0.9%

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 606
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • Canberra Hospital
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital Sydney
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • Newcastle, New South Wales, Australia, 2305
      • John Hunter Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Southport, Queensland, Australia, 4215
      • Gold Coast University Hospital
    • Townsville, Queensland, Australia, 4814
      • The Townsville Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hosptial
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • The Royal Melbourne Hospital
    • Melbourne, Victoria, Australia, 3181
      • The Alfred Hospital
  • Western Australia
    • Perth, Western Australia, Australia
      • Royal Perth Hospital
• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Central Hospital
  • Kuopio, Finland, 70211
    • Kuopio University Hospital
• France
  • Grenoble, France, 38 043
    • Hôpital Michallon
  • Nîmes, France, 30029
    • Hôpital Universitaire Carémeau
  • Paris, France, 75 475
    • Hopital Lariboisiere
  • Paris, France, 94275
    • Hopital de Bicetre
  • Rouen, France, 76 031
    • CHU de Rouen
• Germany
  • Mainz, Germany, D-55131
    • Johannes Gutenberg-Universtität
• Ireland
  • Dublin, Ireland, 9
    • Beaumont Hospital
• New Zealand
  • Dunedin, New Zealand
    • Dunedin Hospital
  • North Island
    • Auckland, North Island, New Zealand, 1023
      • Auckland City Hospital
    • Wellington, North Island, New Zealand, 6021
      • Wellington Regional Hospital
  • South Island
    • Christchurch, South Island, New Zealand, 8011
      • Christchurch Hospital
• Saudi Arabia
  • Riyadh, Saudi Arabia, 22490
    • King Fahad National Guard Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 65 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Erythropoietin; 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; 40,000 IU given as subcutaneous injection weekly up to 3 doses; Other Names: Eprex
PLACEBO_COMPARATOR: Placebo; 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%; 1 m/L given as subcutaneous injection weekly up to 3 doses; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Australian and New Zealand Intensive Care Research Centre
• Collaborators: National Health and Medical Research Council, Australia; Monash University; Australian and New Zealand Intensive Care Society Clinical Trials Group
• Investigators: Study Chair: Alistair D Nichol, MD, Monash University

Publications and helpful links

General Publications

• Skrifvars MB, Bailey M, Moore E, Martensson J, French C, Presneill J, Nichol A, Little L, Duranteau J, Huet O, Haddad S, Arabi YM, McArthur C, Cooper DJ, Bendel S, Bellomo R; Erythropoietin in Traumatic Brain Injury (EPO-TBI) Investigators and the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. A Post Hoc Analysis of Osmotherapy Use in the Erythropoietin in Traumatic Brain Injury Study-Associations With Acute Kidney Injury and Mortality. Crit Care Med. 2021 Apr 1;49(4):e394-e403. doi: 10.1097/CCM.0000000000004853.
• Skrifvars MB, Moore E, Martensson J, Bailey M, French C, Presneill J, Nichol A, Little L, Duranteau J, Huet O, Haddad S, Arabi Y, McArthur C, Cooper DJ, Bellomo R; EPO-TBI Investigators and the ANZICS Clinical Trials Group. Erythropoietin in traumatic brain injury associated acute kidney injury: A randomized controlled trial. Acta Anaesthesiol Scand. 2019 Feb;63(2):200-207. doi: 10.1111/aas.13244. Epub 2018 Aug 21.
• 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.
• Nichol A, French C, Little L, Presneill J, Cooper DJ, Haddad S, Duranteau J, Huet O, Skrifvars M, Arabi Y, Bellomo R; EPO-TBI Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial. Trials. 2015 Feb 8;16:39. doi: 10.1186/s13063-014-0528-6.
• Presneill J, Little L, Nichol A, French C, Cooper DJ, Haddad S, Duranteau J, Huet O, Skrifvars M, Arabi Y, Bellomo R; EPO-TBI Investigators; ANZICS Clinical Trials Group. Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury. Trials. 2014 Dec 20;15:501. doi: 10.1186/1745-6215-15-501.
• Moore EM, Bellomo R, Nichol AD. Erythropoietin as a novel brain and kidney protective agent. Anaesth Intensive Care. 2011 May;39(3):356-72. doi: 10.1177/0310057X1103900306.

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (ACTUAL): May 1, 2015
• Study Completion (ACTUAL): May 1, 2015

Study Registration Dates

• First Submitted: September 29, 2009
• First Submitted That Met QC Criteria: September 30, 2009
• First Posted (ESTIMATE): October 1, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): July 26, 2016
• Last Update Submitted That Met QC Criteria: July 24, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• 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; Hematinics; Epoetin Alfa
• Other Study ID Numbers: ANZIC-RC/RB002