Clinical trial NCT00987454: Erythropoietin in Traumatic Brain Injury (EPO-TBI)
Official title: A Randomised, Placebo-controlled Trial of Erythropoietin in ICU Patients With Traumatic Brain Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Traumatic Brain Injury
Lead sponsor: Australian and New Zealand Intensive Care Research Centre
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Australia
name: Australian and New Zealand Intensive Care Society Clinical Trials Group
name: Monash University
First posted: 2009-10-01
Enrollment: 606
Sex: ALL
Minimum age (years): 15
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Combined proportion of unfavourable neurological outcomes at 6 months: severe disability (defined as GOSE scores 2-4) or death (GOSE score 1).
timeFrame: 6 months
Secondary outcomes:
measure: 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
timeFrame: 6 months
measure: Proportion of surviving patients with unfavourable neurological outcome (GOSE 2-4) at 6 months
timeFrame: 6 months
measure: Quality of life assessment (SF-12 and EQ-5D) at 6 months
timeFrame: 6 months
measure: Mortality at 6 months
timeFrame: 6 months
measure: Rate of proximal deep venous thrombosis detected during screening by compression Doppler ultrasound
timeFrame: 21 days
measure: Proportion of patients with composite thrombotic vascular events (DVT, pulmonary embolus, myocardial infarction, cardiac arrest and cerebrovascular events) at 6 months
timeFrame: 6 months
measure: Cost effectiveness analysis at 6 months (based on EQ-5D)
timeFrame: 6 months
Other outcomes:
Locations:
city: Canberra
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
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: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Townsville
country: Australia
facility: The Townsville Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hosptial
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Melbourne
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Grenoble
country: France
facility: Hôpital Michallon
city: Nîmes
country: France
facility: Hôpital universitaire Caremeau
city: Paris
country: France
facility: Hôpital Lariboisière
city: Paris
country: France
facility: Hôpital de Bicêtre
city: Rouen
country: France
facility: CHU de Rouen
city: Mainz
country: Germany
facility: Johannes Gutenberg-Universtität
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Auckland
country: New Zealand
facility: Auckland City Hospital
state: North Island
city: Wellington
country: New Zealand
facility: Wellington Regional Hospital
state: North Island
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
state: South Island
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Riyadh
country: Saudi Arabia
facility: King Fahad National Guard Hospital
Study officials:
affiliation: Monash University
name: Alistair D Nichol, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
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.
citation: 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.
citation: 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.
citation: 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.