Effects of Erythropoietin on Cerebral Vascular Dysfunction and Anemia in Traumatic Brain Injury

Claudia Sue Robertson

Status and phase: Completed; Phase 3; Phase 2

Conditions: Anemia; Traumatic Brain Injury

Treatments: Other: placebo; Drug: recombinant human erythropoietin, rhEpo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00313716

P01NS038660 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

The purpose of this study is to determine the effect of early administration of recombinant human erythropoietin on long-term neurological outcome after severe traumatic brain injury.

Full description

Traumatic brain injury (TBI) causes a spectrum of cerebrovascular dysfunction, ranging from impaired pressure autoregulation to severe global ischemia (inadequate blood flow). Pressure autoregulation is the ability of an organ to maintain a constant blood flow despite changes in perfusion pressure. Impaired pressure autoregulation causes TBI patients to be more vulnerable to secondary ischemic attacks.

Erythropoietin (Epo) is a substance that is normally made by the kidneys and stimulates the production of red blood cells. It is usually given to patients to treat anemia. Scientists recently discovered that Epo also is made in the brain after injury. In animal models of TBI, the brain's production of Epo has numerous protective effects, including reducing inflammation in the brain, reducing death of brain cells, and improving blood flow to the brain. In the laboratory, the effects of this naturally-occurring, protective agent can be enhanced by giving additional amounts intravenously. Because Epo may have beneficial effects for both the injured brain and anemia, scientists are studying the effects of giving Epo to patients with severe TBI.

The primary objective of this randomized, placebo-controlled study is to determine the effect of early administration of recombinant human Epo (rhEpo), on long-term neurological outcome in patients with severe TBI. The researchers also will examine the effects of rhEpo administration on the cerebrovascular system, hemoglobin concentration, brain oxygenation, the need for blood transfusion, and on systemic complications.

This study consists of 2 parts: 1) a treatment phase, and 2) a monitoring phase. In the treatment phase, participants will be randomly assigned to 1 of 4 groups: a low or high dose rhEPO treatment group or low or high dose placebo group (control group). All other aspects of treatment during the acute post-injury phase will follow the standard treatment protocol for individuals with severe TBI. Generally the treatment phase lasts 1-2 weeks or the amount of time that is required for patients to receive treatment of their TBIs in the ICU (intensive care unit). The monitoring part of the study (which includes recording information from tests performed as part of the standard TBI treatment, as well as some additional tests performed especially for the study) lasts for up to 6 months after the TBI.

Information learned in this study may lead to knowledge about whether rhEpo improves outcomes after TBI and about the optimal hemoglobin concentration to maintain in patients with TBI.

Enrollment: 200 patients

Sex: All

Ages: 15+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Blunt trauma mechanism of brain injury
• Glasgow Coma Score - motor component ≤ 5 (not following commands) on the post-resuscitation neurologic exam
• Available for enrollment and administration of study drug within 6 hours of injury

Exclusion criteria

• Penetrating trauma (i.e. gun shot wounds)
• Glasgow Coma Score = 3 and bilateral fixed and dilated pupils
• Abbreviated Injury Scale score > 5 for any body part except brain
• Severe pre-existing chronic disease
• Uncontrolled hypertension, defined as mean arterial pressure > 130mmHg despite antihypertensive treatment
• Known hypersensitivity to mammalian cell-derived products or human albumin
• Currently taking anticoagulants

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Triple Blind

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200 participants in 6 patient groups, including a placebo group

Epo1 and TT10

Active Comparator group

Description:

recombinant human erythropoietin, rhEpo administration (500 IU/kg within 6 hrs of injury, at 24 and 48 hrs after injury, and at 9 and 16 days after injury) and hemoglobin transfusion trigger of 10gm/dl

Treatment:

Drug: recombinant human erythropoietin, rhEpo

Epo1 and TT7

Active Comparator group

Description:

recombinant human erythropoietin, rhEpo administration (500 IU/kg within 6 hrs of injury, at 24 and 48 hrs after injury, and at 9 and 16 days after injury) and hemoglobin transfusion trigger 7gm/dl

Treatment:

Drug: recombinant human erythropoietin, rhEpo

Epo2 and TT10

Active Comparator group

Description:

recombinant human erythropoietin, rhEpo administration (500 IU/kg within 6 hrs of injury, and at 9 and 16 days after injury) and hemoglobin transfusion trigger 10gm/dl

Treatment:

Drug: recombinant human erythropoietin, rhEpo

Epo2 and TT7

Active Comparator group

Description:

recombinant human erythropoietin, rhEpo administration (500 IU/kg within 6 hrs of injury, and at 9 and 16 days after injury) and hemoglobin transfusion trigger 7gm/dl

Treatment:

Drug: recombinant human erythropoietin, rhEpo

Placebo and TT10

Placebo Comparator group

Description:

Placebo administration and transfusion threshold 10 gm/dl

Treatment:

Other: placebo

Placebo and TT7

Placebo Comparator group

Description:

Placebo administration and transfusion threshold 7 gm/dl

Treatment:

Other: placebo