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

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.

Study Overview

• Status: Completed
• Conditions: Anemia; Traumatic Brain Injury
• Intervention / Treatment: Other: placebo; Drug: recombinant human erythropoietin, rhEpo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine, Ben Taub General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Epo1 and TT10; 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	Drug: recombinant human erythropoietin, rhEpo; The study design is 2x2 factorial with randomization to erythropoietin or placebo and to transfusion trigger 10 gm/dl or 7 g/dl. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (first 74 patients, Epo1 dosing regimen), and then the 24- and 48-hour doses were stopped for the remainder of the patients (remaining 126 patients, Epo2 dosing regimen).
Active Comparator: Epo1 and TT7; 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	Drug: recombinant human erythropoietin, rhEpo; The study design is 2x2 factorial with randomization to erythropoietin or placebo and to transfusion trigger 10 gm/dl or 7 g/dl. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (first 74 patients, Epo1 dosing regimen), and then the 24- and 48-hour doses were stopped for the remainder of the patients (remaining 126 patients, Epo2 dosing regimen).
Active Comparator: Epo2 and TT10; 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	Drug: recombinant human erythropoietin, rhEpo; The study design is 2x2 factorial with randomization to erythropoietin or placebo and to transfusion trigger 10 gm/dl or 7 g/dl. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (first 74 patients, Epo1 dosing regimen), and then the 24- and 48-hour doses were stopped for the remainder of the patients (remaining 126 patients, Epo2 dosing regimen).
Active Comparator: Epo2 and TT7; 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	Drug: recombinant human erythropoietin, rhEpo; The study design is 2x2 factorial with randomization to erythropoietin or placebo and to transfusion trigger 10 gm/dl or 7 g/dl. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (first 74 patients, Epo1 dosing regimen), and then the 24- and 48-hour doses were stopped for the remainder of the patients (remaining 126 patients, Epo2 dosing regimen).
Placebo Comparator: Placebo and TT10; Placebo administration and transfusion threshold 10 gm/dl	Other: placebo; an inactive substance
Placebo Comparator: Placebo and TT7; Placebo administration and transfusion threshold 7 gm/dl	Other: placebo; an inactive substance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glasgow Outcome Scale	Dichotomized to favorable outcome (good recovery or moderate disability) or to unfavorable outcome (severe disability or vegetative or dead)	at 6 months after injury

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disability Rating Scale	Disability rating scale was a secondary outcome measure for the transfusion threshold analysis. Disability rating scale ranges from 0 to 30, with 30 indicating death and 0 indicating return to normal status.	at 6 months
Mortality Rate	mortality rate was a secondary outcome measure for the Epo randomization, and a primary safety outcome measure for the transfusion threshold randomization	up to 6 months after injury
Incidence of Adult Respiratory Distress Syndrome (ARDS)	development of ARDS was a primary safety outcome for the transfusion threshold randomization	within 30 days after injury
Incidence of Infection	occurrence of infection was a primary safety outcome for the transfusion threshold randomization	within 30 days after injury

Collaborators and Investigators

• Sponsor: Claudia Sue Robertson
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Claudia Robertson, MD, Professor, Department of Neurosurgery, Baylor College of Medicine

Publications and helpful links

General Publications

• Robertson CS, Hannay HJ, Yamal JM, Gopinath S, Goodman JC, Tilley BC; Epo Severe TBI Trial Investigators; Baldwin A, Rivera Lara L, Saucedo-Crespo H, Ahmed O, Sadasivan S, Ponce L, Cruz-Navarro J, Shahin H, Aisiku IP, Doshi P, Valadka A, Neipert L, Waguspack JM, Rubin ML, Benoit JS, Swank P. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA. 2014 Jul 2;312(1):36-47. doi: 10.1001/jama.2014.6490.
• Aisiku IP, Yamal JM, Doshi P, Benoit JS, Gopinath S, Goodman JC, Robertson CS. Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury. Crit Care. 2016 Sep 15;20:288. doi: 10.1186/s13054-016-1470-7.
• Yamal JM, Benoit JS, Doshi P, Rubin ML, Tilley BC, Hannay HJ, Robertson CS. Association of transfusion red blood cell storage age and blood oxygenation, long-term neurologic outcome, and mortality in traumatic brain injury. J Trauma Acute Care Surg. 2015 Nov;79(5):843-9. doi: 10.1097/TA.0000000000000834.
• Aisiku IP, Yamal JM, Doshi P, Rubin ML, Benoit JS, Hannay J, Tilley BC, Gopinath S, Robertson CS. The incidence of ARDS and associated mortality in severe TBI using the Berlin definition. J Trauma Acute Care Surg. 2016 Feb;80(2):308-12. doi: 10.1097/TA.0000000000000903.
• Yamal JM, Robertson CS, Rubin ML, Benoit JS, Hannay HJ, Tilley BC. Enrollment of racially/ethnically diverse participants in traumatic brain injury trials: effect of availability of exception from informed consent. Clin Trials. 2014 Apr;11(2):187-94. doi: 10.1177/1740774514522560.

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: April 10, 2006
• First Submitted That Met QC Criteria: April 10, 2006
• First Posted (Estimate): April 12, 2006

Study Record Updates

• Last Update Posted (Estimate): September 10, 2014
• Last Update Submitted That Met QC Criteria: September 2, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: anemia; TBI; erythropoietin; traumatic brain injury; Epo; recombinant human erythropoietin; rhEpo
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hematologic Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Anemia; Hematinics; Epoetin Alfa
• Other Study ID Numbers: P01NS038660 (U.S. NIH Grant/Contract)