Anemia, Traumatic Brain Injury
Conditions
Keywords
anemia, traumatic brain injury, recombinant human erythropoietin, rhEpo, erythropoietin, TBI, Epo
Brief summary
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.
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.
Interventions
DRUGrecombinant 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).
OTHERplacebo
an inactive substance
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Claudia Sue Robertson
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glasgow Outcome Scale | at 6 months after injury | Dichotomized to favorable outcome (good recovery or moderate disability) or to unfavorable outcome (severe disability or vegetative or dead) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disability Rating Scale | at 6 months | 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. |
| Mortality Rate | up to 6 months after injury | mortality rate was a secondary outcome measure for the Epo randomization, and a primary safety outcome measure for the transfusion threshold randomization |
| Incidence of Adult Respiratory Distress Syndrome (ARDS) | within 30 days after injury | development of ARDS was a primary safety outcome for the transfusion threshold randomization |
| Incidence of Infection | within 30 days after injury | occurrence of infection was a primary safety outcome for the transfusion threshold randomization |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Epo1/TT7 Arm Patients received erythropoietin 500 IU/kg within 6 hrs of injury, at 24 and 48 hrs after injury, and at 9 and 16 days after injury and transfused to keep hemoglobin at least 7 g/dl | 18 |
| Epo2/TT7 Arm Patients received erythropoietin 500 IU/kg within 6 hrs of injury, at 24 and 48 hrs after injury, and at 9 and 16 days after injury and transfused to keep hemoglobin concentration at least 7 g/dl | 31 |
| Placebo/TT7 Arm Patients received saline and transfused to keep hemoglobin concentration at least 7 g/dl | 50 |
| Epo1/TT10 Arm Patients received erythropoietin 500 IU/kg within 6 hrs of injury, at 24 and 48 hrs after injury, and at 9 and 16 days after injury and transfused to keep hemoglobin at least 10 g/dl | 20 |
| Epo2/TT10 Arm Patients received erythropoietin 500 IU/kg within 6 hrs of injury, at 24 and 48 hrs after injury, and at 9 and 16 days after injury and transfused to keep hemoglobin concentration at least 10 g/dl | 33 |
| Placebo/TT10 Arm Patients received saline and transfused to keep hemoglobin concentration at least 10 g/dl | 48 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Death | 3 | 2 | 9 | 3 | 5 | 9 |
| Overall Study | Lost to Follow-up | 2 | 5 | 2 | 1 | 0 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Epo2/TT7 Arm | Placebo/TT7 Arm | Epo1/TT10 Arm | Epo2/TT10 Arm | Placebo/TT10 Arm | Total | Epo1/TT7 Arm |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 28 years | 29.5 years | 36.5 years | 30 years | 30.5 years | 30 years | 25.5 years |
| Glucose concentration | 9.1 mmol/L | 8.9 mmol/L | 8.8 mmol/L | 8.6 mmol/L | 7.7 mmol/L | 8.42 mmol/L | 8.3 mmol/L |
| Hemoglobin concentration | 14.7 g/dl | 14.0 g/dl | 14.8 g/dl | 13.9 g/dl | 14.7 g/dl | 14.45 g/dl | 14.7 g/dl |
| IMPACT probability of poor outcome | .35 probability of poor outcome STANDARD_DEVIATION 0.2 | .45 probability of poor outcome STANDARD_DEVIATION 0.3 | .49 probability of poor outcome STANDARD_DEVIATION 0.2 | .46 probability of poor outcome STANDARD_DEVIATION 0.3 | .38 probability of poor outcome STANDARD_DEVIATION 0.3 | .41 probability of poor outcome STANDARD_DEVIATION 0.25 | .29 probability of poor outcome STANDARD_DEVIATION 0.2 |
| Injury Severity Score | 30 units on a scale | 29 units on a scale | 27 units on a scale | 29 units on a scale | 29 units on a scale | 29 units on a scale | 29 units on a scale |
| Marshall CT scan category Diffuse injury 1 or 2 | 15 participants | 24 participants | 5 participants | 15 participants | 20 participants | 89 participants | 10 participants |
| Marshall CT scan category Diffuse injury 3 or 4 | 8 participants | 10 participants | 9 participants | 2 participants | 12 participants | 46 participants | 5 participants |
| Marshall CT scan category Mass lesion | 8 participants | 16 participants | 6 participants | 16 participants | 16 participants | 65 participants | 3 participants |
| Mechanism of injury Assault | 2 participants | 5 participants | 2 participants | 3 participants | 10 participants | 22 participants | 0 participants |
| Mechanism of injury Automobile crash | 19 participants | 29 participants | 9 participants | 22 participants | 27 participants | 116 participants | 10 participants |
| Mechanism of injury Fall or jump | 3 participants | 7 participants | 3 participants | 4 participants | 2 participants | 27 participants | 8 participants |
| Mechanism of injury Motorcycle crash | 7 participants | 7 participants | 5 participants | 4 participants | 8 participants | 31 participants | 0 participants |
| Mechanism of injury Other | 0 participants | 2 participants | 1 participants | 0 participants | 1 participants | 4 participants | 0 participants |
| Motor component of Glasgow Coma Score mGCS 1-3 | 12 participants | 20 participants | 8 participants | 14 participants | 13 participants | 71 participants | 4 participants |
| Motor component of Glasgow Coma Score mGCS 4-5 | 19 participants | 30 participants | 12 participants | 19 participants | 35 participants | 129 participants | 14 participants |
| Prehospital hypotension no | 28 participants | 43 participants | 17 participants | 31 participants | 39 participants | 175 participants | 17 participants |
| Prehospital hypotension yes | 3 participants | 7 participants | 3 participants | 2 participants | 9 participants | 25 participants | 1 participants |
| Prehospital hypoxia no | 29 participants | 34 participants | 17 participants | 28 participants | 35 participants | 161 participants | 18 participants |
| Prehospital hypoxia yes | 2 participants | 16 participants | 3 participants | 5 participants | 13 participants | 39 participants | 0 participants |
| Presence of epidural hematoma no | 27 participants | 47 participants | 17 participants | 25 participants | 37 participants | 168 participants | 15 participants |
| Presence of epidural hematoma yes | 4 participants | 3 participants | 3 participants | 8 participants | 11 participants | 32 participants | 3 participants |
| Presence of subarachnoid hemorrhage no | 9 participants | 13 participants | 17 participants | 11 participants | 37 participants | 93 participants | 6 participants |
| Presence of subarachnoid hemorrhage yes | 22 participants | 37 participants | 3 participants | 22 participants | 11 participants | 107 participants | 12 participants |
| Pupil reactivity Both reactive | 24 participants | 27 participants | 13 participants | 17 participants | 28 participants | 121 participants | 12 participants |
| Pupil reactivity Neither reactive | 3 participants | 15 participants | 4 participants | 15 participants | 15 participants | 56 participants | 4 participants |
| Pupil reactivity One reactive | 4 participants | 8 participants | 3 participants | 1 participants | 5 participants | 23 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 0 participants | 0 participants | 3 participants | 6 participants | 1 participants |
| Race/Ethnicity, Customized Black | 4 participants | 12 participants | 3 participants | 6 participants | 14 participants | 43 participants | 4 participants |
| Race/Ethnicity, Customized Hispanic | 16 participants | 26 participants | 12 participants | 19 participants | 22 participants | 103 participants | 8 participants |
| Race/Ethnicity, Customized White, non-Hispanic | 10 participants | 11 participants | 5 participants | 8 participants | 9 participants | 48 participants | 5 participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 2 Participants | 5 Participants | 5 Participants | 26 Participants | 2 Participants |
| Sex: Female, Male Male | 28 Participants | 41 Participants | 18 Participants | 28 Participants | 43 Participants | 174 Participants | 16 Participants |
| Sum Glasgow Coma Score GCS 3-5 | 10 participants | 20 participants | 8 participants | 13 participants | 11 participants | 66 participants | 4 participants |
| Sum Glasgow Coma Score GCS 6-8 | 13 participants | 19 participants | 8 participants | 16 participants | 23 participants | 89 participants | 10 participants |
| Sum Glasgow Coma Score GCS > 8 | 8 participants | 11 participants | 4 participants | 4 participants | 14 participants | 45 participants | 4 participants |
| Surgery on admission Evacuation epidural hematoma | 2 participants | 1 participants | 0 participants | 1 participants | 5 participants | 9 participants | 0 participants |
| Surgery on admission Evacuation intracerebral hematoma or contusion | 0 participants | 1 participants | 1 participants | 0 participants | 1 participants | 4 participants | 1 participants |
| Surgery on admission Evacuation subdural hematoma | 5 participants | 13 participants | 5 participants | 14 participants | 7 participants | 46 participants | 2 participants |
| Surgery on admission Non-central nervous system injury | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants | 2 participants | 0 participants |
| Surgery on admission No surgery on admission | 24 participants | 34 participants | 14 participants | 18 participants | 34 participants | 139 participants | 15 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 34 / 38 | 57 / 64 | 87 / 98 | 85 / 99 | 93 / 101 |
| serious Total, serious adverse events | 29 / 38 | 50 / 64 | 78 / 98 | 85 / 99 | 93 / 101 |
Outcome results
Primary
Glasgow Outcome Scale
Dichotomized to favorable outcome (good recovery or moderate disability) or to unfavorable outcome (severe disability or vegetative or dead)
Time frame: at 6 months after injury
Population: Intention to treat. Multiple imputation for missing 6-month GOS data was performed assuming data were missing at random using chained equations (R, R Foundation for Statistical Computing).The imputation was based on a logistic regression model with baseline covariates. Results were aggregated over 20 imputed sets using variance formula by Rubin.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Epo1 Group | Glasgow Outcome Scale | Favorable outcome | 17 participants |
| Epo1 Group | Glasgow Outcome Scale | Unfavorable outcome | 18 participants |
| Epo2 Group | Glasgow Outcome Scale | Favorable outcome | 17 participants |
| Epo2 Group | Glasgow Outcome Scale | Unfavorable outcome | 40 participants |
| Placebo Group | Glasgow Outcome Scale | Favorable outcome | 34 participants |
| Placebo Group | Glasgow Outcome Scale | Unfavorable outcome | 55 participants |
| TT7 Group | Glasgow Outcome Scale | Unfavorable outcome | 50 participants |
| TT7 Group | Glasgow Outcome Scale | Favorable outcome | 37 participants |
| TT10 Group | Glasgow Outcome Scale | Favorable outcome | 31 participants |
| TT10 Group | Glasgow Outcome Scale | Unfavorable outcome | 63 participants |
Comparison: The primary analysis plan was a futility trial of the Epo 2 regimen arm. We hypothesized that 30% of subjects in the placebo group would have a favorable outcome at six months and there would be no interaction between the Epo and the transfusion threshold groups. Using a one-sided alpha of 0.15, a sample size of 62 subjects in the Epo 2 regimen group and 100 subjects in the placebo group provided 91% power to test the futility hypothesis.p-value: 0.01Futility analysis
Comparison: The primary analysis plan was a futility trial of the Epo 1 regimen arm. We hypothesized that 30% of subjects in the placebo group would have a favorable outcome at six months and there would be no interaction between the Epo and the transfusion threshold groups.p-value: 0.13Futility analysis
Comparison: We hypothesized that 40% of the patients in the TT7 group would have a favorable GOS score and that there would be no interaction between the Epo and TT groups. Assuming a 2-sided test with an alpha level of 0.05, we estimated that a sample size of 200 patients would provide 80% power to detect a 20% absolute increase in the GOS score for the TT10 group.p-value: 0.342-sample test of proportions
Secondary
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.
Time frame: at 6 months
Population: Intention to treat analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Epo1 Group | Disability Rating Scale | 5 units on a scale |
| Epo2 Group | Disability Rating Scale | 8 units on a scale |
p-value: 0.06Wilcoxon (Mann-Whitney)
Secondary
Incidence of Adult Respiratory Distress Syndrome (ARDS)
development of ARDS was a primary safety outcome for the transfusion threshold randomization
Time frame: within 30 days after injury
Population: Intention to treat analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Epo1 Group | Incidence of Adult Respiratory Distress Syndrome (ARDS) | Developed ARDS | 16 participants |
| Epo1 Group | Incidence of Adult Respiratory Distress Syndrome (ARDS) | Did not develop ARDS | 83 participants |
| Epo2 Group | Incidence of Adult Respiratory Distress Syndrome (ARDS) | Developed ARDS | 25 participants |
| Epo2 Group | Incidence of Adult Respiratory Distress Syndrome (ARDS) | Did not develop ARDS | 76 participants |
p-value: 0.0895% CI: [0.93, 3.45]Regression, Cox
Secondary
Incidence of Infection
occurrence of infection was a primary safety outcome for the transfusion threshold randomization
Time frame: within 30 days after injury
Population: Intention to treat analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Epo1 Group | Incidence of Infection | Developed one or more infections | 27 participants |
| Epo1 Group | Incidence of Infection | Did not develop infection | 72 participants |
| Epo2 Group | Incidence of Infection | Developed one or more infections | 36 participants |
| Epo2 Group | Incidence of Infection | Did not develop infection | 65 participants |
p-value: 0.2695% CI: [-0.22, 0.05]2-sample test - equality of proportions
Secondary
Mortality Rate
mortality rate was a secondary outcome measure for the Epo randomization, and a primary safety outcome measure for the transfusion threshold randomization
Time frame: up to 6 months after injury
Population: Intention to treat analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Epo1 Group | Mortality Rate | Died | 6 participants |
| Epo1 Group | Mortality Rate | Survived | 32 participants |
| Epo2 Group | Mortality Rate | Died | 7 participants |
| Epo2 Group | Mortality Rate | Survived | 57 participants |
| Placebo Group | Mortality Rate | Died | 18 participants |
| Placebo Group | Mortality Rate | Survived | 80 participants |
| TT7 Group | Mortality Rate | Survived | 85 participants |
| TT7 Group | Mortality Rate | Died | 14 participants |
| TT10 Group | Mortality Rate | Died | 17 participants |
| TT10 Group | Mortality Rate | Survived | 84 participants |
p-value: 0.25Log Rank
p-value: 0.75Log Rank
p-value: 0.72Log Rank