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

• Sponsor: Claudia Sue Robertson (Other)
• Overall Status: Completed
• CT.gov ID: NCT00313716
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 200
• Location: 1
• Arms: 6
• Duration (Months): 83
• Patients Per Site Per Month: 2.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Anemia; Traumatic Brain Injury	Drug: recombinant human erythropoietin, rhEpo; Other: placebo	Phase 2/Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Erythropoietin on Cerebral Vascular Dysfunction and Anemia in Traumatic Brain Injury
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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

3. 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

4. Incidence of Infection [within 30 days after injury]

   occurrence of infection was a primary safety outcome for the transfusion threshold randomization

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Baylor College of Medicine, Ben Taub General Hospital	Houston	Texas	United States	77030

Sponsors and Collaborators

• Claudia Sue Robertson
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Claudia Robertson, MD, Professor, Department of Neurosurgery, Baylor College of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Claudia Sue Robertson, Professor, Department of Neurosurgery, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT00313716
• Other Study ID Numbers: P01NS038660; P01NS038660
• First Posted: Apr 12, 2006
• Last Update Posted: Sep 10, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Claudia Sue Robertson, Professor, Department of Neurosurgery, Baylor College of Medicine: anemia; traumatic brain injury; recombinant human erythropoietin; rhEpo; erythropoietin; TBI; Epo
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Anemia; Wounds and Injuries; Epoetin Alfa

Study Results

Participant Flow

Arm/Group Title	Epo1/TT7 Arm	Epo2/TT7 Arm	Placebo/TT7 Arm	Epo1/TT10 Arm	Epo2/TT10 Arm	Placebo/TT10 Arm
Arm/Group Description	High dose Epo (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 hemoglobin transfusion threshold 7 gm/dl	Low dose Epo (patients received erythropoietin 500 IU/kg within 6 hrs of injury, and at 9 and 16 days after injury) and hemoglobin transfusion threshold 7 gm/dl	Placebo (patients received saline) and hemoglobin transfusion threshold 7 gm/dl	High dose Epo (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 hemoglobin transfusion threshold 10 gm/dl	Low dose Epo (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 hemoglobin transfusion threshold 10 gm/dl	Placebo (patients received saline) and hemoglobin transfusion threshold 10 gm/dl
Period Title: Overall Study
STARTED	18	31	50	20	33	48
COMPLETED	13	23	38	16	27	35
NOT COMPLETED	5	8	12	4	6	13

Baseline Characteristics

Arm/Group Title	Epo1/TT7 Arm	Epo2/TT7 Arm	Placebo/TT7 Arm	Epo1/TT10 Arm	Epo2/TT10 Arm	Placebo/TT10 Arm	Total
Arm/Group Description	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	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	Patients received saline and transfused to keep hemoglobin concentration at least 7 g/dl	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	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	Patients received saline and transfused to keep hemoglobin concentration at least 10 g/dl	Total of all reporting groups
Overall Participants	18	31	50	20	33	48	200
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	25.5	28	29.5	36.5	30	30.5	30
Sex: Female, Male (Count of Participants)
Female	2 11.1%	3 9.7%	9 18%	2 10%	5 15.2%	5 10.4%	26 13%
Male	16 88.9%	28 90.3%	41 82%	18 90%	28 84.8%	43 89.6%	174 87%
Race/Ethnicity, Customized (participants) [Number]
Asian	1 5.6%	1 3.2%	1 2%	0 0%	0 0%	3 6.3%	6 3%
Hispanic	8 44.4%	16 51.6%	26 52%	12 60%	19 57.6%	22 45.8%	103 51.5%
Black	4 22.2%	4 12.9%	12 24%	3 15%	6 18.2%	14 29.2%	43 21.5%
White, non-Hispanic	5 27.8%	10 32.3%	11 22%	5 25%	8 24.2%	9 18.8%	48 24%
Prehospital hypotension (participants) [Number]
yes	1 5.6%	3 9.7%	7 14%	3 15%	2 6.1%	9 18.8%	25 12.5%
no	17 94.4%	28 90.3%	43 86%	17 85%	31 93.9%	39 81.3%	175 87.5%
Prehospital hypoxia (participants) [Number]
yes	0 0%	2 6.5%	16 32%	3 15%	5 15.2%	13 27.1%	39 19.5%
no	18 100%	29 93.5%	34 68%	17 85%	28 84.8%	35 72.9%	161 80.5%
Mechanism of injury (participants) [Number]
Assault	0 0%	2 6.5%	5 10%	2 10%	3 9.1%	10 20.8%	22 11%
Fall or jump	8 44.4%	3 9.7%	7 14%	3 15%	4 12.1%	2 4.2%	27 13.5%
Automobile crash	10 55.6%	19 61.3%	29 58%	9 45%	22 66.7%	27 56.3%	116 58%
Motorcycle crash	0 0%	7 22.6%	7 14%	5 25%	4 12.1%	8 16.7%	31 15.5%
Other	0 0%	0 0%	2 4%	1 5%	0 0%	1 2.1%	4 2%
Injury Severity Score (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	29	30	29	27	29	29	29
IMPACT probability of poor outcome (probability of poor outcome) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [probability of poor outcome]	.29 (.2)	.35 (.2)	.45 (.3)	.49 (.2)	.46 (.3)	.38 (.3)	.41 (.25)
Motor component of Glasgow Coma Score (participants) [Number]
mGCS 1-3	4 22.2%	12 38.7%	20 40%	8 40%	14 42.4%	13 27.1%	71 35.5%
mGCS 4-5	14 77.8%	19 61.3%	30 60%	12 60%	19 57.6%	35 72.9%	129 64.5%
Sum Glasgow Coma Score (participants) [Number]
GCS 3-5	4 22.2%	10 32.3%	20 40%	8 40%	13 39.4%	11 22.9%	66 33%
GCS 6-8	10 55.6%	13 41.9%	19 38%	8 40%	16 48.5%	23 47.9%	89 44.5%
GCS > 8	4 22.2%	8 25.8%	11 22%	4 20%	4 12.1%	14 29.2%	45 22.5%
Pupil reactivity (participants) [Number]
Both reactive	12 66.7%	24 77.4%	27 54%	13 65%	17 51.5%	28 58.3%	121 60.5%
One reactive	2 11.1%	4 12.9%	8 16%	3 15%	1 3%	5 10.4%	23 11.5%
Neither reactive	4 22.2%	3 9.7%	15 30%	4 20%	15 45.5%	15 31.3%	56 28%
Marshall CT scan category (participants) [Number]
Diffuse injury 1 or 2	10 55.6%	15 48.4%	24 48%	5 25%	15 45.5%	20 41.7%	89 44.5%
Diffuse injury 3 or 4	5 27.8%	8 25.8%	10 20%	9 45%	2 6.1%	12 25%	46 23%
Mass lesion	3 16.7%	8 25.8%	16 32%	6 30%	16 48.5%	16 33.3%	65 32.5%
Presence of subarachnoid hemorrhage (participants) [Number]
yes	12 66.7%	22 71%	37 74%	3 15%	22 66.7%	11 22.9%	107 53.5%
no	6 33.3%	9 29%	13 26%	17 85%	11 33.3%	37 77.1%	93 46.5%
Presence of epidural hematoma (participants) [Number]
yes	3 16.7%	4 12.9%	3 6%	3 15%	8 24.2%	11 22.9%	32 16%
no	15 83.3%	27 87.1%	47 94%	17 85%	25 75.8%	37 77.1%	168 84%
Hemoglobin concentration (g/dl) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [g/dl]	14.7	14.7	14.0	14.8	13.9	14.7	14.45
Glucose concentration (mmol/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mmol/L]	8.3	9.1	8.9	8.8	8.6	7.7	8.42
Surgery on admission (participants) [Number]
Evacuation epidural hematoma	0 0%	2 6.5%	1 2%	0 0%	1 3%	5 10.4%	9 4.5%
Evacuation subdural hematoma	2 11.1%	5 16.1%	13 26%	5 25%	14 42.4%	7 14.6%	46 23%
Evacuation intracerebral hematoma or contusion	1 5.6%	0 0%	1 2%	1 5%	0 0%	1 2.1%	4 2%
Non-central nervous system injury	0 0%	0 0%	1 2%	0 0%	0 0%	1 2.1%	2 1%
No surgery on admission	15 83.3%	24 77.4%	34 68%	14 70%	18 54.5%	34 70.8%	139 69.5%

Outcome Measures

1. Primary Outcome

Title	Glasgow Outcome Scale
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Epo1 Group	Epo2 Group	Placebo Group	TT7 Group	TT10 Group
Arm/Group Description	Patients received erythropoietin 500 IU/kg within 6hrs of injury, at 24 and 48 hrs after injury, and at 9 and 16 days after injury (Epo1/TT10 arm and Epo1/TT7 arm combined)	Patients received erythropoietin 500 IU/kg within 6hrs of injury, and at 9 and 16 days after injury (Epo2/TT10 arm and Epo2/TT7 arm combined)	Patients received saline (Placebo/TT10 arm and Placebo/TT7 arm combined)	Patients had hemoglobin concentration maintained at least 7 gm/dl (Epo1/TT7 arm, Epo2/TT7 arm, and Placebo/TT7 arm combined)	Patients had hemoglobin concentration maintained at least 10 gm/dl (Epo1/TT10 arm, Epo2/TT10 arm, and Placebo/TT10 arm combined)
Measure Participants	35	57	89	87	94
Favorable outcome	17 94.4%	17 54.8%	34 68%	37 185%	31 93.9%
Unfavorable outcome	18 100%	40 129%	55 110%	50 250%	63 190.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epo2 Group, Placebo Group
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.01
	Comments	H0: Proportion of participants expected to have a favorable GOS outcome in the Epo2 group - in Placebo group is >= 0.2. H1: Proportion in Epo2 group - in Placebo group < 0.2
	Method	Futility analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Epo1 Group, Placebo Group
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments	H0: Proportion of participants expected to have a favorable GOS outcome in the Epo1 group - in Placebo group is >= 0.2. H1: Proportion in Epo1 group - in Placebo group < 0.2
	Method	Futility analysis
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	TT7 Group, TT10 Group
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.34
	Comments
	Method	2-sample test of proportions
	Comments

2. Secondary Outcome

Title	Disability Rating Scale
Description	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

Outcome Measure Data

Analysis Population Description

Intention to treat analysis

Arm/Group Title	TT7 Group	TT10 Group
Arm/Group Description	Patients had hemoglobin concentration maintained at least 7 gm/dl (Epo1/TT7 arm, Epo2/TT7 arm, and Placebo/TT7 arm combined)	Patients had hemoglobin concentration maintained at least 10 gm/dl (Epo1/TT10 arm, Epo2/TT10 arm, and Placebo/TT10 arm combined)
Measure Participants	87	94
Median (Inter-Quartile Range) [units on a scale]	5	8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epo1 Group, Epo2 Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.06
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Mortality Rate
Description	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

Outcome Measure Data

Analysis Population Description

Intention to treat analysis

Arm/Group Title	Epo1 Group	Epo2 Group	Placebo Group	TT7 Group	TT10 Group
Arm/Group Description	Patients received 500 IU/kg erythropoietin within 6 hrs of injury, at 24 and 48 hrs after injury, and at 9 and 16 days after injury (Epo1/TT10 arm and Epo1/TT7 arm combined)	Patients received 500 IU/kg within 6 hrs after injury, and at 9 and 16 days after injury (Epo2/TT10 arm and Epo2/TT7 arm combined)	Patients received saline (Placebo/TT10 arm and Placebo/TT7 arm combined)	Patients had hemoglobin maintained at least 7 gm/dl (Epo1/TT7 arm, Epo2/TT7 arm, and Placebo/TT7 arm combined)	Patients had hemoglobin concentration maintained at least 10 gm/dl (Epo1/TT10 arm, Epo2/TT10 arm, and Placebo/TT10 arm combined)
Measure Participants	38	64	98	99	101
Died	6 33.3%	7 22.6%	18 36%	14 70%	17 51.5%
Survived	32 177.8%	57 183.9%	80 160%	85 425%	84 254.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epo2 Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.25
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Epo1 Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.75
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	TT7 Group, TT10 Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.72
	Comments
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Incidence of Adult Respiratory Distress Syndrome (ARDS)
Description	development of ARDS was a primary safety outcome for the transfusion threshold randomization
Time Frame	within 30 days after injury

Outcome Measure Data

Analysis Population Description

Intention to treat analysis

Arm/Group Title	TT7 Group	TT10 Group
Arm/Group Description	Patients had hemoglobin concentration maintained at least 7 gm/dl (Epo1/TT7 arm, Epo2/TT7 arm, and Placebo/TT7 arm combined)	Patients had hemoglobin concentration maintained at least 10 gm/dl (Epo1/TT10 arm, Epo2/TT10 arm, and Placebo/TT10 arm combined)
Measure Participants	99	101
Developed ARDS	16 88.9%	25 80.6%
Did not develop ARDS	83 461.1%	76 245.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epo1 Group, Epo2 Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.08
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.79
	Confidence Interval	(2-Sided) 95%; .93 to 3.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Incidence of Infection
Description	occurrence of infection was a primary safety outcome for the transfusion threshold randomization
Time Frame	within 30 days after injury

Outcome Measure Data

Analysis Population Description

Intention to treat analysis

Arm/Group Title	TT7 Group	TT10 Group
Arm/Group Description	Patients had hemoglobin concentration maintained at least 7 gm/dl (Epo1/TT7 arm, Epo2/TT7 arm, and Placebo/TT7 arm combined)	Patients had hemoglobin concentration maintained at least 10 gm/dl (Epo1/TT10 group, Epo2/TT10 group, and Placebo/TT10 group combined)
Measure Participants	99	101
Developed one or more infections	27 150%	36 116.1%
Did not develop infection	72 400%	65 209.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epo1 Group, Epo2 Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.26
	Comments
	Method	2-sample test - equality of proportions
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-.08
	Confidence Interval	(2-Sided) 95%; -.22 to .05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Serious adverse events were reported for 30 days after injury
Adverse Event Reporting Description	Each patient is represented twice in the table (once in the Epo1/Epo2/Placebo groups and once in the TT7/TT10 groups)
Arm/Group Title	Epo1 Group		Epo2 Group		Placebo Group		TT7 Group		TT10 Group
Arm/Group Description	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 (Epo1/TT10 arm and Epo1/TT7 arm combined)		Patients received erythropoietin 500 IU/kg within 6 hrs of injury, and at 9 and 16 days after injury (Epo1/TT10 arm and Epo1/TT7 arm combined)		Patients received saline (Placebo/TT10 arm and Placebo/TT7 arm combined)		Patients had hemoglobin concentration maintained at least 7 gm/dl (Epo1/TT7 arm, Epo2/TT7 arm, and Placebo/TT7 arm combined)		Patients had hemoglobin concentration maintained at least 10 gm/dl (Epo1/TT10 arm, Epo2/TT10 arm, and Placebo/TT10 arm combined)
All Cause Mortality
	Epo1 Group		Epo2 Group		Placebo Group		TT7 Group		TT10 Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Epo1 Group		Epo2 Group		Placebo Group		TT7 Group		TT10 Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/38 (76.3%)		50/64 (78.1%)		78/98 (79.6%)		85/99 (85.9%)		93/101 (92.1%)
Blood and lymphatic system disorders
Severe anemia	1/38 (2.6%)		0/64 (0%)		0/98 (0%)		0/99 (0%)		1/101 (1%)
Other severe hematologic disorder	2/38 (5.3%)		2/64 (3.1%)		2/98 (2%)		3/99 (3%)		3/101 (3%)
Cardiac disorders
acute myocardial infarction	0/38 (0%)		1/64 (1.6%)		1/98 (1%)		1/99 (1%)		1/101 (1%)
cardiac arrest with CPR	2/38 (5.3%)		1/64 (1.6%)		2/98 (2%)		2/99 (2%)		3/101 (3%)
Hypotension due to barbiturate coma	2/38 (5.3%)		4/64 (6.3%)		6/98 (6.1%)		3/99 (3%)		9/101 (8.9%)
Pulmonary embolus	0/38 (0%)		4/64 (6.3%)		3/98 (3.1%)		1/99 (1%)		6/101 (5.9%)
Shock	10/38 (26.3%)		15/64 (23.4%)		19/98 (19.4%)		25/99 (25.3%)		19/101 (18.8%)
Endocrine disorders
Diabetes insipidus	1/38 (2.6%)		2/64 (3.1%)		8/98 (8.2%)		7/99 (7.1%)		4/101 (4%)
Gastrointestinal disorders
Abdominal compartment syndrome	1/38 (2.6%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		1/101 (1%)
incarcerated inguinal hernia	1/38 (2.6%)		0/64 (0%)		0/98 (0%)		0/99 (0%)		1/101 (1%)
Pancreatitis	0/38 (0%)		1/64 (1.6%)		2/98 (2%)		0/99 (0%)		3/101 (3%)
peritonitis	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		1/99 (1%)		0/101 (0%)
Infections and infestations
Multiple organ dysfunction syndrome	0/38 (0%)		1/64 (1.6%)		2/98 (2%)		0/99 (0%)		3/101 (3%)
Wound infection, non-central nervous system	0/38 (0%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		0/101 (0%)
Pneumonia	11/38 (28.9%)		8/64 (12.5%)		14/98 (14.3%)		13/99 (13.1%)		20/101 (19.8%)
Sepsis	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		0/99 (0%)		1/101 (1%)
Septic shock	1/38 (2.6%)		2/64 (3.1%)		1/98 (1%)		3/99 (3%)		1/101 (1%)
Injury, poisoning and procedural complications
Carotid cavernous fistula	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		1/99 (1%)		0/101 (0%)
Infected eye injury	0/38 (0%)		0/64 (0%)		1/98 (1%)		0/99 (0%)		1/101 (1%)
Hemothorax	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		1/99 (1%)		0/101 (0%)
Osteomyelitis	0/38 (0%)		0/64 (0%)		1/98 (1%)		0/99 (0%)		1/101 (1%)
Rhabdomyalysis	1/38 (2.6%)		0/64 (0%)		0/98 (0%)		1/99 (1%)		0/101 (0%)
Tongue laceration	0/38 (0%)		0/64 (0%)		1/98 (1%)		0/99 (0%)		1/101 (1%)
internal jugular vein injury	0/38 (0%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		0/101 (0%)
Nervous system disorders
Brain death	3/38 (7.9%)		2/64 (3.1%)		5/98 (5.1%)		6/99 (6.1%)		4/101 (4%)
Brain tissue hypoxia	3/38 (7.9%)		4/64 (6.3%)		8/98 (8.2%)		10/99 (10.1%)		5/101 (5%)
delayed or recurrent intracranial hemorrhage	10/38 (26.3%)		13/64 (20.3%)		18/98 (18.4%)		15/99 (15.2%)		26/101 (25.7%)
hydrocephalus	1/38 (2.6%)		2/64 (3.1%)		2/98 (2%)		3/99 (3%)		2/101 (2%)
intracranial hypertension	7/38 (18.4%)		14/64 (21.9%)		28/98 (28.6%)		22/99 (22.2%)		27/101 (26.7%)
meningitis or ventriculitis	2/38 (5.3%)		2/64 (3.1%)		2/98 (2%)		3/99 (3%)		3/101 (3%)
wound dehiscence	1/38 (2.6%)		0/64 (0%)		0/98 (0%)		0/99 (0%)		1/101 (1%)
stroke	3/38 (7.9%)		0/64 (0%)		0/98 (0%)		1/99 (1%)		2/101 (2%)
Renal and urinary disorders
Acute renal failure	2/38 (5.3%)		1/64 (1.6%)		3/98 (3.1%)		3/99 (3%)		3/101 (3%)
Severe metabolic acidosis	1/38 (2.6%)		0/64 (0%)		2/98 (2%)		1/99 (1%)		2/101 (2%)
Severe mixed acid-base disorder	0/38 (0%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		0/101 (0%)
Electrolyte disturbance	0/38 (0%)		4/64 (6.3%)		7/98 (7.1%)		5/99 (5.1%)		6/101 (5.9%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	3/38 (7.9%)		2/64 (3.1%)		6/98 (6.1%)		2/99 (2%)		9/101 (8.9%)
Airway obstruction post-extubation	0/38 (0%)		2/64 (3.1%)		1/98 (1%)		2/99 (2%)		1/101 (1%)
Severe atelectasis	0/38 (0%)		0/64 (0%)		1/98 (1%)		0/99 (0%)		1/101 (1%)
Pleural effusion	0/38 (0%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		0/101 (0%)
Pneumothorax	1/38 (2.6%)		1/64 (1.6%)		1/98 (1%)		2/99 (2%)		1/101 (1%)
Vascular disorders
Lower extremity deep venous thrombophlebitis	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		0/99 (0%)		1/101 (1%)
Gangrene of extremities	2/38 (5.3%)		0/64 (0%)		0/98 (0%)		0/99 (0%)		2/101 (2%)
Upper extremity deep venous thrombophlebitis	1/38 (2.6%)		1/64 (1.6%)		0/98 (0%)		0/99 (0%)		2/101 (2%)
Other (Not Including Serious) Adverse Events
	Epo1 Group		Epo2 Group		Placebo Group		TT7 Group		TT10 Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/38 (89.5%)		57/64 (89.1%)		87/98 (88.8%)		85/99 (85.9%)		93/101 (92.1%)
Blood and lymphatic system disorders
Anemia	24/38 (63.2%)		33/64 (51.6%)		60/98 (61.2%)		66/99 (66.7%)		51/101 (50.5%)
Other hematologic disorder	13/38 (34.2%)		20/64 (31.3%)		43/98 (43.9%)		37/99 (37.4%)		39/101 (38.6%)
Cardiac disorders
Atrial arrhythmia	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		1/99 (1%)		0/101 (0%)
Hypertension	1/38 (2.6%)		1/64 (1.6%)		0/98 (0%)		0/99 (0%)		2/101 (2%)
Hypotension from barbiturate coma	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		1/99 (1%)		0/101 (0%)
Hypotension	1/38 (2.6%)		0/64 (0%)		2/98 (2%)		3/99 (3%)		0/101 (0%)
Endocrine disorders
Diabetes insipidus	0/38 (0%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		0/101 (0%)
Hyperglycemia	3/38 (7.9%)		0/64 (0%)		4/98 (4.1%)		4/99 (4%)		3/101 (3%)
Hypoglycemia	0/38 (0%)		1/64 (1.6%)		2/98 (2%)		1/99 (1%)		2/101 (2%)
Eye disorders
Exposure keratoconjunctivitis	1/38 (2.6%)		0/64 (0%)		2/98 (2%)		2/99 (2%)		1/101 (1%)
Gastrointestinal disorders
Upper GI bleeding	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		0/99 (0%)		1/101 (1%)
Ileus	0/38 (0%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		0/101 (0%)
Hepatobiliary disorders
Elevated transaminases	11/38 (28.9%)		14/64 (21.9%)		26/98 (26.5%)		25/99 (25.3%)		26/101 (25.7%)
Infections and infestations
Wound infection	0/38 (0%)		0/64 (0%)		2/98 (2%)		1/99 (1%)		1/101 (1%)
Urinary tract infection	1/38 (2.6%)		5/64 (7.8%)		7/98 (7.1%)		7/99 (7.1%)		6/101 (5.9%)
Bacteremia	0/38 (0%)		1/64 (1.6%)		3/98 (3.1%)		2/99 (2%)		2/101 (2%)
Wound infection, non-central nervous system	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		1/99 (1%)		0/101 (0%)
Injury, poisoning and procedural complications
Wound dehiscence	0/38 (0%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		0/101 (0%)
Bleeding complicating a procedure	0/38 (0%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		0/101 (0%)
Rhabdomyalysis	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		1/99 (1%)		0/101 (0%)
Febrile transfusion reaction	1/38 (2.6%)		0/64 (0%)		0/98 (0%)		0/99 (0%)		1/101 (1%)
Metabolism and nutrition disorders
Diffuse edema	0/38 (0%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		0/101 (0%)
Hypothermia	2/38 (5.3%)		0/64 (0%)		0/98 (0%)		1/99 (1%)		1/101 (1%)
Nervous system disorders
Cerebrospinal fluid leak	2/38 (5.3%)		1/64 (1.6%)		2/98 (2%)		1/99 (1%)		4/101 (4%)
Brain tissue hypoxia	9/38 (23.7%)		12/64 (18.8%)		21/98 (21.4%)		21/99 (21.2%)		21/101 (20.8%)
Delayed or recurrent intracranial hematoma	7/38 (18.4%)		5/64 (7.8%)		12/98 (12.2%)		11/99 (11.1%)		13/101 (12.9%)
Hydrocephalus	1/38 (2.6%)		0/64 (0%)		0/98 (0%)		1/99 (1%)		0/101 (0%)
Intracranial hypertension	9/38 (23.7%)		9/64 (14.1%)		15/98 (15.3%)		17/99 (17.2%)		16/101 (15.8%)
Pneumocephalus	1/38 (2.6%)		1/64 (1.6%)		0/98 (0%)		0/99 (0%)		2/101 (2%)
Seizure	3/38 (7.9%)		3/64 (4.7%)		5/98 (5.1%)		4/99 (4%)		7/101 (6.9%)
Subgaleal cerebrospinal fluid collection	1/38 (2.6%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		1/101 (1%)
Renal and urinary disorders
acute renal dysfunction	0/38 (0%)		0/64 (0%)		5/98 (5.1%)		4/99 (4%)		1/101 (1%)
Metabolic acidosis	3/38 (7.9%)		0/64 (0%)		4/98 (4.1%)		4/99 (4%)		3/101 (3%)
Mixed acid-base abnormality	0/38 (0%)		1/64 (1.6%)		0/98 (0%)		0/99 (0%)		1/101 (1%)
Electrolyte imbalance	12/38 (31.6%)		20/64 (31.3%)		36/98 (36.7%)		28/99 (28.3%)		40/101 (39.6%)
Respiratory, thoracic and mediastinal disorders
Respiratory acidosis	1/38 (2.6%)		1/64 (1.6%)		1/98 (1%)		1/99 (1%)		2/101 (2%)
Airway obstruction post-extubation	1/38 (2.6%)		1/64 (1.6%)		0/98 (0%)		2/99 (2%)		0/101 (0%)
Atelectasis	14/38 (36.8%)		14/64 (21.9%)		19/98 (19.4%)		21/99 (21.2%)		26/101 (25.7%)
Pleural effusion	0/38 (0%)		2/64 (3.1%)		6/98 (6.1%)		4/99 (4%)		4/101 (4%)
Pneumothorax	1/38 (2.6%)		1/64 (1.6%)		6/98 (6.1%)		6/99 (6.1%)		2/101 (2%)
Sinusitis	1/38 (2.6%)		0/64 (0%)		1/98 (1%)		1/99 (1%)		1/101 (1%)
Tracheobronchitis	0/38 (0%)		1/64 (1.6%)		2/98 (2%)		0/99 (0%)		3/101 (3%)
Skin and subcutaneous tissue disorders
Decubitis ulcer	2/38 (5.3%)		0/64 (0%)		2/98 (2%)		2/99 (2%)		2/101 (2%)
Vascular disorders
Lower extremity deep venous thrombophlebitis	1/38 (2.6%)		2/64 (3.1%)		4/98 (4.1%)		2/99 (2%)		5/101 (5%)
Upper extremity deep vein thrombophlebitis	7/38 (18.4%)		7/64 (10.9%)		6/98 (6.1%)		10/99 (10.1%)		10/101 (9.9%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.