Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT01378273
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 941
• Locations: 19
• Arms: 2
• Duration (Months): 74.9
• Patients Per Site: 49.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Recombinant human erythropoietin (Epo) is a promising novel neuroprotective agent. Epo decreases neuronal programmed cell death resulting from brain injury; it has anti-inflammatory effects, increases neurogenesis, and protects oligodendrocytes from injury.

We hypothesize that neonatal Epo treatment of ELGANs will decrease the combined outcome of death or severe NDI from 40% to 30% (primary outcome), or the combined outcome of death plus moderate or severe NDI from 60% to 40% (secondary outcome) measured at 24-26 months corrected age.

1. To determine whether Epo decreases the combined outcome of death or NDI at 24-26 months corrected age. NDI is defined as the presence of any one of the following: CP, Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III) Cognitive Scale < 70 (severe, 2 SD below mean) or 85 (moderate, 1 SD below mean). CP will be diagnosed and classified by standardized neurologic exam, with severity classified by Gross Motor Function Classification System (GMFCS).

2. To determine whether there are risks to Epo administration in ELGANs by examining, in a blinded manner, Epo-related safety measures comparing infants receiving Epo with those given placebo.

3. To test whether Epo treatment decreases serial measures of circulating inflammatory mediators, and biomarkers of brain injury.

4. To compare brain structure (as measured by MRI) in Epo treatment and control groups at 36 weeks PMA. MRI assessments will include documentation of intraventricular hemorrhage (IVH), white matter injury (WMI) and hydrocephalus (HC), volume of total and deep gray matter, white matter and cerebellum, brain gyrification, and tract-based spatial statistics (TBSS based on diffusion tensor imaging). As an exploratory aim, we will determine which of the above MRI measurements best predict neurodevelopment (CP, cognitive and motor scales) at 24-26 months corrected age.

Anticipated outcomes: Early Epo treatment of ELGANs will decrease biochemical and MRI markers of brain injury, will be safe, and will confer improved neurodevelopmental outcome at 24-26 months corrected age compared to placebo, and will provide a much-needed therapy for this group of vulnerable infants.

Condition or Disease	Intervention/Treatment	Phase
Extreme Prematurity	Drug: Epo; Other: Control	Phase 3

Detailed Description

This is a randomized, placebo-controlled, study of Epo treatment of preterm infants 24-0/7 to 27-6/7 weeks of gestation, beginning in the first 24 hours after birth. Randomization will be stratified by site and gestational age at birth (<26 week or 26-27-6/7). Study size sample is 940 patients. We expect to evaluate 752 subjects at 24-26 months corrected age, our primary endpoint. There is no enrollment restriction based on gender, ethnicity or race. Enrollment is expected to take 24-26 months, with each subject participating through 24-26 months corrected age when neurodevelopmental outcomes are assessed. The combined outcome of death or severe NDI will be compared between Epo-treated and control subjects. All outcomes will be collected in a blinded manner. Subjects will be randomized by the data-coordinating center (DCC) to Epo treatment or placebo, and Epo treatment will continue until 32-6/7 weeks post menstrual age. Serial measurements of circulating inflammatory mediators and biomarkers of brain injury will be made. A brain MRI will be done at 36 weeks post menstrual age in the same subset of infants. Phone contact will occur at 4, 8, 12, and 18 months. Face to face follow up will occur at 24-26 months corrected age. The primary outcome is death or severe NDI at 24-26 months corrected age, with a secondary outcome of death or moderate NDI. Our primary sample size calculation is based on the conservative assumptions that Epo treatment will result in a 40% reduction in the severe NDI rate (the range in animal studies is 49-70%) and minimal impact on death. This would yield a control group rate for the primary outcome of 40.4% and an expected treated rate of 31.5% thus yielding an 8.9% lower rate of Death + NDI.

Clinical information including co-morbidities of extreme prematurity, information about transfusions, and specific laboratory values were collected in the PENUT database.

Study Design

• Study Type: Interventional
• Actual Enrollment: 941 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)
• Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Feb 28, 2019
• Actual Study Completion Date: Feb 28, 2020

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Control Subjects will receive 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age.	Other: Control; Subjects will receive 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age.; Other Names: Saline
Experimental: Epo 1000 U/kg followed by 400 U/kg Subjects will receive 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects will receive subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age.	Drug: Epo; Enrollment will occur within 24 hours of birth. Study drug will be administered intravenously for the first 6 doses. Subjects in the Epo arm will then receive 400 U/kg/dose three times a week until they reach 32-6/7 weeks postmenstrual age. Control infants will receive sham injections.; Other Names: Epotin Erythropoietin

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Death or Severe Neurodevelopmental Impairment (NDI) at 22-26 Months Corrected Age [22-26 months corrected age]

   Severe NDI was defined as Bayley Scales of infant Development, 3rd edition composite motor score or composite cognitive score <70. This instrument is normed at 100 with standard deviation of 15. Cerebral palsy was classified as hemiplegia, diplegia, or quadriplegia, and severity was determined according to the Gross Motor Function Classification System (GMFCS) (levels range from 0 [no impairment] to 5 [most severe impairment]). Severe cerebral palsy was defined as a GMFCS level higher than 2.

Secondary Outcome Measures

1. Number of Participants With a Serious Adverse Events (SAE) [From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)]

   Serious adverse events were prespecified. These included any symptomatic thrombosis involving a major vessel, unrelated to an infusion catheter requiring anticoagulation therapy, hematocrit level >65% or an increase of ≥15% in hematocrit in the absence of a preceding blood transfusion, hypertension (defined by receipt of antihypertensive therapy for more than 1 month, discharge with medication, or both), severe pulmonary hemorrhage, severe necrotizing enterocolitis (defined as Bell's stage 2b or 3), severe retinopathy of prematurity resulting in laser surgery or bevacizumab therapy, severe sepsis (defined as culture-proven bacterial or fungal sepsis resulting in blood-pressure support or substantive new respiratory support), grade 3 or 4 intracranial hemorrhage, cardiac arrest that did not result in death, and death.

2. Imaging [36 weeks postmenstrual age]

   Brain MRI at 36 weeks PMA. Injury scoring was done using a modified scoring system of Kidokoro, with higher scores indicating greater brain injury. Scoring Range: 0-39

3. Biomarkers [Baseline (first 24 hours after birth), days 7, 9 and 14 after birth]

   Plasma Epo concentrations were measured in both groups within the first 24 h after birth before study drug administration (baseline), 30 minutes after study drug administration on day 7 (peak Epo concentration) and 30 minutes before study drug on day 9 (trough Epo) and a random level on day 14 after transition to subcutaneous dosing.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 24 Weeks to 27 Weeks
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. NICU inpatients between 24-0/7 and 27-6/7 weeks of gestation

2. Less than twenty four hours of age

3. Parental informed consent

Exclusion Criteria:

1. Major life-threatening anomalies (brain, cardiac, chromosomal anomalies)

2. Hematologic crises such as DIC, or hemolysis due to blood group incompatibilities

3. Polycythemia (hematocrit > 65)

4. Congenital infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas	Little Rock	Arkansas	United States	72202
2	University of Florida	Gainesville	Florida	United States	32610
3	South Miami Hospital	Miami	Florida	United States	33146
4	Florida Hospital	Orlando	Florida	United States	32804
5	All Childrens Hospital	Saint Petersburg	Florida	United States	33701
6	Prentice Women's Hospital	Chicago	Illinois	United States	60611
7	Children's Hospital of the University of Illinois	Chicago	Illinois	United States	60612
8	University of Louisville	Louisville	Kentucky	United States	40202
9	Johns Hopkins	Baltimore	Maryland	United States	21224
10	Beth Israel Deaconess Hospital	Boston	Massachusetts	United States	02215
11	Children's Hospital of Minnesota, MN	Minneapolis	Minnesota	United States	55404
12	University of Minnesota Amplatz Children's Hospital	Minneapolis	Minnesota	United States	55455
13	Children's Hospital of Minnesota, St. Paul	Saint Paul	Minnesota	United States	55102
14	University of New Mexico Children's Hospital	Albuquerque	New Mexico	United States	87131
15	Maia Fareri Children's Hospital	Valhalla	New York	United States	10595
16	Wake Forest School of Medicine	Winston-Salem	North Carolina	United States	27157
17	Methodist Children's Hospital	San Antonio	Texas	United States	78229
18	University of Utah	Salt Lake City	Utah	United States	84108
19	University of Washington	Seattle	Washington	United States	98195

Sponsors and Collaborators

• University of Washington
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Sandra E Juul, MD, PhD, University of Washington

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 14, 2019

More Information

Additional Information:

• website for the PENUT Trial

Publications

None provided.

• Responsible Party: Sandra Juul, Professor of Pediatrics, University of Washington
• ClinicalTrials.gov Identifier: NCT01378273
• Other Study ID Numbers: STUDY00007464; U01NS077953
• First Posted: Jun 22, 2011
• Last Update Posted: Aug 26, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Sandra Juul, Professor of Pediatrics, University of Washington: neuroprotection; erythropoietin; Epo; ELGANs; preterm; neonate
• Additional relevant MeSH terms: Premature Birth; Epoetin Alfa

Study Results

Participant Flow

Arm/Group Title	Control	Epo 1000 U/kg Followed by 400 U/kg
Arm/Group Description	Subjects will receive 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age. Control: Subjects will receive 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age.	Subjects will receive 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects will receive subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age. Epo: Enrollment will occur within 24 hours of birth. Study drug will be administered intravenously for the first 6 doses. Subjects in the Epo arm will then receive 400 U/kg/dose three times a week until they reach 32-6/7 weeks postmenstrual age. Control infants will receive sham injections.
Period Title: Overall Study
STARTED	464	477
COMPLETED	460	476
NOT COMPLETED	4	1

Baseline Characteristics

Arm/Group Title	Control	Epo 1000 U/kg Followed by 400 U/kg	Total
Arm/Group Description	Enrollment will occur within 24 hours of birth. Subjects will receive 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age. Subjects are then followed until 22-26 months for neurodevelopmental testing.	Enrollment will occur within 24 hours of birth. Epo 1000 U/kg/dose will be administered intravenously for the first 6 doses. Subjects in the Epo arm will then receive 400 U/kg/dose three times a week until they reach 32-6/7 weeks postmenstrual age. Subjects are then followed until 22-26 months for neurodevelopmental testing.	Total of all reporting groups
Overall Participants	460	476	936
Age, Customized (Count of Participants)
24 weeks of gestation	119 25.9%	113 23.7%	232 24.8%
25 weeks of gestation	124 27%	121 25.4%	245 26.2%
26 weeks of gestation	118 25.7%	103 21.6%	221 23.6%
27 weeks of gestation	99 21.5%	139 29.2%	238 25.4%
Sex: Female, Male (Count of Participants)
Female	218 47.4%	232 48.7%	450 48.1%
Male	242 52.6%	244 51.3%	486 51.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	85 18.5%	115 24.2%	200 21.4%
Not Hispanic or Latino	370 80.4%	354 74.4%	724 77.4%
Unknown or Not Reported	5 1.1%	7 1.5%	12 1.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	7 1.5%	9 1.9%	16 1.7%
Asian	18 3.9%	10 2.1%	28 3%
Native Hawaiian or Other Pacific Islander	6 1.3%	2 0.4%	8 0.9%
Black or African American	120 26.1%	120 25.2%	240 25.6%
White	293 63.7%	317 66.6%	610 65.2%
More than one race	2 0.4%	2 0.4%	4 0.4%
Unknown or Not Reported	14 3%	16 3.4%	30 3.2%
Region of Enrollment (participants) [Number]
United States	460 100%	476 100%	936 100%
Consented and received first study drug dose (Count of Participants)
Count of Participants [Participants]	460 100%	476 100%	936 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Death or Severe Neurodevelopmental Impairment (NDI) at 22-26 Months Corrected Age
Description	Severe NDI was defined as Bayley Scales of infant Development, 3rd edition composite motor score or composite cognitive score <70. This instrument is normed at 100 with standard deviation of 15. Cerebral palsy was classified as hemiplegia, diplegia, or quadriplegia, and severity was determined according to the Gross Motor Function Classification System (GMFCS) (levels range from 0 [no impairment] to 5 [most severe impairment]). Severe cerebral palsy was defined as a GMFCS level higher than 2.
Time Frame	22-26 months corrected age

Outcome Measure Data

Analysis Population Description

936 subjects 24-0/7 to 27-6/7 weeks' gestation were randomized and received Epo (n=476) or placebo (n=460) in a double-blinded manner. Survivors who were fully evaluated at 2 years of age are included in the analysis.

Arm/Group Title	Control	Epo 1000 U/kg Followed by 400 U/kg
Arm/Group Description	Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age.	Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age.
Measure Participants	365	376
Count of Participants [Participants]	94 20.4%	97 20.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Epo 1000 U/kg Followed by 400 U/kg
	Comments	We evaluated the primary outcome of death or neurodevelopmental impairment using generalized estimating equations to account for potential correlation within siblings from the same pregnancy, with adjustment for gestational age at birth and recruitment site as a fixed effect. The primary analysis included infants with complete data and excluded data from infants known to be alive but in whom neurodevelopmental outcomes were not assessed.
	Type of Statistical Test	Superiority
	Comments	We assumed no effect of treatment on death, but that Epo will lead to a decrease in the rate of NDI. If we assume a multiplicative reduction in the NDI rate of 0.45 then we expect a treated NDI rate of 12 percent and an overall rate of death+NDI of 30.4% as compared to the control rate of 40.4% corresponding to an overall treatment rate ratio of 0.75. This leads to a sample size of 376 evaluated subjects per arm or a total evaluated sample size of 752 subjects.
Statistical Test of Hypothesis	p-Value	0.05
	Comments	A two-sided type I error of 0.05 with no formal adjustment for multiple comparisons unless otherwise specified (such as with safety outcomes).
	Method	GEE Wald test based on logistic regressi
	Comments	adjustments were made for gestational age at birth and recruitment site as a fixed effect.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) .05%; 0.81 to 1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	The numerator is the Epo group, denominator is the control group

2. Secondary Outcome

Title	Number of Participants With a Serious Adverse Events (SAE)
Description	Serious adverse events were prespecified. These included any symptomatic thrombosis involving a major vessel, unrelated to an infusion catheter requiring anticoagulation therapy, hematocrit level >65% or an increase of ≥15% in hematocrit in the absence of a preceding blood transfusion, hypertension (defined by receipt of antihypertensive therapy for more than 1 month, discharge with medication, or both), severe pulmonary hemorrhage, severe necrotizing enterocolitis (defined as Bell's stage 2b or 3), severe retinopathy of prematurity resulting in laser surgery or bevacizumab therapy, severe sepsis (defined as culture-proven bacterial or fungal sepsis resulting in blood-pressure support or substantive new respiratory support), grade 3 or 4 intracranial hemorrhage, cardiac arrest that did not result in death, and death.
Time Frame	From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study drug.

Arm/Group Title	Control	Epo 1000 U/kg Followed by 400 U/kg
Arm/Group Description	Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age (PMA)	Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age (PMA).
Measure Participants	460	476
Count of Participants [Participants]	284 61.7%	282 59.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Epo 1000 U/kg Followed by 400 U/kg
	Comments	We hypothesized that Epo would be safe, with no excess of SAEs compared to control infants. Sample size was based on the primary outcome, severe neurodevelopmental impairment or death.
	Type of Statistical Test	Other
	Comments	SAEs were defined prospectively. The rate of total SAEs observed through hospital discharge were compared after accounting for potential within-sibship correlation (with multiple gestations) using Generalized Estimating Equations (GEE) with robust standard errors. We used a GEE Wald test based on Poisson or logistic regression for total SAE count and individual events respectively. All other non-categorical data were assessed with GEE regression models appropriate for continuous outcomes.
Statistical Test of Hypothesis	p-Value	0.05
	Comments	Statistical significance was set at 0.05 for the efficacy analysis and for the final safety analysis comparing the rate of total SAEs between treatment groups, and 0.031 for death and 0.004 for the ten individual SAEs due to sequential monitoring.
	Method	Poisson regression
	Comments	Adjusted for multiple gestation and gestational age
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Epo is numerator and Control is denominator

3. Secondary Outcome

Title	Imaging
Description	Brain MRI at 36 weeks PMA. Injury scoring was done using a modified scoring system of Kidokoro, with higher scores indicating greater brain injury. Scoring Range: 0-39
Time Frame	36 weeks postmenstrual age

Outcome Measure Data

Analysis Population Description

Patients who survived to 36 weeks postmenstrual age at 9 preselected sites

Arm/Group Title	Control	Epo 1000 U/kg Followed by 400 U/kg
Arm/Group Description	Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age (PMA)	Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age (PMA).
Measure Participants	101	93
Mean (Standard Deviation) [score on a scale]	4.1 (2.6)	3.8 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Epo 1000 U/kg Followed by 400 U/kg
	Comments	For all statistical comparisons between groups, Generalized Estimating Equations (GEE) with robust standard errors and a working independence correlation structure for infants included from a multiple gestation were used. A GEE-based Wald test was used to examine differences in the global brain injury severity score between treatment groups, with adjustment for gestational age (GA) at birth used to stratify treatment randomization (24+0 to 25+6 vs. 26+0 to 27+6 in weeks+days of GA).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments	Statistical significance was evaluated using a Wald's test and declared significant if p < 0.05.
	Method	Generalized estimating equation
	Comments	Adjusted for gestational age at birth and treatment assignment.

4. Secondary Outcome

Title	Biomarkers
Description	Plasma Epo concentrations were measured in both groups within the first 24 h after birth before study drug administration (baseline), 30 minutes after study drug administration on day 7 (peak Epo concentration) and 30 minutes before study drug on day 9 (trough Epo) and a random level on day 14 after transition to subcutaneous dosing.
Time Frame	Baseline (first 24 hours after birth), days 7, 9 and 14 after birth

Outcome Measure Data

Analysis Population Description

Patients who had a baseline Epo level drawn

Arm/Group Title	Control	Epo 1000 U/kg Followed by 400 U/kg
Arm/Group Description	Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age. Bayley scores of infant development were assessed at 22-26 months	Enrollment occured within 24 hours of birth. Epo 1000 U/kg/dose was administered intravenously for the first 6 doses. Subjects then received 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age. Bayley scores of infant development were assessed at 22-26 months
Measure Participants	384	391
Baseline	7.6	7
Peak Epo	2.2	2,907
Trough Epo	5.1	15.3
Random (day 14)	4.6	25

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Epo 1000 U/kg Followed by 400 U/kg
	Comments	For statistical inference, we utilized generalized estimating equations (GEE) with robust standard errors to appropriately account for potential correlation of biomarkers for same-birth siblings. Each respective GEE model adjusted for gestational age at birth and treatment assignment as fixed factors associated with the original study design. Biomarker levels at each follow-up time point were analysed using separate GEE models. Epo levels were log-transformed in all statistical analyses.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical significance was evaluated using a Wald's test and declared significant if p < 0.007.
	Method	Generalized estimating equation
	Comments	Adjusted for gestational age at birth and treatment assignment.

Adverse Events

Time Frame	Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Arm/Group Title	Control		Epo 1000 U/kg Followed by 400 U/kg
Arm/Group Description	Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age (PMA)		Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age (PMA).
All Cause Mortality
	Control		Epo 1000 U/kg Followed by 400 U/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/460 (9.8%)		53/476 (11.1%)
Serious Adverse Events
	Control		Epo 1000 U/kg Followed by 400 U/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	284/460 (61.7%)		282/476 (59.2%)
Blood and lymphatic system disorders
Polycythemia	1/460 (0.2%)	1	2/476 (0.4%)	2
Major Thrombosis	2/460 (0.4%)	2	5/476 (1.1%)	5
Cardiac disorders
Hypertension	10/460 (2.2%)	10	6/476 (1.3%)	6
Eye disorders
Severe retinopathy of prematurity	30/460 (6.5%)	30	30/476 (6.3%)	30
Gastrointestinal disorders
Necrotizing enterocolitis	36/460 (7.8%)	36	28/476 (5.9%)	28
General disorders
Nonfatal cardiac arrest	8/460 (1.7%)	8	9/476 (1.9%)	9
Other unexpected life-threatening events	31/460 (6.7%)	31	27/476 (5.7%)	27
Death	45/460 (9.8%)	45	53/476 (11.1%)	53
Infections and infestations
Severe sepsis	38/460 (8.3%)	38	35/476 (7.4%)	35
Nervous system disorders
Severe intracranial hemorrhage	64/460 (13.9%)	64	57/476 (12%)	57
Respiratory, thoracic and mediastinal disorders
Severe pulmonary hemorrhage	19/460 (4.1%)	19	30/476 (6.3%)	30
Other (Not Including Serious) Adverse Events
	Control		Epo 1000 U/kg Followed by 400 U/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	460/460 (100%)		476/476 (100%)
Blood and lymphatic system disorders
Blood transfusion	401/460 (87.2%)	401	341/476 (71.6%)	341
Cardiac disorders
Treated patent ductus arteriosus	172/460 (37.4%)	172	178/476 (37.4%)	178
Eye disorders
Retinopathy of Prematurity (all grades)	258/460 (56.1%)	258	244/476 (51.3%)	244
Gastrointestinal disorders
Necrotizing enterocolitis	53/460 (11.5%)	53	46/476 (9.7%)	46
Nervous system disorders
Intracranial hemorrhage (all grades)	181/460 (39.3%)	181	168/476 (35.3%)	168
Periventricular leukomalasia	43/460 (9.3%)	43	41/476 (8.6%)	41
Cerebellar hemorrhage	10/460 (2.2%)	10	8/476 (1.7%)	8
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary dysplasia	161/460 (35%)	161	172/476 (36.1%)	172

Limitations/Caveats

[Not Specified]

More Information

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.