Preterm Erythropoietin Neuroprotection Trial (PENUT Trial) | NCT01378273

Obsolete or Duplicate NCT IDs

Not provided

ID	Type	Description	Link
U01NS077953	U.S. NIH Grant/Contract		View source

Status Module

Sponsor/Collaborators Module

Name	Class
National Institute of Neurological Disorders and Stroke (NINDS)	NIH

Oversight Module

Description Module

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.

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

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Control	Placebo Comparator	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
Epo 1000 U/kg followed by 400 U/kg	Experimental	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

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Epo	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Death or Severe Neurodevelopmental Impairment (NDI) at 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.	22-26 months corrected age

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With a Serious Adverse Events (SAE)	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.

Eligibility Module

Contacts/Locations Module

Name	Affiliation	Role
Sandra E Juul, MD, PhD	University of Washington	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University of Arkansas		Little Rock	Arkansas	72202	United States
University of Florida

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
27057344	Result	Juul SE, Mayock DE, Comstock BA, Heagerty PJ. Neuroprotective potential of erythropoietin in neonates; design of a randomized trial. Matern Health Neonatol Perinatol. 2015 Dec 2;1:27. doi: 10.1186/s40748-015-0028-z. eCollection 2015.
28821985	Result	Starr MC, Askenazi DJ, Goldstein SL, MacDonald JW, Bammler TK, Afsharinejad Z, D Brophy P, Juul SE, Mayock DE, Hingorani SR. Impact of processing methods on urinary biomarkers analysis in neonates. Pediatr Nephrol. 2018 Jan;33(1):181-186. doi: 10.1007/s00467-017-3779-0. Epub 2017 Aug 19.

Label	URL
website for the PENUT Trial	View source

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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. 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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Oct 14, 2019

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	Control	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.
BG001	Epo 1000 U/kg Followed by 400 U/kg	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.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Customized

Gestational age at birth

Count of Participants

Participants

Title

Denominators

Categories

24 weeks of gestation

Title	Measurements
	BG000119 BG001113 BG002232

25 weeks of gestation

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG000218 BG001232 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG00085 BG001115 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0007 BG0019 BG002

Region of Enrollment

Number

participants

Title

Denominators

Categories

United States

Title	Measurements
	BG000460 BG001476 BG002

Consented and received first study drug dose

Consented subjects who were enrolled according to IRB procedures and who received 1st study drug dose.

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
	BG000460 BG001476

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Death or Severe Neurodevelopmental Impairment (NDI) at 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.

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.

Posted

Count of Participants

Participants

22-26 months corrected age

ID	Title	Description
OG000	Control	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.
OG001	Epo 1000 U/kg Followed by 400 U/kg	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.

Units	Counts
Participants	OG000365 OG001376

Title

Denominators

Categories

Title	Measurements
	OG00094 OG00197

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	GEE Wald test based on logistic regressi	adjustments were made for gestational age at birth and recruitment site as a fixed effect.	0.05	A two-sided type I error of 0.05 with no formal adjustment for multiple comparisons unless otherwise specified (such as with safety outcomes).	Risk Ratio (RR)	1.03			2-Sided	.05	0.81	1.32

Secondary

Number of Participants With a Serious Adverse Events (SAE)

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.

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

Posted

Count of Participants

Participants

From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)

ID	Title	Description
OG000	Control	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)
OG001	Epo 1000 U/kg Followed by 400 U/kg

Secondary

Imaging

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

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

Posted

Mean

Standard Deviation

score on a scale

36 weeks postmenstrual age

ID	Title	Description
OG000	Control	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)
OG001	Epo 1000 U/kg Followed by 400 U/kg	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).

Units	Counts
Participants

Secondary

Biomarkers

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.

Patients who had a baseline Epo level drawn

Posted

Median

Inter-Quartile Range

mU/mL

Baseline (first 24 hours after birth), days 7, 9 and 14 after birth

ID	Title	Description
OG000	Control	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
OG001	Epo 1000 U/kg Followed by 400 U/kg	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

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Control	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)	45	460	284	460	460	460
EG001	Epo 1000 U/kg Followed by 400 U/kg	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).	53	476	282	476	476	476

Serious Adverse Events

Term	Organ System	Assessment Type	Notes	Statistical Information
Polycythemia	Blood and lymphatic system disorders	Systematic Assessment	Hematocrit > 65	EG0001 events1 affected460 at risk EG0012 events2 affected476 at risk
Major Thrombosis	Blood and lymphatic system disorders	Systematic Assessment		EG0002 events2 affected460 at risk EG0015 events5 affected476 at risk
Severe pulmonary hemorrhage	Respiratory, thoracic and mediastinal disorders	Systematic Assessment		EG00019 events19 affected460 at risk EG00130 events30 affected476 at risk
Necrotizing enterocolitis	Gastrointestinal disorders	Systematic Assessment		EG00036 events36 affected460 at risk EG00128 events28 affected476 at risk
Severe sepsis	Infections and infestations	Systematic Assessment	Culture positive and symptomatic	EG00038 events38 affected460 at risk EG00135 events35 affected476 at risk
Severe intracranial hemorrhage	Nervous system disorders	Systematic Assessment	Grade III or IV	EG00064 events64 affected460 at risk EG00157 events57 affected476 at risk
Severe retinopathy of prematurity	Eye disorders	Systematic Assessment	Requiring treatment	EG00030 events30 affected460 at risk EG00130 events30 affected476 at risk
Hypertension	Cardiac disorders	Systematic Assessment	Requiring treatment	EG00010 events10 affected460 at risk EG0016 events6 affected476 at risk
Nonfatal cardiac arrest	General disorders	Systematic Assessment		EG0008 events8 affected460 at risk EG0019 events9 affected476 at risk
Other unexpected life-threatening events	General disorders	Systematic Assessment		EG00031 events31 affected460 at risk EG00127 events27 affected476 at risk
Death	General disorders	Systematic Assessment		EG00045 events45 affected460 at risk EG00153 events53 affected476 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Bronchopulmonary dysplasia	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG000161 events161 affected460 at risk EG001172 events172 affected476 at risk
Treated patent ductus arteriosus	Cardiac disorders	Systematic Assessment	EG000172 events172 affected460 at risk EG001178 events178 affected476 at risk
Necrotizing enterocolitis	Gastrointestinal disorders	Systematic Assessment	EG00053 events53 affected460 at risk EG00146 events46 affected476 at risk
Intracranial hemorrhage (all grades)	Nervous system disorders	Systematic Assessment	EG000181 events181 affected460 at risk EG001168 events168 affected476 at risk
Periventricular leukomalasia	Nervous system disorders	Systematic Assessment	EG00043 events43 affected460 at risk EG00141 events41 affected476 at risk
Cerebellar hemorrhage	Nervous system disorders	Systematic Assessment	EG00010 events10 affected460 at risk EG0018 events8 affected476 at risk
Retinopathy of Prematurity (all grades)	Eye disorders	Systematic Assessment	EG000258 events258 affected460 at risk EG001244 events244 affected476 at risk
Blood transfusion	Blood and lymphatic system disorders	Systematic Assessment	EG000401 events401 affected460 at risk EG001341 events341 affected476 at risk

ID	Term
D047928	Premature Birth

Ancestor Terms

ID	Term
D007752	Obstetric Labor, Premature
D007744	Obstetric Labor Complications
D011248	Pregnancy Complications
D005261	Female Urogenital Diseases and Pregnancy Complications
D000091642	Urogenital Diseases

ID	Term
D047209	Eosinophil Peroxidase
D004921	Erythropoietin
D012965	Sodium Chloride

Ancestor Terms

ID	Term
D010544	Peroxidases
D010088	Oxidoreductases
D004798	Enzymes
D045762	Enzymes and Coenzymes
D047091	Eosinophil Granule Proteins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D003115	Colony-Stimulating Factors
D006023	Glycoproteins
D006001	Glycoconjugates
D002241	Carbohydrates
D016298	Hematopoietic Cell Growth Factors
D016207	Cytokines
D036341	Intercellular Signaling Peptides and Proteins
D010455	Peptides
D001685	Biological Factors
D002712	Chlorides
D006851	Hydrochloric Acid
D017606	Chlorine Compounds
D007287	Inorganic Chemicals
D017670	Sodium Compounds

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).