Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)

Extreme Prematurity Clinical Trial

— PENUT  

Official title:

Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01378273
• Other study ID #: STUDY00007464
• Secondary ID: U01NS077953
• Status: Completed
• Phase: Phase 3
• Start date: December 2013
• Est. completion date: February 28, 2020

Study information

• Verified date: August 2020
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 941
• Est. completion date: February 28, 2020
• Est. primary completion date: February 28, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 24 Weeks to 27 Weeks

Eligibility

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

Related Conditions & MeSH terms

• Extreme Prematurity
• Premature Birth

Intervention

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:
• 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.

Locations

Country	Name	City	State
United States	University of New Mexico Children's Hospital	Albuquerque	New Mexico
United States	Johns Hopkins	Baltimore	Maryland
United States	Beth Israel Deaconess Hospital	Boston	Massachusetts
United States	Children's Hospital of the University of Illinois	Chicago	Illinois
United States	Prentice Women's Hospital	Chicago	Illinois
United States	University of Florida	Gainesville	Florida
United States	University of Arkansas	Little Rock	Arkansas
United States	University of Louisville	Louisville	Kentucky
United States	South Miami Hospital	Miami	Florida
United States	Children's Hospital of Minnesota, MN	Minneapolis	Minnesota
United States	University of Minnesota Amplatz Children's Hospital	Minneapolis	Minnesota
United States	Florida Hospital	Orlando	Florida
United States	Children's Hospital of Minnesota, St. Paul	Saint Paul	Minnesota
United States	All Childrens Hospital	Saint Petersburg	Florida
United States	University of Utah	Salt Lake City	Utah
United States	Methodist Children's Hospital	San Antonio	Texas
United States	University of Washington	Seattle	Washington
United States	Maia Fareri Children's Hospital	Valhalla	New York
United States	Wake Forest School of Medicine	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of Washington	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Juul SE, Comstock BA, Wadhawan R, Mayock DE, Courtney SE, Robinson T, Ahmad KA, Bendel-Stenzel E, Baserga M, LaGamma EF, Downey LC, Rao R, Fahim N, Lampland A, Frantz Iii ID, Khan JY, Weiss M, Gilmore MM, Ohls RK, Srinivasan N, Perez JE, McKay V, Vu PT, L — View Citation

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. Review. — View Citation

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/s00 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	22-26 months corrected age
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.	From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)
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	36 weeks postmenstrual age
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.	Baseline (first 24 hours after birth), days 7, 9 and 14 after birth

External Links

•   website for the PENUT Trial