Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Washington
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Sandra Juul, University of Washington
ClinicalTrials.gov Identifier:
NCT01378273
First received: June 20, 2011
Last updated: May 8, 2014
Last verified: May 2014
  Purpose

Approximately 50,000 infants per year (961 per week) are born at less than 28 weeks of gestation in the US. Cerebral palsy, deafness, blindness, and/or mental retardation are present in up to 50% of surviving extremely preterm infants at school age. Perinatal care costs for these infants exceed US$18 billion every year. The burden of extreme prematurity to each patient and to society is further magnified by the years of productive life lost. New therapies are needed to improve these outcomes.

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 Intervention Phase
Extreme Prematurity
Drug: Epo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)

Resource links provided by NLM:


Further study details as provided by University of Washington:

Primary Outcome Measures:
  • neurodevelopmental outcome [ Time Frame: 24-26 months corrected age ] [ Designated as safety issue: No ]
    neurodevelopmental exam Bayley III: MDI and PDI


Secondary Outcome Measures:
  • safety [ Time Frame: term PMA ] [ Designated as safety issue: Yes ]
    The safety of Epo treatment will be assessed by comparing adverse events and co-morbidities between groups

  • Imaging [ Time Frame: 24-26 months ] [ Designated as safety issue: No ]
    MRI at 36 weeks PMA will be used as a biomarker of long-term outcomes

  • Biomarkers [ Time Frame: 24-26 months of age ] [ Designated as safety issue: No ]
    Circulating biomarkers of inflammation and brain injury will be evaluated and correlated to neurodevelopmental outcomes.


Estimated Enrollment: 940
Study Start Date: December 2013
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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 48 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

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.

  Eligibility

Ages Eligible for Study:   24 Weeks to 27 Weeks
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01378273

Contacts
Contact: Stephanie Hauge, MS shauge@uw.edu
Contact: Elizabeth Howland, BA ehowland@uw.edu

Locations
United States, Arkansas
University of Arkansas Recruiting
Little Rock, Arkansas, United States, 72202
Contact: Carol Sikes, MSN         
Principal Investigator: Sherry Courtney, MD         
Sub-Investigator: Billy Thomas, MD         
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Cindy Miller, RN         
Principal Investigator: Michael Weiss, MD         
Florida Hospital Recruiting
Orlando, Florida, United States
Contact: Robin Barron-Nelson, MSN         
Principal Investigator: Rajan Wadhawan, MD         
All Childrens Hospital Recruiting
St Petersburg, Florida, United States
Contact: Suzi Bell, DNP         
Principal Investigator: Victor McKay, MD         
Sub-Investigator: Sandra Brooks, MD         
United States, Illinois
Children's Hospital of the University of Illinois Recruiting
Chicago, Illinois, United States, 60612
Contact: Malwina Sobanaski         
Principal Investigator: Akhil Maheshwari, MD         
Sub-Investigator: Sachin Amin, MD         
Prentice Women's Hospital Recruiting
Chicago, Illinois, United States, 60611
Contact: Janine Khan, MD         
Principal Investigator: Janine Khan, MD         
United States, Kentucky
University of Louisville Recruiting
Louisville, Kentucky, United States, 40202
Contact: Neviana Dimova, MD,MS         
Principal Investigator: Tonya Ronbinson, MD         
United States, Maryland
Johns Hopkins Not yet recruiting
Baltimore, Maryland, United States, 21224
Contact: Charla Parkinson         
Principal Investigator: Maureen Gilmore, MD         
Sub-Investigator: Francis Northington, MD         
United States, Massachusetts
Beth Israel Deaconess Hospital Recruiting
Boston, Massachusetts, United States, 02215
Contact: Rachel Wegner, MS         
Sub-Investigator: Ivan Frantz, MD         
Principal Investigator: Deirdre O'Reilly, MD, MPH         
Sub-Investigator: Camilia Martin, MD, MS         
United States, Minnesota
Children's Hospital of Minnesota, MN Recruiting
Minneapolis, Minnesota, United States, 55404
Contact: Cathy Worwa, RN         
Principal Investigator: Ellen Bendel-Stenzel, MD         
Sub-Investigator: Neil Mulrooney, MD         
University of Minnesota Amplatz Children's Hospital Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Bridget Davern, CCRP         
Principal Investigator: Raghavendra Rao, MD         
Sub-Investigator: Nancy Fahim, MD         
Children's Hospital of Minnesota, St. Paul Recruiting
St. Paul, Minnesota, United States, 55102
Contact: Cathy Worwa         
Principal Investigator: Mark Mammel, MD         
Principal Investigator: Andrea Lampland, MD         
United States, New Mexico
University of New Mexico Children's Hospital Recruiting
Albuquerque, New Mexico, United States, 87131
Contact: Sandra Beauman, MSN         
Principal Investigator: Robin Ohls, MD         
Sub-Investigator: Jean Lowe, MD         
United States, New York
Maia Fareri Children's Hospital Recruiting
Valhalla, New York, United States, 10595
Contact: Rita Daly         
Principal Investigator: Edmund LaGamma, MD         
Sub-Investigator: Jordan Kase, MD         
Sub-Investigator: Semsa Gogcu, MD         
United States, North Carolina
Wake Forest School of Medicine Recruiting
Winston Salem, North Carolina, United States, 27157
Contact: Kelly Warden, RN         
Principal Investigator: Michael O'Shea, MD         
Sub-Investigator: L.Corbin Downey, MD, MPH         
United States, Texas
Methodist Children's Hospital Recruiting
San antonio, Texas, United States, 78229
Contact: Kaashif Ahmad, MD         
Principal Investigator: Kaashif Ahmad, MD         
Sub-Investigator: Vivek Vijayamadhavan, MD         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84108
Contact: Manndi Loertscher, RN         
Contact: Carrie Rau, RN         
Principal Investigator: Mariana Baserga, MD         
Sub-Investigator: Bradley Yoder, MD         
United States, Washington
University of Washington Recruiting
Seattle, Washington, United States, 98195
Contact: Stephanie Hauge, MS       shauge@uw.edu   
Contact: Elizabeth Howland, BA       ehowland@uw.edu   
Principal Investigator: Dennis E Mayock, MD         
Sub-Investigator: Sandra Juul, MD, PhD         
Sponsors and Collaborators
University of Washington
Investigators
Principal Investigator: Sandra E Juul, MD, PhD University of Washington
  More Information

Additional Information:
No publications provided

Responsible Party: Sandra Juul, Professor of Pediatrics, University of Washington
ClinicalTrials.gov Identifier: NCT01378273     History of Changes
Other Study ID Numbers: U01NS077953-01
Study First Received: June 20, 2011
Last Updated: May 8, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Washington:
neuroprotection
erythropoietin
Epo
ELGANs
preterm
neonate

Additional relevant MeSH terms:
Epoetin Alfa
Hematinics
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 20, 2014