The aim of this NINDS funded trial is to assess whether high dose Epo will improve survival without neurodevelopmental impairment (NDI) in infants born between 24 and 28 weeks of gestation (term is 40 weeks). 940 infants will be enrolled at 16 centers across the U.S. Subjects will be assessed at 2 years of age to see whether Epo treatment will improve neurodevelopmental outcomes.
Principal Investigators, Clinical Coordinating Center: Sandra Juul, MD, PhD
Principal Investigator, Data Coordinating Center: Patrick Heagerty, PhD
Funding: NINDS 1U01NS077953-01
ClinicalTrials.gov Identifier: NCT01378273
Prematurity is defined as a birth that occurs before 37 completed weeks of gestation. It is associated with about one-third of all infant deaths in the United States and accounts for approximately 45 percent of children with cerebral palsy, 35 percent of children with vision impairment, and 25 percent of children with cognitive or hearing impairment. (Ref: UpToDate).
The risk of complications of prematurity increases with increasing immaturity. Thus, infants who are extremely premature, born at or before 28 weeks of gestation, have the highest mortality rate, and if they survive, are at the greatest risk for long-term problems.
In preterm survivors, there is a high rate of long-term neurodevelopment impairment and chronic health problems. These chronic medical and neurodevelopmental complications often require additional health care and educational services, which add to the overall economic cost of caring for the premature infant.
Prematurity can be defined by gestational age or birth weight:
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.
Erythropoietin Neuroprotection: The neuroprotective and neuroregenerative effects of high dose Epo have been well documented in experimental models of neonatal brain injury.1-7 While Epo neuroprotection for preterm infants holds translational promise, only 2 phase I/II trials have been published to date.8, 9 We predict the anti-apoptotic, anti-inflammatory,10-12 oligodendrocyte protective12-19 and neurogenic effects20-26 will decrease acute and chronic brain injury, and support normal brain development, thereby improving the neurologic outcomes of ELGANs. Pragmatically, Epo is FDA approved, widely available, affordable, and has proven safe in over 25 years of randomized controlled trials evaluating neonatal erythropoiesis.
Epo Neuroprotection. The hematopoietic cytokine Epo has neuroprotective and neuroregenerative effects in the brain.7 Mechanisms of Epo neuroprotection include receptor-mediated, cell specific effects that occur both early and late in the healing process, and non-specific effects that also modulate the response to injury. Epo has anti-inflammatory, anti-excitotoxic,27 anti-oxidant,28 and anti-apoptotic effects on neurons and oligodendrocytes, and promotes neurogenesis and angiogenesis, which are essential for injury repair and normal neurodevelopment. Epo effects are dose-dependent, and multiple doses are more effective than single doses.1, 21, 26 Epo reduces neuronal loss and learning impairment following brain injury,29, 30 and even when initiated as late as 48-72 hours after injury, there is evidence of improved behavioral outcomes, enhanced neurogenesis, increased axonal sprouting, and reduced WMI.16, 31
White matter injury. WMI is a common brain injury affecting preterm infants.32-34 Epo decreases WMI in adult and neonatal animal models of brain injury.12-14, 16, 35-38 Mechanisms for this may be Epo protection of vulnerable preoligodendrocytes: functional Epo receptors are expressed by immature oligodendrocytes, Epo promotes the proliferation, maturation and differentiation these cells,19 and protects them from injury induced by interferon-γ, lipopolysaccharide (LPS), and hypoxic-ischemia.16-18
Inflammation. Perinatal inflammation (chorioamnionitis, necrotizing enterocolitis (NEC), or sepsis) is associated with increased risk of NDI.39-41 Microglial activation and increased cytokine expression, particularly TNF-a, interleukin (IL)-6, and IL-8, have been associated with brain injury in preterm infants and in animal models of neonatal brain injury.42 Epo has demonstrated anti-inflammatory effects, which may contribute to neuroprotection in the scenario of preterm birth and increased inflammatory activity.10, 11, 43-47
Apoptosis. Neurons in the developing brain are more likely than adult neurons to undergo apoptosis if exposed to injurious stimuli,48, 49 and the anti-apoptotic properties of Epo may protect these vulnerable neurons.1, 22, 50
Repair. Epo stimulates growth factors required for normal brain growth such as brain-derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF).20, 51 Epo enhances neurogenesis,20-26 angiogenesis, repair and plasticity, thus providing long lasting neuroprotective and trophic effects.21, 23, 31, 52-55
Reactive Iron. Iron is highly reactive and normally sequestered by transport proteins. Unbound iron produces free radicals and subsequent oxidative injury. Preterm infants have measurable free iron, which increases after transfusions of red blood cells or during metabolic instability such as sepsis.56-59 In our phase I/II study of Epo administration in extremely low birth weight infants we observed a transient increase in reticulocytosis, indicating an increase in iron utilization.60 Epo may contribute to neuroprotection by decreasing free iron.
Molecular mechanisms of Epo neuroprotection. EpoR are present on neuron progenitor cells,20 neurons,61 astrocytes,19 oligodendrocytes,62 microglia,63 endothelial cells20 and erythrocyte progenitors. Epo has direct neuroprotective effects via EpoR binding: Epo-bound receptors dimerize to activate anti-apoptotic pathways via phosphorylation of JAK2, phosphorylation and activation of MAPK, ERK1/2, as well as the PI3K/Akt pathway and STAT5, which are critical in cell survival.50, 63 Epo also functions through indirect effects, increasing iron utilization by increasing erythropoiesis, and by decreasing inflammation10, 11 and oxidative injury.64, 65
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940 babies will be enrolled at 16 centers across the US. Half of the babies enrolled in the study will get standard care plus Epo, and half will get standard care plus a placebo (an inactive substance with no medicine). Babies will be followed every 4 months by phone contact until they are 2 years old, and tested in person at 2 years of age to see how they are developing.
Epo is commonly used in preterm infants, children and adults to help them make red blood cells (these are cells that carry oxygen in the blood). The dose used for making red blood cells has been well tested and is safe in premature babies, but the dose needed for brain protection is higher. Epo is considered experimental when given to premature babies to try to protect the baby from neurological (brain) damage. We are doing this research to find out if the research doses are safe in babies and to test whether babies who receive this drug have better outcomes. Read more About Epo.
Babies entering the study will have a head ultrasound done before receiving any study drug. Half the babies will receive Epo and half will receive the inactive medicine. The first 6 doses of study medication will be by intravenous catheter (IV), and will be given every other day starting on day one. The placebo dosing procedure is identical to Epo dosing for the first 6 doses, but no active medicine will be given. The later doses of Epo will be given by subcutaneous injection (shot), which is the recommended way of giving this medication. If your child is in the placebo group, no further doses or shots will be given.
We will measure the Epo levels in the baby's blood at 4 specific times before and after treatment. We will also test for the effects of Epo at these times. The total amount of blood needed for this study is less than 1/2 teaspoon and will not change the need for a transfusion.
We will collect information from the mom and baby's medical records. The information collected will include information about the pregnancy, the baby's gestational age, weight, body length, blood pressure, lab tests, head measurements, and medical problems that occur during their NICU stay. We will do this until the child is discharged from the hospital. If infants are transferred to another hospital before going home, we will continue to follow them until they go home. We will follow the babies development until they are 2 years old.
Epo is often used in preterm infants to help them make red blood cells. Epo treatment is effective when used this way; however, the dose of Epo that we will use in this study to test for brain protection is higher and there may be unknown and unexpected risks for infants. High doses of Epo have been studied in newborns and no safety concerns were noted. Epo will increase the production of red blood cells, and may increase the blood pressure. We will carefully monitor your infant for any side effects that Epo may have.
The risks associated with erythropoietin (Epo) include:
Read more about the trial on the clinicaltrials.gov website.
Sixteen sites across the country are enrolling eligible infants into the PENUT trial. For more information about each site please click on the link below to be added:
Bailey M Clopp
PENUT Trial Coordinator
cloppb@uw.edu
425-359-1853