Mild Encephalopathy in the Newborn Treated With Darbepoetin

Study Overview
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Brief Summary
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This is a Phase II multicenter placebo-controlled randomized, feasibility/safety trial. Infants >34 week gestational age with perinatal acidemia and mild neonatal encephalopathy on the modified Sarnat neurologic examination at less than six hours of age. Participants will be randomized to receive either one dose of Darbepoetin, or placebo within 24 hours of birth. Neurodevelopmental testing (Bayley (III or IV) and Gross Motor Function Assessment) will be performed at 24 months of age. Pharmacokinetics will be assessed on those infants that received Darbe.

Detailed Description
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Therapeutic hypothermia (TH) is the standard of care for newborns diagnosed with moderate to severe neonatal encephalopathy (NE) presumably due to hypoxic ischemia. In order to be eligible for TH an infant must have perinatal acidemia and evidence of moderate or severe encephalopathy on a standardized neurologic examination (Sarnat). However, the majority of newborns with perinatal acidemia do not have a neurologic examination abnormal enough to be classified as moderate or severe NE. In a retrospective review, DuPont et al. found that as many as 20% of newborns with perinatal academia and mild NE have abnormal short-term outcomes such as seizures, death from progressive asphyxia insult, brain MRI findings consistent with NE, abnormal neurologic examination at discharge, gastrostomy tube feeding, or feeding difficulties. Preliminary data from a prospective trial investigating mild NE (PRIME study, NCT01747863) found that 39% had either abnormal electroencephalography at < 9h of age, an abnormal brain MRI finding, or abnormal neurological exam at discharge. Murray et al. recently reported on 5-year outcomes of infants with mild encephalopathy and showed that 25% had neurodevelopmental disability. These data suggest that mild NE likely carries a higher risk of impaired neurological outcome then reported previously. Thus it would appear that neuroprotective strategies would be beneficial in this group of infants. Preliminary data suggest that erythropoiesis stimulating agents (ESA) provide neuroprotection, and improve short and long-term neurologic outcome in neonatal brain injury. ESA may work through several mechanisms including reduced inflammation, limited oxidative stress, decreased apoptosis and white matter injury, as well as via pro-angiogenic and neurogenic properties. Darbepoetin alfa (Darbe), a recombinant human erythropoietin (EPO)-derived molecule has established safety and pharmacokinetics in newborns. Because Darbe has an extended circulating half-life with comparable biological activity to EPO, it has the advantage of requiring less frequent administration

Official Title
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Mild Encephalopathy in the Newborn Treated With Darbepoetin (MEND)

Conditions
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Neonatal Encephalopathy, Hypoxic-Ischemic Encephalopathy Mild

Intervention / Treatment
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* Drug: Darbepoetin Alfa
* Drug: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants will be eligible for the MEND trial if they have a gestational age > 34 weeks by best obstetric estimate, are <24 hours old and have evidence of mild encephalopathy as defined by Shankaran et al based on a modified Sarnat examination performed at <6 hours of age. History of an acute perinatal event (abruption, cord prolapsed, severe fetal heart rate abnormality, or meconium staining) Infant is evaluated for hypothermia therapy and DOES NOT meet clinical criteria for TH. Infant has an IV for clinical treatment Exclusion Criteria: Moderate/Severe encephalopathy on modified Sarnat examination at < 6 hours of age Major congenital and/or chromosomal abnormalities Prenatal diagnosis of brain abnormality or hydrocephalus Severe growth restriction (< 3%) Central venous hematocrit >65%, platelet count >600,000/dL, and/or neutropenia (ANC<500 μL) ECMO Infant judged critically ill and unlikely to benefit from neonatal intensive care by the attending neonatologist

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 24 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darbepoetin Alpha<br>IV,10 mcg/kg/dose, Darbepoetin Alpha, one dose at <24 hours of age | Drug: Darbepoetin Alfa<br>* Single dose of 10 mcg/kg Darbepoetin Alpha given IV at less than 24 hours of age<br>* Other names: Darbepoetin;|
| Placebo Comparator: Placebo<br>IV, Normal saline (placebo dose), one dose at <24 hours of age | Drug: Normal Saline<br>* Single dose of normal saline, IV, given at less than 24 hours of age<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normal Neurodevelopment | The Bayley III and Neuromuscular Assessment were completed between 9-12 months of age. Subjects were abnormal if they had a Bayley III score of less than 70 and/or an abnormal neurological examination. | 9 - 12 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Infants With Adverse Events | Potential adverse events such as (but not limited to) alterations in blood pressure, secondary infections, neutropenia, thrombotic/vascular events, hematologic events (platelets, Hct level, polycythemia), and hepatic/renal function that are outside of normal range for the study population. | 30 days or until hospital discharge whichever comes first | 
| Percent of Infants With Seizures | development of clinical or electrographic seizures | 30 days or until hospital discharge whichever comes first | 
| Percentage of Infants Who Need Gavage Feeds or Gastrostomy at Discharge Home | Infants who require tube feedings at discharge | 30 days or until hospital discharge whichever comes first | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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darbepoetin, Brain Diseases