Mild Encephalopathy in the Newborn Treated With Darbepoetin

Phase 2

Completed

• Conditions: Neonatal Encephalopathy; Hypoxic-Ischemic Encephalopathy Mild
• Interventions: Drug: Normal Saline; Drug: Darbepoetin Alfa

• Registration Number: NCT03071861
• Lead Sponsor: University of New Mexico

Brief Summary

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

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

Study Timeline

• Study First Submitted: 2016-12-01
• Study First Submitted QC: 2017-03-01
• Study First Posted: 2017-03-07
• Study Start: 2017-12-01
• Primary Completion: 2019-12-01
• Study Completion: 2022-09-01
• Results First Submitted: 2022-11-23
• Results First Submitted QC: 2023-07-21
• Results First Posted: 2023-07-25
• Status Verified: 2023-12
• Last Update Submitted: 2023-12-01
• Last Update Posted: 2023-12-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

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.

1. History of an acute perinatal event (abruption, cord prolapsed, severe fetal heart rate abnormality, or meconium staining)
2. Infant is evaluated for hypothermia therapy and DOES NOT meet clinical criteria for TH.
3. Infant has an IV for clinical treatment

Exclusion Criteria

1. Moderate/Severe encephalopathy on modified Sarnat examination at < 6 hours of age
2. Major congenital and/or chromosomal abnormalities
3. Prenatal diagnosis of brain abnormality or hydrocephalus
4. Severe growth restriction (< 3%)
5. Central venous hematocrit >65%, platelet count >600,000/dL, and/or neutropenia (ANC<500 μL)
6. ECMO
7. Infant judged critically ill and unlikely to benefit from neonatal intensive care by the attending neonatologist

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Normal Saline	IV, Normal saline (placebo dose), one dose at \<24 hours of age
Darbepoetin Alpha	Darbepoetin Alfa	IV,10 mcg/kg/dose, Darbepoetin Alpha, one dose at \<24 hours of age

Primary Outcome Measures

Name	Time	Method
Normal Neurodevelopment	9 - 12 months of age	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.

Secondary Outcome Measures

Name	Time	Method
Percent of Infants With Adverse Events	30 days or until hospital discharge whichever comes first	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.
Percentage of Infants Who Need Gavage Feeds or Gastrostomy at Discharge Home	30 days or until hospital discharge whichever comes first	Infants who require tube feedings at discharge
Percent of Infants With Seizures	30 days or until hospital discharge whichever comes first	development of clinical or electrographic seizures

Trial Locations

Locations (1)

University of Utah; 🇺🇸 Salt Lake City, Utah, United States