Mild Encephalopathy in the Newborn Treated With Darbepoetin

Neonatal Encephalopathy Clinical Trial

— MEND  

Official title:

Mild Encephalopathy in the Newborn Treated With Darbepoetin (MEND)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03071861
• Other study ID #: MEND 16-330
• Status: Completed
• Phase: Phase 2
• Start date: December 1, 2017
• Est. completion date: September 1, 2022

Study information

• Verified date: December 2023
• Source: University of New Mexico
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: September 1, 2022
• Est. primary completion date: December 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Hour to 24 Hours

Eligibility

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

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Hypoxia-Ischemia, Brain
• Hypoxic-Ischemic Encephalopathy Mild
• Neonatal Encephalopathy

Intervention

Drug:
• Darbepoetin Alfa
Single dose of 10 mcg/kg Darbepoetin Alpha given IV at less than 24 hours of age
• Normal Saline
Single dose of normal saline, IV, given at less than 24 hours of age

Locations

Country	Name	City	State
United States	University of Utah	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
University of New Mexico	University of Utah

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent With Seizures	development of clinical or electrographic seizures	24 months of age
Other	Percent With Failure to Thrive	Growth at <3%	9 months of age
Other	Percent With Hearing Impairment	Child requires a hearing device	9 months of age
Other	Percent With Vision Impairment	requires corrective lenses	9 months of age
Primary	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	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
Secondary	Percent of Infants With Seizures	development of clinical or electrographic seizures	30 days or until hospital discharge whichever comes first
Secondary	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