Hypoxic-Ischemic Encephalopathy Mild, Neonatal Encephalopathy
Conditions
Keywords
darbepoetin, Brain Diseases
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
Interventions
DRUGDarbepoetin Alfa
Single dose of 10 mcg/kg Darbepoetin Alpha given IV at less than 24 hours of age
DRUGNormal Saline
Single dose of normal saline, IV, given at less than 24 hours of age
Sponsors
University of Utah
University of New Mexico
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Hours to 24 Hours
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Percent of Infants With Seizures | 30 days or until hospital discharge whichever comes first | development of clinical or electrographic seizures |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent With Seizures | 24 months of age | development of clinical or electrographic seizures |
| Percent With Failure to Thrive | 9 months of age | Growth at \<3% |
| Percent With Hearing Impairment | 9 months of age | Child requires a hearing device |
| Percent With Vision Impairment | 9 months of age | requires corrective lenses |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Darbepoetin Alpha IV,10 mcg/kg/dose, Darbepoetin Alpha, one dose at \<24 hours of age
Darbepoetin Alfa: Single dose of 10 mcg/kg Darbepoetin Alpha given IV at less than 24 hours of age | 13 |
| Placebo IV, Normal saline (placebo dose), one dose at \<24 hours of age
Normal Saline: Single dose of normal saline, IV, given at less than 24 hours of age | 15 |
| Total | 28 |
Baseline characteristics
| Characteristic | Darbepoetin Alpha | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 13 Participants | 15 Participants | 28 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 39 weeks STANDARD_DEVIATION 1.9 | 39 weeks STANDARD_DEVIATION 1.5 | 39 weeks STANDARD_DEVIATION 1.7 |
| gestational age less than 36 weeks | 0 Participants | 1 Participants | 1 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 13 participants | 15 participants | 28 participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 15 |
| other Total, other adverse events | 0 / 13 | 0 / 15 |
| serious Total, serious adverse events | 0 / 13 | 0 / 15 |
Outcome results
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.
Time frame: 9 - 12 months of age
Population: one infant was lost to follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Darbepoetin Alpha | Normal Neurodevelopment | 13 Participants |
| Placebo | Normal Neurodevelopment | 14 Participants |
Secondary
Percentage of Infants Who Need Gavage Feeds or Gastrostomy at Discharge Home
Infants who require tube feedings at discharge
Time frame: 30 days or until hospital discharge whichever comes first
Population: Discharge feeding method
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Darbepoetin Alpha | Percentage of Infants Who Need Gavage Feeds or Gastrostomy at Discharge Home | 0 Participants |
| Placebo | Percentage of Infants Who Need Gavage Feeds or Gastrostomy at Discharge Home | 0 Participants |
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.
Time frame: 30 days or until hospital discharge whichever comes first
Population: There were NO adverse events reported
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Darbepoetin Alpha | Percent of Infants With Adverse Events | 0 Participants |
| Placebo | Percent of Infants With Adverse Events | 0 Participants |
Secondary
Percent of Infants With Seizures
development of clinical or electrographic seizures
Time frame: 30 days or until hospital discharge whichever comes first
Population: Patients with seizures after study enrolment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Darbepoetin Alpha | Percent of Infants With Seizures | 0 Participants |
| Placebo | Percent of Infants With Seizures | 0 Participants |
Other Pre-specified
Percent With Failure to Thrive
Growth at \<3%
Time frame: 9 months of age
Population: 27 infants were followed at 9 months of age. One infant in the placebo arm was lost to follow up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Darbepoetin Alpha | Percent With Failure to Thrive | 0 Participants |
| Placebo | Percent With Failure to Thrive | 0 Participants |
Other Pre-specified
Percent With Hearing Impairment
Child requires a hearing device
Time frame: 9 months of age
Population: one infant was lost to follow up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Darbepoetin Alpha | Percent With Hearing Impairment | 0 Participants |
| Placebo | Percent With Hearing Impairment | 0 Participants |
Other Pre-specified
Percent With Seizures
development of clinical or electrographic seizures
Time frame: 24 months of age
Other Pre-specified
Percent With Vision Impairment
requires corrective lenses
Time frame: 9 months of age
Population: one infant was lost to follow up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Darbepoetin Alpha | Percent With Vision Impairment | 0 Participants |
| Placebo | Percent With Vision Impairment | 0 Participants |