Darbe Administration in Newborns Undergoing Cooling for Encephalopathy

Study Overview
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Brief Summary
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Selective head cooling or whole body hypothermia has become the standard of care for neonatal hypoxia-ischemia encephalopathy (HIE). Despite early intervention death or major neurodevelopmental disability still occurs in nearly 50% of infants ≥ 36 weeks gestational age (GA) treated with cooling. No additional therapies have proven to be efficacious in further reducing brain injury and impairment for these high risk infants. Neuroprotective strategies aimed at improving early childhood outcomes are still needed. An important area of study includes therapies that may complement the neuroprotective effects of hypothermia and promote neuronal regeneration, recovery and neurovascular remodeling. Among these therapies, erythropoiesis stimulating agents (ESA) have been shown to provide neuroprotection, improving short and long-term neurologic outcome in brain injury and HIE in neonatal and adult animal models. Parallel with neuroprotective effects in experimental settings, recent small clinical studies suggest improved outcomes after ESA administration in patients with severe traumatic brain injury and HIE. ESA may work through several important 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 an extended circulating half life and comparable biological activity to EPO, including activation of the EPO receptor. The proposed study is a Phase I/II dose safety and pharmacokinetic trial of early Darbe administered concurrent with hypothermia in human newborn infants with moderate to severe birth asphyxia. The long-term objectives of the proposed research are to reduce mortality and to decrease the risk of long-term disabilities in infants with HIE who survive beyond the newborn period.

Official Title
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Darbe Administration in Newborns Undergoing Cooling for Encephalopathy

Conditions
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Hypoxic Ischemic Encephalopathy

Intervention / Treatment
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* Drug: Darbepoetin alfa
* Drug: Darbepoetin alfa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants will be eligible for the DANCE trial if they have a gestational age > 36 weeks by best obstetric estimate, are < 12 hours old and have evidence of moderate-severe acute perinatal HIE. Eligibility will also include criteria presently used in the NICU to initiate hypothermia: < 6 hours after birth History of an acute perinatal event (abruption, cord prolapsed, severe fetal heart rate abnormality) Severe fetal or early (< 1 hour age) neonatal acidosis: arterial pH ≤ 7.0 or a base deficit ≥ 16m mEq/ L If a blood gas is not available or a blood gas at <1 hour of age has a pH between 7.01 and 7.15, or a base deficit is between 10 and 15.9 mEq/L, additional criteria will be required: acute perinatal event AND either a 10-min Apgar score ≤ 5 or assisted ventilation initiated at birth and continued for at least 10 minutes. Exclusion Criteria: Major congenital and/or chromosomal abnormalities Prenatal diagnosis of brain abnormality or hydrocephalus Severe growth restriction (< 1800g) Central venous hematocrit > 65%, platelet count > 600,000/dL, and/or neutropenia (ANC < 500 µL) Maternal history of major vascular thrombosis or multiple fetal losses (> 3 spontaneous abortions) 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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Maximum Age: 12 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High dose Darbepoetin alfa<br>10 mcg/kg/dose Darbe x2 doses, with the first dose within 12 hours of delivery and the second dose at 7 days | Drug: Darbepoetin alfa<br>* 10 mcg/kg/dose x2, with the first dose given as IV within 12 hours of delivery and the second dose given as IV or SQ at 7 days old.<br>|
| Active Comparator: Low dose Darbepoetin alfa<br>2 mcg/kg/dose Darbe x2, with the first dose given within 12 hours of delivery and the second dose given at 7 days old. | Drug: Darbepoetin alfa<br>* 2 mcg/kg/dose x2, with the first dose given IV within 12 hours of delivery and the second dose given IV or SQ at 7 days old.<br>|
| Placebo Comparator: Placebo<br>Placebo given x2 doses, with the first given within 12 hours of delivery and the second given at 7 days old | Drug: Placebo<br>* Placebo given x2, with the first dose given IV within 12 hours of delivery and the second dose given IV or SQ at 7 days old<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Pharmacokinetic Profile of Darbe After the First Dose During Cooling | The pharmacokinetic profile of Darbe wil be determined using population pharmacokinetic sampling in which babies will be randomized to have blood drawn at different intervals. Serum levels will be drawn at 4,12, 18, 24, 36, 60, and 72 hours post initial dose. Area under the plasma concentration versus time curve (AUC) will be used. | For 72 hours after first dose | 
| The Pharmacokinetic Profile of Darbe After the Second Dose. | The pharmacokinetic profile of Darbe will be determined using population pharmacokinetic sampling in which babies will be randomized to have blood drawn at different intervals. A second dose of Darbe will be given at 7 days of age, and serum drug levels will be obtained at 12, 18, 24, and 36 hours post second dose. Area under the plasma concentration versus time curve (AUC) will be used. | For 36 hours after second dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants 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. Complications associated with HIE or cooling therapy will not be considered an AE for this study. AEs reported to be associated with cooling include: bleeding/thrombosis, persistent pulmonary hypertension of the newborn (PPHN), skin changes, arrhythmia, and persistent acidosis. | 30 days or until hospital discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoxic Ischemic Encephalopathy, Cooling Therapy, HIE