Darbe Administration in Newborns Undergoing Cooling for Encephalopathy (DANCE)

Utah System of Higher Education (USHE)

Status and phase: Completed; Phase 2; Phase 1

Conditions: Hypoxic Ischemic Encephalopathy

Treatments: Drug: Darbepoetin alfa; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT01471015

49096

Details and patient eligibility

About

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.

Enrollment: 30 patients

Sex: All

Ages: Under 24 hours old

Volunteers: No Healthy Volunteers

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:

1. < 6 hours after birth

2. History of an acute perinatal event (abruption, cord prolapsed, severe fetal heart rate abnormality)

3. Severe fetal or early (< 1 hour age) neonatal acidosis: arterial pH ≤ 7.0 or a base deficit ≥ 16m mEq/ L

4. 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

1. Major congenital and/or chromosomal abnormalities
2. Prenatal diagnosis of brain abnormality or hydrocephalus
3. Severe growth restriction (< 1800g)
4. Central venous hematocrit > 65%, platelet count > 600,000/dL, and/or neutropenia (ANC < 500 µL)
5. Maternal history of major vascular thrombosis or multiple fetal losses (> 3 spontaneous abortions)
6. ECMO
7. Infant judged critically ill and unlikely to benefit from neonatal intensive care by the attending neonatologist

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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30 participants in 3 patient groups, including a placebo group

High dose Darbepoetin alfa

Active Comparator group

Description:

10 mcg/kg/dose Darbe x2 doses, with the first dose within 12 hours of delivery and the second dose at 7 days

Treatment:

Drug: Darbepoetin alfa

Drug: Darbepoetin alfa

Low dose Darbepoetin alfa

Active Comparator group

Description:

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.

Treatment:

Drug: Darbepoetin alfa

Drug: Darbepoetin alfa

Placebo

Placebo Comparator group

Description:

Placebo given x2 doses, with the first given within 12 hours of delivery and the second given at 7 days old

Treatment:

Drug: Placebo