Darbe Administration in Newborns Undergoing Cooling for Encephalopathy

Status:	Completed
Conditions:	Peripheral Vascular Disease, Infectious Disease, Neurology, Psychiatric
Therapuetic Areas:	Cardiology / Vascular Diseases, Immunology / Infectious Diseases, Neurology, Psychiatry / Psychology
Healthy:	No
Age Range:	Any
Updated:	3/1/2014
Start Date:	September 2012
End Date:	March 2014
Contact:	Carrie Rau, RN
Email:	carrie.rau@hsc.utah.edu
Phone:	801-213-3360

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.

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

We found this trial at

sites

Vanderbilt University School of Medicine

Nashville, Tennessee 37232

from

Nashville, TN