Clinical trial NCT01471015: Darbe Administration in Newborns Undergoing Cooling for Encephalopathy
Official title: Darbe Administration in Newborns Undergoing Cooling for Encephalopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hypoxic Ischemic Encephalopathy
Keywords: Hypoxic Ischemic Encephalopathy
Cooling Therapy
HIE
Lead sponsor: University of Utah
Sponsor class: OTHER
Collaborators: name: Thrasher Research Fund
First posted: 2011-11-11
Enrollment: 30
Sex: ALL
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: The Pharmacokinetic Profile of Darbe After the First Dose During Cooling
timeFrame: For 72 hours after first dose
measure: The Pharmacokinetic Profile of Darbe After the Second Dose.
timeFrame: For 36 hours after second dose
Secondary outcomes:
measure: Number of Participants With Adverse Events.
timeFrame: 30 days or until hospital discharge
Other outcomes:
Locations:
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Nashville
country: United States
facility: Vanderbilt University School of Medicine
state: Tennessee
city: Ogden
country: United States
facility: McKay Dee Hospital- Intermountain Healthcare
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Sandy
country: United States
facility: Intermountain Medical Center
state: Utah
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Utah
name: Mariana Baserga, MD
role: PRINCIPAL_INVESTIGATOR
References: