Darbe Administration in Newborns Undergoing Cooling for Encephalopathy
Overview
- Phase
- Phase 1
- Intervention
- Darbepoetin alfa
- Conditions
- Hypoxic Ischemic Encephalopathy
- Sponsor
- University of Utah
- Enrollment
- 30
- Locations
- 7
- Primary Endpoint
- The Pharmacokinetic Profile of Darbe After the First Dose During Cooling
- Status
- Completed
- Last Updated
- last year
Overview
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.
Investigators
Mariana Baserga
Principal Investigator
University of Utah
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:
- •\< 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)
- •Infant judged critically ill and unlikely to benefit from neonatal intensive care by the attending neonatologist
Arms & Interventions
High dose Darbepoetin alfa
10 mcg/kg/dose Darbe x2 doses, with the first dose within 12 hours of delivery and the second dose at 7 days
Intervention: Darbepoetin alfa
Low dose Darbepoetin alfa
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.
Intervention: Darbepoetin alfa
Placebo
Placebo given x2 doses, with the first given within 12 hours of delivery and the second given at 7 days old
Intervention: Placebo
Outcomes
Primary Outcomes
The Pharmacokinetic Profile of Darbe After the First Dose During Cooling
Time Frame: For 72 hours after first dose
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.
The Pharmacokinetic Profile of Darbe After the Second Dose.
Time Frame: For 36 hours after 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.
Secondary Outcomes
- Number of Participants With Adverse Events.(30 days or until hospital discharge)