Darbe Administration in Newborns Undergoing Cooling for Encephalopathy (DANCE)

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.

Study Overview

• Status: Completed
• Conditions: Hypoxic Ischemic Encephalopathy
• Intervention / Treatment: Drug: Darbepoetin alfa; Drug: Darbepoetin alfa; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131-0001
      • University of New Mexico
  • Tennessee
    • Nashville, Tennessee, United States, 37232-9544
      • Vanderbilt University School of Medicine
  • Utah
    • Ogden, Utah, United States, 84403
      • McKay Dee Hospital- Intermountain Healthcare
    • Salt Lake City, Utah, United States, 84132
      • Primary Children's Hospital
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
    • Sandy, Utah, United States, 841074
      • Intermountain Medical Center
  • Washington
    • Seattle, Washington, United States, 98195-6320
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 12 hours (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 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	Drug: Darbepoetin alfa; 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.; Drug: Darbepoetin alfa; 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.
ACTIVE_COMPARATOR: 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.	Drug: Darbepoetin alfa; 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.; Drug: Darbepoetin alfa; 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.
PLACEBO_COMPARATOR: Placebo; Placebo given x2 doses, with the first given within 12 hours of delivery and the second given at 7 days old	Drug: Placebo; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: Thrasher Research Fund

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (ACTUAL): January 1, 2014
• Study Completion (ACTUAL): January 1, 2014

Study Registration Dates

• First Submitted: November 2, 2011
• First Submitted That Met QC Criteria: November 9, 2011
• First Posted (ESTIMATE): November 11, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): May 22, 2015
• Last Update Submitted That Met QC Criteria: May 6, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Hypoxic Ischemic Encephalopathy; HIE; Cooling Therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Hypoxia; Hypoxia, Brain; Brain Ischemia; Brain Diseases; Hypoxia-Ischemia, Brain; Hematinics; Darbepoetin alfa
• Other Study ID Numbers: 49096