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Darbe Administration in Newborns Undergoing Cooling for Encephalopathy (DANCE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01471015
Recruitment Status : Completed
First Posted : November 11, 2011
Results First Posted : May 22, 2015
Last Update Posted : May 22, 2015
Sponsor:
Collaborator:
Thrasher Research Fund
Information provided by (Responsible Party):
Mariana Baserga, University of Utah

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.


Condition or disease Intervention/treatment Phase
Hypoxic Ischemic Encephalopathy Drug: Darbepoetin alfa Drug: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Darbe Administration in Newborns Undergoing Cooling for Encephalopathy
Study Start Date : September 2012
Actual Primary Completion Date : January 2014
Actual Study Completion Date : January 2014

Resource links provided by the National Library of Medicine


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.

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
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




Primary Outcome Measures :
  1. 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.

  2. 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 Outcome Measures :
  1. Number of Participants With Adverse Events. [ Time Frame: 30 days or until hospital discharge ]

    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.




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Ages Eligible for Study:   up to 12 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01471015


Locations
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United States, New Mexico
University of New Mexico
Albuquerque, New Mexico, United States, 87131-0001
United States, Tennessee
Vanderbilt University School of Medicine
Nashville, Tennessee, United States, 37232-9544
United States, Utah
McKay Dee Hospital- Intermountain Healthcare
Ogden, Utah, United States, 84403
University of Utah
Salt Lake City, Utah, United States, 84108
Primary Children's Hospital
Salt Lake City, Utah, United States, 84132
Intermountain Medical Center
Sandy, Utah, United States, 841074
United States, Washington
University of Washington
Seattle, Washington, United States, 98195-6320
Sponsors and Collaborators
University of Utah
Thrasher Research Fund
Investigators
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Principal Investigator: Mariana Baserga, MD University of Utah
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Responsible Party: Mariana Baserga, Principal Investigator, University of Utah
ClinicalTrials.gov Identifier: NCT01471015    
Other Study ID Numbers: 49096
First Posted: November 11, 2011    Key Record Dates
Results First Posted: May 22, 2015
Last Update Posted: May 22, 2015
Last Verified: May 2015
Keywords provided by Mariana Baserga, University of Utah:
Hypoxic Ischemic Encephalopathy
Cooling Therapy
HIE
Additional relevant MeSH terms:
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Brain Diseases
Brain Ischemia
Hypoxia-Ischemia, Brain
Central Nervous System Diseases
Nervous System Diseases
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Hypoxia, Brain
Darbepoetin alfa
Hematinics