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Darbe Administration in Newborns Undergoing Cooling for Encephalopathy (DANCE)

Primary Purpose

Hypoxic Ischemic Encephalopathy

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Darbepoetin alfa
Darbepoetin alfa
Placebo
Sponsored by
University of Utah
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoxic Ischemic Encephalopathy focused on measuring Hypoxic Ischemic Encephalopathy, Cooling Therapy, HIE

Eligibility Criteria

undefined - 12 Hours (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of New Mexico
  • Vanderbilt University School of Medicine
  • McKay Dee Hospital- Intermountain Healthcare
  • University of Utah
  • Primary Children's Hospital
  • Intermountain Medical Center
  • University of Washington

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

High dose Darbepoetin alfa

Low dose Darbepoetin alfa

Placebo

Arm Description

10 mcg/kg/dose Darbe x2 doses, with the first dose within 12 hours of delivery and the second dose at 7 days

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.

Placebo given x2 doses, with the first given within 12 hours of delivery and the second given at 7 days old

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.

Full Information

First Posted
November 2, 2011
Last Updated
May 6, 2015
Sponsor
University of Utah
Collaborators
Thrasher Research Fund
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1. Study Identification

Unique Protocol Identification Number
NCT01471015
Brief Title
Darbe Administration in Newborns Undergoing Cooling for Encephalopathy
Acronym
DANCE
Official Title
Darbe Administration in Newborns Undergoing Cooling for Encephalopathy
Study Type
Interventional

2. Study Status

Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
September 2012 (undefined)
Primary Completion Date
January 2014 (Actual)
Study Completion Date
January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Utah
Collaborators
Thrasher Research Fund

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoxic Ischemic Encephalopathy
Keywords
Hypoxic Ischemic Encephalopathy, Cooling Therapy, HIE

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
High dose Darbepoetin alfa
Arm Type
Active Comparator
Arm Description
10 mcg/kg/dose Darbe x2 doses, with the first dose within 12 hours of delivery and the second dose at 7 days
Arm Title
Low dose Darbepoetin alfa
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo given x2 doses, with the first given within 12 hours of delivery and the second given at 7 days old
Intervention Type
Drug
Intervention Name(s)
Darbepoetin alfa
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Darbepoetin alfa
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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 Measure Information:
Title
The Pharmacokinetic Profile of Darbe After the First Dose During Cooling
Description
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.
Time Frame
For 72 hours after first dose
Title
The Pharmacokinetic Profile of Darbe After the Second Dose.
Description
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.
Time Frame
For 36 hours after second dose
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events.
Description
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.
Time Frame
30 days or until hospital discharge

10. Eligibility

Sex
All
Maximum Age & Unit of Time
12 Hours
Accepts Healthy Volunteers
No
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) ECMO Infant judged critically ill and unlikely to benefit from neonatal intensive care by the attending neonatologist
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mariana Baserga, MD
Organizational Affiliation
University of Utah
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of New Mexico
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131-0001
Country
United States
Facility Name
Vanderbilt University School of Medicine
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232-9544
Country
United States
Facility Name
McKay Dee Hospital- Intermountain Healthcare
City
Ogden
State/Province
Utah
ZIP/Postal Code
84403
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84108
Country
United States
Facility Name
Primary Children's Hospital
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Intermountain Medical Center
City
Sandy
State/Province
Utah
ZIP/Postal Code
841074
Country
United States
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195-6320
Country
United States

12. IPD Sharing Statement

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Darbe Administration in Newborns Undergoing Cooling for Encephalopathy

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