Darbe Administration in Newborns Undergoing Cooling for Encephalopathy

NCT01471015 | Completed Phase 1 Results DMC

• 1 other identifier: 49096
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 7

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.

Conditions

Hypoxic Ischemic Encephalopathy

Keywords

Hypoxic Ischemic Encephalopathy; Cooling Therapy; HIE

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• Number of Participants With Adverse Events.

  30 days or until hospital discharge

Study Arms (3)

High dose Darbepoetin alfa

ACTIVE COMPARATOR

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

Low dose Darbepoetin alfa

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Darbepoetin alfa DRUG

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.

High dose Darbepoetin alfa

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: Up to 24 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Utah: lead
• Thrasher Research Fund: collaborator

Study Sites (7)

University of New Mexico

Albuquerque, New Mexico, 87131-0001, United States

Location

Vanderbilt University School of Medicine

Nashville, Tennessee, 37232-9544, United States

Location

McKay Dee Hospital- Intermountain Healthcare

Ogden, Utah, 84403, United States

Location

University of Utah

Salt Lake City, Utah, 84108, United States

Location

Primary Children's Hospital

Salt Lake City, Utah, 84132, United States

Location

Intermountain Medical Center

Sandy City, Utah, 841074, United States

Location

University of Washington

Seattle, Washington, 98195-6320, United States

Location

MeSH Terms

Conditions

Hypoxia-Ischemia, Brain

Interventions

Darbepoetin alfa

Condition Hierarchy (Ancestors)

Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Erythropoietin; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Proteins; Amino Acids, Peptides, and Proteins

Limitations and Caveats

Due to the small number of participants, infrequent adverse events may not have been detected. There is a lack of long-term follow up to assess for long-term safety concerns.

Results Point of Contact

• Title: Dr. Mariana Baserga
• Organization: University of Utah

mariana.baserga@hsc.utah.edu

801-581-7052

Study Officials

• Mariana Baserga, MD

  University of Utah

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 2, 2011
• First Posted: November 11, 2011
• Study Start: September 1, 2012
• Primary Completion: January 1, 2014
• Study Completion: January 1, 2014
• Last Updated: July 23, 2024
• Results First Posted: May 22, 2015

Record last verified: 2024-07

Locations

US (7)