Darbepoetin Trial to Improve Red Cell Mass and Neuroprotection in Preterm Infants (Darbe)

• ClinicalTrials.gov Identifier: NCT03169881
• Recruitment Status: Active, not recruiting
• First Posted: May 30, 2017
• Last Update Posted: September 28, 2022
• Sponsor: NICHD Neonatal Research Network
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): NICHD Neonatal Research Network

Study Description

Brief Summary:

Study Hypothesis: Preterm infants administered weekly Darbe during the neonatal period will have improved neurocognitive outcome at 22-26 months compared to placebo

Condition or disease	Intervention/treatment	Phase
Neurocognitive; Neuroprotective; Neonatal; Neurodevelopmental Impairment	Drug: Darbepoetin; Drug: Placebo	Phase 3

Detailed Description:

Advances in neonatal care have led to significant improvements in the survival of the nearly 60,000 very low birth weight (VLBW) infants born each year in the U.S. Improving neurodevelopmental outcomes for these preterm infants continues to be a major goal for neonatal care providers. A subset of these infants sustain a grade 3 or 4 intraventricular hemorrhage (IVH) resulting in an increase in the incidence of developmental delay. Moreover, almost one third of preterm infants with normal head ultrasounds also develop cognitive delay. Although a variety of neuroprotective treatment strategies have been evaluated, no specific treatment has been identified to reduce or prevent brain injury in these most vulnerable preterm infants.

A potential neuroprotective therapy involves administering erythropoiesis stimulating agents (ESAs) such as erythropoietin (Epo) and Darbepoetin (Darbe, a longer acting ESA). In addition to stimulating erythropoiesis, ESAs have been shown to be protective in the developing brain in animal models, making it possibly beneficial for very premature infants who are at risk for intraventricular hemorrhage, hypoxic-ischemic injury, and developmental delay. The neuroprotective mechanisms of ESAs include increased neurogenesis, decreased neuronal susceptibility to glutamate toxicity, decreased neuronal apoptosis, decreased inflammation, decreased nitric oxide-mediated injury, increased antioxidant response, decreased axonal degeneration, and increased protective effects on glia. This is a randomized, masked, placebo controlled clinical study in which enrolled infants will receive weekly Darbe or placebo (sham) dosing.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 650 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, masked, placebo-controlled trial
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Primary providers and bedside caregivers will be blinded to randomization group. If the dose will be administered IV, the study drug will be administered slow IV push by the bedside nurse. If the dose will be administered subcutaneously, the study drug will be brought to the bedside in a closed container, and injections will be shielded behind screens and out of earshot from caregivers and parents. An adhesive bandage (or 2x2 gauze) will be placed over the true and sham injection sites and either taped or held in place until no evidence of the injection is visible. The parents, medical providers, data collection staff and neurodevelopmental follow up personnel will be masked to the treatment arm.
• Primary Purpose: Treatment
• Official Title: Darbepoetin Trial to Improve Red Cell Mass and Neuroprotection in Preterm Infants
• Actual Study Start Date: September 20, 2017
• Estimated Primary Completion Date: August 2023
• Estimated Study Completion Date: September 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Darbepoetin; Darbepoetin 10 micrograms/kg/once every week (IV or SC)	Drug: Darbepoetin; Darbepoetin 10 micrograms/kg/once every week (IV or SC). Infants will be treated until 35 completed weeks gestation, discharge, or transfer to another hospital.; Other Name: Darbe
Placebo Comparator: Placebo; Equal volume normal saline for IV administration, or sham dosing	Drug: Placebo; normal saline for IV administration, or sham dosing. Infants will be treated until 35 completed weeks gestation, discharge, or transfer to another hospital.; Other Name: normal saline for IV administration, or sham dosing

Outcome Measures

Primary Outcome Measures :

1. Composite cognitive score on Bayley Scale of Infant Development III [ Time Frame: Birth to 26 months corrected age ]
   The primary outcome is the Bayley III cognitive score. Deaths will be assigned a score of 54.

Secondary Outcome Measures :

1. Death [ Time Frame: Birth to 26 months corrected age ]
   Death includes any mortality prior to follow-up at 22-26 months of age
2. Cerebral Palsy [ Time Frame: Follow-up at 26 months corrected age ]
3. Length of Hospital Stay [ Time Frame: Birth to 26 months corrected age ]
   Days in hospital following birth.
4. Number of transfusions [ Time Frame: Birth to 35 completed weeks gestational age ]
5. Hematocrit [ Time Frame: Birth to 35 completed weeks gestational age ]
6. Red cell mass [ Time Frame: Birth to 35 completed weeks gestational age ]
7. Volume of transfusions [ Time Frame: Birth to 35 completed weeks gestational age ]
8. Neurodevelopmental impairment (NDI) [ Time Frame: 26 months corrected age ]
   Severe NDI will be defined by any of the following: a BSID III cognitive score < 70, Gross Motor Functional (GMF) Level of 3-5, blindness (<20/200 vision) or profound hearing loss (inability to understand commands despite amplification); moderate NDI will be defined as a BSID III cognitive score 70-84 and either a GMF level of 2 or a hearing deficit requiring amplification to understand commands or unilateral blindness; mild NDI will be defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMF level 1 or hearing loss not requiring amplification. Normal (no NDI) will be defined by a cognitive score ≥ 85 and absence of any neurosensory deficits.
9. Seizures [ Time Frame: Up to 120 days of life ]
   Documented seizures during hospital course
10. Thromboses [ Time Frame: Up to 120 days of life ]
    Documented thromboses during hospital course
11. Hypertension [ Time Frame: Up to 120 days of life ]
    Documented hypertension during hospital course
12. Intra-cranial Hemorrhage (ICH) [ Time Frame: Up to 120 days of life ]
    Documented ICH during hospital course
13. Necrotizing Enterocolitis (NEC) requiring surgery [ Time Frame: Up to 120 days of life ]
    Documented NEC requiring surgery during hospital course
14. Bronchopulmonary dysplasia (BPD) [ Time Frame: Up to 120 days of life ]
    Documented BPD during hospital course
15. Retinopathy of prematurity (ROP) requiring intervention [ Time Frame: Up to 120 days of life ]
    Documented ROP requiring intervention (to include but not limited to laser, cryotherapy, scleral buckle, vitrectomy, avastin Injection) during hospital course
16. Culture positive sepsis [ Time Frame: Up to 120 days of life ]
    Documented culture positive sepsis during hospital course

Eligibility Criteria

• Ages Eligible for Study: 23 Weeks to 28 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Inborn and outborn preterm infants
• 23 0/7-28 6/7 weeks gestation
• ≤24 hours postnatal age

Exclusion Criteria:

• Hematocrit > 60%
• Infants with known congenital or chromosomal anomalies, including congenital heart disease and known brain anomalies
• Hemorrhagic or hemolytic disease
• EEG- confirmed seizures
• Congenital thrombotic disease
• Systolic blood pressures >100 mm Hg while not on pressor support
• Receiving Epo or Darbe clinically, or planning to receive Epo or Darbe during hospitalization
• Infants in whom no aggressive therapy is planned
• Family will NOT be available for follow-up at 22-26 months

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35233

United States, California

Stanford University

Palo Alto, California, United States, 94304

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30303

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, New Mexico

University of New Mexico

Albuquerque, New Mexico, United States, 87131

United States, New York

University of Rochester

Rochester, New York, United States, 14642

United States, North Carolina

RTI International

Durham, North Carolina, United States, 27705

Duke University

Durham, North Carolina, United States, 27710

United States, Ohio

Cincinnati Children's Medical Center

Cincinnati, Ohio, United States, 45267

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States, 44106

Research Institute at Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Pennsylvania

Univeristy of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Rhode Island

Brown University - Women and Infants Hospital of Rhode Island

Providence, Rhode Island, United States, 02905

United States, Texas

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States, 75235

University of Texas Health Science Center at Houston

Houston, Texas, United States, 77030

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84108

Sponsors and Collaborators

NICHD Neonatal Research Network

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Robin Ohls, MD; University of Utah

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vu PT, Ohls RK, Mayock DE, German KR, Comstock BA, Heagerty PJ, Juul SE; PENUT Consortium. Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial. Pediatr Res. 2021 Jul;90(1):109-116. doi: 10.1038/s41390-020-01273-w. Epub 2021 Jan 11.

• Responsible Party: NICHD Neonatal Research Network
• ClinicalTrials.gov Identifier: NCT03169881
• Other Study ID Numbers: NICHD-NRN-0058
• First Posted: May 30, 2017
• Last Update Posted: September 28, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: NIH has had a long-standing policy to share and make available to the public the results and accomplishments of the activities that it funds. The NRN plans to share de-identified data after final publication in an NIH supported data repository such as the NICHD Data and Specimen Hub (https://dash.nichd.nih.gov) or NHLBI BIOLINCC (https://biolincc.nhlbi.nih.gov/home/).

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Darbepoetin alfa; Hematinics