The Neonatal Neurocritical Care Program at Children’s Hospital of Philadelphia (CHOP) aims to provide babies with potential neurologic compromise the best developmental outcomes possible. Three of the ongoing clinical trials in CHOP’s Division of Neonatology involve targeted efforts to improve developmental outcomes: DARBE, HEAL, and Preemie Hypothermia. What follows is a brief description of the 3 trials, as well as information on investigative goals and follow-up evaluations.
The DARBE (darbepoetin) Trial to Improve Red Cell Mass and Neuroprotection in Preterm Infants is a randomized masked placebo-controlled trial (clinicaltrials.gov NCT03169881). This study is funded by the National Heart, Lung, and Blood Institute and conducted in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN). The aim is to determine if preterm infants administered weekly darbepoetin, a long-acting erythropoietin stimulating agent (ESA), will have improved neurocognitive outcome at 22 to 26 months corrected age when compared to infants who received placebo. The trial enrolls infants 23 to 28 6/7 weeks gestation, prior to 24 hours of life. ESAs not only stimulate erythropoiesis but also have been shown to be protective in the developing brain in animal models.
The potential neuroprotective mechanisms include increased neurogenesis; decreased neuronal susceptibility to glutamate toxicity; decreased neuronal apoptosis; decreased inflammation; decreased nitric oxide-mediated injury; increased anti-oxidant response; decreased axonal degeneration; and increased protective effects on glia. The primary outcome is the composite cognitive score on the Bayley Scales of Infant and Toddler Development, Third Edition at 22 to 26 months corrected age.
Enrolled infants will be followed in our Neonatal Follow-up Program at the Buerger Center for Advanced Pediatric Care, Pennsylvania Hospital, and our Specialty Care Center at Virtua on the standard timetable of approximately 3 months post discharge, then at 6, 12, 18, and 24 months corrected age. For the 12-, 18-, and 24-month evaluations, the Bayley-3 will be administered by a developmental psychologist to assess cognitive, receptive, and expressive language, and gross and fine motor skills. Additionally, the infants will be examined by physicians and neonatal nurse practitioners for abnormalities of muscle tone, reflexes, and presence of medical issues. If indicated, physical therapists also will evaluate the infants. Although referrals for early intervention usually are made prior to discharge from the intensive care nursery, therapies may be added and/or increased depending on the infant’s needs.
The High-Dose Erythropoietin (EPO) for Asphyxia and Encephalopathy (HEAL) trial (clinicaltrials.gov NCT02811263), in contrast to DARBE, is enrolling older infants born at >/= 36 weeks gestational age who have been assessed as having moderate or severe hypoxic ischemic encephalopathy (HIE) based on one of the following: Apgar < 5 at 10 minutes, PPV, CPAP, and/or intubation at 10 minutes, pH < 7.0 in cord or first hour blood gas, or base deficit >/= 15 mmol/L . Also, in contrast to DARBE, all enrolled infants will be undergoing therapeutic hypothermia. Because approximately half of babies undergoing cooling for moderate/severe HIE are known to experience adverse outcomes (death, cerebral palsy, neurocognitive impairment), alternate neuroprotective strategies such as use of erythropoietin stimulating agents are being evaluated. Those babies enrolled in the trial will receive either erythropoietin or placebo for a 7-day period.
The goal of this randomized, double-blind, placebo-controlled investigation is to determine whether treatment with EPO as an adjunct to cooling reduces the rate of death or neurodevelopmental impairment at 22 to 26 months in full- term infants with HIE. These babies will have phone follow-up for the trial conducted at 4, 8, 12, and 18 months with a follow- up visit in our Neonatal Follow-up Program at the Buerger Center ~ 24 months of age. At the clinic visit, infants will be administered the Bayley-3 developmental assessment. In addition, they will have a standardized neurologic examination by an examiner who has undergone specific training through the HEAL coordinating center.
Preemie Hypothermia Neonatal Research Network Trial
This randomized controlled trial enrolls preterm infants 33 0/7 to 35 6/7 gestational age, >/= 1 500 grams birth weight, < 6 hours postnatal age who meet criteria for hypoxic ischemic encephalopathy (HIE) through both neurologic and physiologic criteria (clinicaltrials.gov NCT01793129). Prior studies conducted in infants >/= 36 weeks meeting criteria for HIE have shown improved infant outcome after 72 hours of therapeutic hypothermia when compared to infants who did not receive hypothermia. Data regarding outcome of HIE in preterm infants are few.
The goal of this investigation is to assess the safety and effectiveness of whole-body hypothermia for 72 hours in preterm infants. Infants will be randomly assigned to either receive hypothermia or standard care without cooling. The primary outcome is death or moderate/severe disability at 18 to 22 months corrected age as determined by the standard Neonatal Research Network interdisciplinary follow-up exam. Infants will be followed by our Neonatal Follow-up Program at the Buerger Center. At 18 to 22 months corrected age they will be administered the Bayley-3 and undergo a neurodevelopmental examination.
The role of neonatal follow-up
As is noted, the primary outcomes of these groundbreaking studies are, in aggregate, death or neurodevelopmental impairment in a range of 18 to 26 months of corrected age. Assessment of neurodevelopmental outcome can only be achieved through meticulous attention to neurologic and developmental assessments and through the dedicated efforts of numerous individuals involved in retention of families and infants throughout the duration of these investigations. This process begins in the intensive care nursey, with careful and caring discussions with families regarding the consent process during a stressful time. If consented, enrollment procedures continue, with study coordinators subsequently touching base with families throughout the neonatal course. Post discharge, research and clinic coordinators have the arduous responsibility of maintaining contact with families and arranging clinic appointments—tasks that may involve innumerable calls and reminders, with visits tailored to family schedules and needs. It is only through the remarkable efforts of these dedicated individuals that primary developmental endpoints can be achieved.
So, how are we doing?
These are not the first trials of brain protection that the CHOP Division of Neonatology has joined. Prior trials conducted through the NICHD NRN include Optimizing Cooling (JAMA. 2017;318(1):57-67) and Late Hypothermia (JAMA. 2017;318(16):1550-1560). Our center achieved a remarkable 100% follow-up rate for children enrolled in both of these trials. Furthermore, many other ongoing neonatal trials of medical and surgical management of preterm and critically ill neonates focus on neurodevelopment as a primary outcome.
Infants enrolled in all of these trials will continue to be followed by our dedicated multidisciplinary team in the Neonatal Follow-up Program. Evaluation of these children by our team after discharge provides important outcomes data for the studies in which they participate, while also ensuring that our high-risk infants and their families receive essential developmental care during the first few years of life.