Clinical Trials in Neonatal Medicine: Shrinking the Ninety Percent Gap

March 27, 2019 Ninety percent of pharmaceutical agents that are used to treat or prevent various conditions in neonatal patients — medications that have been approved for similar usage in adult patients — have never actually been tested in neonates to determine their pharmacokinetics, pharmacodynamics, optimal dosing patterns, and other criteria.

Use of these agents in this patient population is largely driven by empirical evidence of how they work in adults and physician discretion based on the available clinical guidance or institutional protocols.

“The fact that most of the drugs we use in our neonatal patients have not undergone prior testing in this group is unsatisfactory at best,” says Thomas Diacovo, MD, chief of the UPMC Newborn Medicine Program at UPMC Children’s Hospital of Pittsburgh. “Yes, it is exceptionally difficult to conduct many of these studies. However, it is incumbent upon the field to do more and do better by our patients, regardless of the difficulty or barriers we face in building this badly needed evidence base.”

Increasing the evidence base for the use of pharmaceutical agents in neonatal patients is a priority for Dr. Diacovo and his colleagues in the UPMC Newborn Medicine Program. The program is currently participating in ongoing multicenter investigations examining the efficacy of various medications in neonates.

In addition to the pharmaceutical clinical trials in progress, several new basic and translational investigations are examining aspects of necrotizing enterocolitis, immune and microbial development in the neonatal gastrointestinal tract, and a novel approach to using precision medicine in the diagnosis of genetic disorders in neonates.

Below are summaries of these promising new trials currently in progress that seek to improve the care of neonatal patients everywhere.

Cangrelor Use in Neonates

This investigator-initiated study being conducted at UPMC Children’s and led by Dr. Diacovo, will assess the pharmacodynamics and pharmacokinetics of cangrelor used in neonatal patients who are at risk for thrombosis related to the use of pulmonary arterial shunting.

Dr. Diacovo and his study collaborators will seek to enroll up to 20 participants up to 28 days in age in this trial analyzing the safety and mechanistic properties of cangrelor in four discrete doses. The trial will start with a cohort of four subjects receiving the lowest dose and progress over time to additional cohorts of four — each receiving subsequently larger doses of the agent.

Apixaban and Heart Disease in Children

UPMC Children’s is now participating in a multicenter, randomized study investigating the use of apixaban to prevent thromboembolism in pediatric patients with congenital heart disease or an acquired version of heart disease.

Sponsored by Bristol-Myers Squibb in collaboration with the Pediatric Heart Network and Pfizer, the study — titled “Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist or LMWH in Pediatric Subjects with Congenital or Acquired Heart Disease for Thromboembolism Prevention” — is a badly needed examination of how this antithrombotic functions in pediatric patients, and how it compares in usage and efficacy with low molecular weight warfarin (LMWH) or vitamin K antagonist (VKA).

Dr. Diacovo is serving as the site primary investigator for this study, and is collaborating internally with colleagues from the UPMC Heart Institute at UPMC Children’s Hospital of Pittsburgh.

This apixaban study is being conducted in pediatric patients from age 3 months to 18 years. Various aspects of pharmacokinetics and safety will be examined, as well as outcomes related to bleeding events, fatal bleeding, and bleeding that requires some form of medical or surgical intervention to restore hemostasis.

Searching for High-Risk Markers for Necrotizing Enterocolitis

Liza Konnikova, MD, PhD, FAAP, assistant professor of pediatrics and developmental biology at UPMC Children’s Hospital, is a physician-scientist who broadly investigates how neonatal mucosal immunity develops and its role in the pathogenesis of diseases, including necrotizing enterocolitis (NEC) and very-early-onset inflammatory bowel disease (VEOIBD).

NEC is the leading cause of death in preterm infants. Despite advances in neonatal care, the survival of infants with NEC remains low — less than 50 percent in many cases. In part, this is due to an inability to predict which infants are at risk for the development of NEC and the subsequent failure to utilize preventative strategies.

One of Dr. Konnikova’s current studies seeks to understand Toll-like receptor (TLR) biomarkers in necrotizing enterocolitis and how to use these markers to identify premature neonates who are at high risk for developing NEC.

Dr. Konnikova’s lab has identified that innate immune signaling via the Toll-like receptor 4 (TLR4) plays a key role in the development of NEC. Her team now is searching for novel biomarkers for NEC in a longitudinal cohort study of infants with NEC by assessing the TLR4 signaling capacity of these neonates, using combined in vitro and in silico approaches. In so doing, Dr. Konnikova and her team hope to advance the field by identifying newborns that are at risk for NEC development, thus creating a window for early prophylactic and interventional therapies.

Uncovering the Mysteries of Immune and Microbial Development in the GI Tract 

The gastrointestinal (GI) tract is one of the body’s largest immune organs. It is also host to 500 to 1,000 different bacterial species and as many as 1014 bacteria. The majority of these bacteria represent commensals that play an important role in the development and maintenance of the host immune system. The interplay between the immune cells and the commensal bacteria allows for host’s immune system to respond to pathogenic bacteria while being tolerant of the commensal ones. However, how homeostasis is established and maintained in humans is very poorly understood.

Through translational studies of human tissue throughout gestation, as well as tissue from neonates and young children, Dr. Konnikova is working to decipher how homeostasis is established and maintained.

Dysregulation of the GI immune homeostasis leads to a number of diseases, such as necrotizing enterocolitis (NEC), very-early-onset inflammatory bowel disease (VEOIBD) and IBD. To facilitate studying mucosal immunity in health and diseases, Dr. Konnikova and colleagues have adapted mass cytometry (CyTOF) to perform deep immunophenotyping and functional analysis of immune cells at mucosal surfaces. These advances have allowed Dr. Konnikova to study immune dysregulation in various diseases such as NEC and VEOIBD.

The PreMOD2 Study

Toby D. Yanowitz, MD, MS, associate professor of pediatrics, obstetrics, gynecology, and productive sciences at UPMC Children’s, serves as the site primary investigator for the PreMOD2 study. This study is investigating the benefits of delayed cord clamping (DCC) versus the use of umbilical cord milking (UCM) to mitigate bleeding in the brain in premature neonates and to prevent mortality. The trial is currently enrolling neonatal patients that are 30 to 32 + six weeks gestational age.

Dr. Yanowitz and the other study leaders are primarily interested in both short- and long-term outcomes of the use of UCM or DCC in those neonatal subjects delivered before 32-weeks gestation. In this randomized study, patients will either receive UCM at the time of delivery (four times during a 15 to 20 second period) or DCC for a minimum of 60 seconds. The goal is to see if either method is better at preventing intraventricular hemorrhage or death in premature newborns.

Combatting HIE with EPO: The HEAL Trial

Hypoxic-ischemic encephalopathy (HIE) is a consequence of reduced blood flow and, ultimately, a reduced flow of oxygen to the brain that occurs close to the time of birth. Affecting approximately 12,000 babies each year in the United States, HIE has the potential to inflict devastating, permanent neurologic impairments. It leads to mortality in nearly 10 percent of cases, with higher rates attributable to more severe cases.

The usual therapy for HIE involves the use of hypothermia. The HEAL trial (High-dose Erythropoietin for Asphyxia and Encephalopathy) is a multicenter, randomized investigation of the efficacy of erythropoietin (EPO) that is being conducted to see if its use can improve outcomes when given in tandem with the use of hypothermia.

EPO acts both as a neuroprotective agent and as a growth factor in the brain. The study seeks to determine if EPO given in five doses of 1,000 units per kilogram, in combination with hypothermia, will reduce neurocognitive deficits and mortality in newborns. 

Dr. Yanowitz is the site primary investigator for this trial at UPMC Children’s.

Ceftobiprole Use in Neonates

Kathleen Schwabenbauer, MD, assistant professor of pediatrics and a neonatologist with the UPMC Newborn Medicine program, is the site primary investigator for a multicenter study designed to characterize the pharmacokinetics of ceftobiprole — a broad-spectrum antibiotic in the cephalosporin family that is used to treat a range of Gram-positive and Gram-negative bacterial pathogens.

The dynamics of the medication are being tested in neonates and infants who are up to three months of age but greater than or equal to 28-weeks gestation.

This open-label interventional study will evaluate the dynamics and safety of a single dose of ceftobiprole given to patients currently undergoing some form of systemic antibiotic treatment at a dose of 7.5 mg/kg body weight via a four-hour infusion.

Dr. Diacovo is serving as the co-primary investigator of this trial. ClinicalTrials.gov Identifier: NCT02527681.

Genetics and Precision Medicine

Co-primary investigators Thomas Diacovo, MD, and Jerry Vockley, MD, PhD, chief of medical genetics at UPMC Children’s, currently are engaged in a collaborative effort between the UPMC Newborn Medicine Program, the Division of Medical Genetics at UPMC Children’s Hospital of Pittsburgh, and the Institute for Precision Medicine (IPM) — a collaborative effort between the University of Pittsburgh and UPMC — to provide rapid genomic testing for NICU patients who present with rare and difficult-to-diagnose conditions that may have an underlying genetic cause.

UPMC Children’s also is participating in a new national precision medicine clinical trial sponsored by the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health. This trial is studying the use of rapid, targeted, next-generation sequencing technology to diagnose underlying genetic causes for disease in high-risk neonates.

Led by researchers at Floating Hospital for Children at Tufts Medical Center, researchers at UPMC Children’s will enroll neonates who may have a variety of genetic disorders, but whose diagnoses are unable to be determined through the use of standard testing. The new five-year study entails the conduction of whole-genome sequencing of the neonates, as well as a targeted examination of 1,722 genetic disorders known to afflict newborns.

The study will then compare the results between the targeted screening and the whole-genome sequencing to determine the viability of the targeted panel approach.