Randomized clinical trials are considered the gold standard in clinical research. However, they often require a great deal of time and cost, and may not be feasible to conduct in vulnerable populations such as premature infants.
To overcome these difficulties, the Pediatric Trials Network (PTN) developed a repository of electronic health record (EHR) data gathered from nearly 265,000 pediatric patients to better guide research.
“This real-world data can be used to target drugs, conditions, and subpopulations for clinical studies that will maximize public health benefit and help identify areas for future study,” said Dr. Christoph Hornik of the Duke Department of Pediatrics, who led the development of the data repository.
The Best Pharmaceuticals for Children Act (BPCA) mandates the National Institutes of Health to prioritize areas where there is a critical need for information to guide medical treatments in children. With funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the PTN conducts studies designed to determine the dosing, safety, and efficacy of drugs that have been approved for adults but lack information for the pediatric population.
The repository, which includes data collected from 9 participating sites from 2013 to 2017, will aid in PTN’s mission by providing a multicenter data source to support its studies. It will facilitate both trial planning and the analysis of the uses and effects of a variety of medications in infants and children.
“Findings from this initiative will benefit children receiving care by not only shedding light on existing treatment practices, but also determining best practices for the future,” Hornik said.
The data collection, validation, and storage process was managed by Duke Health Technology Services and conducted in accordance with the Federal Information Security Management Act.
The Pediatric Trials Network (PTN) will be presenting its research at the Pediatric Academic Societies (PAS) Meeting May 5-8 at the Metro Toronto Convention Centre in Toronto, Canada.
The annual PAS Meeting brings together thousands of researchers, academics, and clinical care providers united by a common mission: to improve the health and well-being of children worldwide. It is supported by the American Pediatric Society, the Society for Pediatric Research, the Academic Pediatric Association, and the American Academy of Pediatrics.
During the annual meeting, PTN investigators will share information on a variety of studies involving antibiotic safety, treatment of hospital-associated and ventilator-acquired bacterial pneumonia, infant weight estimation, personal protective equipment, and the development of a data repository to aid in pediatric research. See a detailed schedule of PTN-related presentations below or view the online program guide on the PAS website.
Saturday, May 5
1:15 p.m. – Validation and Human Factors Evaluation of a New Device for Infant Weight Estimation – Dr. Susan Abdel-Rahman, Children’s Mercy Kansas City (Poster)
1:15 p.m. – The Use of PPE during Pediatric Resuscitation: Which Tasks are Most Affected? The Results of a Survey during a Simulation Trial – Dr. Aaron Donoghue, Children’s Hospital of Philadelphia (Poster)
Sunday, May 6
11 a.m. – The Impact of Personal Protective Equipment on Performing Critical Procedures for Pediatric Patients in the Pre-Hospital Setting – Dr. Maybelle Kou, Inova Fairfax Hospital (Platform)
3:45 p.m. – Population Pharmacokinetics of Milrinone in Infants and Children – Dr. Christoph Hornik, Duke University (Platform)
4:45 p.m. – Development of an Electronic Health Record Derived Multicenter Inpatient Pediatric Data Repository – Dr. Christoph Hornik, Duke University (Platform)
5:45 p.m. – Hospital Associated and Ventilator Acquired Bacterial Pneumonias in Infants and Children – Dr. Jessica Ericson, Penn State Milton S. Hershey Medical Center (Poster)
5:45 p.m. – Population Pharmacokinetics and Safety of Sildenafil in Premature Infants – Dr. Daniel Gonzalez, UNC Eshelman School of Pharmacy (Poster)
Monday, May 7
2 p.m. – Antibiotic Safety and Efficacy in Infants with Complicated Intra-Abdominal Infections (cIAIs) – Dr. Michael Smith, Duke University (Platform)
5:45 p.m. – Dosing-Safety Relationship for Acyclovir in the Treatment of Neonatal Herpes Simplex Virus Disease – Dr. Jessica Ericson, Penn State Milton S. Hershey Medical Center (Poster)
5:45 p.m. – Impact of Personal Protective Equipment on Pediatric Cardiopulmonary Resuscitation Performance – Dr. Aaron Donoghue, Children’s Hospital of Philadelphia (Poster)
5:45 p.m. – Weight Gain and Metabolic Syndrome in Children Exposed to Second-Generation Antipsychotic Medications – Dr. Angela Czaja, Children’s Hospital Colorado (Platform)
Tuesday, May 8
7:30 a.m. – Correlating Pulmonary Hypertension by Echocardiogram with Mortality in Premature Infants – Dr. Rachel Torok, Duke University (Platform)
The Pediatric Trials Network (PTN) welcomed its first two Australian sites in February. Sydney Children’s Hospitals Network and the Royal Children’s Hospital in Melbourne are now participating in PTN’s Pharmacokinetics of Understudied Drugs in Infants and Children (POPS) study.
The sites are currently involved in the Paediatric Trials Network Australia (PTNA), a counterpart of PTN that brings together pediatric researchers from across Australia who are committed to improving child health through the facilitation of pediatric clinical trials.
“These sites bring considerable experience in pediatric research and will make a significant contribution to PTN’s work,” said Dr. Danny Benjamin, principal investigator for the PTN. “In addition, their involvement will expand PTN’s global footprint, allowing us to gather data from a more diverse and widespread group of children and infants that can better inform our research.”
The POPS study is designed to assess the pharmacokinetics of a variety of commonly used drugs in children and infants that have limited safety and dosing information in the pediatric population. More than 70 drugs used to treat nearly 50 diseases and conditions have been studied so far.
The Pediatric Trials Network (PTN) is undertaking a groundbreaking study to assess the safety of commonly used off-patent medications when they are given to breastfeeding mothers. The study will track how different drugs are passed through breastmilk to determine dosing levels that are safe for both mom and baby.
Although the U.S. Food and Drug Administration (FDA) has implemented a guidance document on conducting lactation studies, off-patent drugs are not included in that rule. The PTN seeks to fill this knowledge gap.
“Although the benefits of breastfeeding are well-documented, we still don’t know enough about the effects of many prescription and over-the-counter off-patent drugs when they are passed to infants through their mother’s breastmilk,” said Dr. Kevin Watt, an assistant professor of pediatrics at Duke University who is leading the study. “As a rule, we discourage unnecessary drug use during lactation, but it’s quite common for new mothers to have symptoms or medical conditions that must be treated with drugs.”
“Many breastfeeding moms struggle with the decision to take medications because of the fear that these drugs will harm their children,” Watt said. “In the end, it often comes down to either stopping breastfeeding or discontinuing needed medications. We want to take the guesswork out of this decision and allow moms to breastfeed without worry.”
The study is expected to begin in April of 2018 and will enroll approximately 50 lactating women, along with their breastfed infants, for each drug studied. Initially 10 off-patent drugs will be studied, including medications used to treat bacterial infections, depression and anxiety, high blood pressure, diabetes, and chronic pain. Mothers will be enrolled in the study only if they are already taking one of the study drugs as part of their routine care.
Mothers who participate in the study will provide samples of breastmilk, their blood, their infants’ blood, or a combination to help researchers measure drug levels and determine the safest dose. Mothers and infants are expected to remain in the study until the infants reach 180 days of age.
The study, supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), will also explore the effects of maternal obesity on drug exposure and long-term outcomes of breastfed infants exposed to drugs in breastmilk.
See the NIH LactMed database for more information on the levels of various substances in breastmilk and infant blood, and possible adverse effects.
Fifteen sites in states participating in the NIH Institutional Development Award (IDeA) program are being onboarded into the Pediatric Trials Network’s (PTN) POPS study of commonly used medications in children.
The IDeA program aims to build research capacities in states that have historically received low levels of NIH funding by supporting research, faculty development, and infrastructure improvements. The IDeA States Pediatric Clinical Trial Network (ISPCTN), a network of IDeA sites established by the NIH’s Environmental Influences on Child Health Outcomes (ECHO) Program, recruits study participants from states whose populations are disproportionately rural and medically underserved.
“Historically, these populations have been underrepresented in multicenter clinical trials and their involvement in this study will provide them an opportunity to participate in clinical research,” said Jeannette Y. Lee, principal investigator for the ISPCTN and Professor of Biostatistics at the University of Arkansas for Medical Sciences. “PTN will also provide the sites with a way of interacting with a large community of clinical trial researchers and a venue for contributing to clinical research.”
“We are excited to welcome these sites, and feel confident that they will make a vital contribution to the POPS study,” said Dr. Chiara Melloni, co-investigator of the study and Assistant Professor of Medicine at Duke University. “Their participation will allow PTN to expand enrollment and ensure that a more diverse and inclusive population of children is represented in this important study.”
The 15 new study sites are:
Alaska Native Medical Center in Anchorage, Alaska
Kapiolani Medical Center for Women and Children in Honolulu, Hawaii
University of Kansas Medical Center in Kansas City, Kansas
Tulane University Health Science Center in New Orleans, Louisiana
University of Mississippi Medical Center in Jackson, Mississippi
Children’s Mercy Hospitals and Clinics in Kansas City, Missouri
University of Montana in Missoula, Montana
Dartmouth-Hitchcock Medical Center in Dartmouth, New Hampshire
University of New Mexico Health Sciences Center in Albuquerque, New Mexico
University of Nebraska Medical Center in Omaha, Nebraska
Board of Regents of the University of Oklahoma in Oklahoma City, Oklahoma
Rhode Island Hospital in Providence, Rhode Island
University of Vermont Medical Center in Burlington, Vermont
University of South Carolina in Columbia, South Carolina
West Virginia University Hospital in Morgantown, West Virginia
Four IDeA sites are already participating in the study: the Arkansas Children’s Research Institute in Little Rock, Arkansas; the Alfred I. DuPont Hospital for Children in Wilmington, Delaware; the University of Louisville Norton Children’s Hospital in Louisville, Kentucky; and the Medical University of South Carolina Children’s Hospital in Charleston, South Carolina.
When treating gastroesophageal reflux disease (GERD) in obese kids, the common practice of dosing stomach acid blockers based on children’s weight could actually cause more harm than good, said Dr. Valentina Shakhnovich, investigator for the Pediatric Trials Network (PTN) and Associate Program Director for the Gastroenterology Fellowship Research Program at Children’s Mercy Hospitals in Kansas City, Missouri. Shakhnovich shared her research on The Children’s Mercy’s Transformational Pediatrics podcast.
GERD, commonly called acid reflux, is a long-term condition in which stomach acid comes back up into the esophagus, causing heartburn, indigestion, and tissue damage. Because the occurrence of GERD is associated with excess weight gain, pediatricians are seeing more cases, as the number of overweight and obese children increases.
Pantoprazole belongs to a class of drugs known as proton-pump inhibitors (PPIs), which have long been used to treat GERD and other conditions related to excess stomach acid. Pediatricians typically dose pantoprazole based on a child’s weight. However, this common practice can actually put bigger kids at risk for unwanted long-term side effects, associated with higher doses of PPIs, such as low bone density and vitamin deficiencies.
“A lot of us have the knee-jerk reaction that if we see a 10-year-old who’s twice the size of an average 10-year-old, maybe we should double the dose,” Dr. Shakhnovich said. “What our research has shown is that’s actually not the best thing to do for obese kids, and it appears that they actually require a lower dose of proton-pump inhibitors than their non-obese counterparts.”
Dr. Shakhnovich suggested including a statement on the pantoprazole label, warning pediatricians not to give more of the drug to overweight and obese children. “Until clear dosing guidelines come from the FDA, think twice before dose escalating just because a child is obese,” she said.
She commended PTN for its awareness of the problem and for leading the way in finding the safest and most effective dose of commonly used medications for overweight and obese children.
“One in 6 children is obese. One in 3 is overweight,” Dr. Shakhnovich said. “It’s essential to start including obese patients in clinical trials so we’re not trying to guess at the correct dose and we’re not trying to play catch-up.”
The Pediatric Trials Network (PTN), with support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, is conducting an interventional study to examine the safety and efficacy of sildenafil in treating bronchopulmonary dysplasia (BPD) in premature infants.
BPD is a common chronic lung disease that can affect premature newborns, often leading to life-long medical problems, prolonged hospitalization, and even death. Approximately 17,500 U.S. infants develop BPD each year.
Sildenafil, which is approved for the treatment of pulmonary hypertension in adults, may help improve lung development and is increasingly being used off-label in premature infants with BPD. However, the efficacy and safety of sildenafil in premature infants at risk for BPD is currently unknown.
“Our hope is that this study benefits premature infants and their families by providing more information on the safest and most effective dose of sildenafil to treat this life-threatening condition,” said Dr. Matthew Laughon, principal investigator and neonatologist at the University of North Carolina Hospitals in Chapel Hill, N.C.
The study, Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary Dysplasia, draws on a previous safety study conducted by the PTN from 2013 to 2016. This study enrolled 34 infants of less than 28 weeks gestational age who were receiving sildenafil to treat BPD. Health care providers administered varying doses of sildenafil and collected plasma samples to determine the optimal starting dosing for sildenafil in premature infants.
The current study is expected to enroll approximately 120 infants and will be guided by dosing data from the previous phase 1 safety study. The first study site, Golisano Children’s Hospital at the University of Rochester Medical Center in Rochester, N.Y., was activated Jan. 2 and is currently recruiting participants.
“Anthropometric data are invaluable for informing the development of pediatric growth charts, assisting in policy making decisions, and supporting health initiatives,” said the article’s lead author, Dr. Susan Abdel-Rahman of Children’s Mercy Hospitals and Clinics in Kansas City, Missouri. “However, only a limited set of measures are available in publicly accessible databases.” These measures typically include weight, length, and head circumference of infants.
The PTN study captured additional measurements, such as humeral, ulnar, femoral, tibial, and fibular lengths, as well as mid-upper arm, mid-thigh, chest, abdominal, and neck circumference. More than 2000 infants were involved in the study at 8 U.S. medical centers from February to December 2015.
The data generated through the study can be used as indicators of nutritional status, predictors of morbidity and mortality, and can serve as proxy measurements when total body weight is difficult to obtain by traditional means.
“Weight is the single most important predictor of newborn mortality and an essential piece of information for therapeutic decision-making,” Dr. Abdel-Rahman said. “Though a weighing scale remains the universal gold standard for obtaining weight, there exist a number of settings wherein access to a functional, calibrated scale is limited.”
Dr. Abdel-Rahman subsequently used the data to develop a weight estimation strategy for infants in cases where scales are unavailable, or when their use is impractical, such as when infants are connected to monitoring or life-support equipment in the neonatal intensive care unit. The related publication, A Weight Estimation Strategy for Preterm and Full-term Infants, was recently published in Global Pediatric Health. A separate PTN study is currently evaluating a prototype of this weight estimation device.
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
In 2004, Dr. Ram Yogev, Director of the Section on Pediatric, Adolescent and Maternal HIV Infection at the Ann & Robert H. Lurie Children’s Hospital of Chicago, was invited to serve on an FDA advisory committee on anti-retroviral, anti-fungal and anti-tuberculosis drugs. As the only pediatrician on the committee, he was surprised to see that drugs were approved for pediatric usage with minimal supporting data and that information on optimal dosing for pediatric patients was virtually nonexistent.
The lesson stuck with him. In 2012, he became an investigator for the Pediatric Trials Network (PTN), conducting trials related to dosing of commonly used medications in children.
“The beauty of PTN research is that it gives us the basis for making better decisions in how we treat our patients,” he said.
For the past 5 years, Dr. Yogev has been an invaluable member of the PTN team. He was involved in several studies related to antibiotics, anti-epileptic drugs, and a measuring tape used to determine an infant’s weight when using a scale is impractical. He also enrolled the highest number of participants of any site in a 2012 trial assessing appropriate dosing for a variety of understudied drugs, and contributed more than 44,500 patient records to the PTN Data Repository, which will be used to inform the design of future PTN studies.
After more than 40 years as a practicing physician, Dr. Yogev is retiring at the end of this year. Taking over Dr. Yogev’s role with PTN will be Dr. William Muller, attending physician for pediatric infectious diseases at Lurie Children’s, who lists Dr. Yogev among his mentors.
Laying the foundation
Dr. Yogev has specialized in pediatric and maternal HIV since 1986, when he treated a young patient who had been infected with HIV during a blood transfusion. He found, to his dismay, that many physicians refused to treat HIV-positive patients.
“For me, it was obvious what I needed to do,” he said. “The essence of medicine is the humanity of it. Medicine is important, but more important to me is how the child and his or her family are coping with the disease socially and emotionally.”
In his quest to find innovative solutions for his most vulnerable patients, Dr. Yogev became a champion of clinical research. Named director of the Experimental Therapeutics Program of Children’s Memorial Research Center in 2005, he is credited with building the hospital’s clinical research program from the ground up.
“I had to develop an infrastructure to support my own studies,” Dr. Yogev said. “It quickly became obvious what the obstacles were, so I began to work to address them.” For example, after finding that transportation was a major challenge for people participating in trials, he acquired a van and a driver. He also hired his own phlebotomist to meet the research PK demands more efficiently and to keep from overburdening the hospital staff.
“Soon we were expanding the clinical research unit, educating physicians on clinical research, and developing a mechanism where people were recognized for their contributions and expertise,” he said. After about 5 years, the unit, now known as Clinical and Translational Research (CTR), was providing critical services to more than 125 physicians conducting clinical research at the hospital.
With funding from the NIH, Dr. Yogev also helped develop clinical research sub-units in Thailand and South Africa. Now independent sites, both are successfully conducting clinical trials on their own.
“There’s nothing more rewarding than seeing a sub-unit performing as well as the main site,” he said. “It’s like the pride a father feels when he sees his son or daughter is getting better than him.”
Taking the reins
Dr. William Muller, who will assume Dr. Yogev’s role of site investigator at the end of this year, has worked closely with Dr. Yogev since joining Lurie Children’s 10 years ago. They also both teach pediatric infectious diseases at Northwestern University’s Feinberg School of Medicine.
Dr. Muller’s area of study relates to the effects of viruses such as herpes simplex, Zika, and HIV on neurocognitive development. His current research explores how to most effectively prevent and treat herpes simplex encephalitis in newborns. He also researches infections in immune-compromised patients.
His ultimate goal is to make sure the results of clinical trials are communicated in the field, where they can be incorporated in decisions made when treating patients.
“You spend a lot of time in the lab trying to tease out why something happens, but that doesn’t necessarily help patients,” Dr. Muller said. “We have to look at how this can lead to better outcomes in the people we’re treating.”
Dr. Yogev credits Dr. Muller and the rest of the dedicated team at Lurie Children’s with his success. “They don’t mind what time of day or night; if something is needed, they are there,” he said. “I’ve truly been standing on the shoulders of giants.”
Friday, November 17th marks World Prematurity Day. Part of the March of Dimes’ Prematurity Campaign, the event is designed to raise awareness of the problem of premature birth and to support ongoing efforts to reduce rates of premature birth in the United States and around the world.
According to the March of Dimes, roughly 10 percent of U.S. births each year are premature, meaning that they take place before the 37th week of pregnancy. The World Health Organization identifies complications resulting from premature birth as the leading cause of death for children under the age of 5, and premature infants have a substantially elevated risk for a host of serious medical problems, some of them lifelong.
“With premature babies, pretty much every organ system is immature – everything is still developing. The human body wants a chance to mature for 9 months, and when it doesn’t get that chance, there are challenges,” says Dr. Rachel Greenberg, a neonatologist at the Duke Department of Pediatrics and a researcher with the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Pediatric Trials Network. She notes that these challenges are complicated by the fact that some therapies that are vital to sustaining premature infants can cause them additional harm. Worse, many medicines used to treat premature infants are not well-studied in this fragile population.
“We have to make an educated guess on what the dose is, based on the dose in adults,” says Greenberg, whose work with the Pediatric Trials Network is focused on gathering evidence to guide the use of medications in children and infants.
Premature birth also takes a heavy toll on parents, who often endure tremendous emotional stress while their child undergoes treatment—sometimes for weeks or months—in a hospital neonatal intensive care unit. “It can be the happiest day of their lives, and it can be the scariest,” notes Dr. Greenberg. “They’re so excited to have a child, but the baby’s sick.”
While neonatologists like Greenberg seek better treatments for premature infants, World Prematurity Day is part of efforts to prevent premature birth in the first place. This is a particularly urgent issue, as rates of premature birth have been rising around the globe in recent years, including in the United States, whose overall performance earns it a grade of “C” on the March of Dimes’ 2017 Premature Birth Report Card. Although infections and other underlying health issues in the mother are known to play a role, Duke’s Greenberg points out that the chain of events leading to a premature birth is often far from clear.
“Many times, we don’t know what causes it,” she says.
The March of Dimes’ Prematurity Campaign is supporting research into preventing premature birth, with the goal of reducing the U.S. rate of premature birth to 8.1 percent by 2020. The campaign also supports efforts to improve care delivery and foster advocacy and community engagement.
More information on World Prematurity Day activities, as well as ways to get involved, can be found at the March of Dimes website.
WordPress is a content management system and should not be used to upload any PHI as it is not an environment for which we exercise oversight, meaning you the author are responsible for the content you post. Please use this system accordingly.