The PTN digoxin study achieved a major study milestone by enrolling its first participant. The study team aims to enroll up to 48 infants to determine the pharmacokinetics (how a drug travels through the body) and safety of digoxin prescribed to infants with single ventricle congenital heart disease (CHD).
While digoxin has been approved by the U.S. Food and Drug Administration for the treatment of heart failure in children and adults, more information is needed, particularly in children with single ventricle CHD.
Each year 40,000 infants born in the U.S. are diagnosed with CHD. Single ventricle CHD is the most serious and complex form of the disease. Currently, there are no drugs proven to reduce death during this period.
According to study Principal Investigator, Dr. Christoph Hornik of the Duke Department of Pediatrics, “Despite significant efforts by a number of different providers that treat infants with CHD, the mortality rate remains quite high and there are no drugs that have been shown to decrease mortality.”
This study will try to answer questions about the side effects of digoxin and learn more about how it is processed in the bodies of children with single ventricle CHD.
“Digoxin is an old drug, but there is some evidence to suggest it may be helpful, so studying it in this population is essential,” said Hornik.
The Pediatric Trials Network (PTN) recently enrolled the fortieth infant in the Safety of Sildenafil in Premature Infants study. This is a major study milestone, as it rounds out the first cohort (or group of study participants).
The study aims to assess the safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia (BPD) and determine preliminary effectiveness and pharmacokinetics (how a drug travels through the body). The study aims to enroll a total of up to 120 participants.
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 annual International Children’s Advisory Network (iCAN) Summit took place June 24-28 in Kansas City, Mo. Representatives from the Pediatric Trials Network (PTN) were in attendance, along with global representatives from pharmaceutical and clinical research groups.
The mission of iCAN is to empower pediatric patients worldwide by providing children and families a voice in health, research, medicine, and innovation. “One of iCAN’s goals is to educate the world—especially our youth—about the importance of not only participating in clinical trials, but also of being actively involved in the process of designing pediatric clinical trials,” said Leanne West, president of iCAN and chief engineer of pediatric technologies at the Georgia Institute of Technology in Atlanta, Ga.
The summit included a number of sessions that explored pediatric clinical research and patient engagement from unique viewpoints. PTN Program Manager Phyllis Kennel and PTN Project Leader Cheryl Alderman both attended the summit. “Having the opportunity to watch youth and their parents learn and grow in their knowledge of clinical research and how they can impact outcomes was an amazing experience,” Kennel said. “The passion that they have to improve clinical care for children is inspiring and I believe our future is in great hands.”
Three Different Perspectives of a Case Study: Patient, Parent, and Provider
Hannah Nilsson was diagnosed with Burkitt lymphoma, a rare and highly aggressive disease, when she was only 13 years old. After spending nearly 300 days in the hospital, and experiencing a reoccurrence after nine months, Hannah went on to graduate high school and college and is now a mother, wife, and full-time professional.
After Hannah’s experience, her mother, DeeJo Miller, devoted her life to helping families who enter the hospital system with their children. “I was hired by Children’s Mercy Kansas City as a ‘parent on staff’ in 2008 to collaborate with staff by serving as a voice of the families.”
Dr. Karen Lewing, director of medical informatics for hematology/oncology at Children’s Mercy, was also part of the session and shared her impression of the journey Hannah and DeeJo experienced.
This session shed light on the unique experiences patients, parents, and providers have while addressing a vital health need and how all parties can collaborate to ensure patients receive the best treatment.
The Role of the Institutional Review Board (IRB)
This session explored the purpose of an IRB and provided young attendees with an opportunity to review a study protocol to determine if the materials met the criteria for IRB approval. The activity gave session attendees an intimate look at and hands-on experience with the IRB process and how it ensures the rights and welfare of human subjects are protected.
Patient Engagement: The Power of Patients in Healthcare
Kelly Ranallo, founder and president of the Turner Syndrome Global Alliance (TSGA), became a parent advocate after her daughter was diagnosed with Turner Syndrome, a chromosomal condition that affects development in women and girls. As part of her commitment to helping other parents with children diagnosed with rare diseases, Kelly built RareKC, a non-profit organization established to accelerate the diagnosis, care and treatment of rare conditions through patient-driven collaboration and innovation.
This session highlighted the support available for parents who have children with rare diseases. It also incorporated a tour of Mercy Children’s centers for genomics and innovation, which work to implement groundbreaking ideas in the rare disease field.
iCAN and PTN Partnership
The Pediatric Trials Network (PTN) has established a partnership with iCAN in an effort to engage participants and their families in research conducted by PTN. As part of the partnership, iCAN will review the design of PTN trials as well as patient consent and recruitment materials to ensure they actively involve participants and their families and take their needs and concerns into consideration.
“Giving children and families an active role in the design of clinical studies that affect them is critical, not only for conducting the highest quality and most meaningful research, but also for making the experience as positive as possible for everyone involved,” said Dr. Danny Benjamin, principal investigator for the PTN. “If we can help make the experience better for children, we’ve achieved our goal.”
During a PTN-hosted symposium at the Pediatric Academic Societies (PAS) Annual Meeting on Sunday, April 28, Dr. Janice Sullivan of the University of Louisville School of Medicine discussed the successes and lessons learned from the IDeA States Pediatric Clinical Trials Network’s (ISPCTN) participation in the PTN POPS Study.
The ISPCTN is one component of ECHO (Environmental Influences on Child Health Outcomes), an NIH-funded initiative launched in 2016 to study the effects of early environmental exposures on child health and development. The ISPCTN’s 17 sites are tasked with conducting clinical trials with a focus on rural and underserved areas.
“[These sites] do not typically get a lot of federal dollars to support research, so there are a lot of unique needs in these areas,” Dr. Sullivan said. “It was challenging in those first months trying to figure out how to organize ourselves and move things forward.”
The PTN offered the opportunity for ISPCTN sites to participate in POPS (Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care), a study designed to determine the safest and most effective doses of a variety of understudied drugs that are regularly prescribed to children.
The ISPCTN agreed to join the study in June 2017. It was a quick way to get involved in a low-risk clinical trial, Dr. Sullivan said, because patients were already receiving the drugs and blood samples were being collected as part of regular care. In addition, POPS was in line with the goals of ISPCTN and provided an opportunity for capacity building and mentorship.
“The PTN did an incredible job trying to prepare these sites,” Dr. Sullivan said. They provided each site with a study overview and detailed agenda for their qualification visits, toured the facilities and met staff at each site, and came prepared with a list of additional items to discuss.
Despite this preparation, there were still challenges. When the ISPCTN sites joined POPS, many of them had no experience negotiating contracts. Others required oversight of a tribal IRB, which required working through these specific needs. Many had to develop new policies for specimen storage, equipment maintenance, temperature monitoring, and dealing with different systems for electronic medical records.
After working to address these issues, Dr. Sullivan said, the sites got up to speed incredibly quickly. Fourteen sites have been activated to date and have enrolled a total of 139 patients. In addition, sites had to work internally to determine how to query their electronic medical record to identify potential subjects. Within a few months some sites were able to reduce their data query time from several hours to about 20 minutes.
Dr. Sullivan pointed to five common themes that determined success: getting sites enrolling, engaging new sites and investigators, building capacity, improving the network’s interaction with the IRB and regulatory agencies, and gaining buy-in and engagement from patients and the community.
Everyone has benefited from the partnership, she added, especially the children. The PTN has reached out to several ISPCTN sites to invite them to get involved in additional studies. “This will really help us be more sustainable and help us collaborate,” she said. “Sharing of ideas has helped everyone win.”
During a PTN-hosted symposium at the annual Pediatric Academic Societies (PAS) Meeting on Sunday, April 28, Dr. Kelly Wade of the Children’s Hospital of Philadelphia and Dr. Matthew Laughon of the University of North Carolina at Chapel Hill shared how PTN’s work is informing on the doses of medications commonly given to infants in the neonatal intensive care unit (NICU).
While improved survival of the smallest, most premature babies is a victory for health care, Dr. Wade said, it also presents a challenge: ensuring a safe passage through a sometimes months-long stay in the NICU. This stay often involves a number of medications that are prescribed “off-label,” or without specific safety and dosing information for this particular – and very vulnerable – population. The NICU, she said, presents a unique opportunity to study these medications in the youngest patients to learn how to dose them appropriately and, consequently, improve their outcomes.
According to a PTN publication, 65 percent of the top 100 most commonly prescribed medications are not adequately studied or labeled for use in the NICU. The PTN is making it a priority to study a number of these drugs, especially “top-10” drugs such as ampicillin, furosemide, and caffeine. These three medications alone, Dr. Laughon said, represent 80 percent of off-label use in the NICU.
“The PTN is really going for these high-effect, high-impact type studies,” he said.
Since this population is so vulnerable, however, there are a number of challenges to enrolling babies in these studies. Dr. Laughon listed a number of measures that the PTN has put in place to make sure the studies are minimally burdensome on these children and their families.
“The blood sampling is aligned with standard of care to prevent extra needle sticks, smaller blood volumes are taken, and sometimes we’re able to measure two or more drugs in a single sample,” he said.
Drs. Wade and Laughon pointed out the wide variation in dosing of ampicillin, the most commonly used drug in the NICU. To ensure infants were getting the safest and most effective dose of this drug, PTN did a study of 73 babies that used standard of care dosing. The results of the study indicated that the most common dose used in clinical care is probably too high, and that high doses of ampicillin may increase the risk of seizures.
Dr. Laughon added that there are currently no FDA-indicated therapies for the prevention or treatment of bronchopulmonary dysplasia (BPD), a chronic lung disease that affects mostly preterm and term infants. The PTN is conducting a randomized study that has enrolled 80 participants so far to determine the appropriate dose of furosemide, the top diuretic used to treat BPD.
In addition to studying these medications, PTN work has led to recent label changes for meropenem for intra-abdominal infections and acyclovir for herpes simplex infection. Data are also currently at the FDA to support label changes for piperacillin-tazobactam and fluconazole, and are currently being collected for anti-staph antibiotics, furosemide, sildenafil, and timolol for the treatment of infantile hemangiomas (often called strawberry birthmarks).
“We still have a lot of work to do to understand what’s the best dose to provide the optimal response,” Dr. Wade said.
The PTN Long-term Antipsychotic Pediatric Safety (LAPS) Trial, which aims to assess the long-term health risks of risperidone and aripiprazole in children, has now enrolled more than 100 children. Risperidone and aripiprazole have been shown to be effective for the treatment of conditions such as schizophrenia and bipolar disorder in adults, but little is known about the long-term health risks and quality-of-life benefits for their use in children.
While several antipsychotics are FDA-approved in children, it is common for these drugs to be prescribed without FDA approval for conditions such as attention-deficit disorder, obsessive-compulsive disorder, and major depression.
The ultimate goal of the study is to provide long-term safety data to the FDA to update the risperidone and aripiprazole labels to include correct safety and dosing information. This information will allow doctors to provide the safest, most effective dose to children who require treatment with antipsychotics.
The enrollment of more than 100 children helps achieve nearly 30 percent of the overall enrollment goal of the LAPS Trial and is a key accomplishment for the two-year observational study.
The Summer Training in Academic Research (STAR) Program welcomed 25 participants at its kickoff event Monday, June 17, at the Duke Clinical Research Institute (DCRI) in Durham, N.C. Now in its seventh year, the program provides hands-on research experience for undergraduate students, high school students, and middle and high school teachers during the summer academic break.
“The purpose of the program is to make sure we’re giving these students the opportunity to learn each day about various aspects of clinical research,” said Dr. Kanecia Zimmerman, leader of the program and associate professor of pediatrics at Duke University Medical Center. “The students may have never thought seriously about a career in medical research, and they come away thinking, ‘This is actually something I can do.’”
During the eight-week program, participants are placed in teams and matched with faculty mentors to work on original, hypothesis-driven projects. Participants also receive intensive instruction in developing scientific manuscripts, applied statistics, and data analysis.
A goal of the program is to have every trainee qualify for co-authorship on a peer-reviewed manuscript related to their team’s project. The research completed by the students will actually be used to further pediatric studies being conducted for the National Institutes of Health (NIH).
Nicholas Paredes, STAR program participant and rising high school sophomore from Sarasota, Fla., plans to earn a doctorate in biochemistry and biological engineering so he can focus his career on the testing of different medical treatments.
“I am particularly interested in conducting medical research and collaborating with others, knowing that the results would be used to improve existing technology,” he said. “Through the STAR program and the mentorship that is offered to its participants, I expect to work with renowned mentors and cooperate with my fellow members in a research team to write an academic paper that will successfully demonstrate the findings of our investigations.”
In addition to the research project, program participants attend lectures on neonatology, antimicrobial therapy, pharmacoepidemiology, and medical ethics. Eligible students also experience clinical medicine firsthand by shadowing a physician on hospital rounds.
The Pediatric Trials Network (PTN) recently published research in Antimicrobial Agents and Chemotherapy that tested the safety of intravenous rifampin for both premature and term infants. Rifampin is used to treat many different infections, including those caused by methicillin-resistant staphylococcus bacteria and tuberculosis. The newly published study shares findings from a study led by PTN investigator Dr. P. Brian Smith of the Duke Department of Pediatrics.
The study, which enrolled 27 infants total, analyzed plasma pharmacokinetic samples and safety data to determine the appropriate dosing of rifampin for infants. No adverse effects related to rifampin were seen, and drug clearance increased as weight and maturation increased.
Results showed that, for infants less than 14 days old, 8 milligrams of rifampin per kilogram of weight resulted in comparable exposure to adults receiving rifampin as a therapy against staphylococci infections and tuberculosis. In infants 14 days old or older, 15 milligrams per kilogram of weight showed similar results.
Representatives from the International Children’s Advisory Network (iCAN), a worldwide consortium of children’s advisory groups that provide a voice for children and families in medicine and research, shared their insights at a recent PTN symposium held Sunday, April 28, at the annual Pediatric Academic Societies (PAS) Meeting in Baltimore, Md.
Reece Ohmer, a high school senior who is preparing to go to college in the fall, has lived with type 1 diabetes since she was 8 years old. She discussed the experience of “turning a negative into a positive” by using her voice to advocate for better research for young people.
She joined iCAN when she was 12, after an especially taxing doctor’s appointment. She had received upsetting lab results, but no one had engaged her in the conversation.
“The doctor was talking to my mom and my mom was talking to my doctor, and I pretended I wasn’t listening,” she said. “But I was.”
After the appointment, she tearfully shared her frustrations with her mother, who responded by asking her what she would do to make that experience better for another child. Reece eventually joined the hospital’s teen advisory council, which in 2014 became one of seven hospitals participating in iCAN.
Through the consortium, she has worked to advocate for better funding for pediatric research, ensure access for more children, provide input on assent and consent forms to make them more understandable, and verify that available research is actually the research children need.
“We’ve helped increase understanding within the medical community that in patient-centered care, even the youngest voice matters,” Reece said.
iCAN representatives acknowledged that there is an element of distrust when researchers approach patients and families. Patients are often unsure where the researchers are coming from and whether they have their best interest at heart.
“They don’t know me and my life,” said Sophia Klaudt, an iCAN member and high school junior living with cystic fibrosis. “It’s hard to build that relationship with researchers when I’m just a case study to them.”
The iCAN representatives suggested that researchers may not be the best people to make the initial contact about research opportunities. “Have existing families who have already been through this experience help bridge that gap for you,” said Amy Ohmer, Reece’s mother and director of iCAN. “These patient ambassadors can share that empathy because they understand what it’s like to be in their shoes.”
When researchers need to approach patients directly, iCAN representatives suggested that a nurse or someone in a trusted position introduce them as a new member of the team who is coming from a genuine place of care and concern.
The iCAN representatives acknowledged the challenges of getting adolescents, who enjoy more freedom and are less bound by their parents’ demands, to adhere to their medications.
To better incentivize patients, Reece encouraged clinicians to get to know them and where they are in their care journey. Treating a 7-year-old is completely different than treating a 17-year-old, she said, and each group has its own motives.
“When I was seven, candy would have motivated me, or a chart on my refrigerator,” she said. “Now things that would incentivize me would be being able to do things on my own independently of my family, which is something I had to work for.”
Sophia stressed the importance of compromise, and trusting adolescents to make responsible decisions. “Ultimately, I know it’s my health,” she said.
Amy Ohmer added that, as a parent, it is critical to stop scolding and start empathizing.
“We don’t say enough to our young people that what they’re doing is tough,” she said. “We need to remind them of what’s happening that’s positive in their life.”
Communicating with patients
Asked how researchers can better communicate with young patients, Sophia recommended that they tailor communications to the patient’s age and maturity level, and that they ensure the patient is informed throughout the process.
“I’ve been in studies where I felt informed at the beginning, but I wasn’t informed throughout,” she said. “[Patients] need to understand what’s going on throughout the whole process and be informed of the results.”
iCAN representatives reminded researchers to keep the patient first in mind when developing materials. They recommended putting the most important information front and center, providing clear timelines so patients get a better sense of the level of commitment involved, and thanking participants and informing them of the impact they have had. Finally, they encouraged the use of newer technologies to communicate with young people, meeting them where they are.
“We are the future, and we are going to be the biggest return on your clinical research investment,” Reece concluded.
The Pediatric Trials Network (PTN) will host an informational symposium on Sunday, April 28, from 7:30 – 11:00 p.m. at the annual Pediatric Academic Societies (PAS) Meeting in Baltimore, Md. Register today to learn about the PTN’s contributions to child health and its unique perspectives as a network of more than 100 pediatric clinical research sites across the globe.
The symposium will begin with a brief overview of the PTN and the Best Pharmaceuticals for Children Act (BPCA), which aims to encourage the pharmaceutical industry to perform pediatric studies to improve labeling for medical products used in children. Perdita Taylor-Zapata, Pediatric Medical Officer at the NICHD, and Kanecia Zimmerman, Assistant Professor of Pediatrics at the Duke University School of Medicine, will provide opening remarks.
Three presentations will follow:
Matthew Laughon of the University of North Carolina at Chapel Hill and Kelly Wade of the Children’s Hospital of Philadelphia will provide real-world applications of PTN’s work and discuss the impact of clinical research in practice.
Parents and adolescent participants in the International Children’s Advisory Network (iCAN) will participate in a panel discussion on how researchers can better engage with participants and caregivers.
Janice Sullivan of the University of Louisville will spotlight partnering opportunities and work being done within and across research networks.
The symposium will conclude with a discussion of future opportunities for the PTN and pediatric research by Perdita Taylor-Zapata.