Investigator shares successes, lessons learned from PTN, IDeA States partnership

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.”

Investigators explore PTN’s impact on clinical practice at PAS

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.

PTN LAPS Trial enrolls more than 100 patients

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 patients. 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 patients 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.

Annual STAR Program trains next generation of researchers

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.

Visit the STAR Program website for more information.

PTN Study Finds Dosage of Rifampin Safe for Infants

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.

Dr. P. Brian Smith

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.

iCAN shares guidance on better engaging young people in research

Reece Ohmer (left) and Sophia Klaudt

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.

Building trust

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.

Encouraging adherence

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.

Learn more about the 5th Annual iCAN Research & Advocacy Summit in Kansas City, Mo., June 24-28.

 

PTN to host symposium at PAS Meeting

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.

PTN Evaluates Systemic Exposure of Timolol as Treatment for Infantile Hemangiomas

The Pediatric Trials Network (PTN) recently published research in the Journal of the American Academy of Dermatology (JAAD) that explores whether topicaltimolol used on infants is absorbed through the skin and can be detected in the blood. The newly published research shares findings from a study led by Drs. Beth Ann Drolet and Kristen Holland of the Medical College of Wisconsin in Milwaukee. In this study, 76 children less than two years of age receiving timolol, as prescribed by their doctor, were monitored for a 90-day period and blood samples were collected.

Timolol is a beta blockerB that has increasingly been used for the treatment of Infantile Hemangiomas (IH), also commonly called “strawberry” birthmarks, on infants’ skin. However, little is known regarding the safety of topical timolol’s use.

In the PTN study, 75 children received a 0.5% concentration of timolol and one child received 0.25%. While it was predicted that young infants would have higher concentrations of timolol in their blood, the study found that older infants and those with thicker hemangiomas had the highest concentrations. There were no reports of serious unexpected adverse events during the 90-day study period.

An additional Phase IItrial will aid in determining the best and most effective dose of timolol in infants. However, the published research indicates that two drops of 0.5% timolol per day should not be exceeded in the treatment of small, thin hemangiomas. For the treatment of thicker hemangiomas, oral medicationD is recommended.

To learn more about the PTN timolol study, visit the timolol study page and the timolol highlight on clinicaltrials.gov.

 


Terms Guide

ATopical – Medication applied to body surfaces, such as the skin

BBeta Blocker – Medication that reduces blood pressure

CPhase II – A trial that explores the effectiveness of a medication that can last several months to years, and involve several hundred patients  

DOral Medication – Medication taken by mouth

FDA approves Zovirax (acyclovir) labeling supplement

Research conducted by the Pediatric Trials Network (PTN) has led the U.S. Food and Drug Administration (FDA) to update the prescribing information, or drug label, of acyclovir to include dosing for infants with Neonatal Herpes Simplex Virus (HSV) based upon the infants post-menstrual age. Acyclovir (brand name Zovirax) is an antiviral drug used in the pediatric population to treat HSV, a highly contagious virus that can be very serious for babies.

Because an infant’s immune system is not fully developed to fight off the virus, the disease can result in death or mental disabilities. While appropriate dosing of acyclovir was known for adults and children, acyclovir had not been adequately studied in full-term or preterm infants.

In the two associated PTN studies, 32 infants were enrolled. The first study was conducted at a single medical center in preterm and term infants with suspected HSV infection. The second study involved multiple medical centers and enrolled only preterm infants with suspected HSV infection.

Based upon the pharmacokinetic (how a drug travels through the body) results, the FDA updated the label to include dosing in infants based on their post-menstrual age (PMA), or the time that had elapsed since the mother’s last menstrual cycle. PMA is especially useful in preterm infants because it characterizes the baby’s expected developmental age.

 

Spotlight on Dr. Christine Turley, University of South Carolina

With a nearly 30-year history in academic research, Dr. Christine Turley offers a variety of perspectives into the world of clinical research. After a start in private practice, Dr. Turley went on to spend a large portion of her career in vaccine research and development. A general pediatrician by trade, Dr. Turley currently serves as director of the Research Center for Transforming Health at the University of South Carolina. The mission of the center is to help investigators and their teams conduct transformative research by helping overcome barriers that are often present in newer research settings.

Prior to her current position, Dr. Turley served in a variety of roles at the University of Texas Medical Branch (UTMB) in Galveston, Tex. She worked in clinical education, was the vice chair of Clinical Programs, and was heavily involved in the institution’s clinical operations.

She is currently involved in the administration of the Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care (PTN POPS) study at the University of South Carolina. We recently spent time discussing the importance of the study as well as clinical research in general.

Q: How would you explain the importance of clinical research, specifically for children?

A: We treat children every day and we try to treat them with the best evidence possible. But what we’re realizing is that, in many cases, the evidence is limited. In many cases we’re treating based on experience instead of data. The other thing about research, specifically in children, that is really important is that many chronic diseases originate in childhood. Our opportunity to help prevent this trajectory has never been more compelling than it is now. It’s too late to start working on hypertension when people are 50. We’re realizing now that it’s better to start at the very beginning of a person’s life.

Q: Why should people care about the findings of the PTN POPS study?

A: Over time, we’ve seen the level of variability that exists in children. The physiology of children changes very much over the child’s lifespan. It may seem obvious, but a 17 year old is very different than a seven month old. As we’re using medications on children, it’s important that we get better information so that we’re providing the best care possible and not running the risk of worsening conditions. We know we can do better, and studies like PTN POPS provide us with the opportunity to do better and provide better care for children.

Q: USC became involved in PTN as part of the IDeA States Pediatric Clinical Trials Network (ISPCTN). Can you explain the importance of (ISPCTN)?

A: ISPCTN is a component of the larger NIH Environmental Influences on Child Health Outcomes (ECHO) program. The IDeA State initiative weaves together the pediatric research community in a very interesting way by including other pediatric investigators and populations that are important, but otherwise may not have an opportunity to participate in ECHO. As a result, the research community becomes much more holistic and places an equal value on all components, creating synergy for pediatric research across the country. The capacity enhancements are wonderful and it’s very gratifying to invite other groups into research that may not have an opportunity otherwise.

Q: What are the benefits of having the University of South Carolina involved in the PTN POPS study?

AThere are three levels at which I see a benefit to USC’s involvement with PTN POPS. The most traditional is that we’ve been able to enroll patients in this study and engage with clinical investigators in other areas. At the bedside level, the teams are very interested in this project because they feel like there is the opportunity to impact patients they see every day. The second benefit is that it has proven the value of research to our group, which is relatively small and young in comparison to others. The third is that it has proven the value of research to our leadership. Even though we’re not enrolling 1,000 kids and making a huge amount of money for our institution, it is extremely relevant to the safety and quality of our care, which we all care about very much.

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