The Pediatric Trials Network (PTN) has enrolled the last patient in its Efficacy, Safety and Pharmacokinetics of Topical Timolol in Infants with Infantile Hemangioma (TIM01) study.
In the study, approximately 110 participants will be randomized to either 0.25% or 0.5% timolol for 180 days to determine the most appropriate dosing level for children younger than three months old.
Timolol is a beta blocker that has increasingly been used for the treatment of Infantile Hemangiomas (IH), commonly called “strawberry” birthmarks, on infants’ skin. The popularity of timolol is likely due to its perceived safety as a topical drug. However, little is known regarding the safety of topical timolol’s use.
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.
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.
The American Academy of Pediatrics (AAP) posted an article on the AAP News website to spotlight the work done by the Pediatric Trials Network (PTN) to provide much-needed dosing, safety and efficacy information for off-patent drugs used in children. The article was written by Perdita Taylor-Zapata of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and P. Brian Smith of the PTN and the Duke Department of Pediatrics.
Despite pediatric medicine’s long history of catastrophic events resulting from inadequate study of drugs prior to their widespread use, the majority of drugs used in children have undergone insufficient study to receive pediatric-specific labeling from the FDA. To fill this troubling information gap, the NICHD established the PTN at the Duke Clinical Research Institute. The PTN generates data to help regulators update drug labels for safer and more effective use of medications in infants and children, in keeping with the goals of the Best Pharmaceuticals for Children Act (BPCA).
BPCA became law in 2002 and provides a mechanism to study off-patent drugs through a collaborative effort of the National Institutes of Health (NIH) and the FDA. This effort includes identifying drugs and therapeutic areas that lack pediatric dosing, safety or efficacy data; sponsoring clinical trials for prioritized drugs; and submitting study results to the FDA for consideration of label modification.
PTN trials are conducted across the U.S. and other countries in partnership with the NIH, and eight clinical trials are ongoing. More than 100 clinical sites are enrolling children in PTN trials, and more than 7,000 children have been enrolled to date.
The PTN has submitted data to the FDA for 21 drugs and devices. To date, eight label changes have been made based on clinical trials sponsored by the NIH BPCA program, including recent label changes to lisinopril and meropenem.
The American Academy of Pediatrics (AAP) has updated the 2018 edition of the Red Book to include fluconazole dosing information determined by a Pediatric Trials Network (PTN) study. The Red Book is the leading resource on pediatric infectious disease, providing the most up-to-date information on a wide variety of diseases that doctors see in children.
The updates include dosing information for the treatment of Cryptococcus neoformans and Cryptococcus gattii infections, as well as Cryptococcal meningitis in children. The updates, which can be viewed on Red Book Online, will enable doctors to provide a safer, more accurate dose of the antifungal drug fluconazole to treat these diseases in children.
The changes were based on a study conducted from 2008 to 2011 in collaboration with PTN that analyzed safety data on the use of fluconazole to treat infections caused by the Candida yeast. While Candida and Cryptococcus yeasts are not the same, they are treated similarly enough to allow dosing information for one to apply to the other. The study examined data from nearly 800 infants in three randomized trials.
The research was supported in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
The first site has been activated for the Long-term Antipsychotic Pediatric Safety (LAPS) Trial, which aims to determine the safety of long-term antipsychotic treatments in children. Dr. Ahmed Elmaadawi’s was the first site activated on Tuesday, Dec. 11. Dr. Elmaadawi is the director of the Interventional Psychiatry Program at Beacon Health System in South Bend, Ind.
The two-year LAPS study will follow children aged 3 to 17 who are already taking an antipsychotic (risperidone or aripiprazole) to treat disorders such as schizophrenia, bipolar disorder, and irritability associated with autism. The study will assess both the long-term health risks and quality-of-life benefits of these two drugs, which have been shown to be effective and may even prevent mental illness in adulthood.
“Antipsychotic treatment of children and adolescents has greatly increased over the past 20 years,” said Dr. Linmarie Sikich, principal investigator for the study and associate professor in the Department of Psychiatry and Behavioral Sciences at the Duke University School of Medicine. “At the same time, new evidence suggests an association between antipsychotic use and weight gain. In addition, the incidence of long-term adverse effects such as involuntary movements and hormonal changes is unknown.”
These findings have led to a growing concern that the potential benefits of long-term antipsychotic use may not outweigh the risks, especially for 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. Antipsychotics are also frequently used to promote weight gain and reduce anxiety in children and teens with eating disorders.
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 U.S. Food and Drug Administration (FDA) recently updated the label for the drug lithium to include appropriate dosing for children. The change was made after a trial supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) showed that lithium was safe and effective for children with bipolar disorder. Prior to this change, lithium had no safety or dosing information for anyone under age 18.
Researchers enrolled 81 children ages 7 to 17, who were divided into two groups. Fifty-three received lithium for a period of 8 weeks, and 28 received a placebo. Based on a questionnaire, researchers found that children receiving lithium experienced improved symptoms over those in the placebo group. In addition, children taking lithium did not experience significant metabolic side effects such as weight gain, as compared to other medications for bipolar disorder.
The Best Pharmaceuticals for Children Act (BPCA), which became law in 2002, funds research on medications for infants and children. The PTN was created by NICHD to make these pediatric trials more efficient. Read more on the NICHD website.
Complicated intra-abdominal infections (cIAIs) are common and often fatal in premature infants. The most common cIAI in neonates is necrotizing enterocolitis (NEC), a devastating disease that causes inflammation and can eventually destroy the wall of the bowel.
“In extremely low-birth-weight infants, the death rate for NEC can be as high as 50 percent,” said Dr. Michael Smith, investigator for the SCAMP study and associate professor of pediatrics at the Duke University School of Medicine. “Even survivors can suffer from lifelong complications such as short bowel-syndrome and poor neurodevelopmental outcomes.”
The most commonly used antibiotics in infants with cIAI include ampicillin, metronidazole, clindamycin, piperacillin-tazobactam, and gentamicin. However, since safety and efficacy data are lacking, these drugs are not labeled for use in infants with cIAI.
The PTN is filling this information gap with SCAMP, a partially randomized, multicenter, open-label study to determine the safety of these drug regimens in this specific and highly vulnerable population. Nearly 300 infants participated in the study at 58 sites in the U.S. and Canada. The infants were enrolled for 100 days, including 10 days of treatment and up to 90 days of follow-up assessments.
As a next step, the results of the SCAMP study will be submitted to the FDA for potential drug label changes.
Daniel Gorham was a 17-year-old high school student when his mother, a data scientist at the Duke Clinical Research Institute, showed him an article about the Summer Training in Academic Research (STAR) Program.
Although he dismissed the idea at first, he began reading up on the program and became more intrigued. He applied in 2016, and it is a decision he doesn’t regret.
“I always knew I wanted to do something in the sciences, but I didn’t know which route I wanted to take,” he said. “Learning about the different career fields and meeting different doctors and professionals, I ended up learning more about myself.”
The annual STAR Program gives high school students, college students, and middle and high school teachers hands-on experience conducting an original research project. It also provides classroom training in epidemiology, global health, medical ethics, statistics, and writing.
Although Gorham was initially more interested in cancer research than pediatrics, the eight-week program changed his mind. He spent the summer researching bronchopulmonary dysplasia (BPD), a dangerous lung disease that affects approximately 17,500 premature infants in the U.S. every year, often leading to life-long medical problems and even death.
His research on how BPD impacts the lives of premature infants, along with lectures in neonatology and tours of the neonatal intensive care unit (NICU), quickly instilled a love of pediatrics. The fact that Gorham’s older brother had been born preterm made the research hit even closer to home.
“I had always heard these stories about how tiny and sick he was, and how his chances of life were so slim,” Gorham said. “After spending time on rounds and being around these babies and their families, I realized how important this work really is.”
After graduating from the program, Gorham kept in close contact with program director Dr. Danny Benjamin. When an opening became available for a summer intern at the Pediatric Trials Network (PTN), where Benjamin is principal investigator, Gorham jumped at the chance.
For the entire summer, he conducted research on blood plasma stability, or how certain drugs stay stable in the blood of infants and children. At the end of his internship, he presented his findings on 70 different drugs to an audience of doctors and other professionals at the DCRI.
Gorham is now returning to East Carolina University, where he will be a junior this year. After completing his degree, he plans to come back to Durham to take the next steps toward a career in pediatric research.
“When I say the STAR Program changed my life, it sounds cliché,” he said. “But without it, I would have ended up approaching a career that I didn’t have much passion for.”
He recommends the STAR Program to others, and has even encouraged three of his friends to apply.
“It takes you out of the mindset of a high school student and turns you into an adult,” Gorham said. “My outlook on science completely transformed from, ‘I need to get an A in this class’ to ‘This actually saves lives.’”