PTN’s Clindamycin research informs FDA label change

RX Drugs The U.S. Food and Drug Administration (FDA) has updated the prescribing information, or drug label, of Clindamycin, based on data provided by the Pediatric Trials Network (PTN). The updated label now includes dosing guidelines for children with obesity.

“Sometimes in children with obesity, the way the body absorbs and processes drugs is different than in other children because of the way their weight is distributed throughout their bodies. This means that it is important to study drugs in children with and without obesity, to make sure we are prescribing doses that are safe and effective for all children,” said Dr. Kanecia Zimmerman, from the PTN Steering Committee.

This study, which completed in 2016, determined the PK of intravenous and oral Clindamycin in pediatric patients with obesity and characterized the safety profile of Clindamycin in children and adolescents with obesity.

“Updating labels for commonly used pediatric drugs, such as Clindamycin, is an excellent way to ensure that children with obesity receive the best possible pharmacologic care. While many drugs remain to be studied in this population, seeing this updated Clindamycin label should certainly be encouraging for all PTN members and sites involved in these studies,” said Dr. Christoph Hornik, from the Duke Department of Pediatrics and one of the PTN investigators involved in the study.

Stay data may be viewed on NICHD’s Data and Specimen Hub (DASH).

 

PTN CUDDLE achieves study milestone

PTN’s study (NICHD-2017-BMS01) of Pharmacokinetics and Safety of Commonly Used Drugs in Lactating Women and Breastfed Infants (CUDDLE,) has completed study enrollment for nine off-patent drugs; marking a substantial milestone in determining the safety of drugs passed through breastmilk.

The study, which began in 2018, has enrolled approximately 50 lactating women, per drug, along with their breastfed infants. Enrolled mothers were already taking one of the following study drugs* as part of their routine care.

  • Azithromycin
  • Clindamycin
  • Labetalol
  • Metformin
  • Nifedipine
  • Ondansetron
  • Oxycodone
  • Sertraline
  • Tranexamic Acid

“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 the University of Utah Health and CUDDLE co-investigator.

It is common for new mothers to have symptoms or medical conditions that must be treated with drugs. With this study, PTN will find doses of commonly used drugs that are safe for both mothers and their breastfed infants.

“Many moms often are faced with the decision to either stop breastfeeding or discontinue their needed medications. We want to remove the mystery from this decision and help allow moms to breastfeed without additional burden,” said Kanecia Zimmerman, MD, CUDDLE PI, associate professor of pediatrics at Duke University School of Medicine, and Co-PI for the PTN.

See the NIH LactMed database for more information on the levels of various substances in breastmilk and infant blood, and possible adverse effects.

*The CUDDLE study will also assess the safety of Escitalopram, Ciprofloxacin, Doxycycline, Levofloxacin, Methylphenidate, and Sumatripan but has not completed enrollment.

PTN’s Caffeine, Doxycycline research results in two new FDA label changes

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 two medications: Caffeine citrate and Doxycycline.

Newborn baby in incubator

Caffeine citrate is the most commonly used non-antimicrobial medications for premature infants used in the in the newborn intensive care unit. When given to premature infants, caffeine reduces episodes of apnea and bradycardia. In lay terms, premature babies have a central nervous system that is immature, and part of that immaturity is that they forget to breathe. This apnea then leads to slowing of the heart rate and that can be life threatening. However, the label for this medication was missing crucial information about the correct age, dosing, and other information. PTN completed several studies and worked with the FDA to get new, important information into the label.

Doxycycline colorful word on white background with stethoscope

Doxycycline, which was studied as part of PTN POPS, is an antibiotic used to treat some diseases such as Rocky Mountain Spotted Fever and methicillin resistant staph aureus.  This drug has never been well studied in children under 8 years of age. PTN research has led to a label change that now gives pediatricians better information when using this drug to treat children.

“These label changes reflect the flexible and creative approach that everyone working with the PTN has collectively advanced,” said Danny Benjamin, MD, PhD, principal investigator for the PTN, an NIH-supported research network conducting trials to improve drug labeling for children. “The network is well-positioned for the next several years to continue to improve the health of children, thanks to legislation that supports pediatric and the quality of our work.”

“With each label change, PTN is giving pediatricians more of the critical information they need to improve the lives of their patients and give parents more confidence in their children’s care,” said Kanecia Zimmerman, MD, associate professor of pediatrics at Duke University School of Medicine and Co-PI for the PTN.

To learn more about PTN’s work regarding Caffeine and Doxycycline and associated data, you may access the related Caffeine NICHD Data and Specimen Hub (DASH) and Doxycycline DASH pages.

Mercy babyTAPE approved for marketing

The U.S. Food and Drug Administration (FDA) has approved marketing of Mercy babyTAPE. Developed by PTN’s Dr. Susan Abdel-Rahman of Children’s Mercy Hospital, the Mercy babyTAPE device is intended for use by health care professionals to estimate the body weight of infants from birth to 90 days of age.

“Weight is the foremost marker of health and health outcomes in infants. A weighing scale remains the universal gold standard for obtaining weight in children and is highlighted by the World Health Organization as one of four essential pieces of equipment needed when caring for newborns. However, the vast majority of healthcare providers in remote, resource-constrained settings simply do not have access to functional, calibrated scales with the precision necessary to accurately determine weight,” Dr. Abdel-Rahman said.

Many critically ill newborns in the U.S. suffer similar challenges when it comes to weight assessment. For infants receiving care in a neonatal intensive care unit, it can be nearly impossible to remove or account for the weight of life-sustaining medical equipment, prior to obtaining a scale-based weight. The relative error introduced by such equipment can significantly affect the safety profile of the medicines these infants receive. As a result, dosing errors are more likely to occur.

The approved marketing of Mercy babyTAPE is a substantial accomplishment in PTN’s quest to improve healthcare for children by determining optimal dosing of commonly used medications.

New project supports inclusion of children with Down syndrome in clinical trials

Portrait of beautiful young girl on the playground

The Pediatric Trials Network (PTN) has received an award to contribute to the National Institutes of Health’s (NIH) INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) project. The INCLUDE directive calls for a trans-NIH research initiative to address critical health and quality-of-life needs for individuals with Down syndrome across the lifespan.

One of the three primary components of the INCLUDE initiative is to support clinical trials on conditions and diseases that affect people with Down syndrome, both to accelerate the development of new therapies for individuals with Down syndrome and to include them in ongoing clinical trials.

PTN will work to characterize the pharmacokinetics (PK)A, pharmacodynamics (PD)B and pharmacogenomics (PGx)C of understudied off-patent drugsD administered to children and young adults with Down syndrome. By studying individuals who are receiving these drugs as part of routine care provided by their physicians, researchers will be able to determine if the doses of medications given to individuals with Down syndrome are appropriate and safe.

Additionally, investigators will work to develop a training program for clinical researchers, both within the PTN and with external Down syndrome experts, to provide insight and guidance in trial design, recruitment, and engagement specifically in this population.

Down syndrome is a condition in which a person is born with an extra copy of chromosome 21. The condition is associated with intellectual disability, a characteristic facial appearance, and weak muscle tone, particularly in infancy. Children with this condition may have a variety of associated co-morbidities. For example, about half of all affected children are born with a heart defect, and there are high rates of hearing loss, thyroid disease, autoimmune conditions, sleep apnea, and certain types of cancers in individuals with Down syndrome.

The National Institute of Child Health and Human Development (NICHD) supports this work through the Best Pharmaceuticals for Children Act (BPCA). Dr. Daniel Benjamin, Principal Investigator and Chair of PTN, will partner with Dr. Mara Becker of the Duke Department of Pediatrics as the INCLUDE Principal Investigators. For more information on the NIH’s efforts to support children with Down syndrome and their families, visit DSConnect.

Reading Guide

A Pharmacokinetics (PK): How a drug travels through the body

B Pharmacodynamics (PD): The effects of a drug

C Pharmacogenomics (PGx): How genes affect a person’s response to a drug

DOff-patent drug: Also referred to as a “generic drug,” it is not protected by patent but contains the same chemical substance as a drug that was originally protected by chemical patents

 

First participant enrolled in digoxin study

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.

To learn more about the digoxin study visit ClinicalTrials.gov.

Sildenafil safety study achieves major milestone

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.

To learn more about Safety of Sildenafil in Premature Infants visit ClinicalTrials.gov.

iCAN 2019 summit helps inform pediatric clinical research

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.”

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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.