PTN Research Informs Rifampin Label Change

Cheerful young boy

A PTN pharmacokinetic (PK) study recently contributed to a medication label change for the drug rifampin.

This research effort, Pharmacokinetics (PK) of Antistaphylococcal Antibiotics in Infants, contributed pharmacokinetic and dosing data for rifampin.

27 participants were enrolled. Overall, a total of 86 plasma concentrations from 22 participants were used to construct the population PK model. Rifampin PK was well characterized by a 1 compartment PK model; only body weight and postnatal age (PNA) were retained as significant for clearance. No adverse events were related to rifampin and there were no serious adverse events reported. Rifampin was well tolerated in the study population.

The results of the study were submitted to FDA in support of an update to the rifampin label. The new label includes PK data for infants and the following dosing recommendations: 12 mg/kg infused over 60 min daily in infants < 7 days PNA, and dosing of 14 mg/kg infused over 60 minutes daily in infants > 7 days.

Thanks to this collaborative effort among PTN and FDA researchers, authorized medical providers now have appropriate guidance on how to prescribe and administer rifampin to infants.

PTN Investigator Spotlight: Dr. Chi Hornik

Q: Could you tell us about yourself? What PTN studies are you currently involved with? What are you hoping to learn from the study/studies?

A: As a clinical researcher and clinician, I am committed to improving the efficacy and safety of therapeutics in infants, children, and adolescents. To accomplish this goal, I strive to help design and implement clinical trials to close knowledge gaps in children’s drug dosages, while educating trainees to become clinician scientists, and applying evidence-based practice at the bedside. To impact children beyond the walls of the Duke Children’s Hospital, I am committed to multi-center clinical research. This commitment is exemplified through my roles in leading the site team at Duke University Medical Center in the Division of Pediatric Critical Care Medicine and leading several clinical coordinating center teams at the Duke Clinical Research Institute (DCRI).

I have experience in collaborating with many sites and investigators. I currently serve as coordinating center Principal Investigator (PI) of an Infant Platform, a posterior tibial nerve stimulation (POSITRON-C) device study, and a safety, pharmacokinetics (PK), and pharmacodynamics study evaluating understudied drugs (NICHD funded POP02) in special populations, with a sub-study evaluating therapeutics and clinical course of acute COVID-19 and multisystem inflammatory syndrome (MIS-C) patients (POP02-COVID). My prior role as Co-PI of the multicenter PK study of understudied drugs of interest (NICHD funded POP01) study, while coordinating >60 international sites with >4000 enrollments, allowed me to leverage existing infrastructure to create the POP02-COVID study that was quickly able to enroll affected children through the rapid activation of new sites. As one of the study PIs leading prospective studies in children with COVID-19, I have been collaborating as an investigator in National Institutes of Health CARING (Collaboration to Assess Risk and Identify Long-term outcomes) for Children with COVID-19 and an invited member of the trans-NIH Pediatric COVID-19 Biomedical Common Data Elements for Post-Acute Sequelae of Children with COVID-19 Working Group.  In addition, I am a member of the CURE Drug Repurposing Collaboratory (CDRC) that is a public-private partnership led by the Critical Path Institute and the US Food and Drug Administration.

I am involved in both sides of PTN studies, on the clinical coordinating teams at DCRI as well as serving as site Principal Investigator conducting the studies at Duke Hospital.  I’m the DCRI PI for the POP02 Study to close knowledge gaps in medications that are prescribed commonly but are still understudied ( Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children per Standard of Care (POP02) | Pediatric Trials Network ), evaluating a posterior tibial nerve stimulation device in children, and helping to lead trials in infants, including therapeutics for prevention of bronchopulmonary dysplasia in preterm infants and treatment of viral infections like congenital cytomegalovirus.

Q:  Can you recall an especially impactful encounter with a participant and/or family of a participant?

A: There are two encounters I have experienced that remind me daily of WHY research is critical.

One of the most impactful encounters I have had in my role as site PI was during a conversation with a teenager with acute pain due to sickle cell crisis. The teen was alone in the room, because their parent was at work. I spoke to the teen about how they were feeling and asked if I could speak to them about one of the studies that they qualified for. Despite having a 10 out of 10 pain score, the teen repositioned in the bed and perked up. The teen wanted to participate and spent some time convincing their reluctant mother to agree to consent for the trial. Learn more about this participant’s experience

The other encounter was with a family of a child who was critically ill. As I was kneeling next to the family to discuss the possibility of participating in a trial their child qualified for, the family said they would do anything to help advance research to improve the care for another child who has a similar condition. They felt that most researchers would not approach them during a time in which they were overwhelmed as research procedures may be perceived as a burden to the family. However, this family wanted their child’s life to have a positive impact even if their child did not survive. Their altruism reminded me that research can provide hope and an opportunity to contribute to something larger.

Q: Why is the work of PTN important to you? What goals do you hope to achieve through your PTN-related work?

A: I believe in PTN’s mission.  I am a clinician, educator, and researcher for this very reason.  I hope to help children beyond the walls of Duke Hospital, and I hope to mentor clinician scientists to join in the mission of ensuring that the research we conduct has representation of children from all races/ethnic backgrounds and social-economic status, so we can continue to move the needle forward to improve health for all children.

PTN Video Highlights the Importance of Diversity in Clinical Research

In March 2022, the Pediatric Trials Network (PTN) and the International Children’s Advisory Network (iCAN) collaborated to produce a video that discusses the importance of diversity and representation in pediatric clinical research. The video features kids involved with iCAN who have personal experience with clinical trials as well as PTN researchers. They shared why they think diversity is important and their reflections on increasing diversity and lowering barriers to participation in pediatric clinical research. The video also summarizes an analysis of participant representation across 33 Best Pharmaceuticals for Children Act (BPCA) studies and highlights opportunities for improvement.

The PTN believes it’s important to amplify the voices of participants in pediatric clinical research. Doing so can help other kids and parents feel more comfortable with enrolling in clinical trials, and it provides valuable insight to researchers. The video largely features kids involved with iCAN responding to questions about the importance of diversity in clinical research and how it has impacted their personal experiences.

“I 100 percent think that researchers should include a more diverse group of kids,” said Rhiannon, one of the participants featured. “It’s really important that we represent different perspectives.”

Several kids indicated similar sentiments — that diversity among pediatric clinical research is essential for representing different perspectives and walks of life. Chelsea, a participant, also emphasized the importance of seeing other kids and researchers that look like you. For participants, seeing others that look like or have similar experiences to them helps them feel more comfortable. Seeing diverse research staff also is a comfort and helps build a connection with the team. One participant, Abby, pointed out that study staff that looks like their family can make parents feel more comfortable with letting their child participate in the trial.

Many diverse groups have been excluded from clinical research due to barriers such as exclusion criteria, language differences, cultural differences, financial restraints, historical mistrust, and more. An extra effort needs to be made to engage these groups so that they have equal opportunities and access to treatments and information. Diverse participants are also needed so that study results are generalizable to the whole population affected.

“It’s up to us to accept accountability for ensuring our studies meet the needs of every child we serve,” said Susan M. Abdel-Rahman, Pharm.D, M.A., the narrator of the video and member of the PTN Steering Committee.

At the end of the video, the PTN presented an analysis of diversity in enrollment of 33 BPCA studies compared to census data of the places where the studies were conducted. It included data from 2008 – 2020, 167 study sites, 46 U.S. states, 5 countries, and over 10,000 participants. The studies were found to be largely representative of the areas they serve. Progress has been made to increase representation, but there’s still work to be done.

In the words of Imaan, a participant featured in the video, “It’s not impossible. You (just) have to want it.”

Watch the full video.

Our Commitment to Thanking Trial Participants

The Pediatric Trials Network (PTN) has sent thank you cards to thousands of trial participants and their families this summer recognizing the critical role families play in advancing pediatric research. PTN has sent thank you notes domestically and internationally, translating the notes into foreign languages when appropriate.

The thank you note is customized for each study that PTN is coordinating. For example, if blood draws are a requirement of the study, then blood draws and the associated frequency are explicitly mentioned in the thank you note so that participants’ contributions are specifically acknowledged.

Researching the art of gratitude

The ability to send thank you notes did not happen overnight. In partnership with the BASE (Bioethics & Stakeholder Engagement) Lab, the Duke Clinical Research Institute’s (DCRI) Research Communications & Engagement team (RCE) conducted formative research in 2019 to understand how to make thank you cards and plain language results summaries an effective and meaningful engagement tactic for trial participants and families.

For this research, the RCE team developed three sample thank you notes, one with minimal text and graphics, and the other two with expanded text and images of children and families in the header. These notes were mailed to 24 caregivers and three adolescent participants in advance. Two trained interviewers from the BASE Lab followed up with one-on-one interviews.

The interviewees overwhelmingly preferred the expanded text/graphic thank you notes, with some saying that the version with the image of children and families made them feel like PTN acknowledged the whole family’s efforts in clinical trial participation. Some stated that an additional paragraph of text, which was missing from the other more streamlined version of the thank you note, did a better job expressing gratitude, recognizing participants’ time and effort, and making them feel that they were contributing to discoveries that would improve children’s health.

The added text was: “Your involvement in this study has been instrumental in helping us determine the safest and most effective dose of ampicillin for newborns. Without you and other volunteers like you, we could not conduct research that will improve medical care for our youngest patients. We are grateful to you for sacrificing your time and effort to help infants and children worldwide.”

Incorporating Gratitude into Studies

Ultimately, there are a variety of ways to make trial participants feel appreciated and important. Thank you notes are just one of many options and expressing sincere gratitude towards trial participants should always be a key focus of any trial design.  Other options could include using YouTube for thank you videos and disseminating them via social media or posting them on the study website. However, it is important to ensure that thank you messages and results summaries do not come across as promotional. Through the research process, the PTN team learned that it is important to remove any language that could be construed as publicity.

Danny Benjamin, Principal Investigator of the PTN, hopes to see wider adoption of thank you messages throughout more projects. “It’s just the right thing to do,” he said.

The Work of PTN Recently Highlighted by Clinical Pharmacology & Therapeutics

The work of the Pediatrics Trial Network (PTN) was recently highlighted in an editorial by the Editor-in Chief of Clinical Pharmacology & Therapeutics, Dr. Piet Hein van der Graaf of Leiden University.

The editorial, which highlights examples of diversity in clinical pharmacology, features a PTN-led study and resulting publication titled: “Use of Real-World Data and Physiologically-Based Pharmacokinetic Modeling to Characterize Enoxaparin Disposition in Children With Obesity.” This publication was included in the August issue of Clinical Pharmacology & Therapeutics.

This study used real-world electronic health record (EHR) data to develop a physiologically-based pharmacokinetic model that evaluated the disposition and dosing requirements of enoxaparin, a commonly prescribed anticoagulant medication, in children with obesity vs. children without obesity.

Ultimately, this study suggests that dosing of some drugs like enoxaparin, often prescribed to children with obesity, should be adjusted according to the age and obesity status of the child. The systematic approach used in this study, which incorporated real-world data, can be applied to other drugs dosed in children with obesity.

“Studying specific populations, such as children with obesity, is imperative to advancing public health for our youngest of patients. For far too long we have operated with limited data on the most effective way to dose drugs in children with obesity,” said Dr. Daniel Gonzalez, Principal Investigator of the study.

A focus on including specific populations in clinical trials is at the very heart of PTN’s mission of making drugs and devices safer and more effective for the youngest of patients. Learning more about the implications of drug dosing for children with obesity is vital, as nearly 20% of children in the United States are classified as obese.

For more information on the important work currently being done by PTN, review the PTN studies page.

 

Raising Awareness for Pediatric Clinical Trials and Patient Engagement: PTN Presents at 2022 iCAN Research and Advocacy Summit

Group of students meeting at iCAN Summit

The Pediatric Trials Network (PTN) Project Team, along with global representatives from pharmaceutical and clinical research groups, recently participated in the annual International Children’s Advisory Network (iCAN) Research and Advocacy Summit in Lyon, France.

iCAN is comprised of dedicated youth member groups that work in unison, around the world, to provide a voice for children and families in medicine, research, and innovation. The Annual Research and Advocacy Summit is a dedicated forum to share with and learn from members of the medical community.

“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’s presentation titled, “How You Are Making A Difference: How DCRI, PTN, and iCAN are making clinical research accessible and meaningful for participants and their families” focused on all the unique ways in which PTN and iCAN work together. The session was interactive and involved the participants reviewing a clinical trial assent and providing ways to make it more useful and understandable. The feedback was incredibly valuable to help increase understanding of research and its process for children and their parents.  In addition, the presentation highlighted a current project featuring an anthology of submissions, ranging from jewelry designs to comics that highlight iCAN members’ perspectives on the pediatric clinical research process. Eventually all submissions will be compiled into a hard copy publication and shared with pediatric clinical trial participants and their families.

Cheryl and Phyllis at iCAN Summit
Project Leader, Cheryl Alderman and Program Director, Phyllis Kennel pose in front of art at annual iCAN Summit.

“The work of PTN is profoundly important and it is partnerships, such as the partnership with iCAN that help make the work of PTN fully accessible and truly meaningful. We are privileged to work with iCAN to raise pediatric clinical trial awareness, ensuring the youngest of patients, and their families, are impacted for generations to come,” said Phyllis Kennel DCI Associate Director, Government and Network Trials and PTN Program Director.

Review anthology submissions here and click here to learn more about iCAN.

Safety of Sildenafil in Premature Infants Study to Open Third Cohort Soon

Infant and adult hands

The Pediatric Trials Network (PTN) plans to open the third and final cohort (or group of study participants), in the Safety of Sildenafil in Premature Infants study in the near future. A total of 80 premature infants have been enrolled in the study so far, into the first and second study cohorts. These first and second cohorts received 0.125 mg/kg and 0.5 mg/kg of sildenafil in order to determine the safety in premature infants. The third, and final, cohort will receive the highest dose of 1 mg/kg.

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). 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.

Headshot of Jason Lang “More than 17,000 infants develop BPD each year so finding a drug that can help is an important public health goal. BPD can create prolonged hospitalization and in some cases, death. We hope that our study findings will help support families of infants with BPD so that there are less unknowns regarding the effectiveness of Sildenafil in treatment of infants with BPD.” said Dr. Jason Lang, the study’s Principal Investigator.

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

 

2020/2021 PTN Annual Report is Available

father and child

The 2020/2021 PTN Annual Report is now available. Click here to access.

A note from the PTN Steering Committee Chairs:

The COVID-19 pandemic has continued to challenge us in unparalleled ways and we are grateful for the commitment the Pediatric Trials Network (PTN) has exemplified in learning more about COVID as related to our youngest of patients. PTN’s Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children per Standard of Care (POP02) Study continues to make strides in supporting the treatment of younger COVID-19 patients and is currently evaluating several therapeutics to potentially treat COVID-19 pediatric patients younger than 21 years of age. In fact, POP02 has been engaged in a multi-institution, multi-study collaboration with National Institutes of Health (NIH) called The Collaboration to Assess Risk and Identify LoNG-term outcomes for Children with COVID (CARING for Children with COVID). This collaboration has worked to make de-identified data (or data that cannot be linked to a person’s identity) from children with COVID publicly available, in order to accelerate research on this important topic. The POP02 team was the first study to reach the important milestone of submitting these data and having them become available, and it is a testament to their tremendous effort and dedication. Click here for more on this. Additionally, this year PTN has released more than 20 publications and informed new label changes for clindamycin and diazepam. The Annual Review is recognition of all our hard-earned accomplishments over the past year. We look forward to all that is to come and am grateful for your commitment to determining the safest and most effective use of medications and devices in children.

Clindamycin Label Updated to Include Dosing Information for Premature and Term Infants

Mother and baby

A Pediatric Trials Network (PTN) pharmacokinetic (PK) study recently contributed to a medication label change for the drug clindamycin.

This research effort, which involved analysis data from 4 studies (Pharmacokinetics of Antistaphylococcal Antibiotics in Infants, Pharmacokinetics of Understudied Drugs Administered to Children, and Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral Clindamycin, and Antibiotic Safety in Infants With Complicated Intra-abdominal Infections), determined the pharmacokinetics in premature and term infants for treatment of staphylococcal infections.

PTN researchers measured the levels of clindamycin in each infant participant, thereby helping to determine the best dose of these drugs to treat infections in these patients. The studies found that clindamycin behaves differently in premature infants than it does in older children and adults due to the immaturity of their metabolic and kidney pathways; thus, identifying the correct dosages of drugs like clindamycin represents a critical public health need.

Thanks to this collaborative effort among PTN researchers, authorized medical providers now have appropriate guidance on how to prescribe and administer clindamycin to infants.

To learn more about the PTN studies that informed the clindamycin label change, please visit the study pages below:

PTN Research Informs Diazepam Label Change

Girl finger painting

A PTN pharmacokinetic (PK) study recently contributed to a medication label change for the drug diazepam.

This research effort, Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus, contributed pharmacokinetic and dosing data for the intravenous (IV) administration of diazepam.

This drug is a benzodiazepine clinically indicated in children for the management of status epilepticus and severe recurrent seizures. These seizure episodes are medical emergencies and can result in long-term adverse consequences and even mortality in children.

Pharmacokinetic and dosing data for the usage of diazepam in children 3 months of age up to 17 years of age has now been incorporated into the FDA drug label as a result of data analyzed in this PTN study.

Thanks to this collaborative effort among PTN researchers, authorized medical providers now have appropriate guidance on how to prescribe and administer diazepam to children with status epilepticus and severe recurrent seizures.