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

 

Safety of Sildenafil in Premature Infants

Describe the safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia (BPD) and determine preliminary effectiveness and pharmacokinetics (PK) of sildenafil.

Summary

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.

Safety will be assessed following initial study-specific procedure (e.g., screening blood draws, dosing through 14 days post last study dose) and it will be assessed by frequency and incidence of adverse events and serious adverse events. The study team aims to enroll up to 120 participants.

 

OVERVIEW

Status:
Enrolling

ClinicalTrials.gov Identifier:
NCT03142568

Principal Investigator:
Matthew Laughon, MD, MPH
University of North Carolina
Chapel Hill, NC

NEWS

  • Sildenafil safety study achieves major milestone August 28, 2019 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 ...
  • Sildenafil safety studied for premature infants with bronchopulmonary dysplasia January 18, 2018 The Pediatric Trials Network (PTN), with support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, is conducting an interventional study to examine the safety and efficacy of sildenafil in treating bronchopulmonary dysplasia (BPD) in premature infants. BPD is a common chronic lung disease that can affect premature newborns, often leading to ...
  • A busy week for the PTN sildenafil trial February 26, 2013 The week of February 18–22 saw many milestones in the PTN sildenafil trial. On Tuesday, the first investigator’s meeting was held. By Wednesday, the trial’s first two sites had been activated — one at the Medical University of South Carolina Children’s Hospital (MUSC) and the other at the University of North Carolina–Chapel Hill. And, on ...

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.

Anesthesia and Analgesics in Children (ANA)

Study characterizing the pharmacokinetic (PK) and safety of anesthetics and analgesics used in children and adolescents

Summary

Anesthesia and analgesia drugs are commonly used in inpatient and outpatient management of infants, children, and adolescents. Anesthetics (such as ketamine) and analgesics (such as hydromorphone and ketorolac) help alleviate pain and anxiety, and provide adequate conditions for invasive procedures. These benefits account for the substantial increase in the number of anesthetics and analgesics administered to pediatric populations in different clinical settings, for different procedures, and to those of increasingly younger ages. However, many anesthetics and analgesics are not approved by the US Food and Drug Administration for use in children due to inadequate information on drug efficacy, safety, and dosing in pediatric populations. The ANA study aims to explore the PK and safety of both of these drugs in children and adolescents to advise on the best dosing. Approximately 120 children aged 2 to 17 will be enrolled in this study who are already receiving one of the two study drugs as part of their regular care: 60 for ketamine and 60 for hydromorphone.

 

OVERVIEW

Status:
Enrolling

ClinicalTrials.gov Identifier:
NCT03427736

Principal Investigator:
Kanecia Zimmerman, MD, MPH
Duke Health, Durham, NC

NEWS

    Pharmacokinetics and Safety Profile of Digoxin in Infants with Single Ventricle Congenital Heart Disease

    Study characterizing pharmacokinetics and safety of enteral digoxin used in infants with single ventricle congenital heart disease (CHD) 

    Summary

    Each year 40,000 infants born in the US are diagnosed with CHD. Single ventricle CHD is the most serious and complex form of the disease. 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. The team conducting this research hopes that the information collected in this study will help doctors improve the dosing of digoxin in children who have single ventricle CHD in the future. This study aims to enroll up to 48 infants diagnosed with single ventricle CHD, receiving digoxin per standard of care during the interstage period.

     

    OVERVIEW

    Status:
    Enrollment to start

    ClinicalTrials.gov Identifier:
    NCT03877965

    Principal Investigator:
    Christoph Hornik, MD
    Duke Health, Durham, NC

    NEWS

    • First participant enrolled in digoxin study September 5, 2019 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 ...

    Efficacy and Safety Study Comparing Lorazepam and Diazepam for Children in the Emergency Department With Seizures

    Study comparing efficacy and safety of diazepam and lorazepam, two commonly used drugs for the treatment of seizures in children

    Summary

    Children with seizures are frequently seen in the emergency department. The drug lorazepam, which is commonly used as initial therapy for children with seizures, is not labeled for this use by the FDA. Despite this fact, many experts support the use of lorazepam over diazepam for seizures in children, citing longer duration, increased effectiveness, and a lower incidence of respiratory depression. The FDA requested that a study be performed comparing lorazepam with diazepam, a drug that is labeled by the FDA for this indication. The study will show whether one drug is more effective and safe than the other.

    View study data for diazepam on NICHD's Data and Specimen Hub (DASH).

    OVERVIEW

    Status:
    Clinical study report submitted to FDA

    ClinicalTrials.gov Identifier:
    NCT00621478

    NICHD Data and Specimen Hub (DASH):
    Diazepam

    Principal Investigator:
    James Chamberlain, MD
    Children's National, Washington, DC

    NEWS

      Pharmacokinetics and Safety of Commonly Used Drugs in Lactating Women and Breastfed Infants (CUDDLE)

      Summary

      This groundbreaking study, conducted by the PTN, is designed to assess the safety of commonly used off-patent medications when they are given to breastfeeding mothers.

      While unnecessary drug use is generally discouraged during lactation, it is common for new mothers to have symptoms or medical conditions that must be treated with drugs. These mothers often struggle with their decision to take their medications because of the fear that the drugs will harm their children. With this study, PTN aims to find doses of commonly used drugs that are safe for both mothers and their breastfed infants.

      The study enrolled its first participant in October 2018 and will enroll approximately 50 lactating women, along with their breastfed infants, for each drug studied. Initially 10 off-patent drugs will be studied, including medications used to treat bacterial infections, depression and anxiety, high blood pressure, diabetes, and chronic pain. Mothers will be enrolled in the study only if they are already taking one of the following study drugs as part of their routine care.

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

      Mothers who participate in the study provide samples of breastmilk, their blood, their infants’ blood, or a combination to help researchers understand which drugs pass into breastmilk and determine the safest dose. Mothers and infants are expected to remain in the study until the infants reach 180 days of age.

      OVERVIEW

      Status:
      Enrolling

      ClinicalTrials.gov identifier:
      NCT03511118

      Principal Investigator:
      Kevin Watt, MD, PhD
      Duke Health, Durham, NC

      NEWS

      • Groundbreaking study to assess safety of drugs passed through breastmilk February 13, 2018 The Pediatric Trials Network (PTN) is undertaking a groundbreaking study to assess the safety of commonly used off-patent medications when they are given to breastfeeding mothers. The study will track how different drugs are passed through breastmilk to determine dosing levels that are safe for both mom and baby. Although the U.S. Food and Drug Administration ...

      Baby TAPE III

      Summary

      Validation and Analysis of Mercy’s babyTAPE for Weight Estimation in Neonates and Young Infants

       The primary objective of this prospective, multi-center, masked, observational study is to ensure that users can effectively and reliably perform the critical tasks identified for human factor assessments for the babyTAPE in a device-use environment with infants aged 0-90 days, and to validate the comparability of the weight estimates obtained against the previous study’s (TAP02) regression model. Critical tasks being evaluated in this investigation include:

      1. Identification of the correct anatomic landmarks,
      2. Proper use and orientation of the babyTAPE device, and
      3. Accurate observation and recording of the babyTAPE device output.

      The evaluation of these critical tasks will inform about the need for other risk reduction measures for safe use of the babyTAPE, and generate data that can be used to confirm the predictive performance and inform the effective use of the device. Additional data collected as part of this investigation will examine variability in device use between users.

       

      Pharmacokinetics of Trimethoprim-Sulfamethoxazole and Clindamycin

      Assessing the safety and pharmacokinetics of trimethoprim-sulfamethoxazole and clindamycin, antibiotics for the treatment of skin and soft tissue infections, in children by analyzing data from completed studies.

      Summary

      Despite the common use of trimethoprim-sulfamethoxazole and clindamycin in children for the treatment of skin and soft tissue infections, there is a lack of pharmacokinetics (PK) and safety studies to adequately define optimal dosing. Challenges associated with pediatric clinical trials limit the ability to conduct large PK and dosing trials in this patient population. Capitalizing on all available data sources to characterize the PK and safety of these two drugs is therefore essential.  Data from three Pediatric Trials Network clinical trials (all registered via ClinicalTrials.gov: NCT01431326NCT01728363, and NCT01744730) were studied and submitted to the FDA using the NIH/BPCA 409I mechanism.

      Publications

      Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children. Autmizguine J, Melloni C, Hornik C, Dallefeld S, Harper B, Yogev R, Sullivan J, Atz A, Al-Uzri A, Mendley S, Poindexter B, Mitchell J, Lewandowski A, Delmore P, Cohen-Wolkowiez M, Gonzalez D, on behalf of the Pediatric Trials Network Steering Committee.
      Antimicrobial Agents and Chemotherapy • October 2017 [Free online access]

      OVERVIEW

      Status:
      Analysis ongoing

      ClinicalTrials.gov identifiers:
      NCT01431326, NCT01728363, NCT01744730

      NEWS

      • PTN determines appropriate TMP/SMX dosing in infants and children November 13, 2017 The Pediatric Trials Network (PTN), with funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), recently completed a multicenter study of trimethoprim/sulfamethoxazole (TMP/SMX) to determine appropriate dosing for infants and children. The results of the study were published in the journal Antimicrobial Agents and Chemotherapy on Oct. 30. TMP/SMX is ...

      Pharmacokinetics of Anti-epileptic Drugs in Obese Children (AED)

      Studying the pharmacokinetics of anti-seizure medications (levetiracetum, valproic acid, topiramate, and oxcarbazepine) in obese children to inform dosing guidelines.

      Summary

      Childhood obesity has increased over the last decade. Due to altered pharmacokinetics (PK) associated with obesity, dosing for anti-epileptics in obese children may vary from that in non-obese children.  Inappropriate dosing may increase the risk for drug toxicity or therapeutic failure.  PK studies are urgently needed to determine appropriate dosing strategies for anti-epileptics in obese children.

      The Pharmacokinetics of Anti-epileptic Drugs in Obese Children (AED) study will enroll approximately 100 children, 2 to < 18 years of age, with a body mass index (BMI) > 95th percentile, who are receiving levetiracetum, valproic acid, topiramate, or oxcarbazepine, per standard of care.

      OVERVIEW

      Status:
      Enrolling

      ClinicalTrials.gov identifier:
      NCT02993861

      Principal Investigator:
      Kanecia Zimmerman, MD, MPH
      Duke Health, Durham, NC

      NEWS