Pharmacokinetics and Safety of Antiretroviral and Related Drugs in Lactating Women and Breastmilk Fed Infants (BMS02)

Study that will help answer important questions about breastfeeding for women living with HIV/AIDS around the world

Summary

The Pharmacokinetic and Safety of Antiretroviral and Related Drugs in Lactating Women and Breastmilk Fed Infants (BMS02) study will help answer important questions about breastfeeding for women living with HIV/AIDS around the world.

Botswana, like many other countries in Africa, was hit hard by the HIV/AIDs pandemic more than a decade ago. However, with its government’s leadership and commitment to providing free antiretroviral medications, the once devastating disease has become a chronic condition for many.

Today, over 20% of the adult population lives with HIV and 82% of those people take antiretroviral medications every day. But many women taking these medications who are also breastfeeding their infants have unanswered questions about safety. While studies indicate that the transmission of HIV from mother to child is reduced if the mother is on antiretroviral medications, there are not many studies that describe the extent of antiretroviral drug transfer into breastmilk.

Because of the prevalence of HIV in Botswana and its government’s commitment to treating the disease, many women are likely to be interested in helping to find answers to these important questions. The BMS02 study will specifically study the following drugs:

  • Dolutegravir
  • Emtricitabine
  • Tenofovir disoproxil fumarate
  • Lamivudine

A better understanding of the safety of common antiretroviral medications in breastfeeding infants will provide data to help clinical professionals everywhere to advise breastfeeding mothers who live with HIV/AIDs. Confirmed safety might promote breastfeeding and benefit both mothers and their children.

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.

 

OVERVIEW

Status:
Enrolling

ClinicalTrials.gov identifier:
NCT04862975

Principal Investigator:
Angelique Boutzoukas, MD, MPH
Duke Health, Durham, NC

Co-Investigators:

Matthew Kelly, MD, MPH
Duke University Associate Professor of Pediatrics and Global Health
Duke Health, Durham, NC

PTN’S CUDDLE Study Will Assess Additional Drugs

Mother and baby

Pediatric Trials Network (PTN)’s BMS study (NICHD-2017-BMS01) of Pharmacokinetics and Safety of Commonly Used Drugs in Lactating Women and Breastfed Infants (CUDDLE), has added new drugs to the list of drugs being studied; marking a substantial milestone in determining the safety of drugs passed through breastmilk.

The study will assess the following additional drugs to determine safety for both mothers and their breastfed infants.

  • Amoxicillin
  • Bupropion
  • Buprenorphine
  • Duloxetine
  • Hydrocodone
  • Levetiracetam
  • Paroxetine

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.

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

 

Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose Intravenous Methadone in Healthy Adult Volunteers (MTH02)

Study evaluating pharmacokinetics of methadone administered through IV to healthy adults

Summary

This study will evaluate how healthy adults process methadone administered through IV. It is needed to determine the optimal dose of methadone and to understand variations in drug disposition. Methadone is already approved by the U.S. Food and Drug Administration for treatment of pain management and Opioid Use Disorder (OUD) in adults. Results from MTH02 will help update information on dosing methadone for adults, and they will lay the foundation for studies to label methadone for treating acute pain and OUD in children.

 

Publications

 

OVERVIEW

Status:
Enrollment completed

ClinicalTrials.gov identifier:
NCT05425420

Principal Investigator:
Kanecia Zimmerman, MD, MPH
Duke University School of Medicine Department of Pediatrics; Duke Clinical Research Institute

NEWS

  • PTN Enrolls Participants in Methadone Study for Adults
    The Pediatric Trials Network (PTN) has enrolled the first participants in a study titled Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose Intravenous Methadone in Healthy Adult Volunteers (MTH02). This study will evaluate how healthy adults process methadone administered through IV. It is essential for determining the optimal dose of methadone and to understand variations in ...

A Prospective, Blinded, Cross-Over Trial of the Exposure-Response Relationship of Terbutaline Sulfate in Adults with Asthma (TBS02)

Study characterizing the pharmacokinetics and optimal IV dosing of terbutaline for adults with asthma

Summary

TBS02 will compare the pharmacokinetic and pharmacodynamic relationship in intravenous administration of terbutaline versus subcutaneous injection in people 18-50 years old with asthma. This will help researchers understand the optimal IV dosing of terbutaline for adults with asthma. It is essential to determine the optimal dose of terbutaline in adults in an effort to lay the foundational understanding needed to research optimal dosing in children.

Publications

 

OVERVIEW

Status:
Enrolling

ClinicalTrials.gov identifier:
NCT04973345

Principal Investigator:
Jason Lang, MD, MPH
Duke University School of Medicine Department of Pediatrics; Duke Clinical Research Institute

NEWS

ANA Study Updates Protocol to Include New Medications

Two children standing on bridge

The PTN’s Anesthesia and Analgesics in Children (ANA) study has updated its study protocol to include new medications to be studied in pediatric populations. These new medications being studied, known as drugs of interest (DOI), include morphine, oxycodone, and ketamine. Although often prescribed by providers for anesthetic and analgesic (or pain relief) reasons, the safety, efficacy, and dosing information of these medications have not been established in pediatric populations.

The drug morphine is an analgesic, or opiate drug used for patients with severe pain. While this medication is approved to be prescribed for adults, for children it is often prescribed off-label by doctors or authorized medical professionals to treat symptoms of pain. Morphine is the most commonly prescribed opiate pain reliever in children, despite not having enough safety and efficacy data to establish FDA-approved dosing guidelines. Researchers will be studying this medication when administered through an intravenous line to inform guidelines for pediatric dosing.

Oxycodone is another new DOI being researched in the PTN ANA study. This drug is also an analgesic drug popularly prescribed off-label by prescribers for severe pain management in children and currently has no safety and efficacy data for dosing in children under the age of 18. Like morphine, oxycodone is an alternative treatment prescribed when previously prescribed pain medications are shown to be ineffective. Researchers will be studying this medication when administered via oral tablet and oral liquid solution.

An anesthetic drug, ketamine, was also added to this pharmacokinetic (PK) study. Ketamine is approved for adults as an introductory anesthetic drug prior to receiving further anesthetics for diagnostic and surgical procedures. This is another drug given off-label as an anesthetic in children undergoing invasive medical procedures. Although data in adults suggests this anesthetic produces minimal side effects, the correct and safe dose for children under the age of 16 is unknown. With support of Duke University’s Population Health Sciences Department, the PTN will also be testing a new tool to measure the sedation level in children to see how this new tool compares to prior measurement tools.

The PTN is thrilled to add these medications to the ANA study, which has enrolled participants aged 2 to 17 who currently receive anesthetic or analgesic drugs as part of their routine care. Once this study is completed and data are analyzed, the PTN will submit results to the Food and Drug Administration (FDA) to change the label of the medications studied and establish information and dosing guidelines for children.

Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children per Standard of Care (POP02)

Determining the appropriate dosing of several understudied drugs in children using samples collected as part of regular care.

Summary

The Pediatric Trials Network (PTN) Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children per Standard of Care (POP02) study expands upon the work done as part of PTN POP01 study, to continue to shrink the gap between pediatric and adult data available to clinicians and families for therapeutics used in children.

The goal is to characterize the pharmacokinetics of understudied drugs for which specific dosing recommendations and safety data are lacking. By taking advantage of procedures done as part of routine medical care (for example, blood draws), this study will provide better understanding of drug exposure in children. POP02 is a master protocol that will help provide valuable information for therapeutics used in special populations, such as critically ill children receiving ECMO or CRRT, premature infants, children with Down Syndrome, and children with obesity.

“This study and what we collectively learn through collaboration with site investigators and staff will be instrumental in helping inform the decisions parents and healthcare providers make when caring for children.” said Dr. Chi Hornik, POP02 Study Principal Investigator.

At the onset of the COVID-19 pandemic, POP02 expanded to include a substudy, called POP02-COVID, that would collect real-time COVID-19 related data in children affected by acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C). POP02-COVID also supports the treatment of younger COVID-19 patients by evaluating several therapeutics to potentially treat COVID-19 patients age 0 – <21 years old.

“We will evaluate biomarkers, genetics, and outcomes of a comparator arm of SARS-CoV-2 positive participants not receiving one of the COVID-19 drugs of interest.  We do not have sufficient safety or efficacy data on many therapeutics used in children, and this is more critical during a time such as what we are currently facing,” said Hornik.

To learn more about POP02, visit the study listing on Clinicaltrials.gov.

OVERVIEW

Status:
Enrolling

ClinicalTrials.gov identifier:
NCT04278404

Principal Investigator:
Dr. Chi Hornik
Duke Health, Durham, NC

NEWS

  • PTN Studying Multi-System Inflammatory Syndrome in Children
    While there have been relatively few confirmed cases and deaths from COVID-19 in children, researchers have been reporting an increased incidence of multi-system inflammatory syndrome in children (MIS-C) that is associated with prior or concurrent SARS-CoV-2 infections in children. Between March and October 1, 2020, over 1,000 MIS-C patients were reported from 44 state health ...
  • PTN evaluates COVID-19 in younger patients
    The Pediatric Trials Network (PTN), NICHD Funded, Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children per Standard of Care (POP02) Study continues to evolve in an effort to support the treatment of younger COVID-19 patients. POP02 is now evaluating several therapeutics to potentially treat COVID-19 patients age 0 – <21 years old. “With ...
  • POP02 begins study enrollment
    The Pediatric Trials Network (PTN) has started enrolling participants in the Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children per Standard of Care (POP02) study. POP02 aims to expand upon the work done as part of PTN POPS, with hopes to shrink the gap between pediatric and adult dosing information available to prescribing ...

Enrollment Goal Rapidly Approaches for PTN Digoxin Study

Toddler keeps red plush heart. Closeup

The Pediatric Trial Network’s (PTN) Digoxin study is rapidly approaching an enrollment milestone for its unique study participant population.

Digoxin’s original study timeline projected enrollment to be completed by the end of May 2021. However, due to the onset of the COVID-19 pandemic and related shutdowns and delays, the study team adjusted its target to finish enrollment by June or July of 2021. Through, teamwork, diligence, and determination the study team was able to meet the original target enrollment date, much quicker than anticipated after COVID-19 delays. Investigators and clinical coordinators on this study team worked together to quickly identify and enroll prospective participants, and with the engagement of two new study sites, the team anticipates to soon reach the target population of 48 enrollees.

About 40,000 infants born in the U.S. are diagnosed with single ventricle congenital heart disease (CHD). Digoxin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of heart failure in congenital heart disease and heart failure patients, yet more information is needed for dosing this drug in children with single ventricle CHD. According to study Principal Investigator, Dr. Christoph Hornik of the Duke Department of Pediatrics, “Although many different providers that treat infants with CHD have made significant efforts, the mortality rate is still high.”

Infant participants enrolled in this study have been diagnosed with single ventricle CHD, the most complex and fatal form of the disease. Researchers of the Digoxin study aim to find appropriate dosing and determine safety measures of the drug, as it is promising in reducing mortality rate in this population.

To review more about the digoxin study, visit ClinicalTrials.gov.

PTN Studying Multi-System Inflammatory Syndrome in Children

While there have been relatively few confirmed cases and deaths from COVID-19 in children, researchers have been reporting an increased incidence of multi-system inflammatory syndrome in children (MIS-C) that is associated with prior or concurrent SARS-CoV-2 infections in children. Between March and October 1, 2020, over 1,000 MIS-C patients were reported from 44 state health departments, the District of Columbia, and New York City. The cases seem to be disproportionately affecting Black and Latino children. According to the CDC,

  • 41% were Hispanic or Latino
  • 35% were Black
  • 14% were non-Hispanic White

The average age for these patients was 8 years old, and obesity was the most commonly reported underlying medical condition, occurring in 30.5% of Hispanic, 27.5% of Black, and 6.6% of White MIS-C patients according to CDC data published in August.

The Pediatric Trials Network (PTN) is poised to prospectively gather data from children with COVID-19 and MIS-C and how best to treat them. The NICHD-funded Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children per Standard of Care (POP02) Study continues to evolve in an effort to support the treatment of younger COVID-19 patients. POP02 is evaluating several therapeutics to potentially treat COVID-19 in patients age 0 – <21 years old. About 60 different sites across the United States and Canada are being selected to participate in this important research.

Dr. Chi Hornik, POP02 study principal investigator, said that this platform and the opportunistic design of the study helps researchers find urgent answers on how these therapeutics work in children by enrolling a wide and diverse cohort of children.  “Some asymptomatic patients are presenting weeks later with MIS-C. We need more information, as quickly as possible, to help clinicians and families make the best decisions on treatment for children affected by acute COVID-19 as well as MIS-C,” she said adding. “We need to find the right dose and combination of treatments to ensure safety with optimal outcomes in all affected children.”

Of the affected children who have been enrolled in POP02, approximately 75% of them are from minority populations. “This pandemic is hitting communities of color disproportionately hard which is why a broad, national platform like POP02 is so important,” said Hornik.

POP02 begins study enrollment

Picture of children's hands The Pediatric Trials Network (PTN) has started enrolling participants in the Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children per Standard of Care (POP02) study.

POP02 aims to expand upon the work done as part of PTN POPS, with hopes to shrink the gap between pediatric and adult dosing information available to prescribing physicians for their pediatric patients. In the initial phases, POP02 will focus on six drugs that have the potential to be involved in the treatment of COVID-19. The completed list of drugs that will be studied are: Anakinra, Aspirin, Azithromycin, Colchicine, Canakinumab, Interferon alpha & beta, Lopinavir/Ritonavir, Remdesivir, Ribavirin , Ruxolitinib, Sarilumab, and Tocilizumab.

The goal is to characterize the pharmacokinetics of understudied drugs for which specific dosing recommendations and safety data are lacking. By taking advantage of procedures done as part of routine medical care (for example, blood draws), this study will provide better understanding of drug exposure in children. The data collected will also provide valuable pharmacokinetic and dosing information for drugs in different pediatric age groups, as well as special pediatric populations.

“Site investigators and staff are working extremely hard to enroll participants in POP02. This study and what we learn through our work will be instrumental in helping inform the decisions parents and healthcare providers make when caring for children.” said Dr. Chi Hornik, POP02 Study Principal Investigator.

To learn more about POP02, visit the study listing on Clinicaltrials.gov.

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