Children's National

Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with cblA, cblB and mut classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. The frequency of these complications and their precipitants remain undefined. Furthermore, current treatment protocol outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Increasingly, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered transport and intracellular metabolism of vitamin B12 produces a distinct group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class (cblC, cblD, cblF, cblJ and cblX) and are also heterogenous, clinically and biochemically. The genetic disorders underlying cblE and cblG feature an isolated impairment of the activity of methionine synthase, a critical enzyme involved in the conversion of homocysteine to methionine and these disorders feature (hyper)homocysteinemia. Lastly, a group of patients can have increased methylmalonic acid and/or homocysteine in the blood or urine caused by variant(s)in recently identified (ACSF3) and unknown genes. In this protocol, we will clinically evaluate patients with methylmalonic acidemia and cobalamin metabolic defects. Routine inpatient admissions will last up to 4-5 days and involve urine collection, blood drawing, ophthalmological examination, radiological procedures, MRI/MRS, skin biopsies in some, and developmental testing. In a subset of patients who have or will receive renal, hepato- or hepato-renal transplants or have an unusual variant or clinical course and have MMA, a lumbar puncture to examine CSF metabolites will be performed. In this small group of patients, CSF metabolite monitoring may be used to adjust therapy. The study objectives will be to further delineate the spectrum of phenotypes and characterize the natural history of these enzymopathies, query for genotype/enzymatic/phenotype correlations, search for new genetic causes of methylmalonic acidemia and/or homocysteinemia, identify new disease biomarkers and define clinical outcome parameters for future clinical trials. The population will consist of participants previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the Organic Acidemia Association, Homocystinuria Network America and other national and international support groups. Most participants will be evaluated only at the NIH Clinical Center. However, if the NIH team decides that a patient under the age of 2 years is a candidate subject for this research protocol, that patient may enroll at the Children s National Medical Center (CNMC) site, pending approval by Dr Chapman, the Principal Investigator of the CNMC location Individuals may also enroll in the tissue collection only part of the study at the UPMC Children s Hospital of Pittsburgh or share medical history and clinical data via telemedicine visits remotely. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.

Type: Observational

Start Date: Jun 2004

open study

This is an open-label phase 1 safety and feasibility study that will employ multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) directed against proteogenomically determined personalized tumor-specific antigens (TSA) derived from a patient's primary brain tumor tissues. Young patients with embryonal central nervous system (CNS) malignancies typically are unable to receive irradiation due to significant adverse effects and are treated with intensive chemotherapy followed by autologous stem cell rescue; however, despite intensive therapy, many of these patients relapse. In this study, individualized TSA-T cells will be generated against proteogenomically determined tumor-specific antigens after standard of care treatment in children less than 5 years of age with embryonal brain tumors. Correlative biological studies will measure clinical anti-tumor, immunological and biomarker effects.

Type: Interventional

Start Date: Sep 2024

open study

The main purpose of the master is to help the research sites and sponsor carry out several clinical trials more efficiently by providing a common research protocol. Individual clinical trials under this master protocol define drug/disease-specific research goals and activities to test them. New studies will be added as new drugs emerge against different cancers. Participation in the trial will depend on how long the benefit lasts.

Type: Interventional

Start Date: Jan 2020

open study

This phase III trial compares memantine to placebo in treating patients with primary central nervous system tumors. Memantine may block receptors (parts of nerve cells) in the brain known to contribute to a decline in cognitive function. Giving memantine may make a difference in cognitive function (attention, memory, or other thought processes) in children and adolescents receiving brain radiation therapy to treat a primary central nervous system tumors.

Type: Interventional

Start Date: May 2022

open study

Clinical Trial to investigate whether the use of a novel device to be used in conjunction with ultrasound in pediatric vessel cannulations is superior to ultrasound-only pediatric vessel cannulations in terms of number of cannulation attempts.

Type: Interventional

Start Date: Feb 2024

open study

This is a multicenter, prospective, observational Phase 4 study in the United States. The study is designed to collect both medical history and prospective data on Duchenne muscular dystrophy (DMD) treatment outcomes in participants receiving delandistrogene moxeparvovec as part of clinical care, compared to participants with DMD receiving or prescribed to start chronic glucocorticoid treatment at baseline in routine clinical practice. In addition, treatment outcomes will be collected prospectively from post-trial participants who have received delandistrogene moxeparvovec through participation in select SRP-9001 studies.

Type: Observational

Start Date: Feb 2024

open study

This phase II trial tests effects of nivolumab in combination with chemotherapy drugs prior to radiation therapy patients with nasopharyngeal carcinoma (NPC). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Researchers want to find out what effects, good and/or bad, adding nivolumab to chemotherapy has on patients with newly diagnosed NPC. In addition, they want to find out if children with NPC may be treated with less radiation therapy and whether this decreases the side effects of therapy.

Type: Interventional

Start Date: Jun 2024

open study

This clinical trial will test the safety and efficacy of combining trametinib and azacitidine in patients with juvenile myelomonocytic leukemia (JMML). Newly diagnosed lower-risk JMML patients will receive trametinib and azacitidine. High-risk JMML patients will receive trametinib, azacitidine, fludarabine, and cytarabine.

Type: Interventional

Start Date: Oct 2024

open study

The current study will use a new treatment approach based on the molecular characteristics of each participant's tumor. The study will test the feasibility of performing real-time drug screening on tissue taken during surgery, and of having a specialized tumor board assign a treatment plan based on the results of this screening and genomic sequencing. The aim of this trial is to allow every child and young adult with medulloblastoma to receive the most effective and least toxic therapies currently available, and will pave the way for improved understanding and treatment of these tumors in the future.

Type: Interventional

Start Date: Feb 2022

open study

This Phase I-II dose-finding trial to determine the optimal dose of intravenous (IV) injection dose of donor-derived cytotoxic T lymphocytes (CTLs) specific for CMV, EBV, BKV and Adenovirus. A maximum of 36 patients will be treated in up to 18 cohorts each of size 2, with the first cohort treated at the lowest dose level 1, all successive doses chosen by the EffTox method, and no untried dose level skipped when escalating. The scientific goal of the trial is to determine an optimal IV-CTL cell dose level among the three doses 1.0x107cells/m2, 2 x107cells/m2 and 5x107cells/m2., hereafter dose levels 1, 2, 3. Dose-finding will be done using the sequentially adaptive EffTox trade-off-based design of Thall et al.

Type: Interventional

Start Date: Jan 2018

open study

The Childhood Cancer Survivor Study (CCSS) will investigate the long-term effects of cancer and its associated therapies. A retrospective cohort study will be conducted through a multi-institutional collaboration, which will involve the identification and active follow-up of a cohort of approximately 50,000 survivors of cancer, diagnosed before 21 years of age, between 1970 and 1999 and 10,000 sibling controls. This project will study children and young adults exposed to specific therapeutic modalities, including radiation, chemotherapy, and/or surgery, who are at increased risk of late-occurring adverse health outcomes. A group of sibling controls will be identified and data collected for comparison purposes.

Type: Observational

Start Date: Jan 1995

open study

This research trial studies kidney tumors in younger patients. Collecting and storing samples of tumor tissue, blood, and urine from patients with cancer to study in the laboratory may help doctors learn more about changes that occur in deoxyribonucleic acid (DNA) and identify biomarkers related to cancer.

Type: Observational

Start Date: Feb 2006

open study

It is generally recognized that pain assessment and management especially in newborns, children and other nonverbal populations is an unmet need. According to the American Medical Association, "the pediatric population is at risk of inadequate pain management, with age-related factors affecting pain management in children. Children are often given minimal or no analgesia for procedures that would routinely be treated aggressively in adults. Although much is now known about pain management in children, it has not been widely or effectively translated into routine clinical practice". These two factors combine to emphasize the necessity for an objective tool to quantify pain and monitor the effectiveness of analgesia, especially during treatments. Further, it is reported that many patients require a combination of treatments, and it is often necessary to test a variety of treatments before the personal match for treatment is found. The method in place to change the care on a subjective basis is difficult, time consuming, and not easily individualized. This pilot study is part of an ongoing effort to develop a method to objectively assess response to specific analgesic interventions. It specifically aims to discern the impact of analgesic interventions on sensory nerve fiber sensitivity in a diverse patient population.

Type: Observational

Start Date: Oct 2018

open study

Human milk has several well-established benefits but does not adequately meet the increased nutritional demands of the growing preterm infant, necessitating additional nutrient supplementation in a process known as fortification. In U.S. neonatal intensive care units (NICUs), human milk is primarily supplemented using standardized fortification, in which a multicomponent fortifier is added to human milk to achieve assumed nutrient content based on standard milk reference values. However, this method does not account for the significant variability in human milk composition or in preterm infant metabolism, and up to half of all very premature infants experience poor growth and malnutrition using current nutritional practices. Poor postnatal growth has adverse implications for the developing preterm brain and long-term neurodevelopment. Recent advances allow for individualized methods of human milk fortification, including adjustable and targeted fortification. Adjustable fortification uses laboratory markers of protein metabolism (BUN level) to estimate an infant's protein requirements. In targeted fortification, a milk sample is analyzed to determine its specific macronutrient and energy content, with additional macronutrient supplementation provided as needed to achieve goal values. Emerging data suggest that both methods are safe and effective for improving growth, however information on their comparable efficacy and neurodevelopmental implications are lacking, particularly using advanced quantitative brain MRI (qMRI) techniques. Through this prospective, randomized-controlled trial, the investigators will compare the impact of individualized human milk fortification on somatic growth and neurodevelopment in preterm infants. Infants will be randomized to receive one of three nutritional interventions: standardized (control group), adjustable, or targeted human milk fortification. Infants will undergo their assigned nutritional intervention until term-equivalent age or discharge home, whichever is achieved first. Brain qMRI will be performed at term-corrected age, and neurodevelopmental follow-up will be performed through 5 years of age.

Type: Interventional

Start Date: Feb 2024

open study

This is an open label, phase I dose-escalation study to evaluate the safety of coronavirus-specific T cell (CST) therapy for prevention of SARS-CoV-2 infection in immunocompromised patients following hematopoietic stem cell transplantation (HSCT). Participants will receive donor-derived CSTs for prevention of SARS-CoV-2 infection after HSCT (≥28 days and <4 months after HSCT). In this dose escalation trial, three doses (1x107/m2, 2x107/m2, and 4x107/m2) will be tested for safety, with study arms for adult (≥18 years of age and <80 years) HSCT recipients (Arm A) and pediatric (≥12 years of age and <18 years) HSCT recipients (Arm B), and defined dose escalations in each study arm. The study agent will be assessed for safety (stopping rules defined) and antiviral activity.

Type: Interventional

Start Date: Oct 2021

open study

This phase II trial determines if the combination of ONC201 with different drugs, panobinostat or paxalisib, is effective for treating participants with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for participants with DMGs, and there are few treatment options. ONC201, panobinostat, and paxalisib are all enzyme inhibitors that may stop the growth of tumor cells by clocking some of the enzymes needed for cell growth. This phase II trial assesses different combinations of these drugs for the treatment of DMGs.

Type: Interventional

Start Date: Oct 2021

open study

This phase III trial compares the effects of nivolumab with chemo-immunotherapy versus chemo-immunotherapy alone in treating patients with newly diagnosed primary mediastinal B-cell lymphoma (PMBCL). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Treatment for PMBCL involves chemotherapy combined with an immunotherapy called rituximab. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving nivolumab with chemo-immunotherapy may help treat patients with PMBCL.

Type: Interventional

Start Date: Oct 2021

open study

Few studies are specifically designed to address health concerns that are already relevant during pregnancy. The consequence is a lack of evidence on best clinical practice. This includes mothers and their babies when pregnancy is complicated by an abnormally slow heart rate due to maternal antibody-mediated heart disease in the unborn baby (fetus). Since the late seventies, it has been possible to detect and monitor fetal disease by ultrasound images and to treat selected conditions with pharmaceuticals administered via the mother. To this day, physicians need to make decisions about the management of such pregnancies without evidence from prospective clinical trials on drug efficacy and safety. The SLOW HEART REGISTRY is a multi-centered prospective observational study that will address the knowledge gap to guide future management of high-degree immune-mediated heart block to the best of care. The study seeks to establish an international database of the management and outcome of affected fetuses, to be used to publish information on the results of currently available prenatal care and to evaluate the need for additional research.

Type: Observational [Patient Registry]

Start Date: Jan 2020

open study

The purpose of this initiative is to improve care and outcomes for infants with HLHS by expanding the NPC-QIC national registry to gather clinical care process, outcome, and developmental data on infants with HLHS between diagnosis and 12 months of age, by improving the use of standards into everyday practice across pediatric cardiology centers, and by engaging parents as partners in the process.

Type: Observational [Patient Registry]

Start Date: May 2016

open study

This is an observational longitudinal study to determine the natural history and genotype-phenotype correlations of disease causing mutations in Charcot Marie Tooth disease (CMT) type 1B (CMT1B), 2A (CMT2A), 4A (CMT4A), and 4C (CMT4C). The investigators will also be determine the capability of the newly developed CMT Pediatric Scale (CMT Peds scale) and the Minimal Dataset to measure impairment and perform longitudinal measurements in patients with multiple forms of CMT over a five year window

Type: Observational

Start Date: Apr 2010

open study

The purpose of this research study is to test a new device called the PUMA-G Pediatric System. The research will measure if the device works well to safely aid doctors placing gastrostomy feeding tubes in children. The PUMA-G Pediatric System is an investigational device that uses ultrasound and magnets to guide insertion of a feeding tube.

Type: Interventional

Start Date: Jul 2023

open study

The objective of the International Rare Brain Tumor Registry (IRBTR) is to better understand rare brain tumors through the collection of biospecimens and matched clinical data of children, adolescents, and young adult patients diagnosed with rare brain tumors.

Type: Observational [Patient Registry]

Start Date: Jan 2023

open study

The purpose of this study is to conduct post-marketing surveillance of carglumic acid (Carbaglu) to obtain long-term clinical safety information. Carglumic acid was approved by the United States Food and Drug Administration (FDA) for treatment of acute hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency. Much of the FDA-required data is already collected through the Longitudinal Study of Urea Cycle Disorders (RDCRN Protocol #5101). This study will collect additional data on adverse events (interim events), adverse reactions, pregnancy, and fetal outcomes.

Type: Observational [Patient Registry]

Start Date: Apr 2012

open study

The Myelin Disorders Biorepository Project (MDBP) seeks to collect and analyze clinical data and biological samples from leukodystrophy patients worldwide to support ongoing and future research projects. The MDBP is one of the world's largest leukodystrophy biorepositories, having enrolled nearly 2,000 affected individuals since it was launched over a decade ago. Researchers working in the biorepository hope to use these materials to uncover new genetic etiologies for various leukodystrophies, develop biomarkers for use in future clinical trials, and better understand the natural history of these disorders. The knowledge gained from these efforts may help improve the diagnostic tools and treatment options available to patients in the future.

Type: Observational [Patient Registry]

Start Date: Dec 2016

open study

The overarching hypothesis of the ARRC trial is that administration of Azithromycin (AZM) during acute, Respiratory Syncytial Virus (RSV)-induced respiratory failure will be beneficial, mediated through the matrix metalloproteinase (MMP)-9 pathway.

Type: Interventional

Start Date: Feb 2022

open study