Research Studies

Our mission is to advance medical research on rare diseases by providing support for clinical studies and facilitating collaboration, study enrollment and data sharing. Learn more here about RDCRN clinical studies, which are grouped by consortium and recruiting status. Click on the arrow to reveal a study summary; click on the protocol number and name to view a study page with more detailed information.


Brittle Bone Disorders Consortium

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The purpose of this natural history study is to perform a long-term follow-up of a large group of people with osteogenesis imperfecta (OI). OI is a rare disorder that causes bones to break easily. People with OI may have broken bones with little or no trauma, curvature of the spine, dentinogenesis imperfecta (DI), and, in adult years, hearing loss. It is seen in both genders and all races. OI can range from very severe to very mild. This study will observe the progression of the disease from participants of all ages, races, and genders. We will see how often people with type I OI have vertebral compression fractures of the spine. We will follow people with all forms of OI to see how often they develop scoliosis (curvature of the spine) and how it affects lung function, ability to walk and quality of life. We will look at dental health in people with OI and how that impacts a person’s quality of life. The genetic cause of the brittle bone disease will be compared with things like severity, various features and response to treatments. The overall goal is to improve the health and quality of life of people with OI.

Third-party Collaboration

The purpose of this study is to determine if it is safe to use clear aligners in correcting the misalignment of teeth in people with Osteogenesis imperfecta (OI). OI can affect the shape of the face, mouth and overall quality of life. Misalignment of teeth may interfere with oral hygiene, gum health, jaw function, opening of the jaw, chewing, breathing, and speech. There is very little information on the appropriate treatment for teeth misalignment in OI. Clear aligners are transparent plastic trays that are designed to fit over the teeth. With each new tray, teeth are moved a little at a time until they reach the desired position.

The overall purpose of this study is to understand the mental health concerns, psychosocial functioning, and priority treatment needs of individuals with OI. There are numerous health difficulties linked with OI. These difficulties can negatively impact the overall health of those affected. Despite the importance of mental health and pain in the OI community, there is limited research available on these topics. The primary goal of this project is to improve understanding about the mental health concerns, psychological and social functioning, and priority treatment needs of individuals with OI by engaging those with relevant expertise in a focused interview format.

Closed to Recruiting

The purpose of this study is to determine if fresolimumab is safe as a treatment for Osteogenesis Imperfecta (OI). OI is a rare disorder that causes bones to break easily. Studies have shown that TGF-β is a protein important in bone formation and that increased TGF-β activity leads to lower bone mass, strength and increased fractures. Fresolimumab is an antibody that can silence TGF-β. In studies with mice with OI, it has been shown that silencing TGF-β can lead to higher bone mass, quality and strength. In this study, we will evaluate the safety of of fresolimumab in two stages. In stage 1, we will evaluate the effect of two doses of fresolimumab on bone turnover and determine the dose that shows the greatest increase in bone density as compared to no treatment. This dose will be used for the repeat dose study where we will evaluate the effectiveness of multiple doses in increasing bone density, quality and strength.


Clinical Research in ALS and Related Disorders for Therapeutic Development

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The PGB2 (Phenotype-Genotype and Biomarker) Study of the CReATe Consortium will prospectively and systematically study approximately 300 patients with amyotrophic lateral sclerosis (ALS) or a related neurodegenerative disorder such as ALS-frontotemporal dementia (FTD), primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), progressive muscular atrophy (PMA), and multisystem proteinopathy (MSP). The study is broadly inclusive, enrolling patients with both familial and sporadic forms of disease. All enrolled patients will undergo five in-person evaluations at one of the CReATe consortium clinical sites as well as annual remote evaluations. In-person evaluations will include motor, cognitive and functional assessments as well as collection of biological fluids. Remote evaluations will focus on functional status and disease staging. Family members of patients with apparently sporadic disease (i.e. no family history) may also participate through a remote-evaluation process in which they provide limited information about their medical history as well as biological samples (blood and urine). Every effort will be made to integrate study procedures into multi-disciplinary clinic visits to minimize the burden of participation on patients and their families.


Congenital and Perinatal Infections Consortium

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The purpose of this study is to get a better understanding of what causes neonatal viral sepsis and to assess the impact of the infection on the babies’ health over time. Enterovirus (EV) or human parechovirus (HPeV) are very common viruses that can cause neonatal viral sepsis. Information gained from this study may guide diagnosis and treatment of babies with neonatal viral sepsis in the future. This study will observe babies with neonatal EV or HPeV sepsis to assess and characterize the complications affecting them. The study will also identify key clinical measurements and tests that help predict the health outcomes of children with neonatal EV and HPeV sepsis. Further, although EV and HPeV are common causes of neonatal viral sepsis, this study seeks to identify other unknown viruses linked to neonatal viral sepsis. The information generated by this study will lay the foundation for clinical trial studies of antiviral drugs to treat neonatal viral sepsis.

Not Yet Recruiting

The purpose of this study is to evaluate at-risk babies to determine the appropriate dose of oral valacyclovir comparable to the intravenous (IV) acyclovir doses typically used to treat babies with neonatal Herpes Simplex Virus (HSV) disease. IV acyclovir is best for the treatment of babies who already have HSV disease, but it is not ideal to prevent HSV disease because there are risks associated with IV use in babies. Valacyclovir is metabolized to become acyclovir, and although it has been studied in babies as young as one month old, there are no dosing recommendations for those less than three months old. This study focuses on at-risk babies whose mothers have a history of genital HSV infection and have been taking oral acyclovir or valacyclovir for several weeks before delivery. By studying the blood concentration, metabolism, clearance and safety profile of valacyclovir in infants less than one month old, we will determine the best dose of valacyclovir to prevent HSV infection when babies are exposed to it at birth. We will also inform larger studies using valacyclovir to treat neonatal HSV disease.

Congenital cytomegalovirus (CMV) infection is common and the leading viral cause of sensorineural hearing loss (SNHL) and mental retardation in infants. Despite current treatment options, babies with symptomatic congenital CMV disease are still at risk for hearing loss and neurologic deficits. Letermovir is the first new antiviral treatment of CMV to be licensed in over two decades. Two groups will be enrolled, and letermovir will be administered for 14 days in subjects in both groups. All subjects also will receive valganciclovir as standard of care. Group 1 (n=4) will be given a single dose based on their weight of letermovir on Study Day 0, with a full PK profile obtained over the next 24 hours to verify that the selected dose does not exceed the targeted exposure. Blood specimens will be shipped within approximately 24 hours to the UAB Pharmacokinetic Lab and processed in real time in order to get results back to the study site within an anticipated 7 days. If the drug levels are acceptable, the subject begin a 14-day course of once daily oral letermovir. If the dose is not acceptable, the dose will be adjusted down in 2.5mg increments. Once 4 subjects have been enrolled in group 1, the data and safety monitoring board will review all safety and drug level data. If no concerns are identified, then 8 additional subjects will be enrolled in group 2. The group 2 subject will start the 14 day course of study medication. The dose for group will be based on the data reviewed by the safety committee for the group 1 subjects.

Congenital cytomegalovirus (CMV) infection is the leading non-genetic cause of sensorineural hearing loss (SNHL) and the most frequent viral cause of mental retardation. Approximately 10% of infants born with CMV infection are symptomatic at birth, and of these, one-third will develop SNHL and two-thirds will experience developmental delays. A previous clinical trial run by the Collaborative Antiviral Study Group (CASG study 112) studied babies with congenital CMV infection who received either 6 weeks or 6 months of oral valganciclovir therapy. The results from this study suggested that 6 months of oral valganciclovir improved measures of neurodevelopment and hearing compared to 6 weeks of the treatment. The purpose of the current study is to assess participants from previous CASG studies and patients treated clinically for cCMV. The goal is to determine if there are long-term benefits of antiviral therapy on hearing and neurodevelopmental outcomes. Further, the current study will examine the long-term safety profile of valganciclovir when administered during infancy by assessing reports of cancer diagnoses and signs of puberty.


Consortium of Eosinophilic Gastrointestinal Disease Researchers

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CEGIR is conducting this study because they want to learn more about Eosinophilic Gastrointestinal Diseases (EGIDs). As part of that goal, one area of study will compare how well a patient feels – their symptoms – with what the tissue samples look like under a microscope. The study aims to answer a series of questions, including the following: - What if the tissue looks good, but you are still experiencing symptoms? - What if the symptoms have subsided, but the eosinophil counts haven’t changed?

This study is being conducted to determine the safety and effectiveness of a study drug called dupilumab in adolescents and adults with eosinophilic gastritis (EG) with or without esophageal and/or duodenal eosinophilia.


Dystonia Coalition

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This research includes four related projects each having different but overlapping goals. The first three projects, Natural History, Objective Measures, and Biobank, go together because they are related. The Patient-Centered Outcomes project is optional and depends on the type of dystonia you have and its treatment. 1. Natural History Project: The aim of this observational project is to better characterize the heterogeneity of clinical manifestations among subjects with dystonia, how these manifestations evolve over time, and how they relate to other family members. 2. Objective Measures Project: The aim of this project is to exploit technological advances for the development of objective tools to measure the severity of dystonia. 3. Biobank Project: The aim of this project is to develop a resource that expands the existing dystonia DNA biorepository to include other biomaterials. To date, no large multi-center open-access biorepository exists for any type of dystonia. 4. Patient-Centered Outcomes Project: The aim of this project is to delineate both between-subject and within-subject variations over time in response to the standard of care treatment with Botulinum toxin (BoNT) injections.


Frontiers in Congenital Disorders of Glycosylation

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The investigators are conducting a natural history study of patients with congenital disorders of glycosylation (CDG). The study will look into the progression of the disease amongst the participants and also look at the clinical symptoms and how they vary amongst different diseased population groups. The participants will be asked to fill out questionnaires either on their own or with a provider that will grade the severity of disease and document symptoms and diet. Participants will have an opportunity to submit blood, urine, and stool samples that will be tested for biomarkers for CDG. Participants will also complete dietary food records, physical exams, CDG scores, and the PROMIS questionnaires to assess disease progression and severity.

Not Yet Recruiting

This study is double-blind, placebo-controlled, 1:1 randomized clinical therapeutic trial of acetazolamide for the treatment of ataxia in patients with PMM2-CDG. Clinical history and screening data will be reviewed to determine subject eligibility. Potential subjects who have a molecularly and/or biochemical confirmed diagnosis of PMM2-CDG will be consented. Baseline data will be collected prior to randomization and at treatment initiation. Subjects who meet all inclusion criteria and none of the exclusion criteria will be enrolled into the study. Each subject who meets all the inclusion and none of the exclusion criteria will then be randomized to placebo or acetazolamide. They will be administered weight-dependent doses of acetazolamide or an equivalent volume of placebo twice daily by mouth. Enrollment will be open to individuals with a diagnosis of PMM2-CDG, 4 years and older. The trial will be performed at Seattle Children’s Hospital (Dr. Irene Chang and Dr. Christina Lam), Children’s Hospital of Philadelphia (Dr. Andrew Edmondson), and Mayo Clinic (Dr. Eva Morava-Kozicz).


Genetic Disorders of Mucociliary Clearance Consortium

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Closed to Recruiting

This longitudinal study is designed to define the rate of progression of PCD lung function in participants between 5-18 years of age using spirometry, which tracks well with lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis (assessed by high-resolution computerized tomography, HRCT, of the chest).

This study is designed to study the way in which patients with chronic airway disease are evaluated and diagnosed. The goal of these studies is to improving diagnostic techniques, including genetic testing. In addition, clinical features (phenotype) across these disorders will be studied to better understand the disorders. This will lead not only to a better standard of clinical care, but will assist in identifying of new treatment options.

Primary Ciliary Dyskinesia (PCD) is a genetic defect in airway host-defense, and typically results in chronic infection of the airways. Patients with PCD have chronic lung, sinus and ear infections. This longitudinal study is designed to define the rate of progression of PCD lung function in participants prior to 10 years of age using special lung function tests, which helped to track lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis (assessed by high-resolution computerized tomography, HRCT, of the chest).


Global Leukodystrophy Initiative Clinical Trials Network


The purpose of this study is to: (a) define novel homogeneous groups of patients with leukodystrophies and work toward finding the cause of these disorders; (b) assess the validity and utility of next-generation sequencing in the diagnosis of leukodystrophies; (c) establish disease mechanisms in selected known leukodystrophies; (d) track current care and natural history of these patients to define the longitudinal course and determinants of outcomes in these disorders; and (e) contacting subjects with specific diagnoses (or lack thereof) with information about other research studies or clinical programs that may be beneficial.

This study seeks to query the Electronic Health Record (EHR) at participating institutions in an automated fashion in order to development a large-scale library of clinically pertinent natural history data for individuals with a confirmed diagnosis of leukodystrophy. Automated data extraction techniques will be supplemented by traditional/manual chart abstraction approaches to ensure data integrity. Data collection and analysis methodologies will undergo face validation, inter-rater reliability, reproducibility, longitudinal stability, internal validation and construct validity under the careful oversight of the GLIA-CTN Data Integration Core (DIC) based at the Children's Hospital of Philadelphia.

The goal of this clinical project is to create a portfolio of disease-specific outcome assessments to facilitate design and execution of future therapeutic trials for adults with AMN. Specifically, investigators will determine the ability of a novel AMN rating scale to measure function, including a comparison of the trajectory between this rating scale and the Patient Reported Outcome (PRO) data obtained via RDCRN Protocol No. 8501. Finally, investigators will assess the rate of change in quantitative ataxia measures using force plate technology, and then compare this to wearable devices in enrolled individuals.

The primary objective of this research study is to identify and validate novel biomarkers in CSF, and to establish their correlation to clinical features and outcomes in specific leukodystrophies; for example, we propose to explore known protein biomarkers in AGS and AxD, including GFAP, NFL, and IP10, as well as candidate biomarkers such as inflammatory proteins including cytokines and chemokines, structural proteins, cell surface proteins, and markers of myelination and neuronal function. The study also seeks to characterize the stability of known and novel biomarkers under different shipping and storage conditions, which will allow investigators to explore the feasibility of multi-center biomarker collection procedures, with centralized processing and storage, in preparation for similar approaches in the context of future clinical trials for various leukodystrophies. Assay validity will be investigated using both intra- and inter-assay measurements.


Inherited Neuropathy Consortium

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A lack of high quality natural history data, based on a uniform, quantitative evaluation of patients continues to hinder the efforts to perform clinical trials for most forms of CMT. This study aims to determine the natural history of CMT1B, CMT2A, CMT4A, CMT4C, and other types of CMT in order to refine the overall picture of disease for use in future clinical trials.

Despite great success of gene identification in CMT, there is still much more genetic heterogeneity to uncover. In addition, modifying factors are an important aspect of CMT, but have been rarely studied in a systematic fashion. This study will apply innovative study designs and the latest technology to tackle some of the most pressing genetic issues in CMT, ultimately paving the way for new therapeutic approaches. This study aims to determine if gene modifiers exist for CMT1A, and to find new genetic causes of CMT.

It is likely that progression also varies during different pediatric age groups for different forms of CMT. However, there are no large-scale epidemiological data available for the genetic distribution or natural history of inherited neuropathies in the pediatric age group. This study aims to develop and test the CMT Peds scale (CMTPedS) in children with CMT in order to refine the scoring for future natural history and therapeutic trials. This study involves designing a pediatric scale(s) to measure impairment in children with CMT and to test the scale’s ability to measure disease progression in patients.

No CMT-specific clinical outcome measure currently exists to measure disease severity or progression in children from birth to 3 years of age. This is an important omission since future clinical interventions may be most effective in slowing disease progression if given early in life.The purpose of this study is to develop and validate a clinical outcome measure to evaluate disability and disease progression of children ≤3 years of age (infants and toddlers) with various types of Charcot-Marie-Tooth disease (CMT).

Closed to Recruiting

Charcot Marie Tooth (CMT) disease is the most common inherited peripheral neuropathy. Foot deformities are common complications in people with CMT and orthopedic surgery is often needed. The purpose of this study is to understand the current surgical approach to orthopedic complications in patients with CMT. Approximately 45 orthopedic surgeons who perform surgical procedures for foot deformities on CMT patients attending centers participating in the Inherited Neuropathies Consortium (INC) will be asked to complete a survey.

This is an observational study. The questionnaires in this study are considered Patient Reported Outcome (PRO) measures. These questionnaires are filled out by participants and do not involve an examination or treatment. The study questionnaires may range from 19 to 160 questions and focus on your ability to do a number of physical activities. The questionnaires include a series of questions which are meant to evaluate how CMT affects your ability to perform specific physical tasks and activities. There are questions about your overall physical health, physical activities, everyday activities, and which tasks or physical activities may be difficult for you. You can skip any question that you wish.

The purpose of this study is to learn about Carpal Tunnel Syndrome (CTS) in patients with Charcot-Marie-Tooth (CMT) disease or Hereditary Neuropathy with liability to Pressure Palsies (HNPP). CMT and HNPP are two types of inherited neuropathy. Symptoms of inherited neuropathies vary according to the type and may include numbness, tingling, pain and weakness in the hands and feet. HNPP is a unique type of inherited neuropathy, in that the peripheral nerves in the arms and legs are vulnerable to pinching. CMT is a progressive disease and (unlike HNPP) the vulnerability of peripheral nerves to pinching is not a known feature of the disease. Carpal Tunnel Syndrome (CTS) affects 3-6% of adults (4-10 million Americans) and is usually very treatable. CTS is caused by pinching of a nerve (median nerve) at the wrist. It can cause numbness, tingling, pain and weakness in the hand. There is some evidence to suggest that CTS might be more common in people who have inherited neuropathies such as CMT or HNPP. Despite the fact that CTS is relatively common, there is currently little information about CTS in people who have CMT or HNPP. This study is important, because we believe it will help us better understand how CTS affects people with CMT or HNPP and which treatments for CTS are best for patients with CMT or HNPP.

The purpose of this study is to determine the best way to measure the progression of Charcot-Marie-Tooth Disease Type 1A (CMT1A) over time. This study is important to help us to prepare for clinical trials. We are looking at new ways of measuring changes in CMT1A progression over a short period of time and assessing their usefulness in measuring effects of treatments in future clinical trials.


Myasthenia Gravis Rare Disease Network

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EXPLORE MG 2 is a natural history study designed to better understand disease characteristics and identify treatment predictive and responsive biomarkers for myasthenia gravis. A total of 300-400 participants with confirmed diagnosis of myasthenia gravis are expected to be enrolled in the study.

The Adapting Disease Specific Outcome Measures Pilot Trial for Telehealth in Myasthenia Gravis is a pilot study designed to better understand the use of modified clinical assessments during telehealth visits for patients with Myasthenia Gravis. A total of 50 adult participants with confirmed diagnosis of MG, with a range of disease severity will be enrolled across sites.


Nephrotic Syndrome Study Network


NEPTUNE is a study network to improve the identification and management of patients with Nephrotic Syndrome (NS) from Minimal Change Disease (MCD), Focal and Segmental Glomerulosclerosis (FSGS), and Membranous Nephropathy (MN). NEPTUNE includes study sites located at universities and medical facilities across North America and brings together patients, patient advocates, doctors and scientists working together to find better treatments for NS. The network allows experts from many areas to share research information to fast-track results that lead to new discoveries.


Porphyrias Consortium

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The porphyrias are a group of rare metabolic diseases that may present in childhood or adult life and are due to deficiencies of enzymes in the heme biosynthetic pathway. Porphyrias have various symptoms depending on the type, but these can range from neurological symptoms to sun sensitivity. See the descriptions of each type to get more information. The natural history of these disorders is not well described and it is not known why some patients are more severe than others. Therefore, the purpose of this long-term follow-up study is to collect a large group of patients with the different types of porphyria and to provide a better understanding of the natural history of these disorders. The hope is that this information will help in developing new forms of treatment. The research aims are: 1. To study the prevalence of specific indicators of disease severity. To study the effects on quality of life and health of various porphyrias. 2. To determine the relationships between disease severity and various biological characteristics, genetic information, and environmental factors.

The purpose of this study is to collect information on acute porphyria attacks that may have been caused by a medication. Individuals who have tested positive for an acute porphyria, or have been told by a doctor that they may have the disease may join this study. We are particularly interested in the following: (1) Attacks that appeared to be due to a specific medication; (2) Use of a medication that is considered risky in porphyria but caused no problems; and (3) Use of medications for which the safety profile in porphyria is unknown.

Third-party Collaboration

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. EPP and XLP, collectively called the protoporphyrias, result in the accumulation of the light-sensitive molecule protoporphyrin IX initially in the bone marrow during hemoglobin synthesis and secondarily in erythrocytes, plasma, and the liver. In addition to photosensitivity, protoporphyria can also result in anemia, gallstones, and liver failure. No therapy has been demonstrated to reduce protoporphyrin levels or prevent the potentially life-threatening complications of EPP. Cimetidine has gained attention as a possible treatment for human porphyrias because of a potential off-target effect of inhibition of delta-aminolevulinate synthase (ALAS), the first enzyme of heme biosynthesis. The objective of this study is to determine the efficacy and safety of oral cimetidine administration in the protoporphyrias. Efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires. If the results are positive, this would be the first study providing quality evidence for an agent acting as a disease-modifying therapy for EPP. The study is also attractive because it repurposes an already approved drug with few side effects to treat a rare human disease.

AIP is rare a genetic disorder caused by mutations in the hydroxymethylbilane synthase gene (HMBS) that reduce the function of an enzyme (a type of protein) in the body that is necessary for the production of heme. Heme is important for your body to use oxygen and for your liver to work properly. When a person does not produce enough of this enzyme, substances called ALA and PBG can accumulate, and this can cause symptoms of AIP. These symptoms may include abdominal pain; pain in the arms, legs and back; muscle weakness; nausea and vomiting; and confusion, hallucinations, and seizures. A small portion of AIP patients have recurrent attacks, while many others who have a mutation in the HMBS gene never develop symptoms. The purpose of this research study is to learn more about genetic factors (specific patterns in a gene) that predispose or protect an individual with a change (or mutation) in the gene that causes Acute Intermittent Porphyria (AIP) to develop symptoms.

Not Yet Recruiting

The purpose of this study is to establish an independent, public, online database, called the International Porphyria Molecular Diagnostic Database. This Database will have all published, newly identified, and biochemically/clinically verified pathogenic mutations for the eight major porphyrias, as well as a list of genomic variants for each gene from the latest genomic/exonic databases (e.g., GnomAD) that are benign, likely-benign, or unknown. The eight major porphyrias include: Acute Intermittent Porphyria (AIP), due to pathogenic mutations in the Hydroxymethylbilane Synthase (HMBS) gene, Hereditary Coproporphyria (HCP), due to pathogenic mutations in the Coproporphyrinogen Oxidase (CPOX) gene, Variegate Porphyria (VP), due to pathogenic mutations in the Protoporphyrinogen Oxidase (PPOX) gene, Porphyria Cutanea Tarda (PCT) due to pathogenic mutations in the Uroporphyrinogen Decarboxylase (UROD) gene, Erythropoietic Protoporphyria (EPP) due to pathogenic mutations in the Ferrochelatase (FECH) gene, Congenital Erythropoietic Porphyria (CEP) due to pathogenic mutations in the Uroporphyrinogen III Synthase (UROS) gene, X-Linked Protoporphyria (XLP) due to pathogenic mutations in the Aminolevulinic Acid Synthase 2 (ALAS2) gene, and ALA-Dehydrogenase Deficient Porphyria (ADP), due to pathogenic mutations in the ALADehydrogenase (ALAD) gene. Efforts will be directed to verify each published or new mutation in conjunction with the European Porphyria Network (EPNET) by elevated urinary, stool, erythrocyte, or plasma porphyrin precursor levels as well as by specific enzymatic activity, when available, from de-identified patients with the respective clinical manifestations for each porphyria.

Closed to Recruiting

This study examines the possibility that abnormal expression of the gene mitoferrin-1, which codes for the protein that transports iron in the mitochondria of cells, is a contributing factor to the phenotype in individuals with EPP. Erythropoietic protoporphyria (EPP) is a human genetic/metabolic disorder in which accumulation of the compound protoporphyrin causes skin sensitivity to sunlight. Some individuals with the disorder also have mild anemia, and a few have hepatobiliary disease. Iron is joined to protoporphyrin to form heme in the mitochondria of cells, under control of the enzyme ferrochelatase. Defects in this process cause the accumulation of protoporphyrin, leading to the biochemical and clinical features of EPP. Abnormalities in the ferrochelatase gene are the major cause of the defect, but do not satisfactorily explain the severity of the phenotype in all subjects. Mitoferrin-1 transports iron to ferrochelatase in the mitochondria of cells for heme formation, and also transports iron for the formation of a compound that keeps ferrochelatase active and stable. Thus, a deficiency of this iron transporter could reduce ferrochelatase activity and contribute to the phenotype in EPP.

This study aims to provide high quality evidence for the effectiveness and safety of hemin (PanhematinTM , Recordati) for treatment of acute attacks of porphyria. These types of studies have not been done before with either PanhematinTM or the hemin preparation available in Europe (NormosangTM, Orphan Europe). There are two treatment groups in this study. One group will be treated with PanhematinTM plus glucose, and the other group will be treated with glucose plus an inactive salt solution (called a "placebo"). To avoid prejudice, the treatment given to each participant will be blinded (meaning the participants and most of the hospital staff will not know which treatment the participant will receive) and randomized (meaning participants will have an equal chance of receiving either treatment, like the flip of a coin). A placebo-controlled, randomized study is the standard method used to prove treatments are effective and safe. PanhematinTM and glucose will be given in the same manner as is usual for treating an attack of porphyria. For participants who are chosen to receive the placebo, their treatment will be switched to real PanhematinTM at any time if their symptoms do not improve. This is called "rescue" treatment, and assures that they study is safe and patients who need hemin will receive it. Treatment with hemin will be for 4 days, or longer if needed. Since the study treatment is started as soon as possible after symptoms appear, there will be very little delay in providing hemin to those who need it.

This study will determine if the activity of aminolevulinic acid synthase (ALAS), the first and rate limiting step in heme biosynthesis, can be down-regulated by limiting the available plasma supply of, pyridoxal-5’-phosphate (PLP), an obligate cofactor required for synthesis of ALA by ALAS. Isoniazid, a drug commonly used to treat tuberculosis, binds PLP (a derivative of vitamin B6) forming a hydrazone that is excreted in the urine. The reaction between isoniazid and PLP and the subsequent excretion of the newly formed hydrazone limits the availability of PLP for binding to enzymes including ALAS that require it as a cofactor. We hypothesize that by dampening the activity of ALAS by restricting availability of PLP, isoniazid can be used to ameliorate the symptoms of erythropoietic protoporphyria (EPP) that are a consequence of accumulation of toxic metabolites of the heme biosynthetic pathway. The primary outcome measured in this pilot study will be plasma protoporphyrin, the toxic metabolite that causes the photosensitivity that is the clinical hallmark of EPP. This study will be conducted in patients who have EPP due to inherited genetic mutations either in the ferrochelatase gene or in the gene that encodes the red blood cell form of ALA (ALAS2). EPP is characterized by photosensitivity that is due to excess accumulation of protoporphyrin IX (PPIX), the last intermediate in the heme biosynthetic pathway that is formed prior to incorporation by ferrochelatase (FECH) of iron into the tetrapyrrole ring that results in formation of the heme molecule. Subjects will be given a standard dose of isoniazid (INH), 5 mg/kg up to 300 mg daily in a single dose, to be taken daily for eight weeks, and the effect of this treatment on the concentration of plasma PPIX will be monitored every two weeks for 12 weeks.

Porphyria cutanea tarda (PCT) is the most common human porphyria and the most responsive to treatment. Two very different approaches to therapy are considered effective. Repeated phlebotomy is most widely used, but has disadvantages that include discomfort, inconvenience and expense. A low-dose regimen of the 4-aminoquinoline antimalarial drugs, either hydroxychloroquine or chloroquine, is more convenient and cost-effective but is not widely used as first line therapy. A randomized study with frequent and detailed assessment of efficacy is proposed to compare these treatments. Up to 120 patients with well-documented PCT will be enrolled in this prospective, randomized, unblinded phase 2 noninferiority study comparing treatment by phlebotomy with treatment by low-dose hydroxychloroquine. Sixty will be randomized and those who do not qualify for randomization will be assigned the most appropriate treatment and be followed in a substudy. The study will be conducted under an active IND with the PI as sponsor (IND 66,042). Patients will be characterized in terms of known risk factors for PCT, including ethanol use, smoking, hepatitis C, HIV infection, estrogen use, HFE mutations and autosomal dominant inheritance of a partial deficiency of uroporphyrinogen decarboxylase (UROD) due to UROD mutations (as in familial PCT). Plasma and urine porphyrin concentrations will be measured at 2-week intervals for 6 months. The main measure of efficacy to be compared will be time to achieving a normal plasma porphyrin concentration. Skin manifestations, tolerability of treatment and safety measures will also be followed. It is likely that this study will justify more general use of low-dose hydroxychloroquine and eventually lead to treatment of PCT as an approved indication. Greater acceptance of this approach will lower health care costs and increase the convenience of treating PCT.

The initial objective of this protocol is to assemble a well-documented group of patients with confirmed diagnoses of the erythropoietic protoporphyrias, including autosomal recessive Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP) for clinical, biochemical, and genetic studies. The long-term objectives are (1) to conduct a longitudinal investigation of the natural history, complications, and therapeutic outcomes in people with erythropoietic protoporphyria, (2) to systematically investigate the psychological effects of the erythropoietic protoporphyrias on children and adults, and (3) to investigate the correlation between the identified genotypes and the resulting clinical presentation, also determining the possible interaction of other genetic markers.

This is a clinical trial, which means its purpose is to study an intervention or treatment. In this study all patients with EPP or XLP will be given a standard dose of iron pills and monitored for one year. There is currently no effective Food and Drug Administration (FDA) approved treatment for EPP or XLP in the US. Giving iron to patients with low ferritin (a measure of body iron stores) levels may help improve their EPP symptoms by decreasing erythrocyte protoporphyrin levels. Patients will be asked come to the study site once every three months over the course of a year for a total of five visits. At these visits the study doctors will check in with participants and some blood and urine samples will be taken. Participants will not be charged for any of the lab tests that are being done for part of this study alone. In between these study visits there will be phone call to check in and see how participants are doing. All patients in this study will receive iron pills at no cost to them.

The purpose of this study is to learn if treating patients who have porphyria cutanea tarda (PCT) and hepatitis C (HCV) with Harvoni, a treatment for HCV, will also treat PCT symptoms. This is a clinical trial, which means its purpose is to study an intervention or treatment. In this study all patients with PCT will be given a standard dose of Harvoni and monitored for two years. Currently there are two standard therapies for PCT, phlebotomies (removing certain amounts of blood at specific intervals), or low dose hydroxychloroquine (an oral pill). These treatments are used for patients with PCT whether or not they also have HCV. For patients with HCV however, we do not know whether treating the HCV first will also resolve the PCT symptoms. There will be an initial visit to determine whether participants are eligible to be in the study. If a participant is found to be eligible, he/she will be asked come to the study site once every month over the course of one year, and then once every 3 months for an additional year. There will be approximately 17 visits over the course of the whole study. At these visits the study doctors will check in with the participant and some blood and urine samples will be taken. Participants will not be charged for any of the lab tests that are being done as a part of this study alone. All participants in this study will receive the Harvoni pills at no cost to them.


Urea Cycle Disorders Consortium

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Long-term observation of the impact of UCDs on physical and neurological functioning, the relationship between health indicators and disease severity and the efficiency of UCD therapies.

A 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.

Study of how UCDs affect thinking, body chemistry and brain structure using magnetic resonance imaging (MRI) and behavioral testing.

The purpose of this research is to determine if silent seizures (electrographic seizures) occur during a hyperammonemic (HA) episode in patients with urea cycle disorders (UCD). Urea cycle disorders lead to accumulation increased ammonia due to problems breaking down protein. The symptoms of UCD may present at birth, childhood or adulthood (milder deficiencies) and are associated with cognitive deficits, changes in behavior, brain swelling and seizures. Sometime the seizures are not clinically obvious, but can be picked up if a video recording and concurrent EEG (video EEG is used, cVEEG). cVEEG is used in many intensive care units across the country to pick up seizures. We want to determine if having seizures due to HA leads to any adverse cognitive outcomes, and want to use the EEG to identify any changes that may be associated with that.

The purpose of this study is to measure liver stiffness and chemicals in the blood that test liver injury and function in four urea cycle disorders. Sometimes the seizures are not clinically obvious, but can be picked up if a video recording and concurrent EEG (video EEG is used, cVEEG). cVEEG is used in many intensive care units across the country to pick up seizures. We want to determine if having seizures due to HA leads to any adverse cognitive outcomes, and want to use the EEG to identify any changes that may be associated with that.

We are doing this study to see how the results of two sets of tools used to measure developmental progress relate to one another and how acceptable completing each of these measures is to children and families of children with Urea Cycle Disorders. We are anxious to make longitudinal assessment (repeated observations over time) of cognition easier, quicker and more accessible for families of children with urea cycle disorders. In order to do so we want to understand the relationship between the 2 sets of measures.

Closed to Recruiting

In this research study, Carbaglu was given to 5 patients with CPS1 deficiency and similar outcome measures were tested. Four patients demonstrated increased ureagenesis (urea production) and a decrease in the overall median ammonia levels with Carbaglu treatment (115 vs 82 μmol/L). One patient was given a longer-term trial of Carbaglu and had long-term stabilization of ammonia levels and was slowly weaned off of sodium phenylbutyrate. Future research will include identifying CPS1 mutations that may be responsive to NCG and a clinical trial of NCG in patients who experience acute hyperammonemia (high blood ammonia levels).

In this study, the investigators used mice with arginino-succinate lyase deficiency (ASLD) and cells from patients with ASLD to study the mechanisms involved in causing high blood pressure in this disorder, which is the second most common UCD (Figure 4). The investigators show that loss of the urea cycle enzyme ASL in the lining cells of the blood vessels leads to reduction of a chemical called nitric oxide (NO) and an increase in oxidative stress that lead to vascular dysfunction. Using data from a hu-man trial that was funded by the Urea Cycle Disorders Consortium (UCDC), they also show that the blood pres-sure in individuals with ASLD can be elevated.