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PCORI Urea Cycle Disorder Study

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ClinicalTrials.gov Identifier: NCT02740153
Recruitment Status : Active, not recruiting
First Posted : April 15, 2016
Last Update Posted : April 6, 2018
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Center for Advancing Translational Science (NCATS)
Patient-Centered Outcomes Research Institute
The George Washington University Milken Institute School of Public Health (GWU)
The National Urea Cycle Disorders Foundation (NUCDF)
Studies of Pediatric Liver Transplantation (SPLIT)
Information provided by (Responsible Party):
Nicholas Ah Mew, Children's Research Institute

Brief Summary:

Urea cycle disorders (UCD) are genetic disorders caused by the liver's inability to break down ammonia from proteins; ammonia then accumulates and is toxic to the brain. UCD cause brain damage and intellectual and developmental disabilities and even death.

Treatment for UCD is either conservative management which involves a low-in-protein diet, drugs, and amino acid supplements or liver transplantation; each carries their own risks.

This study aims to help patients to make the decision about different management alternatives by providing them with scientific information that is currently lacking.

Aim 1 of this study will compare survival, neurocognitive function, and patient-reported quality of life. Aim 2 of this study will consist of interviews and focus groups with patients, their families, and their medical providers to determine important issues to consider when deciding whether to continue conservative management or opt for liver transplantation.


Condition or disease Intervention/treatment
Urea Cycle Disorders Other: No Intervention Given

Detailed Description:

Urea cycle disorders (UCD) are genetic disorders caused by the liver's inability to break down ammonia from proteins; ammonia then accumulates and is toxic to the brain. UCD cause brain damage and intellectual and developmental disabilities and even death.

Treatment involves a special diet low in protein, drugs that help metabolize ammonia and amino acid supplements (conservative management). Many patients and families choose liver transplantation rather than conservative treatment; both alternatives are effective in reducing or normalizing blood ammonia. While liver transplantation eliminates the ammonia problem, conservative management does so only temporarily and in many patients, blood ammonia can rise during an infection.

The long-term objective of this study is to help patients make decisions about management alternatives (conservative vs. liver transplantation) by providing them with scientific information that is currently lacking. The questions the investigators will address are:

  1. What is the disease's risk of mortality and illness in the two treatment approaches?
  2. What can parents expect in terms of the development of their child and his/her school performance?
  3. What are the expected effects of each treatment on short-term and long-term quality of life?

This research will have two components. In one the investigators will use statistical methods to compare numbers or percentages of survival, illness, psychological testing for IQ, executive function, memory, behaviors, and quality of life among patients that choose conservative management and those who have chosen liver transplantation. Some of this information is already being collected by the Urea Cycle Disorders Consortium (UCDC) in 14 metabolic clinics (11 of them in the US) as part of its long-term follow-up study. To ensure that the information the investigators analyze is representative of the UCD patient population in the US, the investigators will also obtain data from the Studies of Pediatric Liver Transplantation (SPLIT) registry, which collects information about children who undergo liver transplantation for many different diseases (including UCD).

The second component will consist of individual interviews and focus groups with patients and/or families and their medical providers to determine important issues to consider when deciding whether to opt for liver transplantation or continue conservative management.

The National Urea Cycle Disorders Foundation (NUCDF) and the Patients' Research Working Group collaborated with the clinical investigators to design this research and to ensure that it that it covers the questions that are most important to patients and their families. The results of this study will be disseminated to patients, their doctors, and clinical staff so they receive current, validated information before making a decision about the best treatment for them.


Study Type : Observational
Estimated Enrollment : 321 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Comparative Effectiveness of Therapy in Rare Diseases: Liver Transplantation vs. Conservative Management of Urea Cycle Disorders
Actual Study Start Date : March 4, 2016
Estimated Primary Completion Date : February 2019
Estimated Study Completion Date : February 2019


Group/Cohort Intervention/treatment
Urea Cycle Disorder with Liver Transplant
  • Age 18 and under
  • Diagnosed with the following Neonatal-type urea cycle disorders: CPSD, OTCD, ASD or ALD, as defined as follows:
Other: No Intervention Given
Urea Cycle Disorder without Transplant
  • Age 18 and under
  • Diagnosed with the following Neonatal-type urea cycle disorders: CPSD, OTCD, ASD or ALD, as defined as follows:
Other: No Intervention Given
Primary Caretakers
  • Primary caretaker(s) of a patient age 25 and under who has been diagnosed with either CPSD, OTCD, ASD or ALD (typically a parent, but broadly defined as those individuals who are responsible for making the child's treatment decisions and who also provide the majority of the child's physical and emotional care)
  • Considered, are currently considering, or opted for, liver transplantation as a treatment for UCD.
  • Willing to participate in a 60-minute semi-structured interview and/or a 60-90 minute focus group discussion

OR

  • Health care provider (e.g. metabolic disease physician, liver transplant surgeon, gastroenterologist, genetic counselor, or nurse) that participates in treating patients diagnosed with either CPSD, OTCD, ASD or ALD,
  • Willing to participate in a 60-minute semi-structured interview and/or a 60-90 minute focus group discussion
Other: No Intervention Given



Primary Outcome Measures :
  1. Survival [ Time Frame: At Close of Study, On Average 3 Years ]
    This aspect of Aim 1 is retrospective in nature, and will evaluate the clinical outcomes of subjects with urea cycle disorders. These clinical outcomes will be largely retrospective, looking at medical records to assess survival rates among UCD patients.

  2. Neurocognitive Function [ Time Frame: At Close of Study, On Average 3 Years ]
    Developmental outcomes will be assessed through a standard pediatric neuropsychological battery of tests. Neuropsychological testing will be based on age-matched norms for the specific test used.

  3. Patient Reported Quality of Life [ Time Frame: At Close of Study, On Average 3 Years ]
    Quality of life assessments are self-reported by participating patients. Parents of participants aged 1 month to 18 years will be administered the PedsQL parent-report or parent proxy-report questionnaire. Participants between 13 and 18 years of age will complete the PedsQl child questionnaires for their age group. Adult participants will respond to the SF-36v2 questionnaire and the Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires.


Secondary Outcome Measures :
  1. Caretaker Decision Making [ Time Frame: At Close of Study, One Average 3 Years ]

    This aspect of the study will collect qualitative data from caretakers in the form of guided interviews and focus groups, which will be analyzed into QSR NVivo codes and sub-codes, with the objective of identifying the important elements in the decision making process for caretakers regarding whether or not to have the affected patient receive transplant.

    This aspect of the study will examine, through a representative sample of pediatric patient's primary caretakers (usually a parent or guardian) how UCD treatment decision are made, describing the factors that influenced the patient/family's decision to continue with conservative management or elect liver transplantation. Guided interviews will be conducted by research staff to ascertain which factors led to decision making.


  2. Medical Provider Decision Making [ Time Frame: At Close of Study, One Average 3 Years ]

    The study will collect qualitative data via guided interviews with UCD providers, which will be analyzed into QSR NVivo codes and sub-codes, with the objective of identifying the important elements in the decision making process for providers regarding whether or not to have the affected patient receive transplant.

    This aspect of the study will examine, through a representative sample of pediatric patient's medical providers, how UCD treatment decision are made, describing the factors that influence the provider's decision to continue with conservative management or elect liver transplantation.


  3. Dissemination of Information (Aim 3) [ Time Frame: At Close of Study, One Average 3 Years ]
    Aim 3 will develop a dissemination strategy for study findings of Aim 1 that aligns with the decision-making considerations and process illustrated through Aim 2 and which is responsive to the expressed needs of UCD patients and their primary caretakers.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

The study population for Aim 1 includes children aged 18 and younger who are diagnosed with one of the following Neonatal-type urea cycle disorders: CPSD, OTCD, ASD, or ALD. Participants will come from children's hospitals and pediatric clinics that treat urea cycle disorders throughout the country.

The study population for Aim 2 and 3 will include the primary caretakers of the Aim 1 population, as well as medical providers (for example metabolic disease physician, pediatric liver transplant surgeon, gastroenterologist, genetic counselor, or nurse) that works with disease management of the Aim 1 population.

Criteria

Inclusion Criteria:

Aim 1 (UCD patients):

  • Age 18 and under
  • Diagnosed with the following Neonatal-type urea cycle disorders:
  • CPSD, OTCD, ASD or ALD, as defined as follows:

    • Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control) CPS I enzyme activity in liver, and/or an identified pathogenic mutation, and/or hyperammonemia and first-degree relative meets at least one of the criteria for CPS I deficiency
    • Diagnosis of OTC deficiency, defined as the identification of a pathogenic mutation, and/or less than 20% of control of OTC activity in the liver, and/or elevated urinary orotate (greater than 20 uM/mM) in a random urine sample or after allopurinol challenge test, and/or hyperammonemia and first degree relative meets at least one of the criteria for OTC deficiency
    • Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal to 10-fold elevation of citrulline in plasma, and/or decreased (less than 20% of control) AS enzyme activity in cultured skin fibroblasts or other appropriate tissue, and/or identification of a pathogenic mutation in the AS gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for AS Deficiency
    • Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the presence of argininosuccinic acid in the blood or urine, and/or decreased (less than 20% of control) AL enzyme activity in cultured skin fibroblasts or other appropriate tissue, and/or identification of a pathogenic mutation in the AL gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for AL Deficiency
  • Willing to participate in at least 1 neurocognitive assessment and 1 quality of life assessment
  • Permit access to medical records and medical providers

Aims 2 & 3:

  • Primary caretaker(s) of a patient age 25 and under who have been diagnosed with either CPSD, OTCD, ASD or ALD (broadly defined as those individuals who are responsible for making the child's treatment decisions and who also provide the majority of the child's physical and emotional care)
  • Considered, are currently considering, or opted for, liver transplantation as a treatment for UCD.
  • Willing to participate in a 60-minute semi-structured interview and/or a 60-90 minute focus group discussion

OR

  • Health care provider (e.g. metabolic disease physician, liver transplant surgeon, gastroenterologist, genetic counselor, or nurse) that participates in treating patients diagnosed with either CPSD, OTCD, ASD or ALD,
  • Willing to participate in a 60-minute semi-structured interview and or a 60-90 minute focus group discussion

Exclusion Criteria:

Aim 1:

  • Rare and unrelated comorbidities (e.g., Down's syndrome, intraventricular hemorrhage in the newborn period, and extreme prematurity)

Aim 2 and 3:


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02740153


Locations
United States, District of Columbia
Childrens Research Institute
Washington, District of Columbia, United States, 20010
Sponsors and Collaborators
Children's Research Institute
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Center for Advancing Translational Science (NCATS)
Patient-Centered Outcomes Research Institute
The George Washington University Milken Institute School of Public Health (GWU)
The National Urea Cycle Disorders Foundation (NUCDF)
Studies of Pediatric Liver Transplantation (SPLIT)
Investigators
Study Chair: Mendel Tuchman, MD Children's Research Institute
Principal Investigator: Nicholas Ah Mew, MD Children's Research Institute

Responsible Party: Nicholas Ah Mew, MD, Children's Research Institute
ClinicalTrials.gov Identifier: NCT02740153     History of Changes
Other Study ID Numbers: 7282
First Posted: April 15, 2016    Key Record Dates
Last Update Posted: April 6, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Disease
Urea Cycle Disorders, Inborn
Pathologic Processes
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases