PCORI Urea Cycle Disorder Study

Comparative Effectiveness of Therapy in Rare Diseases: Liver Transplantation vs. Conservative Management of Urea Cycle Disorders

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.

Study Overview

• Status: Completed
• Conditions: Urea Cycle Disorders
• Intervention / Treatment: 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?

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 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
• Enrollment (Actual): 187

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Childrens Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Exclusion Criteria:

Aim 1:

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

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; History of liver transplant	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; No history of liver transplant, managed medically	Other: No Intervention Given

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	This aspect of Aim 1 is prospective by design based on selection by exposure (liver transplant or medical managed) evaluating the clinical outcomes of subjects with urea cycle disorders.	436 person years in the Liver Transplant Group and 386 person-years in the Without Transplant Group
Neurocognitive Function: Full-Scale IQ	Neuropsychological tests were based on age-matched norms for the specific test used. All neurocognitive scores have been standardized to the following: norm, mean of 100, and sd of 15. In all tests higher scores are interpreted as higher functions. The WPPSI and WASI were combined to create a single measure of Full-Scale IQ. Full-Scale IQ; Wechsler Preschool and Primary Scales of Intelligence, 4th edition (WPPSI-IV: Children 3-5 years of age); Wechsler Abbreviated Scales of Intelligence, 1st and 2nd editions (WASI-I & II: Persons 6+ years of age)	Neuropsychological testing was conducted once for each patient at baseline during the study on age-matched norms for the specific test used.
Total Quality of Life	Quality of life assessments are self-reported by participating patients or by their parent/caretaker using the following reports: Pediatric Family Impact (PedsQL), Version 4 is reported as a total score All were scored on a 0-100 scale. Higher scores indicated a better health-related quality of life	Quality of life testing was conducted and reported at baseline for each patient during the study.

Collaborators and Investigators

• Sponsor: Children's National Research Institute
• Collaborators: Patient-Centered Outcomes Research Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); George Washington University; National Center for Advancing Translational Sciences (NCATS); The National Urea Cycle Disorders Foundation; Studies of Pediatric Liver Transplantation
• Investigators: Principal Investigator: Nicholas Ah Mew, MD, Children's National Research Institute; Study Chair: Mendel Tuchman, MD, Children's National Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2016
• Primary Completion (Actual): June 10, 2019
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: March 29, 2016
• First Submitted That Met QC Criteria: April 12, 2016
• First Posted (Estimate): April 15, 2016

Study Record Updates

• Last Update Posted (Actual): January 26, 2021
• Last Update Submitted That Met QC Criteria: January 25, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn
• Other Study ID Numbers: 7282 (NIHR)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No