PCORI Urea Cycle Disorder Study

NCT ID: NCT02740153

Last Updated: 2021-01-26

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 187 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2016-03-04
• Study Completion Date: 2020-06-30

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.

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.

Conditions

Urea Cycle Disorders

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

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

No Intervention Given

Intervention Type: OTHER

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

No Intervention Given

Intervention Type: OTHER

Interventions

No Intervention Given

Intervention Type: OTHER

Eligibility 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

Exclusion Criteria

Aim 1:

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

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

National Center for Advancing Translational Sciences (NCATS)

NIH

Sponsor Role: collaborator

Patient-Centered Outcomes Research Institute

OTHER

Sponsor Role: collaborator

George Washington University

OTHER

Sponsor Role: collaborator

The National Urea Cycle Disorders Foundation

UNKNOWN

Sponsor Role: collaborator

Studies of Pediatric Liver Transplantation

UNKNOWN

Sponsor Role: collaborator

Children's National Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Nicholas Ah Mew

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mendel Tuchman, MD

Role: STUDY_CHAIR

Children's National Research Institute

Nicholas Ah Mew, MD

Role: PRINCIPAL_INVESTIGATOR

Children's National Research Institute

Locations

Childrens Research Institute

Washington D.C., District of Columbia, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

7282

Identifier Type: -

Identifier Source: org_study_id