Clinical trial NCT02740153: PCORI Urea Cycle Disorder Study
Official title: Comparative Effectiveness of Therapy in Rare Diseases: Liver Transplantation vs. Conservative Management of Urea Cycle Disorders
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Urea Cycle Disorders
Lead sponsor: Children's National Research Institute
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Center for Advancing Translational Sciences (NCATS)
name: Patient-Centered Outcomes Research Institute
name: George Washington University
name: The National Urea Cycle Disorders Foundation
name: Studies of Pediatric Liver Transplantation
First posted: 2016-04-15
Enrollment: 187
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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)

Primary outcomes:
measure: Mortality
timeFrame: 436 person years in the Liver Transplant Group and 386 person-years in the Without Transplant Group
measure: Neurocognitive Function: Full-Scale IQ
timeFrame: Neuropsychological testing was conducted once for each patient at baseline during the study on age-matched norms for the specific test used.
measure: Total Quality of Life
timeFrame: Quality of life testing was conducted and reported at baseline for each patient during the study.
Secondary outcomes:
Other outcomes:
Locations:
city: Washington
country: United States
facility: Childrens Research Institute
state: District of Columbia
Study officials:
affiliation: Children's National Research Institute
name: Mendel Tuchman, MD
role: STUDY_CHAIR
affiliation: Children's National Research Institute
name: Nicholas Ah Mew, MD
role: PRINCIPAL_INVESTIGATOR
References: