Comparative Effectiveness of Therapy in Rare Diseases: Liver Transplantation vs. Conservative Management of Urea Cycle Disorders
Conditions: Urea Cycle Disorders
Sponsor: Children's National Research Institute

RDCRN Protocol #5117 
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RDCRN 
 
Rare Diseases Clinical Research Network 
 
Comparative Effectiveness of Therapy in Rare 
Diseases: Liver Transplantation vs. Conservative 
Management of Urea Cycle Disorders 
 
 
 
 
Nicholas Ah Mew 
Children’s National Health System 
111 Michigan Avenue, NW 
Washington, DC 20010 
(202) 476-5863 
 
This protocol is for research purposes only, and should not be copied, 
redistributed or used for any other purpose. The procedures in this 
protocol are intended only for use by Consortium investigators in carefully 
controlled settings. The Chair of this study should be consulted before using 
or attempting any procedure in this protocol. 

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Participating Institutions/Investigators Table  
 
Principal Investigator: Nicholas Ah Mew, MD 
Institution: Children’s National Health System 
Address: 111 Michigan Avenue NW, Washington DC, 20010 
Phone: 202-476-5863 
Fax: 202-476-2390 
Email: nahmew@childrensnational.org 
  
  
     Co-Investigator:   Mendel Tuchman, MD 
Institution: Children’s National Health System 
Address: 111 Michigan Avenue NW, Washington DC, 20010 
Phone: 202-476-2549 
Fax: 202-476-6014 
Email: mtuchman@childrensnational.org 
  
  
     Co-Investigator:   Robert McCarter, ScD 
Institution: Children’s National Health System 
Address: 111 Michigan Avenue, NW, Washington DC, 20010 
Phone: 202-476-3140 
Fax: 202-476-3425 
Email: rmccarter@childrensnational.org 
  
 
     Co-Investigator:   Anne Markus, JD, PhD, MHS 
Contact: Maya Gerstein, MPH 
Institution: The George Washington University 
Address: 950 New Hampshire Ave NW, Suite 600, Washington DC, 20052 
Phone: 202-994-4301 
Email: mgerstein@gwu.edu 
Sub-Investigators: Maya Gerstein, MPH 
  
 
     Co-Investigator:   Cynthia Le Mons 
Institution: National Urea Cycle Disorders Foundation 
Address: 75 S. Grand Ave., Pasadena, CA 91105 
Phone: 626 578-0833 
Fax: 626 578-0823 
Email: cindy@nucdf.org 
  
 
     Co-Investigator:   Ravinder Anand, PhD 
Institution: Studies of Pediatric Liver Transplantation 
Address: 401 N Washington Street, Suite 700, Rockville, MD 20052 
Phone: 301-251-1161 
Fax: 301-251-1355 
Email: ranand@emmes.com 
 
 
 

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Data Management and Coordinating Center 
Principal Investigator: Jeffrey Krischer, PhD 
Contact:  Amy Holbert, MA 
Statistician: Hye-Seung Lee, PhD 
Institution/ 
Department: 
Data Management and Coordinating Center; Health Informatics Institute 
University of South Florida 
Address: 3650 Spectrum Blvd, Suite 100, Tampa, FL 33612 
Phone: 813-396-9567 
Fax: 813-910-5967 
Email: amy.holbert@epi.usf.edu 
 
 
 
 

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Table of Contents 
 
1. Protocol Synopsis........................................................................................................ 6 
1.1. Overview ............................................................................................................... 9 
2. Specific Aims (Hypothesis and Objectives) ............................................................... 10 
3. Background ............................................................................................................... 10 
3.1. Overview of Urea Cycle Disorders ...................................................................... 10 
3.2. Impact of Hyperammonemia on the Health of Patients with UCD ....................... 11 
3.3. Gap of Evidence with Respect to Best Treatment for Patients with UCD............ 12 
3.3.1. Conservative Management and Outcome .................................................... 12 
3.3.2. Liver Transplantation and Outcome ............................................................. 13 
3.3.3. The Process of Making UCD Treatment Decisions ...................................... 13 
3.3.4. Gaps in Knowledge to be Addressed by this Project .................................... 14 
4. Study Design and Methods ....................................................................................... 15 
4.1. Inclusion Criteria ................................................................................................. 16 
4.2. Exclusion Criteria ................................................................................................ 17 
4.3. Recruitment of Participants ................................................................................. 17 
4.4. Retention Strategies ........................................................................................... 19 
4.5. Data Elements and Schedule of Events .............................................................. 19 
5. Data and Safety Monitoring Plan ............................................................................... 21 
5.1. Study Oversight .................................................................................................. 21 
5.2. Definitions and Standards ................................................................................... 21 
5.3. Reporting Timeline .............................................................................................. 22 
5.4. RDCRN Adverse Event Data Management System (AEDAMS) ......................... 22 
5.5. Study Discontinuation ......................................................................................... 23 
5.6. Subject Discontinuation....................................................................................... 23 
5.7. Data Quality and Monitoring Measures ............................................................... 23 
6. Statistical Considerations .......................................................................................... 24 
6.1. Sample Sizes ...................................................................................................... 24 
6.2. Analysis Plan ...................................................................................................... 25 
7. Data Management ..................................................................................................... 28 
7.1. Registration ......................................................................................................... 28 

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7.2. Data Entry ........................................................................................................... 28 
8. Human Subjects ........................................................................................................ 29 
8.1. GCP Statement ................................................................................................... 29 
8.2. Risks (and Protection Against Risks) .................................................................. 29 
8.3. Benefits ............................................................................................................... 29 
8.4. Written Informed Consent ................................................................................... 29 
8.5. Process of Consent ............................................................................................. 30 
8.6. Certificate of Confidentiality ................................................................................ 31 
9. References ................................................................................................................ 32 
 
 

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1. Protocol Synopsis 
 
Observational Synopsis 
Protocol Number: UCDC 5117 
Protocol Title: 
Comparative Effectiveness of Treatment in Rare 
Diseases: Liver Transplantation vs. Conservative 
Management of Urea Cycle Disorders 
Study Chair: Nicholas Ah Mew, MD 
Statistician: Robert McCarter, ScD 
Consortium: Urea Cycle Disorders Consortium 
Participating Sites: 
Children’s National Health System  
The George Washington University 
National Urea Cycle Disorders Foundation 
Activation Date: March 4, 2016 
Sample Size: 
Aim 1:185 (92 with liver transplant, 93 without liver 
transplant) 
Aim 2: 32-48 primary caretakers, 25-40 providers 
Aim 3: 64-48 primary caretakers  
Target Enrollment 
Period: 3 years 
Study Design: 
Mixed method concurrent study design. Quantitative 
research methods to address primary outcomes. 
Qualitative research methods to obtain information on 
the UCD patient/family experience when making 
critical treatment decisions 
Primary Study 
Objective: 
To study two urea cycle disorder (UCD) patient 
cohorts, one managed conservatively and the other 
treated by liver transplantation; comparing survival 
rate, neurocognitive function and patient-reported 
quality of life. (Aim 1) 
Secondary Study 
Objective: 
To examine, through a representative sample of 
pediatric patient’s primary caretakers (typically a 
parent) and medical providers, including the treating 
physician and other clinicians on the team, how UCD 
treatment decisions are made, describing the factors 
that influence the patient/family’s decision to continue 
conservative management or elect liver 
transplantation. (Aim 2) 
To 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. (Aim 3) 
Study Population and 
Main Eligibility/ 
Exclusion Criteria: 
Aim 1  
- 
Age 18 and under 
- 
Diagnosed with the following neonatal-type 

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urea cycle disorders: CPSD, OTCD, ASD or 
ALD, as defined as follows: 
 
Diagnosis of CPS1 deficiency, defined as 
decreased (less than 20 % of control) CPS1 
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 CPS1 
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 µM/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 at least 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 

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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 
Statistical 
Considerations 
Aim 1: Covariate-balancing propensity scoring based 
on the CBPS package in R to create comparable 
(balanced) groups based on their risk factor (covariate) 
profile in subjects according to their propensity 
(probability) to move from conservative management 
to liver transplantation 
 
Aim 2: Thematic content analysis of interview data 
(collected and coded using QSR International NVivo 
10) will form the basis of our interpretation, which will 
move beyond a typology of participant accounts to 
look at the relationship between the identified themes  
 
Aim 3: Focus group data will also be analyzed using 
thematic content analysis 
Sponsors: National Institutes of Health (NICHD/NCATS) 
Funder: Patient-Centered Outcomes Research Institute 
(PCORI) 
 
 
 

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1.1. Overview 
 
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, intellectual, developmental disabilities, and even death. Medical 
treatment involves special diet low in protein, drugs that help metabolize ammonia and 
amino acid supplements (conservative management). However, 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 or 
other stress. The long-term objective of this study is to help patients make decisions 
about management alternatives (medical vs. liver transplantation) by providing them 
with scientific information that is currently lacking.  
 
The questions that will be addressed are:  
1. What is the disease’s risk of mortality and illness in each treatment approach?  
2. What can parents expect in terms of the neurocognitive 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? 
4. What factors do primary caretakers (typically parents) consider when making the 
decision to pursue liver transplantation or continue conservative management for 
their child with UCD? 
 
This research will have two components. In one, we will use statistical methods to 
compare 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 longitudinal natural history study. To ensure that the 
information we analyze is representative of the UCD patient population in the US, we 
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), and from the National Urea Cycle Disorders 
Foundation (NUCDF) a patient advocacy group for patients with UCD.   
 
The qualitative component of this project will consist of individual interviews and focus 
groups with UCD pediatric patient families and caretakers and medical providers, 
including treating physicians and other medical staff on the team, to identify the 
important issues caretakers consider when deciding whether to opt for liver 
transplantation or continue conservative management.  
 
The NUCDF and its Patient-Powered Research Team (PPRT) 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 

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will be disseminated to patients and families, doctors and clinical staff so that they 
receive current, validated information before making a decision about the best treatment 
choice for the individual patients. 
 
2. Specific Aims (Hypothesis and Objectives) 
 
This study will compare the outcomes of liver transplantation vs. medical treatment in 
patients with UCD for survival, neurocognitive status, and quality of life. The specific 
aims are: 
 
Aim 1: To study two urea cycle disorder (UCD) patient cohorts, one managed 
conservatively and the other treated by liver transplantation, comparing survival rate, 
neurocognitive function and patient-reported quality of life. 
Aim 2: To examine, through a representative sample of pediatric patient primary 
caretakers and medical providers, including the treating physician and other clinicians 
on the team, how UCD treatment decisions are made, describing the factors that 
influence a primary caretaker’s decision to continue conservative management or 
proceed to a liver transplant. 
Aim 3: To develop a dissemination strategy for study findings of Aim 1 that aligns with 
the decision-making process illustrated through Aim 2 and which is responsive to the 
expressed needs of UCD patients and their primary caretakers. 
 
This study’s goal is to fill a critical needs gap by providing objective evidence of risk and 
benefit that will serve as a solid foundation for the decision-making process. The current 
decision-making process relies largely on subjective judgment. The study results and 
dissemination will provide patients and families with evidence-based information that is 
currently lacking on the treatment alternatives (conservative management vs. liver 
transplantation), including answers to the following questions: 1.What is the disease-
specific risk of mortality and morbidity in the two approaches? 2. What outcomes can 
patients expect in terms of cognitive development and/or other developmental 
milestones? 3. What are the pros and cons in terms of quality of life considerations? 
The study will provide qualitative information on the decision-making process that 
caretakers undertake when choosing between these treatment alternatives so that 
dissemination efforts around study results can be designed to align with this process 
and better address caretakers’ expressed needs and concerns. 
 
3. Background 
 
3.1. Overview of Urea Cycle Disorders 
 
Urea cycle disorders (UCD) are a group of rare inherited disorders of metabolism 
caused by deficiencies of any one of eight proteins required for ammonia detoxification 
and urea synthesis (Figure 1) [1]. Collectively, they result in hyperammonemia, which in 

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its severe or prolonged form may have devastating effects on development and function 
of the central nervous system [2]. This can manifest soon after birth (neonatal onset) or 
later in childhood or even adulthood [3]. The variations of severity are most evident in 
ornithine transcarbamylase deficiency (OTCD) [4], the most common of UCD and the 
only X-linked disease among them, the rest of which are inherited as autosomal 
recessive traits. Thus, males with severe OTC deficiency may not survive infancy 
without vigorous medical intervention and/or liver transplantation [4]. Even with current 
medical treatment, some evidence suggests that less than 40% of the most severe 
neonatal cases survive [5]. Males with milder deficiencies may present much later, and 
females express a range of severity 
from neonatal onset to being 
asymptomatic throughout life [4]. 
Such asymptomatic or mildly 
affected females represent the 
largest group within the UCD 
population, while the more severely 
affected males and females require 
the most demanding, intensive, and 
expensive medical intervention. The 
classification, abbreviations and 
estimated prevalence of the various 
UCD are shown below; as a group, 
the combined prevalence is 
approximately 1:35,000 [6].   
 N-acetylglutamate synthase 
(NAGS) deficiency (<1:2,000,000) 
 Carbamyl phosphate synthetase I deficiency (CPSD) (1:1,300,000) 
 Ornithine transcarbamylase deficiency (OTCD)  (1:56,100) 
 Argininosuccinate synthase deficiency (ASD, Citrullinemia) (1:250,000) 
 Argininosuccinate lyase deficiency (ALD, argininosuccinic aciduria) (1:218,750) 
 Arginase (ARG) deficiency (argininemia) (1:950,000) 
 Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or 
mitochondrial ornithine carrier deficiency-ORNT) (<1:2,000,000) 
Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency-CITR) 
(<1:2,000,000, 1:21,000 in Japanese origin) 
 
3.2. Impact of Hyperammonemia on the Health of Patients with UCD  
 
Despite significant improvements in medical management following the wider availability 
of specialized diets, hemodialysis and alternate pathway therapy, infants and children 
and even adults with urea cycle disorders (UCD) are at high risk of early and recurrent 
brain damage from hyperammonemia [7, 8]. The insult that the brain suffers from high 
blood ammonia levels can manifest as cytotoxic brain edema and vascular compromise 
which frequently leads to intellectual and developmental disabilities [2, 9-11]. Moreover, 
clinical hyperammonemia recurs at variable intervals increasing the cumulative damage 
to the brain and the chance of irreversible coma and death during a hyperammonemia 
episode due to vascular compromise and/or brain herniation. This can, unfortunately, be 
aFigure 1. The Urea Cycle and Enzymes 
MITOCHONDRION
ornithine
carbamyl
phosphate
CPS1
bicarbonate
ammonia
N-acetyl
glutamate
acetyl-CoA
+
glutamate
argininosuccina
aspartate
fumarate
arginine
urea
orotic acid
citrulline
ornithine
citrulline
NAGS
OTC
ATP
+
ORNT
CITR
ARG
CYTOSOL
AS
AL
The Urea Cycle

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the outcome even in those patients whose condition appears to be amenable to 
conservative management (CM) since the ammonia can “get out of hand” during an 
intercurrent infection or another stress and cause the demise of the patient [12]. 
Because hyperammonemia in patients with UCD can occur at any time as a result of 
catabolic conditions (such as otherwise trivial infections), an increasing number of 
patients with recurrent hyperammonemia have been undergoing orthotopic liver 
transplantation as a procedure that “cures” the hyperammonemia [13-15], removing 
what the patients describe as a “ticking time bomb”. However, liver transplantation is a 
complicated surgical procedure which carries a significant risk of both mortality and 
morbidity. Patients, families and their providers are therefore facing a difficult dilemma. 
Should the patient be managed conservatively with diet, medications, and amino acid 
supplements or should he/she consider undergoing a liver transplant?  
 
3.3. Gap of Evidence with Respect to Best Treatment for Patients with UCD 
 
There are two major options in the management of severe UCD. One is conventional 
conservative management and the second is liver transplantation. The goal of 
conservative management is to prevent or reverse the accumulation of toxic ammonia in 
the body. This can be accomplished by a combination of the following interventions: 1) 
reducing protein catabolism by providing a high caloric intake [16]; 2) reducing dietary 
protein intake, except for required essential amino acids [16]; and 3) providing 
substrates for alternate pathways of nitrogen excretion (citrulline, arginine, sodium 
benzoate, phenylacetate, and phenylbutyrate) [17]. In milder cases, the first two 
nutritional interventions may be sufficient.  In severe cases, all these approaches may 
need to be employed plus the use of hemodialysis to remove nitrogen during life-
threatening hyperammonemic crises [18].  Liver transplantation represents a curative 
approach for the hyperammonemia by replacing the liver with the defective gene with a 
normal liver [13-15]. This approach, however, carries considerable risks. 
 
3.3.1. Conservative Management and Outcome 
 
The most effective medical advances in the acute and chronic treatment of UCD are 
the employment of substrates to promote alternative pathways of waste nitrogen 
excretion [7, 17]. Sodium benzoate combines with glycine to form hippurate, which 
can be readily excreted, removing one atom of nitrogen for each molecule of 
benzoate provided. Sodium phenylacetate combines with glutamine to form 
phenylacetylglutamine, also readily excreted in the urine and removing two atoms of 
nitrogen for each molecule of phenylacetate. The same phenylacetate pathway 
occurs with administration of sodium phenylbutyrate (Buphenyl®) or its prodrug 
glycerol phenylbutyrate (Ravicti®), which have a much less pungent odor and 
repugnant taste than phenylacetate itself. Combined therapy with intravenous 
infusion of glucose, lipid, arginine, and sodium benzoate/sodium phenylacetate 
(Ammunol®) is now used routinely for treatment of acute hyperammonemia, whereas 
sodium phenylbutyrate or glycerol phenylbutyrate are commonly used for chronic, 
long-term oral administration [19, 20]. All of these treatments carry risks of serious 
side effects. Among patients treated conservatively, many have been reported to 
succumb to hyperammonemic crises. Most survivors show significant 

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neurodevelopmental disabilities, the severity of which seems to correlate with the 
severity of the enzyme deficiency. In a longitudinal study performed by our NIH-
funded Rare Diseases Clinical Research Center for Urea Cycle Disorders (UCDC) 
[21], the proportion of patients with a poor cognitive outcome (IQ/Developmental 
Quotient <70) was high, ranging from 47-68% in the various UCD. This was 
observed in patients below and above 4 years of age. Poor cognitive outcome was 
not fully explained by age of onset (<4 vs. >4 years), peak ammonia level or duration 
of the initial admission. Thus, we currently do not know what variables are 
associated with a poorer cognitive outcome in patients with UCD on conservative 
management, making it difficult to make progress in improving this approach. 
 
3.3.2. Liver Transplantation and Outcome 
 
Liver transplantation for UCD patients was initiated in the early 1990’s, before 
alternate pathway medical therapy was widely available. There were anecdotal case 
reports of liver transplantation in four of the urea cycle disorders (CPSD, OTCD, 
ASD, and ALD) [13, 15, 22]. A larger survey of 16 US patients who had received 
liver transplants from four major transplant centers found that 14 of these cases had 
survived at least 1-6 years [14]. Their neurological status post-transplantation was in 
most cases moderately to severely impaired and correlated closely with their 
condition prior to transplantation.  However, the quality of their lives seemed to have 
improved.  Subsequently, to determine if aggressive medical therapy could improve 
the outcome of severe infantile onset UCD, 5 such cases were monitored at Baylor 
College of Medicine before and after liver transplantation, including 2 males with 
OTCD, 2 with CPSD, and one female with OTCD deficiency and intractable 
hyperammonemia [23]. Three of these infants had serial developmental testing 
(Griffiths scale) before and after transplantation. It was found that their pre-
transplantation overall developmental scales (51, 86, 56) were stabilized after 
transplantation (70-83, 80-76, 51-47, respectively). Therefore, the authors 
recommended that early transplantation be considered as the treatment of choice in 
these severely affected infants. 
 
Most recently, a retrospective analysis of 186 patients with UCD who underwent liver 
transplantation, [24] showed an increased frequency of liver transplantation for UCD 
and organic acidemia over the last decade, with 5-year survival rates of 88-99% 
depending on age. In summary, liver transplantation is now performed frequently to 
treat UCD and survival seems to have improved over time. However, the outcome of 
neurocognitive function following liver transplantation is unclear, and it is unknown 
how it compares to conventional conservative management. 
 
3.3.3. The Process of Making UCD Treatment Decisions   
 
Despite the importance of and complexity surrounding the decision to continue 
conservative management or consider liver transplant in UCD, no research has been 
conducted to date on how primary caretakers of pediatric UCD patients make these 
treatment choices and the issues that influence their decision to pursue one option 
over another. Some existing research investigating parent decision making in 

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pediatric treatments has been published in other disease areas such as end-of-life 
care, cardiac transplantation, lung transplant in patients with cystic fibrosis, and 
cancer treatment. A 2012 narrative review of the current research on parent decision 
making about pediatric treatment found that in addition to consulting their provider, 
most parents consider their child’s health status, the perspectives of other members 
of their community, their prior knowledge, and other personal factors such as 
emotions and faith when making treatment decisions for their child [25]. Although the 
findings from these studies can help inform our understanding of the treatment 
decision-making process among the caretakers of pediatric patients with UCD, the 
characteristics of this disease group and the risks associated with its treatment 
options vary in several important ways from other disease areas, effectively limiting 
the applicability of these previous studies in this population. One of the most critical 
differences concerns the acuteness and unpredictable nature of severe 
hyperammonemia episodes, which carry the risk of death or increased 
neurocognitive dysfunction. Even if a patient’s condition appears to be amenable to 
conservative management, he or she is still susceptible to acute hyperammonemia 
during incurrent infections or while experiencing other stressors. This “ticking bomb” 
phenomenon is factored in the treatment decision of patients on whether pursuing 
liver transplant, thus increasing the need for better research that focuses specifically 
on the experience of making treatment decisions by the UCD population. 
 
3.3.4. Gaps in Knowledge to be Addressed by this Project 
 
In spite of a number of reports (mostly case reports) on UCD, the mortality rate from 
these disorders remains uncertain. A mortality rate of up to 50% has been quoted in 
the literature for patients with neonatal onset UCD [22]. However, we have seen 
much lower mortality rates among the UCDC longitudinal study cohort (23%-34%) 
but it is unclear whether this discrepancy reflects a real improvement in the 
management of UCD during the last two decades or whether there exists an 
ascertainment bias; an effort is underway in the UCDC to remove survivorship bias 
and reassess the risk of mortality. Conservative management and liver 
transplantation are associated with mortality and morbidity, due to hyperammonemia 
in the former, and peri- and post-surgical complications in the latter. It is, therefore, 
important that we have information to compare survival as well as other outcomes of 
the two approaches, taking appropriate account of specific disorders ( a type of 
UCD) and severity (neonatal or late onset). The second major gap in knowledge is 
with respect to neurocognitive outcome in patients with UCD. While we have both 
cross-sectional and longitudinal information about patients with UCD managed 
conservatively [8, 26], we need more information about patients with UCD who 
underwent liver transplantation. Our collaboration with SPLIT (Studies of Pediatric 
Liver Transplantation) will enable us to capture all or most patients with UCD who 
undergo liver transplantation and thus provide a nonbiased evaluation of their 
outcomes. The third gap in knowledge is regarding the quality of life in patients with 
UCD, both those managed conservatively and by liver transplantation. Although 
being on a restrictive diet contributes to a compliance issue, and has been shown to 
have a detrimental effect on children’s quality of life [27], no comparisons with other 
treatments have been reported. Last but not least, there is a paucity of evidence 

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about how patients with UCD, their families, and their providers reach a shared 
decision on which management strategy to choose, how frequently and by what 
mechanisms these decisions are revisited, and what clinical, social, and/or system 
level factors influence this decision process. To date, there have been no published 
studies that examine the experience of providers or patients with UCD and their 
families in making this critical and difficult treatment decision.  
 
4. Study Design and Methods  
 
Overview: We will employ a mixed method concurrent study design utilizing quantitative 
research methods to address our primary outcomes, while simultaneously employing 
qualitative research methods to obtain information on the UCD patient/family experience 
when making critical treatment decisions (Figure 2). 
 
Figure 2. Overall Design of the Study 
A randomized controlled trial (RCT) in 
UCDs is not a feasible option to fill an 
information gap because of the nature of 
the alternatives and dearth of affected 
patients. In the quantitative component 
of this study (Aim 1), we, therefore, 
propose to implement a natural history 
observational trial, relying on existing 
historical and concurrently collected 
registry data to identify our population of 
interest. This population consists of 
patients age 18 and under. Many such 
patients are already enrolled in a 
Longitudinal (natural history) Study of 
Urea Cycle Disorders conducted by the 
Urea Cycle Disorders Consortium 
(UCDC). This UCDC study captures 
data regarding survival, neurocognitive 
status and quality of life. In order to 
achieve our target sample size and 
broaden our subject population, we intend to merge data from the existing UCDC data 
set with two additional registries maintained by: 1) the Studies of Pediatric Liver 
Transplantation (SPLIT) Research Group, housed at the EMMES Corporation and 2) 
National Urea Cycle Disorders Foundation (NUCDF) patient stakeholders. To study the 
two UCD patient cohorts, one managed conservatively and the other treated by liver 
transplantation, we will use covariate balanced propensity score matching to greatly 
reduce bias in this non-randomized study. Propensity score matching is widely 
recognized as a best practice alternative when an RCT is not feasible.  
 

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In the qualitative component of this study (Aims 2 and 3), we intend to enroll a 
representative sample of pediatric patient caretakers (guided by referrals from the 
NUCDF) and medical providers, including the treating physician and other clinicians on 
the team (guided by referrals from UCDC site coordinators) to participate in semi-
structured interviews that will explore how decisions about UCD treatment are being 
made. Patient caretakers will also be asked to take part in focus groups to provide 
feedback on themes that emerged from the semi-structured interviews and to discuss 
effective strategies for the dissemination of evidence-based information obtained in this 
study. 
 
4.1. Inclusion Criteria 
 
Aim 1 (UCD patients): 
- 
Age 18 and under 
- 
Diagnosed with the following Neonatal-type urea cycle disorders:  
o 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 has been diagnosed 

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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 
 
4.2. 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: 
 None 
 
4.3. Recruitment of Participants 
 
Aim 1:  De-identified data from the Longitudinal (natural history) Study (LS) of the Urea 
Cycle Disorders (UCD) will be supplemented with data from subjects identified from two 
sources:  the Studies of Pediatric Liver Transplantation (SPLIT) Research Group and 
the National Urea Cycle Disorders Foundation (NUCDF).  
 
Longitudinal Study participants will not be recruited to participate in this study, but their 
data used for this analysis, as is permissible per the LS consent form.   
 
By agreement, when this project is implemented, SPLIT will contact its respective 
transplant centers to describe the study and its eligibility criteria indicating the number 
and descriptive characteristics of eligibility based on SPLIT anonymized records asking 
study staff to contact eligible patients and provide general recruitment materials. 
NUCDF will also distribute recruitment materials and directly enroll eligible participants 
to the study. In all cases, interested patients will contact one of the study sites to 
express their interest in participating in the study.  
 
Enrollment in the UCDC LS will be offered to any patient not already enrolled, so that 
they can take advantage of the rare disease protocol to capture laboratory data, 
neurocognitive function and quality of life information, using the resources already in 
place through the UCDC. Participants interested in enrolling in the LS will be put in 

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touch with the study coordinator and PI at the nearest (or preferred) UCDC site. The 
PCORI site coordinator will work closely with LS coordinators to ensure that contact with 
interested participants is not delayed. We anticipate that a large proportion will agree to 
participate in the PCORI study, which will require only two visits for neuropsychological 
testing and self-reported quality of life questionnaire. 
 
Aim 2 and 3: UCD patient primary caretakers (typically a parent) will be recruited for 
interviews and focus groups from NUCDF’s outreach to the UCD community and its 
membership (over 2000 UCD family members) and consented and enrolled by GW 
staff. We will work collaboratively with NUCDF and Children’s National on the content of 
recruitment materials and means of distributing the materials most effectively, as well as 
recruiting approximately 40-50% of our primary caretaker interview and focus group 
sample from families attending NUCDF’s Virtual Family Conferences, held annually in 
July, with a webinar and distribution of recruitment materials and a breakout session for 
interested families. Additional recruitment will also be conducted on a rolling basis 
through NUCDF’s communication portals, social media site, and discussion boards, and 
one-on-one outreach, in order to capture families that are unable to attend this 
conference and thus minimize selection bias. NUCDF has begun to gauge preliminary 
interest among its membership and has identified approximately 65 families, with 
varying levels of access to expert care, disease severity, and transplant status, who 
have expressed interest in participating. NUCDF has established a patient stakeholder 
research working group, the Patient Powered Research Team (PPRT). Additional 
families will be invited to participate in the PPRT to expand the representative diversity 
of the group to meet the aims of the study. Additional recruitment outreach may be 
conducted on a rolling basis from the pool of patients recruited through SPLIT for Aim 1 
of the study. 
 
UCD providers, defined as treating physicians, nurses, and counselors, will be recruited 
for interviews from a population of approximately 55+ metabolic disease physicians, 
liver transplant surgeons, gastroenterologists, genetic counselors, and nurses within the 
11 U.S. sites participating in the UCDC and additional participating SPLIT sites. GW will 
work with Children’s to reach out to UCDC and SPLIT investigators to request their 
participation in interviews. NUCDF will identify and refer additional providers (with a 
focus on liver transplant surgeons) for participation in interviews. 
 
We will use a purposeful sampling strategy (via the NUCDF conference and via the 
NUCDF communication portals)  to recruit a representative sample of 32-48 patient 
primary caretakers (roughly 20-30% of the available target population) for participation 
in semi-structured interviews about their experience making treatment decisions for their 
child with UCD. With the assistance of NUCDF, we will also stratify our sample by 1) 
access to expert care, 2) disease severity, and 3) transplant status (see section 6.1).   
 
In stage 2 of qualitative data collection, primary caretakers and providers of participants 
will be asked to take part in focus groups to provide feedback on themes that emerged 
from our structured interviews and to discuss effective strategies for the dissemination 
of evidence-based information obtained through this study. Additional patient caretakers 
will be recruited via NUCDF outreach as described above for participation in these focus 

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groups until a sample size of 64-80 has been reached. We will conduct 6-8 focus 
groups with 8-10 participants per group. Additional provider focus groups will be 
conducted after interviews to further discussion treatment decision making and 
dissemination strategies. 
 
4.4. Retention Strategies 
 
Aim 1: Since this component comprises only 2 visits for neuropsychological testing, we 
expect a high retention rate among highly motivated patients referred from and enrolled 
by NUCDF. In comparison, we have observed ~90% retention in the LS protocol since 
enrollment began in 2006; the LS is more demanding with regard to laboratory and 
neuropsychiatric testing. UCD appears to affect equally all ethnic groups, except African 
American, who are underrepresented (~3%). We will make every effort to enroll African 
American patients in this study. 
 
Aim 2: As this component consists of 60-90 minute interviews and/or participation in 
focus groups, after which subjects exit the study, retention is anticipated to be near 
100% (barring the rare occasion when a participant may voluntarily terminate the 
interview and/or participation in the focus group). 
 
4.5. Data Elements and Schedule of Events 
 
Aim 1: 
 
Baseline Visit  
Confirmation of Eligibility: Once enrolled into the study, the participant’s diagnostic 
testing will be reviewed to assure that the correct UCD diagnosis has been made and 
eligibility requirements are met based on study inclusion and exclusion criteria.  
 
Baseline Assessment: Historical and new data will be collected at baseline as 
summarized below. We will use a variety of methods to obtain these data. Certain 
information will be obtained from a historical review of existing charts and laboratory 
/treatment data. Careful attention will be paid to accurately note dates for historical 
information. Other data will be obtained from patients or their families through a 
standard interview. A Quality of Life survey will also be administered at the baseline visit 
or afterward by phone or through the RDCRN database. Neuropsychological testing will 
be performed at the same visit, or at another date. 
 
Historical Data:  
 Eligibility 
 Enrollment/demographic information 
 Review of past medical records, including: 
o growth charts 
o neurodevelopmental testing 
o neurological evaluation 
o biochemical and diagnostic testing (e.g., ammonia, plasma amino acids, 
DNA sequencing of UCD genes) 

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o history of hospitalizations 
o medications and other treatments (e.g., dialysis) 
o other comorbidities 
 
Neuropsychological testing and Quality of life questionnaires:  
Neuropsychological tests will be based on age-matched norms for the specific test used 
(Table 1). These tests overlap with those currently used in the UCDC LS. The findings 
will be discussed with the participant/parents at the time of the testing, and a report of 
the results of this testing will be provided to the participant/parent.  
 
 
 
Table 1. Validated tests and scales to be used in this study 
Test 
Domain 
6-35 
mo. 
3-5 y 
6-16 y 
>17 y 
Reference 
Bayley-II/III 
Overall 
Development 
(IQ/DQ) 
X 
 
 
 
[36] 
WPPSI-IV 
 
X 
 
 
[37] 
WASI/WASI-II 
 
 
X 
X 
[38] 
ABAS-II 
Adaptive Skills 
X 
X 
X 
X 
[39] 
CBCL 
Mood and Behavior 
 
X 
X 
 
[40] 
BRIEF  
 
Attention/Executive 
Skills  
 
X 
X 
X 
[41] 
TEA-Ch 
 
 
X 
 
[42] 
RCFT 
 
 
X 
X 
[43] 
TOL-Dx 
 
 
X 
X 
[44] 
NEPSY 
Attention/Executive, 
Language 
 
 
X 
X 
 
[45] 
D-KEFS 
 
 
X 
X 
[46] 
WRAVMA 
Motor 
 
 
X 
 
 
[47] 
Grooved Pegboard 
 
 
X 
X 
 
Grip Strength 
 
 
X 
X 
[49] 
Beery VMI 
Visual Motor 
 
X 
X 
 
[50] 
CVLT-C/II 
Learning and 
Memory 
 
X 
X 
X 
[51] 
PedsQL 
 
Quality of Life 
 
X 
X 
X 
 
[52] 
SF-36 
 
 
X 
X 
[53] 
PROMISE 
 
 
 
X 
[54-56] 
 
The Quality of Life questionnaires will be administered at the baseline visit to assess the 
impact the disorder has on the participant’s quality of life. Parents of participants aged 1 
month to 18 years old 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 (over 18 years of 
age) will respond to the SF-36v2 questionnaire and the Patient Reported Outcomes 
Measurement Information System (PROMIS) questionnaires annually (43, 44). PROMIS 
questionnaires: Satisfaction with Social Roles and Activities, Cognitive Function 
(previously called Executive Function), Anxiety, Depression, Emotional/Behavioral 
Dyscontrol. The site neuropsychologist and/or the site PI will review PROMIS 
questionnaires within 30 days of administration and follow up with the participant and 
his/her family, as appropriate, such as if there is any indication that the participant may 
harm himself/herself or others 
 

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Aim 2 & 3: 
 
Once referred to the study, primary caretakers (mostly parents) and providers will 
initially be contacted by the study team to schedule an in person, telephone or video 
conference interview. Subjects will participate in a single semi-structured interview. 
Primary caretakers and providers that participate in a semi-structured interview will also 
be invited to participate in a follow-up focus group. Additional primary caretakers will 
also be recruited to increase the # of focus group participants and meet our proposed 
focus group sample size. Focus groups will be conducted during year 2 of the study. As 
described in detail in section 6.2, data from semi-structure interviews and focus 
groups will be rendered into codes and subcodes.  
 
5. Data and Safety Monitoring Plan 
 
The study protocol will be reviewed and approved by the National Institutes of Health 
(NIH) before submission to individual center IRBs for approval.  Participant enrollment 
may only begin with IRB approved consent forms.  
 
This is an observational study that meets the federal definition of minimal risk. 
 
5.1. Study Oversight 
 
The Study Chair has primary oversight responsibility of this clinical trial. The NIH 
appointed Data (Observational) Safety Monitoring Board (OSMB) has oversight 
responsibility of the Data Safety Monitoring Plan (DSMP) for this clinical trial. The 
D/OSMB will review accrual, patterns and frequencies of all adverse events, and 
protocol compliance every 12 months. The OSMB makes recommendations to the NIH 
regarding the continuation status of the protocol. 
 
Each site’s Principal Investigator and their research team (co-Investigators, research 
nurses, clinical trial coordinators, and data managers) are responsible for identifying 
adverse events. Aggregate report- detailed by severity, attribution (expected or 
unexpected), and relationship to the study drug/study procedures – will be available 
from the DMCC for site review.  Adverse events will be reviewed every 12 months by 
the research team. A separate report detailing protocol compliance will also be available 
from the DMCC for a site review on a monthly basis. The research team will then 
evaluate whether the protocol or informed consent document requires revision based on 
the reports. 
 
5.2. Definitions and Standards 
 
The Rare Diseases Clinical Research Network defines an adverse event as:  “…an 
unfavorable and unintended sign, symptom or disease associated with a participant’s 
participation in a Rare Diseases Clinical Research Network study.” 
 

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Serious adverse events include those events that:  “result in death; are life-threatening; 
require inpatient hospitalization or prolongation of existing hospitalization; create 
persistent or significant disability/incapacity, or a congenital anomaly/birth defects.”  
 
An unexpected adverse event is defined as any adverse experience, the specificity or 
severity of which is not consistent with the risks of information described in the protocol.  
 
Expected adverse events are those that are identified in the research protocol as having 
been previously associated with or having the potential to arise as a consequence of 
participation in the study 
 
All reported adverse events will be classified using the current version of the Common 
Terminology Criteria for Adverse Events (CTCAE) developed and maintained by CTEP 
at National Cancer Institute. 
 
Only those events associated with the conduct of the study and as defined above are 
reportable.  
 
5.3. Reporting Timeline 
 
 Within 24 hours (of learning of the event), investigators must report any reportable 
Serious Adverse Event (SAE) that: 
o 
Is considered life-threatening/disabling or results in death of subject 
-OR- 
o 
Is Unexpected/Unanticipated  
 Investigators must report all other reportable SAEs within 5 working days (of learning 
of the event). 
 All other (suspected) reportable AEs must be reported to the RDCRN within 20 
working days of the notification of the event or of the site becoming aware of the 
event. 
 
Local institutional reporting requirements to IRBs, any oversight committee, and the 
FDA, if appropriate, remain the responsibility of the treating physician and the Study 
Chair. 
 
5.4. RDCRN Adverse Event Data Management System (AEDAMS) 
 
Upon entry of a serious adverse event, the DMCC created Adverse Event Data 
Management System (AEDAMS) will immediately notify the Study Chair, site PIs, the  
Medical Review Officer, and any additional agencies (if applicable- industry sponsor, 
CTEP, etc) of any reported adverse events via email.  
 
Serious adverse events: The NIH appointed Medical Review Officer (MRO) determines 
causality (definitely not related, probably not related, possibly related, probably related, 
definitely related) of the adverse event. The MRO may request further information if 
necessary and possibly request changes to the protocol or consent form as a 
consequence of the adverse event. A backup notification system is in place so that any 

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delays in a review by the MRO beyond a specified period of time are forwarded to a 
secondary reviewer. The Adverse Event Data Management System (AEDAMS) 
maintains audit trails and stores data (and data updated) and communication-related to 
any adverse event in the study.  
 
Non-serious expected adverse events: Except those listed above as immediately 
reportable, non-serious expected adverse events that are reported to or observed by 
the investigator or a member of his/her research team will be submitted to the DMCC in 
a timely fashion (within 20 working days). The events will be presented in tabular form 
and given to the MRO and RDCRN DSMB on an annual basis. Local site investigators 
are also required to fulfill all reporting requirements of their local institutions. 
 
The DMCC will post aggregate reports of all reported adverse events for site 
investigators and IRBs. 
 
5.5. Study Discontinuation  
 
This study will not have study discontinuation rules as it is purely observational as it 
exercises no control over treatment decisions or their outcomes. The NIH and local 
IRBs (at their local site) have the authority to stop or suspend this study at any time. 
 
5.6. Subject Discontinuation 
 
An intent to treat approach will be used. All data acquired prior to termination for the 
reasons outlined below will be included in the primary analysis unless patient withdraws 
consent. Every effort will be made to conduct a final study visit with the participant and 
participants will be followed clinically until, if applicable, all adverse events resolve.  
 
 Withdrawal of consent 
 Withdrawal by the participant 
 Withdrawal by the investigator 
 
5.7. Data Quality and Monitoring Measures 
 
As much as possible, data quality is assessed at the data entry point using intelligent 
on-line data entry via visual basic designed screen forms. Data element constraints, 
whether in independent range and/or format limitations or ‘relative’ referential integrity 
limitations, can be enforced by all methods employed for data input. QA reports assess 
data quality post-data entry. As we note, data quality begins with the design of the data 
collection forms and procedures and incorporates reasonable checks to minimize 
transcription and omission errors.  Of the more important quality assurance measures 
are the internal validity checks for reasonableness and consistency.  
 
 Data Monitoring: The RDCRN DMCC identifies missing or unclear data and 
generates a data query to the consortium administrator contact.  
 Data Delinquency Tracking: The Data Management and Coordinating Center will 
monitor data delinquency on an ongoing basis.   

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6. Statistical Considerations 
 
6.1. Sample Sizes 
 
Aim 1. Of the 185 projected members of the target population, 92 (49.7%) are expected 
to have received liver transplants and 93 (50.3%) to remain on conservative 
management. Based on previously published results and characteristics of the UCD 
patients currently enrolled in our longitudinal study, we expect these groups to be very 
comparable with respect to UCD severity. As described below, we will use the method 
of covariate-balanced propensity score matching to create additional groups that are 
more closely matched on additional severity indicators for the comparative effectiveness 
analysis. Table 2 provides a detailed breakdown of the characteristics of study groups. 
  
For Aims 2 and 3, we plan to recruit a representative sample of 32-48 patient primary 
caretakers for participation in semi-structured interviews on their experience making 
treatment decisions for their child with UCD and an additional 16-48 patient primary 
caretakers (until a sample of 64-80 is reached) for participation in focus groups to 
validate information obtained through interviews and to discuss effective dissemination 
strategies for the evidence-based information obtained through this study.   
 
Table 2. Characteristics of Eligible Transplanted Cases and Comparable Controls 
e 
 
Type of UCD 
Sex 
Onset 
Peak NH3 (µmol/l)  
Surgery 
Group 
Total 
CPSD 
OTCD 
ASD 
ALD 
M/F 
(days) 
# >200, % 
Median, IQR 
Age 
(mo.) 
Transplanted 
92 
12 
44 
22 
14 
 
2 
90 
 
11.7 
 
 
(14%) 
(47%) 
(24%) 
(15%) 
62/30 
(1-21) 
(98%) 
958, 938 
(1.5-186) 
Conservatively  
93 
1 
21 
37 
34 
 
3. 
69 
 
 
Managed 
 
(1%) 
(22%) 
(39%) 
(38%) 
48/45 
(1-21) 
(74%) 
403, 781 
--- 
 
Interview and focus group participants will be stratified by their child’s: 1) access to 
expert care (i.e. yes/no), 2) disease severity (i.e. neonatal onset/post-neonatal onset), 
and 3) transplant status (pre/no transplant, post-transplant,) (Tables 3 and 4). Although 
not included as an explicit level of stratification, we will also aim to recruit primary 
caretakers that are diverse in terms of their child’s geographic distribution, 
socioeconomic status, and race/ethnicity.    
 
Table 3. Sample Sizes for Stage 1 Patient Caretaker Interviews 
 
Pre/No Transplant 
 
 
Access to Expert Care 
Sample Size 
Yes 
No 
Disease 
Severity 
Neonatal onset 
4-6 
4-6 
8-12 
Post-neonatal onset 
4-6 
4-6 
8-12 
Post-Transplant 
Neonatal onset 
4-6 
4-6 
8-12 
Post-neonatal onset 
4-6 
4-6 
8-12 
TOTAL 
16-24 
16-24 
32-48 
 

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Table 4. Sample Sizes for Stage 2 Patient Caretaker Focus Groups 
  
Pre/No Transplant 
 
Access to Expert Care 
Sample Size 
Yes 
No 
Disease 
Severity 
Neonatal onset 
8-10 
8-10 
16-20 
Post-neonatal onset 
8-10 
8-10 
16-20 
Post-Transplant 
Neonatal onset 
8-10 
8-10 
16-20 
Post-neonatal onset 
8-10 
8-10 
16-20 
TOTAL 
32-40 
32-40 
64-80 
 
We will also recruit a national cross-section of 25-40 providers from the UCDC and 
SPLIT sites for participation in semi-structured interviews. Our provider sample will 
include metabolic disease physicians, liver transplant surgeons, gastroenterologists, 
genetic counselors, and nurses (Table 5). 
 
Table 5. Sample Sizes For Provider 
Interviews & Focus Groups 
Type of Provider 
Sample Size 
Metabolic Disease 
Physician 
5-8 
Liver Transplant 
Surgeon 
5-8 
Gastroenterologist 
5-8 
Genetic Counselor 
5-8 
Nurse 
5-8 
TOTAL 
25-40 
 
6.2. Analysis Plan 
 
For Aim 1, we will use covariate balancing propensity scoring based on the CBPS 
package in R [28] to create comparable (balanced) groups based on their risk factor 
(covariate) profile in subjects according to their propensity (probability) to move from 
conservative management to liver transplantation. This approach leads to a model that 
predicts treatment assignment (conservative vs. liver transplantation) and balances 
covariables, especially those related to study outcome(s), and offers the best 
opportunity to simulate RCT results from observational data. From prior experience, 
many through the UCDC [26,31,32}, we know many of the important risk factors, which 
include neonatal vs. late onset, number of prior hyperammonemic events, event severity 
in terms of hyperammonemic coma score [2], ammonia and glutamine levels at 
regularly scheduled clinic visits, and duration from birth to transplant or index date. In 
addition to these, we will consider comorbidities, organ function, and other laboratory 
assessments. The CBPS software will help us choose the model that maximizes 
covariate balance and generate the CBPS for each participant.  The next steps will be 
to order the dataset according to the CBPS. It is useful at this point to select CBPS to 
cut points to form homogeneous strata to assess the number of subjects with a liver 
transplant and conservative management per stratum.  Those strata where there are 

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insufficient numbers (mismatches) of conservative treatment or liver transplant subjects 
will be described, documented and excluded from the primary analysis due to lack of 
covariate balance. Before conducting model-based analyses for Aim 1, we will compare 
survival times based on the log-rank test in Kaplan-Meier analysis and the difference 
between mean scores based on t-tests by treatment for neurodevelopment and quality 
of life within each stratum to evaluate evidence of heterogeneity. Evidence of 
heterogeneity will provide clues to interactive effects based on UCD severity which will 
be modeled in regression analyses below by including a cross products term of 
treatment type with CBPS.   Based on these results, we will develop general linear 
random effects longitudinal regression models in STATA 14 
[http://www.stata.com/stata14/] to perform analysis of covariance that will enable us to 
evaluate Aim 1 outcomes of neurodevelopment and quality of life. Each model will 
include treatment type, the baseline measurement of each outcome, as well as the 
CBPS and if necessary the cross product of treatment type by CBPS. When we address 
survival, we will implement Cox Regression models to predict survival time by treatment 
and will either control for CBPS or stratify on it in the case of heterogeneity. 
 
We used PASS 12 [33] to evaluate statistical power to address study aims for sample 
sizes per group (liver transplantation vs. conservative management) of 90 and 80 in 2-
tailed testing at an alpha of 0.05, which assumes some losses in the sample entering 
analysis in order to maintain adequate covariate balance between groups. For 
neurodevelopmental and quality of life assessments, we have 80% power to detect 
modest 0.4sd effect size differences between groups assuming two repeated 
measurements per person correlated at 70% (ICC).  For mortality, assuming the rate in 
the conservatively treated group remains about 28%, the study will have 80% power to 
detect and increase in the liver transplant group of about 60% which is robust to 
differences in sample size between 80 and 90 per group.  The study is well powered to 
detect any clinically meaningful difference in neurocognitive outcomes and QOL and 
adequately powered to detect a moderate difference in mortality between groups.  
 
For Aim 2, interview data will be managed using QSR International NVivo 10 software 
[http://www.qsrinternational.com/products_nvivo.asp], a program that allows us to 
collect, organize, and code qualitative data sources. Although not explicitly a grounded 
theory study, our approach to the analysis of primary caretaker and provider interview 
data will borrow from aspects of Strauss and Corbin’s systematic procedures for 
grounded theory work [34]. No existing framework or theory currently exists that 
describes the process which UCD patients and their families undertake when making 
the difficult decision to pursue liver transplant or continue conservative management. 
Thus, some of Strauss and Corbin’s analysis techniques are suitable for this study aim, 
which seeks to describe a process/experience in a field where there is little pre-existing 
evidence.  
 
 
Initial data abstraction will be conducted through the line-by-line open coding of a cross-
section of 10-15 primary caretaker and provider interview transcripts. This will allow key 
issues regarding the liver transplant vs. conservative management decision-making 
process to emerge directly from the collected data and will ensure that important 
aspects of this phenomenon are not precluded through the use of a more selective 

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coding schema. We will use this initial process of open coding to generate a preliminary 
set of codes, which will be continuously refined via team consensus (i.e. merged, 
modified, and reduced) until a final structure of codes and sub-codes emerges. This 
coding structure will then be applied systematically across all interview transcripts, 
employing thematic content analysis to categorize data into recurrent or common 
themes [35]. 
 
 
Thematic content analysis will form the basis of our more sophisticated interpretation, 
which will move beyond a typology of participant accounts to look at the relationship 
between the themes we’ve identified and to build a framework that describes how 
primary caretakers of pediatric patients with UCD, their families, and their providers 
reach a shared treatment decision and the key clinical, social, and/or system level 
factors that influence this process. Our stratified purposive sampling strategy will allow 
us to examine differences and similarities among sub-populations of patients and their 
families in terms of how they experience this decision process. This will help facilitate 
the identification of issues that are common across groups as well as the factors that 
create differences in the way patients and families approach/experience this decision. 
To facilitate this level of analysis, we will employ common framework analysis 
techniques such as charting (i.e. reorganizing data according to thematic content in 
side-by-side charts to visualize/compare a range of perspectives across cases) and 
mapping and interpretation (i.e. using diagrams and tables to physically explore the 
relationship between themes) [35]. A team of 2-3 researchers will be used to code all 
interview data and inter-rater reliability scores will be calculated to assess agreement 
between coders.  Members of the research team will code data independently but will 
collaborate to reach consensus on coding definitions as well as emerging key themes 
and the relationships between them.  
 
For Aim 3, focus group data will be analyzed using thematic content analysis (see 
description above) to validate the decision-making framework developed through Aim 2 
and to identify key opportunities for improved dissemination of evidence-based 
information to families of UCD patients including when information should be delivered, 
who should deliver it, how it should be delivered, and what additional supports should 
be provided to improve the families’ experience as they navigate the difficult decision to 
pursue liver transplant or continue conservative management. Focus group and 
interview data findings will be used in conjunction to draft a dissemination strategy that 
is responsive to the expressed needs of patients and their families, that aligns with the 
decision-making process illustrated through Aim 2, and that makes use of patient-
preferred mechanisms of communication. Focus group participants will also be asked to 
provide feedback on portions of this dissemination strategy as it is being developed. 
Focus group data will also be managed using QSR International NVivo 10 software and 
coded by a team of 2-3 researchers as described above. 
 

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7. Data Management 
 
Aim 1: All study data will be collected via systems created in collaboration with the 
RDCRN Data Management and Coordinating Center and will comply with all applicable 
guidelines regarding patient confidentiality and data integrity. 
 
Aim 2 and 3: All qualitative study data (i.e. interview and focus group transcriptions) will 
be collected by research partners at the GW Milken Institute School of Public Health 
and managed by GW investigators using QSR International NVivo 10 software 
[http://www.qsrinternational.com/products_nvivo.asp].  After qualitative study data 
collection efforts are complete, data will be exported from NVivo to text files and 
submitted to the RDCRN Data Management and Coordinating Center.  
  
7.1. Registration   
 
Registration of participants on this protocol will employ an interactive data system in 
which the clinical sites will attest to the participant’s eligibility as per protocol criteria and 
obtain appropriate informed consent. IRB approval for the protocol must be on file at the 
DMCC before accrual can occur from the clinical sites. 
 
The DMCC will use a system of coded identifiers to protect participant confidentiality 
and safety.  Each participant enrolled will be assigned a local identifier by the enrollment 
site.  This number can be a combination of the site identifier (location code) and a serial 
accession number.  Only the registering site will have access to the linkage between 
this number and the personal identifier of the subject.  When the participant is registered 
to participate in the study, using the DMCC-provided web-based registration, the system 
will assign a participant ID number.  Thus, each participant will have two codes: the 
local one that can be used by the registering site to obtain personal identifiers and a 
second code assigned by the DMCC.  For all data transfers to the DMCC, both numbers 
will be required to uniquely identify the subject.  In this fashion, it is possible to protect 
against data keying errors, digit transposition or other mistakes when identifying a 
participant for data entry since the numbers should match to properly identify the 
participant.  In this fashion, no personal identifiers would be accessible to the DMCC.  
 
7.2. Data Entry 
 
Aim 1: Data collection for this study will be accomplished with online electronic case 
report forms.  Using encrypted communication links, on-line forms will be developed that 
contain the requisite data fields.   
 
Aim 2 and 3: Interviews and focus groups will be audio recorded with participant 
permission and transcribed. All audio recordings will be deleted following their 
transcription and transcriptions will be uploaded to a QSR International NVivo 10 
software database, which will be password protected and stored on a secure hard drive 
with access limited to designated investigators.  
 

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8. Human Subjects 
 
8.1. GCP Statement 
 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, and that are consistent with Good Clinical Practice 
and all applicable regulatory requirements. 
 
8.2. Risks (and Protection Against Risks) 
 
The primary risk is a breach of confidentiality and privacy. However, the study staff is 
trained in procedures for maintaining the security and confidentiality of data. All files will 
be stored in a locked suite on a secure floor in the Children’s Research Institute, or The 
George Washington University, or in a locked suite at the National Urea Cycle Disorders 
Foundation. However, the primary research coordinator at the Children’s Research 
Institute will house copies of all relevant study materials. Study databases will be 
password-protected, and all staff will be trained in the importance of maintaining the 
confidentiality of study data.  
 
While participation in interviews or focus groups does not pose any physical risks to 
subjects, caretakers, or providers, some questions may make subjects feel 
uncomfortable or anxious. Participants will be informed of their right to stop the interview 
at any time and/or decline to answer any question. We will facilitate online interviews 
and focus group discussions for patients and families who do not ordinarily attend 
NUCDF meetings and consider extra time and travel to be burdensome.  
 
Because of neuropsychological testing, the participants could find out that they have an 
intellectual disability. However, developmental testing is also part of routine care; the 
participant might find out they have an intellectual disability regardless of involvement in 
the study.  
 
8.3. Benefits  
 
Participants will have access to neuropsychological testing that may assist in 
educational planning. Additionally, patients with UCD and their families will have access 
to reliable information on the outcome of conservative vs. liver transplant treatment for 
their conditions.  
 
8.4. Written Informed Consent 
 
Aim 1: Written informed consent will be obtained from each participant before any 
study-specific procedures or assessments are done and after the aims, methods, 
anticipated benefits, and potential hazards are explained.  The participant’s willingness 
to participate in the study will be documented in writing in a consent form, which will be 
signed by the participant with the date of that signature indicated.  The investigator will 
keep the original consent forms and signed copies will be given to the participants.  It 
will also be explained to the participants that they are free to refuse entry into the study 

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and free to withdraw from the study at any time without prejudice to future treatment.  
Written and/or oral information about the study in a language understandable by the 
participant will be given to all participants. 
 
Aim 2 & 3: No written informed consent will be obtained for either interview or focus 
group participants. Instead, prospective subjects will be provided an information sheet 
about the study, as described in 8.5. 
 
8.5. Process of Consent 
 
The mechanisms described in section 4.3 will be used to recruit and consent 
participants. Any contact to recruit families will adhere to standards for ethical conduct 
of research and be fully HIPAA compliant. 
 
After eligibility has been confirmed and the prospective participant has expressed 
interest in participating in the study, consent to participation will be obtained. 
 
Aim 1 
Consent to Participate in the Study: 
Consent and assent forms will be given to potential participants prior to enrollment so 
that they have ample time to review the information and ask questions about the study. 
We will try to mail consent forms to the individuals in advance of their participation so 
that they can read and ask any questions before considering participating. Investigators 
will ensure that the participant or their legally authorized representative understands the 
information provided and obtain informed consent. Institutions may conduct consent by 
phone and receive the signed consent form by mail, fax, or electronic mail. All consent 
discussions will take place in private, closed-door locations. 
 
Cognitive Impairment: Some of the prospective participants may be cognitively 
impaired. If the participant is 18 years old or older with significant cognitive impairments 
such that their mental age is younger than 18 years old, their legal guardian will consent 
to participation in the protocol. If the cognitively impaired participant is between the ages 
of 7 and 17, the parent or legal guardian will consent and assent will be waived. If the 
participant’s mental age is the same as their actual age, we will follow the usual consent 
procedures with those 18 and over signing consent forms and 7-17-year-olds signing 
assent forms.  
 
Aim 2 & 3: 
Primary caretakers will first be approached for participation in interviews and focus 
groups by the NUCDF Study Staff (NUCDF Study Coordinator, NUCDF Genetic 
Counselor, or NUCDF Executive Director) via telephone and/or e-mail. Primary 
caretakers will be provided a preliminary information sheet about the study by mail or e-
mail. If they express interest in participating, NUCDF’s Staff will pass on their contact 
information (telephone and/or e-mail) to a member of the GW research team. A member 
of the GW research team will then reach out to schedule either an in-person, telephone 
or video conference interview with each primary caretaker, depending on availability 
and convenience.  

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Providers will first be approached for participation in interviews by their UCDC, SPLIT, 
or NUCDF site PI or coordinator. They will be provided a preliminary information sheet 
about the study in the digital or hard copy. If they express interest in participating, the 
NUCDF Study Staff, UCDC or SPLIT site coordinator will pass on their contact 
information (telephone and/or e-mail) to a member of the GW research team. A member 
of the GW research team will then reach out to schedule either an in-person, telephone 
or video conference interview either, depending on availability and convenience.  
 
Primary caretakers and providers will be sent an information sheet by e-mail or mail at 
least 48 hours prior to their scheduled interview/focus group allowing them an 
opportunity to review the document. 
 
At the scheduled interview/focus group time, a member of the GW research team will 
review the informational document with the participant, including their right to decline or 
withdraw participation at any time and respond to any questions or concerns. Each 
participant will be asked to provide their oral consent for participation before the 
interview/focus group begins. At the conclusion of the interview, participants will be 
informed that they will receive at $100 Amazon gift card for their contribution. Should 
they decline the gift card, this money will be utilized as a mini-scholarship for 
participating families to travel to the annual NUCDF conference to partake in focus 
groups for this study. All funds will be tracked by GW and Children’s National. 
 
All consent discussions and interviews/focus groups will take place in a private, closed-
door location. 
 
8.6. Certificate of Confidentiality 
 
To help protect participant privacy, a Letter of Confidentiality has been obtained from 
the National Institutes of Health (NIH). With this Certificate, the researchers cannot be 
forced to disclose information that may identify a study participant, even by a court 
subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings.  The researchers will use the Certificate to resist any demands for 
information that would identify a participant, except as explained below. 
 
The Certificate cannot be used to resist a demand for information from personnel of the 
United States Government that is used for auditing or evaluation of Federally-funded 
projects or for information that must be disclosed in order to meet the requirements of 
the federal Food and Drug Administration (FDA). 
 
Even with the Certificate of Confidentiality, the investigators continue to have ethical 
obligations to report child abuse or neglect and to prevent an individual from carrying 
out any threats to do serious harm to themselves or others.  If keeping information 
private would immediately put the study participant or someone else in danger, the 
investigators would release information to protect the participant or another person. 
 

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Department of Health and Human Services (DHHS) personnel may request identifying 
information for purposes of performing audits, carrying out investigations of DHHS grant 
recipients, or evaluating DHHS-funded research projects. 
 
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