Long-Term Registry of Patients With Urea Cycle Disorders (UCDs)
Conditions: Urea Cycle Disorder
Sponsor: Amgen

 
 
 
150 S. Saunders Road, Lake Forest, IL 60045 
 
 
 
Study: HPN-100-014 
 
NCT#: 01948427 
 
TITLE: 
PROTOCOL 
 Long-Term Registry of Subjects with Urea Cycle Disorders (UCDs) 
 
Date of Document: 
PROTOCOL: 11 February 2013 

Horizon Therapeutics, Inc.  
 RAVICTI 
Date:  15 December 2015
Admin. Chg. 1 to Protocol:  HPN-100-014
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS, Inc.                                               Page 1 of 5
CLINICAL STUDY PROTOCOL FOR RAVICTI®
Administrative Change 1 to Protocol Number:  HPN-100-014 
Long-Term Registry of Patients with Urea Cycle Disorders (UCDs)  
Short title: THRIVE 
Version 2.0, incorporating Amendment 1 
Date:  11 February 2013 
Sponsor:
Horizon Therapeutics, Inc. 
520 Lake Cook Road 
Suite 520 
Deerfield Illinois 60015 
This protocol is the confidential information of Horizon Therapeutics, Inc. and is intended solely for the guidance of the 
clinical investigation.  This protocol may not be disclosed to parties not associated with the clinical investigation or used for 
any purpose without the prior written consent of Horizon Therapeutics, Inc.
CONFIDENTIAL

Horizon Therapeutics, Inc.  
 RAVICTI 
Date:  15 December 2015
Admin. Chg. 1 to Protocol:  HPN-100-014
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS, Inc.                                               Page 4 of 5
The Study sponsor has changed from Hyperion Therapeutics, Inc. to Horizon Therapeutics, Inc.,
an affiliate of Horizon Pharma, due to the acquisition of Hyperion Therapeutics, Inc. by 
Horizon Pharma Ireland Limited. The following sections within the protocol are changed from 
“Hyperion” to “Horizon”.
Protocol Synopsis, Retrospective 
Data Collected at Study 
Enrollment
Currently reads:
Patients who have participated in other Hyperion studies 
may be enrolled in this registry, and the data available 
from those studies may be used.
Protocol Synopsis, Retrospective 
Data Collected at Study 
Enrollment
Changed to:
Patients who have participated in other Horizon studies 
may be enrolled in this registry, and the data available 
from those studies may be used.
Section 5.2.1 Retrospective Data 
Collected at Study Enrollment
Currently reads:
Patients participating in other Hyperion studies and 
already receiving glycerol phenylbutyrate may be 
enrolled in this registry, and the data available from 
those studies may be used. 
Section 5.2.1 Retrospective Data 
Collected at Study Enrollment
Changed to:
Patients participating in other Horizon studies and 
already receiving glycerol phenylbutyrate may be 
enrolled in this registry, and the data available from 
those studies may be used. 
Section 6.2.2 Serious Adverse 
Events
Currently reads:
Hyperion will assess any hospitalization or death that is 
unexpected and deemed to be related to Glycerol 
phenylbutyrate or any other Hyperion product, by the 
Investigator, and will file a report of the event to the 
FDA. 
Section 6.2.2 Serious Adverse 
Events
Changed to:
Horizon will assess any hospitalization or death that is 
unexpected and deemed to be related to Glycerol 
phenylbutyrate or any other Horizon product, by the 
Investigator, and will file a report of the event to the 
FDA. 

Horizon Therapeutics, Inc.  
 RAVICTI 
Date:  15 December 2015
Admin. Chg. 1 to Protocol:  HPN-100-014
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON THERAPEUTICS, Inc.                                               Page 5 of 5
Section 10.1 Sample Size
Currently reads:
Up to 500 patients of whom at least 100 patients are 
being treated with RAVICTI. According to Wolters 
Kluwer data received by Hyperion in September 2010, 
there were an estimated 406 patients on NaPBA during 
the time period of 01 April 2009 through 31 March 
2010.
Section 10.1 Sample Size
Changed to:
Up to 500 patients of whom at least 100 patients are 
being treated with RAVICTI. According to Wolters 
Kluwer data received by Horizon in September 2010,
there were an estimated 406 patients on NaPBA during 
the time period of 01 April 2009 through 31 March 
2010.
Section 11.5 Monitoring of the 
Study
Currently reads:
The Study Sponsor, Hyperion Therapeutics, and its 
representatives will monitor the study at the clinical site 
according to the Monitoring Plan.
Section 11.5 Monitoring of the 
Study
Changed to:
The Study Sponsor, Horizon Therapeutics, and its 
representatives will monitor the study at the clinical site 
according to the Monitoring Plan.

 
 
 
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Amendment 1 
 
 
 
UCD Registry Protocol 
 
 
Study No: 
HPN-100-014 
Study Title: 
Long-Term Registry of Patients With Urea Cycle Disorders (UCDs) 
Clinical Phase: 
4 
Study Sponsor: 
Hyperion Therapeutics, Inc. 
 
 
Study Medical Monitor: 
 
Vice President Clinical Development and Medical Affairs 
Hyperion Therapeutics, Inc. 
 
 
 
Date of Protocol: 
11 February 2013 (Amendment 1) 
Ethics Statement: 
This study will be conducted in compliance with the protocol, the 
Declaration of Helsinki, the International Conference on Harmonisation 
(ICH) Guideline for Good Clinical Practice (GCP), and all applicable 
regulatory requirements. 
Confidentiality: 
© Hyperion Therapeutics, Inc. 
 
This protocol is the property of Hyperion Therapeutics, Inc. and may 
not—in full or in part—be transferred, reproduced, published, or 
otherwise used without the express permission of Hyperion Therapeutics, 
Inc. 
 

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INVESTIGATOR SIGNATURE PAGE 
Protocol Number: 
 
HPN-100-014 
Protocol Title: 
 
Long-Term Registry of Patients With Urea Cycle Disorders (UCDs) 
 
 
Hyperion Therapeutics, Inc. 
 
 
I have read this protocol and agree to conduct this trial in accordance with this protocol, any 
future amendments, the Declaration of Helsinki, the International Conference on Harmonisation 
(ICH) Guideline for Good Clinical Practice (GCP), and all applicable regulatory requirements. 
 
 
 
Investigator’s Signature 
 
Date 
 
 
Investigator’s Printed Name 
 
 

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PROTOCOL SYNOPSIS 
Title 
Long-Term Registry of Patients With Urea Cycle Disorders (UCDs) 
Protocol Number 
HPN-100-014 
Phase 
4 
Objectives 
To characterize the demographics and clinical course of the patient population 
diagnosed with UCD 
To track growth and neurocognitive outcomes for patients with UCDs. 
To generate comparative effectiveness data in UCD patients. 
Study Design 
This is a multi-center, prospective, non-interventional study designed to collect data 
on safety and outcomes in patients with UCDs. It is designed to permit all interested 
healthcare providers to participate as Investigators, and all interested patients to 
participate. No controls are planned. Patients enrolled in this registry will be required 
to provide a select set of data at baseline and to undergo regular office visits and data 
collection, as indicated in Appendix A. 
Rationale 
UCDs disproportionately affect children and females: depending on the severity of 
the defect, a UCD can manifest shortly after birth or later in life. This study will 
track long-term outcomes in UCD patients and effects of ammonia-scavenging 
agents on neuropsychological functions of UCD patients.  
The main goal of medical management of UCD patients is to prevent chronic or 
acute hyperammonemic states leading to central nervous damage. This requires 
restriction in dietary protein intake and the use of nitrogen scavenging agents if diet 
alone does not adequately control patients. Glycerol phenylbutyrate, sodium 
phenylbutyrate and sodium benzoate are major nitrogen scavenging agents used in 
these patients.  
RAVICTI™ (glycerol phenylbutyrate) Liquid, a prodrug of phenylbutyrate (PBA) 
and a pre-prodrug of the active compound phenylacetate (PAA), has been recently 
approved for chronic treatment of patients with UCDs.12  Previously, NaPBA was 
the only approved drug in the U.S. for the chronic treatment of the most prevalent 
UCDs. Although both drugs share a similar mechanism of action, unlike NaPBA, 
which is a salt, glycerol phenylbutyrate is a triglyceride consisting of 3 molecules of 
PBA joined via ester linkage to glycerol. The chemical form of glycerol 
phenylbutyrate helps mitigate the taste, odor, sodium content, and pill burden 
associated with NaPBA and confers different pharmacokinetic (PK) characteristics. 
PBA enters the circulation more slowly when delivered as glycerol phenylbutyrate 
compared with NaPBA, because glycerol phenylbutyrate requires digestion via 
pancreatic lipases12 Although not approved for UCD, sodium benzoate has also been 
traditionally used as another nitrogen scavenging agent either alone or in 
combination with NaPBA 
RAVICTI™ has been studied in 5 clinical trials, involving  approximately 114 adult 
and pediatric UCD patients ages 2 months and above.14,15 A study in UCD patients 
<6 years of age16 (HPN-100-012) and a continued access protocol for participants in 
UCD clinical trials17 (HPN-100-011) are ongoing. Results to date suggest satisfactory 
safety and ammonia-lowering activity that is at least as good as that afforded by an 
equivalent dose of NaPBA.12,14,15  

 
 
 
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Duration of Study 10 years 
Patient 
Population and 
Key Selection 
Criteria 
x Patients with a confirmed or suspected diagnosis of UCD.   
x Signed informed consent/HIPAA Authorization and medical records release by 
the patient or a legally acceptable representative. 
Number of 
Patients 
Up to 500 UCD patients of whom at least 100 will be receiving RAVICTI™  
(glycerol phenylbutyrate) Liquid 
Outcome 
Variables and 
Assessments  
Control of blood ammonia levels: 
x Mean and maximum blood ammonia levels, retrospectively and during the study 
x Frequency of hyperammonemic crises, retrospectively and during the study 
Serious adverse events (SAEs): 
x Frequency of SAEs 
 
Procedure Training (job specific) 
x Neuropsychological test scores: 
Adaptive Behavior Assessment System, second edition (ABAS-II)18 
The ABAS-II measures adaptive skills for individuals from birth to 89 years. Age-
specific rating forms will be used for evaluation of infants and children by parents 
or caregivers, and self-evaluation by adults. The ABAS-II provides an estimate of 
IQ and has a strong correlation with Wechsler IQ scales. The ABAS-II will be 
completed annually for patients of all ages. 
The Behavior Rating Inventory of Executive Function (BRIEF) 19  
The BRIEF is a set of clinical scales for executive function, including behavior, 
cognition, and the Global Executive Composite. Parent response forms will be 
used for preschool and school-aged children, and a self-report form will be used 
for adults. The BRIEF will be completed annually for patients 4 years and older.  
Growth and development assessments (pediatric patients): 
x Z scores derived from height, weight, body surface area (BSA), and body mass 
index (BMI) compared to standardized values 
x Occurrence of developmental disabilities and delays 
UCD medication discontinuation or change in medication: 
x Reasons for discontinuation of, or change in, ammonia-scavenging medications 
Additional Data Points (when available) 
x For patients on sodium phenylbutyrate or glycerol phenylbutyrate, available 
plasma and urine PK data 
x Actual dietary protein intake (up to 3 consecutive days)  
x Information regarding the common side effects patients have been experiencing 
with their UCD medications 
If these data points are available in electronic format, it may be possible to transfer 
the data to the EDC.   

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Study Procedures 
Eligible patients will be enrolled in the study and followed for up to 10 years, 
(Schedule of Assessments, Appendix A).  
At the time of enrollment, retrospective and baseline data will be collected. During 
the study, patients will be asked to report episodes of hyperammonemic crisis, 
available ammonia levels, and other information. Age-appropriate 
neuropsychological testing will be performed. SAEs will be reported as described in 
Section 6.2.2.3 and the Registry Reference Manual. Patients who become pregnant 
during this study will be invited to participate in the UCD pregnancy registry 
(Protocol HPN-100-018). 
Data Collection 
Procedures 
Data concerning patient treatment and clinical condition will be collected at the 
indicated time points (retrospective, baseline, and prospective) and entered into the 
Registry EDC system by the site personnel. 
Retrospective 
Data  Collected at 
Study 
Enrollment: 
The following data, for the 12 months preceding enrollment, will be obtained 
through abstraction of medical records and family interview. For patients already 
receiving RAVICTI, the 12 months immediately before commencement of 
RAVICTI will also be obtained. Patients who have participated in other Hyperion 
studies may be enrolled in this registry, and the data available from those studies 
may be used. 
x All hyperammonemic crises, including admission and peak ammonia detected 
during the crisis and documented cause, if available and the type of UCD 
medication patients were on at the time 
x All available outpatient ammonia values. For patients with more than 2 ammonia 
values in a given month, only the highest and lowest ammonia values to will be 
reported.     
x All available outpatient glutamine values. For patients with more than 2 values in 
a given month, only the highest and lowest ammonia values to will be reported  
x Duration, dose, frequency, and route of administration of all ammonia-scavenging 
agents such as NaPBA, glycerol phenylbutyrate, or sodium phenylacetate / sodium 
benzoate, and reasons for discontinuation, if applicable 
x Available weight and height values 
x Available age-appropriate neuropsychological test results 
Baseline Data 
Collected at Study 
Enrollment:  
x Demographic data 
x Age at first presentation of symptoms 
x Age at diagnosis 
x Presentation: newborn screening vs. clinical symptoms 
x UCD subtype 
x Ammonia-scavenging medication(s), including dose, frequency, and route of 
administration 
x Other medications of interest, including: arginine, citrulline and amino acid 
supplements 
x Height and weight 
x Developmental status,  disabilities and delays (Appendix D) 
x Neuropsychological tests  
x Prescribed total daily protein and caloric intake 
x Last available ammonia values 

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x Last available glutamine and branched-chain amino acid (BCAA) values 
including leucine, isoleucine and valine 
x Data points of interest (Appendix B) 
Prospective Data 
Collection After 
Enrollment: 
x For patients who begin or alter their UCD treatment close to the time of 
enrollment, ammonia and glutamine values are recommended to be obtained 
within 7 to 30 days after enrollment and if judged  necessary by the treating 
healthcare provider   
x Fasting ammonia and amino acid panel, at least annually after the first 30 days  
x For patients on restricted diet: prescribed diet, including total daily protein and 
caloric intake 
x Hyperammonemic crises, including admission and peak ammonia detected during 
the crisis, and documented cause, if available and the type of UCD medication 
patients were on at the time 
x Ammonia-scavenging medication(s), including dose, frequency, and route of 
administration 
x Reasons for discontinuation of, or changes in, ammonia-scavenging medication. 
x Other medications of interest, including: arginine, citrulline, amino acid 
supplements 
x Height and weight 
x Developmental status, disabilities and delays (Appendix D) 
x Neuropsychological tests  
x Data points of interest (Appendix B) 
x SAEs are to be reported as described in Section 6.2.2.3 and the Registry Reference 
Manual. 
x Available plasma and urine PK data 
x Actual dietary protein intake when available 
Statistical 
Methods 
A formal statistical analysis plan (SAP) that will provide details of all analyses and 
presentation of study data will be approved prior to data analysis. 
Descriptive statistics will comprise the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum for continuous variables; and n 
and percent for categorical variables. 
Sample size: 
Up to 500 patients of whom at least 100 patients are being treated with RAVICTI™ 
Analysis 
Population: 
Data will be presented for all patients enrolled in the study. 
Additional subgroups also may be examined, as deemed appropriate (pediatric 
versus adult, UCD type, etc.). 
Disposition, 
Demographic, and 
Prospective Data: 
Disposition data will be summarized by UCD medication with descriptive statistics 
and presented in listings. Demographic and clinical data will be summarized by 
UCD medication with descriptive statistics and presented in listings.  
Outcome Data: 
Post-baseline values and/or change from baseline in the outcome variables will be 
summarized by UCD medication with descriptive statistics, and, where appropriate, 
graphical presentations, and presented in listings.  
 

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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
PROTOCOL SYNOPSIS.................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................8 
ABBREVIATIONS AND ACRONYMS ......................................................................................11 
1. 
INTRODUCTION ......................................................................................................12 
1.1. 
Background .................................................................................................................12 
1.2. 
Study Rationale ...........................................................................................................13 
2. 
OBJECTIVES AND OUTCOME VARIABLES .......................................................14 
2.1. 
Objectives ...................................................................................................................14 
2.2. 
Outcome Variables .....................................................................................................14 
3. 
STUDY CONDUCT ...................................................................................................15 
3.1. 
Overall Design of the Study .......................................................................................15 
3.2. 
Patient Discontinuation and Study Site or Study Termination ...................................15 
3.2.1. 
Withdrawal of Individual Patients Prior to Study Completion ...................................15 
3.2.2. 
Study or Study Site Termination ................................................................................15 
3.3. 
Bias and Limitations of the Study ..............................................................................16 
3.3.1. 
Selection Bias .............................................................................................................16 
3.3.2. 
Patients Lost to Follow-Up .........................................................................................16 
3.4. 
Registry Reports .........................................................................................................16 
4. 
STUDY POPULATION .............................................................................................17 
4.1. 
Inclusion Criteria ........................................................................................................17 
4.2. 
Exclusion Criteria .......................................................................................................17 
5. 
STUDY PROCEDURES ............................................................................................18 
5.1. 
Site Enrollment and Training ......................................................................................18 
5.2. 
Baseline Visit Procedures and Evaluations ................................................................18 
5.2.1. 
Retrospective Data Collected at Study Enrollment ....................................................18 
5.2.2. 
Baseline Data Collected at Study Enrollment ............................................................19 
5.3. 
Initial Study/Treatment Period/New UCD Treatment, First 30 Days ........................19 
5.4. 
Annual Visits, Years 1 to 10 .......................................................................................20 
5.5. 
Standard Visits ............................................................................................................20 

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5.6. 
Home Study Visits ......................................................................................................21 
6. 
STUDY ASSESSMENTS ..........................................................................................22 
6.1. 
Demographic and Clinical Assessments .....................................................................22 
6.2. 
Outcome Measures .....................................................................................................23 
6.2.1. 
Ammonia-Scavenging Medication and Ammonia Control ........................................23 
6.2.2. 
Serious Adverse Events ..............................................................................................23 
6.2.2.1. 
Definition of Adverse Events .....................................................................................23 
6.2.2.2. 
Definition of Serious Adverse Events ........................................................................23 
6.2.2.3. 
Documentation of Serious Adverse Events ................................................................24 
6.2.2.4. 
Reporting of Serious Adverse Events .........................................................................24 
6.2.3. 
Growth and Development Outcomes (pediatric patients) ..........................................24 
6.2.4. 
Neurocognitive Outcomes ..........................................................................................24 
7. 
PRIOR AND CONCOMITANT MEDICATIONS ....................................................26 
8. 
DISEASE TREATMENTS ........................................................................................27 
9. 
DATA MANAGEMENT ...........................................................................................28 
9.1. 
Medical Record Abstraction .......................................................................................28 
9.2. 
Electronic Case Report Forms and Data Capture System ..........................................28 
10. 
STATISTICAL METHODS .......................................................................................29 
10.1. 
Sample Size ................................................................................................................29 
10.2. 
Study Populations and Analyses .................................................................................29 
10.2.1. 
Disposition, Demographic, and Clinical Analyses .....................................................29 
10.2.2. 
Outcome Measures .....................................................................................................29 
11. 
ETHICAL AND ADMINISTRATIVE ISSUES ........................................................30 
11.1. 
Informed Consent .......................................................................................................30 
11.2. 
Institutional Review Board / Independent Ethics Committee Approval ....................30 
11.3. 
Adherence to the Protocol ..........................................................................................30 
11.4. 
Protocol Amendment ..................................................................................................30 
11.5. 
Monitoring of the Study ..............................................................................................31 
11.6. 
Retention of Patient Records ......................................................................................31 
11.7. 
Confidentiality and Publication ..................................................................................31 
11.7.1. 
Publication Policy .......................................................................................................31 
11.8. 
Steering Committee ....................................................................................................32 
11.9. 
Coordination ...............................................................................................................32 

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12. 
REFERENCES ...........................................................................................................34 
13. 
APPENDIXES ............................................................................................................36 
APPENDIX A. SCHEDULE OF ASSESSMENTS ...................................................................37 
APPENDIX B. DATA POINTS OF INTEREST .......................................................................38 
APPENDIX C. NEUROPSYCHOLOGICAL TESTS................................................................40 
APPENDIX D. DEVELOPMENTAL MILESTONES ..............................................................43 
 

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ABBREVIATIONS AND ACRONYMS 
AE 
adverse event 
ARG 
arginase 
ASL 
argininosuccinate lyase 
ASS 
argininosuccinate synthetase  
BCAA 
branched-chain amino acid  
BMI 
body mass index 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CITRIN 
aspartate glutamate transporter 
CPS 
carbamyl phosphate synthetase 
eCRF 
electronic case report form 
EDC 
electronic data capture 
GCP 
Good Clinical Practice 
HHH 
ornithine translocase 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAGS 
N-acetylglutamate synthetase 
NaPBA 
sodium phenylbutyrate 
NDA 
New Drug Application 
NICU 
neonatal intensive care unit 
OTC 
ornithine transcarbamylase 
PAA 
phenylacetate 
PBA 
phenylbutyrate 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
system organ class 
UCD 
urea cycle disorder 

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1. 
INTRODUCTION 
1.1. 
Background 
A urea cycle disorder (UCD) is an inborn error of metabolism caused by a deficiency in one of 
six enzymes or two mitochondrial transport proteins involved in the production of urea, resulting 
in accumulation of toxic levels of ammonia in the blood (hyperammonemia). UCD subtypes are 
summarized in Table 1.1 these are rare diseases, with an overall estimated incidence in the US of 
1 in 30,000 live births.2  
Table 1: 
Urea Cycle Disorders 
Deficiency 
Abbreviation Inheritance Pattern 
Estimated Prevalence in 
US 
Ornithine transcarbamylase 
OTC 
X-linked 
1:14,000 
Argininosuccinate synthetase 
ASS 
Autosomal recessive 
1:57,000 
Carbamyl phosphate 
synthetase 
CPS 
Autosomal recessive 
1:62,000 
Argininosuccinate lyase 
ASL 
Autosomal recessive 
1:70,000 
Arginase 
ARG 
Autosomal recessive 
1:350,000 
N-acetylglutamate synthetase 
NAGS 
Autosomal recessive 
(unknown/very rare) 
Ornithine translocase 
HHH 
Autosomal recessive 
(unknown/very rare) 
Aspartate glutamate 
transporter 
CITRIN 
Autosomal recessive 
(unknown/very rare) 
The severity and timing of UCD presentation vary according to the severity of the deficiency, 
which may range from minor to extreme depending on the specific enzyme or transporter 
deficiency, and the specific mutation in the relevant gene. UCD patients may present in the early 
neonatal period with a catastrophic illness; or at any point in childhood, or even adulthood, after 
a precipitating event such as infection, trauma, surgery, pregnancy/delivery, or change in diet.2 
Acute hyperammonemic episodes at any age carry the risk of encephalopathy and resulting 
neurologic damage, sometimes fatal; but even chronic, sub-critical hyperammonemia can result 
in impaired cognition.3 UCDs are therefore associated with significant incidence of neurological 
abnormalities and intellectual and developmental disabilities over all ages.4,5 UCD patients with 
neonatal-onset disease are especially likely to suffer cognitive impairment5 and death6 compared 
with patients who present later in life. 
Management of acute hyperammonemic crises may require hemodialysis and/or intravenous (IV) 
administration of sodium phenylacetate and sodium benzoate (marketed in the US as 
AMMONUL®).7 Orthotopic liver transplantation may also be considered for patients with severe 
disease that manifests itself in the neonatal period. Long-term UCD management is directed 
toward prevention of hyperammonemia and includes restriction of dietary protein; arginine and 
citrulline supplementation, which can enhance waste nitrogen excretion for certain UCDs; and 
oral, ammonia-scavenging drug therapy that provides an alternate path for waste nitrogen 
removal. Until the approval of RAVICTI™ (glycerol phenylbutyrate) Liquid, sodium 

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phenylbutyrate (NaPBA; marketed in the US as BUPHENYL®)8 was the only ammonia-
scavenging agent available in the US for maintenance treatment of the most prevalent UCDs. 
NaPBA has been demonstrated to improve long-term survival in UCD patients, by reducing the 
incidence of deaths due to hyperammonemic encephalopathy, when administered at the 
recommended dose levels.8 
Despite dietary and pharmacologic management, UCD patients still experience episodes of 
hyperammonemia, with the risk of hyperammonemic encephalopathy requiring aggressive 
medical intervention2 and chronic hyperammonemia, with cumulative neurocognitive 
impairment.5 Furthermore, compliance with NaPBA treatment is difficult, especially for 
pediatric patients, due to the high pill burden (up to 40 pills or 40 mL of dissolved powder daily 
for patients taking 20 g of NaPBA), foul taste, unpleasant odor, and high sodium content 
(~2300 mg/day for patients taking 20 g). Because NaPBA is rapidly absorbed, and because of the 
short plasma half-life of the active metabolite phenylacetate (PAA), the BUPHENYL label 
recommends dosing 3 to 6 times/day.8 Some pediatric patients with severe deficiency states may 
require nasogastric or gastrostomy tubes to ensure adequate nutrition and compliance with this 
treatment regimen.9,10,11 
1.2. 
Study Rationale 
UCDs disproportionately affect children and females: depending on the severity of the defect, a 
UCD can manifest shortly after birth or later in life. This study will track long-term outcomes in 
UCD patients and effects of ammonia-scavenging agents on neuropsychological functions of 
UCD patients.  
The main goal of medical management of UCD patients is to prevent chronic or acute 
hyperammonemic states leading to irreversible central nervous damage. This requires restriction 
in dietary protein intake and the use of nitrogen scavenging agents if diet alone does not 
adequately control patients. Glycerol phenylbutyrate, sodium phenylbutyrate and sodium 
benzoate are major nitrogen scavenging agents used in these patients.  
Glycerol phenylbutyrate, a prodrug of PBA and a pre-prodrug of the active compound PAA, 
recently has been approved for chronic treatment of patients with UCDs.12  Although glycerol 
phenylbutyrate and NaPBA share a similar mechanism of action, unlike NaPBA, which is a salt, 
glycerol phenylbutyrate is a triglyceride consisting of 3 molecules of PBA joined via ester 
linkage to glycerol. The chemical form of glycerol phenylbutyrate helps to mitigate the taste, 
odor, sodium content, and pill burden associated with NaPBA, and confers more favorable 
pharmacokinetic (PK) characteristics. PBA enters the circulation more slowly when delivered as 
glycerol phenylbutyrate, compared with NaPBA, because glycerol phenylbutyrate requires 
digestion via pancreatic lipases.12 Although not approved for UCD, sodium benzoate has also 
been traditionally used as another nitrogen scavenging agent either alone or in combination with 
NaPBA 
Glycerol phenylbutyrate has been studied in 5 clinical trials, involving approximately 114 adult 
and pediatric UCD patients ages 2 months and above.14,15  A study in UCD patients <6 years of 
age16 (HPN-100-012) and an continued access protocol for participants in UCD clinical trials 17 
(HPN-100-011) are ongoing. Results to date suggest satisfactory safety and ammonia-lowering 
activity that is at least as good as that afforded by an equivalent dose of NaPBA.12,14,15  

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2. 
OBJECTIVES AND OUTCOME VARIABLES 
2.1. 
Objectives  
The objectives of this study are: 
x To characterize the demographics and clinical course of the patient population 
diagnosed with UCD 
x To track growth and neurocognitive outcomes in patients with UCD. 
x To generate comparative effectiveness data in UCD patients 
2.2. 
Outcome Variables 
x Control of blood ammonia levels: 
 Mean and maximum blood ammonia levels, retrospectively and during the study  
 Frequency of hyperammonemic crises, retrospectively and during the study 
x Frequency of serious adverse events (SAEs) 
x Neurocognitive outcomes, evaluated by changes in neuropsychological test scores: 
 Adaptive Behavior Assessment System, second edition (ABAS-II)  
 The Behavior Rating Inventory of Executive Function (BRIEF) 
x Growth and development (pediatric patients): 
 Z scores derived from height, weight, body surface area (BSA), and body mass 
index (BMI) compared to standardized values 
 Occurrence of developmental disabilities and delays 
x UCD medication discontinuation or change in medication: 
 Reasons for discontinuation of, or change in, ammonia-scavenging medication 
x Additional Data Points (when available)  
 Actual dietary protein intake at predefined intervals 
 For patients on sodium phenylbutyrate or glycerol phenylbutyrate:  plasma and 
urine PK  

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3. 
STUDY CONDUCT 
3.1. 
Overall Design of the Study 
This is a non-interventional, multi-center registry to be conducted in patients with UCDs. 
Investigators will prescribe treatments based on usual clinical practice, and there will be no 
restrictions on the use of commercially available medications. As an observational study, this 
study will not change the patient/ healthcare provider relationship, nor influence the healthcare 
provider’s drug prescription or the therapeutic management of the patient. 
Study visits, procedures, and evaluations are summarized in the Schedule of Assessments 
(Appendix A) and described in detail in Sections 5.2. 
Patients with UCDs will be recruited and invited to attend a Baseline visit. After eligible patients 
are enrolled, retrospective and baseline data will be collected.  
Patients will be followed for up to 10 years, during which time they will be assessed by their 
healthcare provider. Patients and healthcare provider will be asked to report episodes of 
hyperammonemic crisis, available ammonia values, and other information. Assessments of 
follow-up information, data points of interest (Appendix B), and age-appropriate 
neuropsychological testing (Appendix C) will be performed annually. SAEs will be reported as 
described in Section 6.2.2.3 and the Registry Reference Manual. 
Patients who become pregnant during this registry will be invited to participate in the UCD 
pregnancy registry (Protocol HPN-100-018) 
3.2. 
Patient Discontinuation and Study Site or Study Termination 
3.2.1. 
Withdrawal of Individual Patients Prior to Study Completion 
Patient may decide to discontinue participation (by notifying their Investigator verbally and in 
writing) at any time without penalty and without affecting future medical care A patient may be 
withdrawn from the study prior to completion for any of the following reasons: 
x Withdrawal of patient consent; 
x Any other reason, such that continuation of the patient's participation is thought by 
the Investigator to be inappropriate. 
If a patient withdraws or is withdrawn, the reason should be documented in the electronic case 
report form (eCRF).  
3.2.2. 
Study or Study Site Termination 
The Sponsor reserves the right, at any time, to discontinue enrollment of additional patients into 
the study, at any site; or to discontinue the study, for medical or administrative reasons.   

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3.3. 
Bias and Limitations of the Study  
3.3.1. 
Selection Bias 
All UCD patients, regardless of treatment they receive, are eligible to enroll in this registry. In 
order to minimize bias in the selection of patients, the Investigators are encouraged to 
consecutively enroll all patients who consent and meet the selection criteria, regardless of 
treatment, health status, or other considerations.  
3.3.2. 
Patients Lost to Follow-Up 
It is expected that some patients will transfer their medical care to a new healthcare provider over 
the course of their participation in the study. If this occurs, contact information for the new 
healthcare provider will be requested, and the new healthcare provider may be invited to 
participate in the study. If the new healthcare provider is not willing to participate in the study, 
the patient will be asked to sign a medical records release form requesting and permitting the 
new healthcare provider to provide copies of the patient’s medical records (per the data 
collection time points, Appendix A) for abstraction of study data.  
A central investigator will be identified to take responsibilities for data collection and data entry 
for patients who may not have access to a participating investigator. The following are examples 
of such cases: 
x If a participating investigator decides to end his/her participation in the study, 
enrolled patients will be asked to transfer to the central investigator.   
x If a patient lives in a geographical area where there is no participating investigator or 
their healthcare provide declines to participate in this registry, the central investigator 
may enroll that patient and assume responsibility for data collection and data entry for 
that patient   
The central investigator will not be involved in direct management of patients but only collection 
of study specific data points. The details of processes involved in these cases will be outlined in 
the Registry Reference Manual.  
3.4. 
Registry Reports 
The Sponsor and/or designee will prepare, at a minimum, an annual summary report to the 
appropriate regulatory authorities where needed. Confidential site-specific and aggregate 
national reports will be provided on a periodic basis. Annual reports will be de-identified and 
include accrual rates; summary demographic, clinical, and safety data; and total person-years of 
follow-up. In addition, these data may be summarized periodically for presentation at 
professional conferences and sessions, as appropriate. 
The Sponsor and/or designee will submit a final registry report to the appropriate regulatory 
authority after all enrolled patients have completed 10 years of follow-up, or have been lost to 
follow-up; or after the registry has been terminated by the Sponsor. 

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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
A patient must meet all of the following criteria to be eligible for participation in the study. 
1. Confirmed or suspected diagnosis of UCD.   
2. Signed informed consent and HIPAA Authorization, by the patient or a legally acceptable 
representative, obtained before any study-related activities are undertaken. Assent should 
be obtained from pediatric patients according to local regulations. 
3. Signed medical records release form, by the patient or a legally acceptable representative, 
permitting abstraction of the patient’s medical records at Baseline and during 
participation in the study. 
4.2. 
Exclusion Criteria 
A patient who meets any of the following criteria is not eligible for participation in the study. 
1. Any other reason that, in the Investigator's opinion, makes the patient unsuitable to 
participate in this study.  

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5. 
STUDY PROCEDURES 
5.1. 
Site Enrollment and Training 
The Sponsor or designee will invite Investigators with sufficient resources (time, personnel, and 
facilities) to participate in the study. Investigators will be required to obtain approval from the 
appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC), and will be 
responsible for maintaining all related documents, before enrollment of any patient into the 
study. The study is designed to minimize the burden of participation. 
Designated study personnel will participate in a training program that will encourage consistency 
of process and procedures at the investigative sites and ensure collection of high-quality data for 
this registry. All sites will be trained on the protocol, registry logistics, and the electronic data 
capture (EDC) system. Retraining will be conducted as needed. Investigators will be reminded of 
the processes and importance of reporting SAEs, deaths, changes in treatments due to AEs, and 
other information.    
5.2. 
Baseline Visit Procedures and Evaluations 
An initial Baseline Visit will be scheduled for patients who are considered for study participation 
at the discretion of the investigator. After written informed consent is obtained, each patient will 
be entered into the registry database and assigned a unique study ID number. Study eligibility 
will be determined by review of the inclusion/exclusion criteria. Patients who are enrolled in the 
study will then have the following information abstracted from their medical records and 
undergo the baseline assessments. For patients who may be enrolled by the central investigator 
the data required for the Baseline Visit may be obtained from their treating physicians after 
signing appropriate medical records release forms.  
5.2.1. 
Retrospective Data Collected at Study Enrollment 
The following retrospective data, for the 12 months preceding enrollment into the study, will be 
abstracted from the patient’s medical record and obtained from family interviews. Patients 
participating in other Hyperion studies and already receiving glycerol phenylbutyrate may be 
enrolled in this registry, and the data available from those studies may be used. Available data 
for all patients may be transferred electronically from other databases to the registry data base.  
x All available outpatient ammonia values.  
x All available glutamine values.  
x Duration, dose, frequency, and route of administration of all ammonia-scavenging 
agents such as NaPBA, glycerol phenylbutyrate, or sodium phenylacetate / sodium 
benzoate, or carglumic acid, and reasons for discontinuation, if applicable. 
x All hyperammonemic crises, including admission, peak and discharge ammonia 
detected during the crisis and documented cause, if available. 
x Available weight and height. 
x Available age-appropriate neuropsychological test results. 

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5.2.2. 
Baseline Data Collected at Study Enrollment 
The following data will be recorded at the time of enrollment into the study. 
x Demographic information (Section 6.1). 
x Age at first presentation of symptoms. 
x Age at diagnosis. 
x Presentation: newborn screening vs. clinical symptoms. 
x UCD subtype. 
x Ammonia-scavenging medication(s), including dose, frequency, and route of 
administration. 
x Other medications of interest, including dose: arginine, citrulline, and amino acid 
supplements. 
x Height and weight. 
x Developmental status and disabilities and delays (Appendix D) .  
x Neuropsychological testing (may be performed ≤2 months after enrollment). If 
neuropsychological testing was performed within 6 months preceding enrollment, the 
data may be used as baseline values for this study.  
x Prescribed total daily protein and caloric intake. 
x Most recent available ammonia values. 
x Most recent available glutamine and branched-chain amino acid (BCAA) values 
including leucine, isoleucine and valine. 
x Data points of interest (Appendix B). 
x Plasma and urine PK for patients on sodium phenylbutyrate or glycerol 
phenylbutyrate 
x Actual dietary protein intake at predefined intervals 
x Liver function tests and hematology parameters when available  
5.3. 
Initial Study/Treatment Period/New UCD Treatment, First 30 Days 
In patients who start a new nitrogen scavenging agent or switch to a new UCD treatment a visit 
is typically performed within 30 days to assess the effects of the drug. Therefore, it is 
recommended that data from such visits be recorded.  
The following data, when available, will be recorded, within 30 days of starting a new UCD 
treatment or switching treatments.  
x Ammonia and glutamine values, as judged necessary by the Investigator.  
x Ammonia-scavenging medication, including dose, frequency, and route of 
administration. 

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x Reasons for discontinuation of, or changes in, ammonia-scavenging medication. 
x Hyperammonemic crises if any since last visit, including admission, peak and 
discharge ammonia detected during the crisis, and documented cause, if available. 
x SAEs will be reported as described in Section 6.2.2.3 and the Registry Reference 
Manual. 
x Plasma and urine PK for patients on sodium phenylbutyrate or glycerol 
phenylbutyrate.  
x Liver function tests and hematology parameters  
5.4. 
Annual Visits, Years 1 to 10 
The following data will be recorded, at least annually: 
x Ammonia and amino acid panel. Collection of fasting ammonia is highly 
recommended. 
x Prescribed total daily protein and caloric intake. 
x Hyperammonemic crises since the last recorded visit, including admission, peak and 
discharge ammonia detected during the crisis, and documented cause, if available. 
x Ammonia-scavenging medication(s), including dose, frequency, and route of 
administration. 
x Reasons for discontinuation of, or changes in, ammonia-scavenging medication since 
the last recorded visit. 
x Other medications of interest, including dose: arginine, citrulline, and amino acid 
supplements. 
x Height and weight. 
x Developmental status, disabilities and delays (Appendix D).  
x Neuropsychological testing, annually.  
x Data points of interest (Appendix B). 
x SAEs will be reported as described in Section 6.2.2.3 and the Registry Reference 
Manual. 
x Plasma and urine PK for patients on sodium phenylbutyrate or glycerol 
phenylbutyrate 
x Actual dietary protein intake at predefined intervals 
x Liver function tests and hematology parameters when available  
5.5. 
Standard Visits 
Additional visits as part of standard of care may occur between annual study visits. If such visits 
occur, any available data from the list below will be collected (All visits will be recorded as 
sequential study visits in the database): 

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x Ammonia and amino acid panel. Collection of fasting ammonia is highly 
recommended. 
x Prescribed total daily protein and caloric intake. 
x Hyperammonemic crises if any since last visit, including admission, peak and 
discharge ammonia detected during the crisis, and documented cause, if available. 
x Ammonia-scavenging medication(s), including dose, frequency, and route of 
administration. 
x Reasons for discontinuation of, or changes in, ammonia-scavenging medication since 
the last recorded visit. 
x Other medications of interest, including dose: arginine, citrulline and amino acid 
supplements 
x Height and weight. 
x Developmental status, disabilities and delays (Appendix D).  
x Neuropsychological testing.  
x Data points of interest (Appendix B). 
x SAEs will be reported as described in Section 6.2.2.3 and the Registry Reference 
Manual. 
x Plasma and urine PK for patients on sodium phenylbutyrate or glycerol 
phenylbutyrate 
x Actual dietary protein intake at predefined intervals. 
x Liver function tests and hematology parameters  
5.6. 
Home Study Visits 
The option of utilizing a home health care nurse will be provided to investigators and patients. 
The home health care nurse will not be involved in direct management of patients or obtaining 
any blood samples but only oversight of collection of certain data points that are typically 
collected through completing questionnaires or forms such as BRIEF, ABAS-II, and data points 
of interest. The details of processes involved in these cases will be outlined in the Registry 
Reference Manual. Home health care nurses involved in this study will be properly trained on the 
protocol and necessary procedures.  

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6. 
STUDY ASSESSMENTS 
6.1. 
Demographic and Clinical Assessments 
Demography: 
x Age 
x Sex 
x Race 
x Ethnic origin 
Urea Cycle Disorder History: 
x Age at first presentation of symptoms 
x Presentation: newborn screening vs. clinical symptoms 
x Age at diagnosis 
x UCD subtype 
x G tube placement  
Past and Current Treatments: 
x Ammonia-scavenging medication(s), including dose, frequency, and route of 
administration 
x Prescribed total daily protein and caloric intake 
x Other medications of interest, including dose: arginine, citrulline, and amino acid 
supplements 
Patient Clinical Status: 
x Height and weight 
x Ammonia values, including time of blood draw in relation to last meal and last 
ammonia-scavenging drug administration 
x Fasting glutamine and BCAA values including leucine, isoleucine and valine 
x Data points of interest (Appendix B) 
Additional Data Points (when available) 
x Patients on sodium phenylbutyrate or glycerol phenylbutyrate:  plasma and urine PK 
samples  
x Actual dietary protein intake  
If these data points are available in electronic format, it may be possible to transfer the data to 
the EDC.  

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6.2. 
Outcome Measures 
6.2.1. 
Ammonia-Scavenging Medication and Ammonia Control  
The following data will be used to evaluate control of blood ammonia levels: 
x Mean and maximum blood ammonia levels  
x Frequency of hyperammonemic crises 
The EDC will include CRF pages to capture all the hyperammonemic crises. The captured data 
points may include ammonia values at admission, maximum and at discharge, medication used 
to treat the crisis and any known precipitating factors.  
Reasons for any change in ammonia-scavenging medication, or discontinuation of medication, 
will be recorded. 
6.2.2. 
Serious Adverse Events 
Since this registry is observational in nature, recording of adverse events by investigational sites 
will not be mandated. However, occurrence of hospitalizations and deaths will be collected as 
part of the observation in all patients.  
Hyperion will assess any hospitalization or death that is unexpected and deemed to be related to 
Glycerol phenylbutyrate or any other Hyperion product, by the Investigator, and will file a report 
of the event to the FDA.  
6.2.2.1. 
Definition of Adverse Events 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not the event is considered causally related to the use of the product. 
6.2.2.2. 
Definition of Serious Adverse Events 
A serious AE (SAE) is an AE that has any of the following outcomes: 
x Is fatal  
x Is fatal or life-threatening, i.e., in the view of the Investigator, places the patient at 
immediate risk of death from the reaction as it occurred. A life-threatening SAE 
would not be an AE that, had it occurred in a more serious form or was left untreated, 
might have caused death. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening, even though 
drug-induced hepatitis can be fatal.  
x Results in persistent or significant disability or incapacity. Disability is defined as a 
substantial disruption of a person's ability to conduct normal life functions. 
x Requires inpatient hospitalization or prolongation of an existing hospitalization. 
Hospitalization will not itself be considered an AE. It will be considered an outcome 
of an AE. Therefore, if there is no associated AE, there is no SAE. For example, 
hospitalization for elective treatment of a pre-existing condition that did not worsen 
after the signing of the informed consent will not be considered an AE. 

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x Is a congenital anomaly/birth defect.  
x Any other important medical event that may not result in death, be life-threatening or 
require hospitalization, but based upon appropriate medical judgment, may jeopardize 
the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed above.   
6.2.2.3. 
Documentation of Serious Adverse Events 
SAE data will be recorded in the patient eCRF, including start and end dates, Investigator-
specified severity and relationship, action taken, and outcome.  
6.2.2.4. 
Reporting of Serious Adverse Events 
SAE reporting will commence after a patient has provided informed consent. In the event of an 
SAE, the Investigator will notify the Sponsor or designee, as instructed in the Registry Reference 
Manual, within 5 business days of the investigator becoming aware of the event. The sponsor or 
designee must be notified of any fatal or life-threatening SAEs within 24 hours of the 
Investigator becoming aware of the event. A written report, including the investigator’s 
assessment of causality, must be recorded in the eCRF. The event must also be documented in 
source documentation. See the Registry Reference Manual for complete instructions.  
After receipt of the initial report, the information will be reviewed, and the Investigator will be 
contacted to request additional information or for data clarification. If required, a follow-up 
report including all new information obtained on the event must be prepared and sent to 
designated contact for SAE reporting. Follow-up reports will be filed as necessary until the event 
has resolved or attained a stable outcome. 
The Sponsor assumes responsibility for appropriate reporting of SAEs assessed as related to 
sponsor specific products to regulatory authorities. The Investigator will report SAEs to the 
IRB/IEC that approved the registry protocol per institutional requirements, unless otherwise 
required by local regulations and documented by the IRB/IEC. 
6.2.3. 
Growth and Development Outcomes (pediatric patients)  
x Z scores derived from height, weight, BSA, and BMI comparison to standardized 
values 
x Occurrence of developmental disabilities and delays (Appendix D) 
6.2.4. 
Neurocognitive Outcomes 
Neurocognitive outcomes will be evaluated by neuropsychological test scores at baseline and 
during the study (see also Appendix C). Since these tests are primarily self-reported or parent-
reported questionnaires the completion of these tests may be done during an office visit or at 
home. See the Registry Reference Manual for complete instructions. 
x Adaptive Behavior Assessment System, second edition (ABAS-II)18  
The ABAS-II measures adaptive skills for individuals from birth to 89 years. Age-specific rating 
forms will be used for evaluation of infants and children by parents or caregivers, and self-

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evaluation by adults. The ABAS-II provides an estimate of IQ and has a strong correlation with 
Wechsler IQ scales.  
The ABAS-II will be completed annually for patients of all ages. 
x 
The Behavior Rating Inventory of Executive Function (BRIEF)19 
The BRIEF is a set of clinical scales for executive function, including behavior, cognition, and 
the Global Executive Composite. Parent response forms will be used for preschool and school-
aged children, and a self-report form will be used for adults.  
The BRIEF will be completed annually for patients 4 years and older. 

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7. 
PRIOR AND CONCOMITANT MEDICATIONS 
Dose, frequency, and route of administration will be recorded for medications of interest, 
including: arginine, citrulline, and amino acid supplements within 12 months prior to enrollment 
and during the study.  

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8. 
DISEASE TREATMENTS 
Treatment for UCDs will be prescribed by the Investigator according to usual clinical practice. 
No attempt will be made to regulate the use of UCD drugs.  
Duration, dose, frequency, and route of administration of all ammonia-scavenging agents, such 
as BUPHENYL® (NaPBA) , Carbaglu (carglumic acid), other forms of NaPBA, glycerol 
phenylbutyrate, sodium benzoate, or sodium phenylacetate / sodium benzoate (AMMUNOL®), 
will be recorded. 

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9. 
DATA MANAGEMENT 
All data collected in the context of this study will be stored and evaluated in accordance with 
regulatory requirements and applicable guidance for electronic records. 
9.1. 
Medical Record Abstraction 
Electronic case report forms (eCRFs) will be used. Data will be extracted from the patient’s 
medical record and entered into the EDC system according to the schedule presented in 
Appendix A. Patients will be identified by use of the ID number assigned to them when they 
enroll in the registry. 
Before the first patient's medical record is abstracted, the Sponsor and/or designee will meet with 
the Investigator and the study center’s personnel to train them on recording the data on the 
eCRFs using the EDC system.   
9.2. 
Electronic Case Report Forms and Data Capture System 
Only authorized personnel will have access to the EDC system. Data will be entered into eCRFs 
in accordance with instructions from the Sponsor and/or designee. Each Investigator is 
responsible for ensuring that accurate data are entered into the EDC system in a timely manner.  
On-line logic checks will be built into the system, so that illogical data are not submitted. In the 
event that inconsistent data persist, queries may be issued electronically to the clinical study site 
and answered electronically by that study site’s personnel. The identifying information (assigned 
user name, date, and time) for both the originator of the query and the originator of the data 
change (if applicable), as well as the Investigator’s approval of all changes performed on the 
data, will be collected. 
The Investigator will be responsible for reviewing eCRFs, resolving data queries generated by 
the Sponsor and/or designee via the system, providing missing or corrected data, approving all 
changes performed on the patient data, and endorsing these data within the EDC system. This 
approval method will include applying an electronic signature, a uniquely assigned user name, 
and a password that together will represent a traditional handwritten signature. 

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10. 
STATISTICAL METHODS 
A formal statistical analysis plan (SAP) that will provide details of all analyses and presentation 
of study data will be approved prior to data analysis. To adapt to the evolving research needs of 
the UCD community, the analysis plans may be modified for new objectives identified during 
the course of the study, and minor modifications to the case report form may be made to address 
new treatments and diagnostics if needed. 
10.1. 
Sample Size 
Up to 500 patients of whom at least 100 patients are being treated with RAVICTI. According to 
Wolters Kluwer data received by Hyperion in September 2010, there were an estimated 406 
patients on NaPBA during the time period of 01 April 2009 through 31 March 2010. The 
enrollment target of at least 100 patients receiving glycerol phenylbutyrate was selected due to 
feasibility, and an attempt to capture a significant portion of the probable glycerol phenylbutyrate 
patient population, which is estimated, at peak, to be similar to the number of patients on 
NaPBA.  
10.2. 
Study Populations and Analyses 
x Disposition data will be presented for all patients who attended a Baseline visit. 
x All other analyses will be based on all patients who enrolled in the study. 
x Additional subgroups also may be examined, as deemed appropriate (pediatric versus 
adult, UCD type, presentation, type of UCD treatment, etc.). 
Descriptive statistics will comprise the number of observations (n), mean, standard deviation 
(SD), median, minimum, and maximum for continuous variables; and frequency (n and percent) 
for categorical variables. 
10.2.1. 
Disposition, Demographic, and Clinical Analyses 
Disposition, demographic and clinical data (data points of interest, Appendix B) will be 
summarized descriptively by UCD medication and presented in listings. 
10.2.2. 
Outcome Measures 
Post-baseline values and/or change from baseline in the outcome variables will be summarized 
by UCD medication with descriptive statistics, and where appropriate, graphical presentations, 
and in listings. A complete statistical analysis plan will be developed.  
SAEs will be coded using MedDRA Version 13.1 or later. Incidence of SAEs will be 
summarized descriptively by UCD medication, system organ class, and preferred term. All SAEs 
will be presented in listings. 
Incidence of key outcome variables will be presented in listings. 

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11. 
ETHICAL AND ADMINISTRATIVE ISSUES 
11.1. 
Informed Consent 
Patients considered for enrollment will be given a package containing details about the Registry 
study, informed consent for participation in the Registry, and Health Insurance Portability and 
Accountability Act (HIPAA) authorization to access patient’s protected health information. 
Before any protocol-specified procedures are carried out, the Investigator or designee will 
explain details of the protocol and study procedures, as well as the risks involved, to patients 
(and if applicable, their legally acceptable representative). Patients will be informed that they are 
free to withdraw from the study at any time. 
Each patient, or a legally acceptable representative, must sign an informed consent form (ICF), 
approved by the IRB/IEC, indicating their consent to participate. Assent should be obtained from 
pediatric patients according to individual IRB/IEC requirements. ICFs and assent forms will 
conform to the requirements of 21 CFR 50.20-27 and International Conference on 
Harmonisation (ICH) E6 4.8, Principles of Good Clinical Practices (GCP). The original signed 
ICFs must remain in the patient's file at the study site. Each patient will receive a copy of the 
signed ICF. During the registry, patients reaching the age of 18 years, or the legal age of majority 
according to local regulations, must provide written informed consent to continue participation in 
the registry. 
Each patient enrolled in the study, or a legally acceptable representative, also must sign a 
medical records release form permitting abstraction of medical data from other healthcare 
providers for entry in the study EDC system. Individual patient data included in the study 
database will be treated in compliance with all applicable laws and regulations regarding privacy 
protection. 
11.2. 
Institutional Review Board / Independent Ethics Committee 
Approval 
The protocol and the ICF must be reviewed and approved by the study site’s IRB/IEC before the 
study is initiated. The Investigator is then responsible for informing the IRB/IEC of the 
completion of the study and should provide any required study status and/or safety report(s).  
11.3. 
Adherence to the Protocol 
The study must be conducted as described in the approved protocol.   
11.4. 
Protocol Amendment 
Any amendment to the protocol will be created by the Study Sponsor, and subsequently 
submitted by the site to the IRB/IEC and appropriate regulatory authority as appropriate. If the 
protocol amendment substantially alters the study design or increases the potential risk or 
discomfort to the patients, written consent for continued participation in the study must be 
obtained. 

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11.5. 
Monitoring of the Study 
The Study Sponsor, Hyperion Therapeutics, and its representatives will monitor the study at the 
clinical site according to the Monitoring Plan. At the monitoring visits, the progress of the study 
and any procedural or data issues will be discussed with the Investigator and/or designee. Patient 
source documents should be available for review; the Investigator will permit the Sponsor, 
representatives of the Sponsor, the IRB/IEC, or regulatory authorities to inspect facilities and 
original records relevant to this study.  
11.6. 
Retention of Patient Records 
When the registry is completed, the Investigator must retain the essential documents for as long 
as needed to comply with regulatory guidelines and Sponsor requirements. The Investigator will 
notify the Sponsor prior to moving or destroying any of the study documents. 
11.7. 
Confidentiality and Publication 
The information in this and related documents from the Study Sponsor includes information that 
is confidential and may not be disclosed, unless such disclosure is required by federal or other 
laws or regulations. In any event, persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 
Individual patient medical information obtained as a result of this study is considered 
confidential, and disclosure to third parties, other than those noted below, is prohibited.  Such 
medical information may be given to the patient's personal physician or to other appropriate 
medical personnel responsible for the patient's welfare. 
Data generated as a result of this study are to be available for inspection on request of the 
Sponsor's representative, the IRB/IEC, or local regulatory agency. 
An investigator-led steering committee will be established and chartered to guide the scientific 
discourse and publications related to this study. None of the parties involved in the 
management/conduct/analysis of this study may publish any study-related data without the 
written permission of the steering committee. 
11.7.1. 
Publication Policy 
As this is a multicenter study, it is the intent of the Sponsor to publish or present the study results 
as agreed with the Steering Committee. The Steering Committee, in conjunction with the 
Sponsor, will establish a uniform procedure for the publication and dissemination of results from 
this study. For manuscripts based on multi-center study results which are subsequent to the 
primary publications on such results, the investigational site shall furnish the Sponsor with a 
copy of any proposed publication at least thirty (30) days in advance of the proposed submission 
date. Within this thirty-day period, the Sponsor shall review the proposed publication for 
technical content, including patentable inventions, and for the disclosure of Confidential 
Information. Not later than the end of the thirty-day period, the Sponsor shall inform the 
investigational site or Investigator in writing of any objection to inclusion of specific content in 
the proposed publication. Any Sponsor objection shall be limited to, and specify, the location 
and content of each item of Confidential Information contained in the proposed publication, 
publication of which is deemed objectionable by the Sponsor, and of each potentially patentable 

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invention which is disclosed in the proposed publication. Upon receiving the written objection 
from the Sponsor, the Investigator shall edit the proposed publication to remove the 
objectionable Confidential Information before submission. In addition, the Investigator shall 
either delete disclosure of all potentially patentable inventions or delay submission of the 
proposed publication for up to ninety (90) days so that any appropriate patent application(s) can 
be filed. In addition, the Steering Committee must approve any publication that involves results 
not solely based on site-specific study results prior to submission or disclosure to a third party. 
For manuscripts solely based on site-specific study results, the Sponsor requests a thirty-day 
review process from the investigational site as described above, with the right to request removal 
of Confidential Information and delay for filing patent application(s). However, manuscripts 
solely based on site-specific study results do not require approval of the Sponsor or the Steering 
Committee, and neither the Sponsor nor the Steering Committee has the right to require removal 
of the investigational site’s site-specific study results or to approve the manuscript.  
The detailed of the publication and additional information will be further defined in the Charter 
for Steering Committee.   
11.8. 
Steering Committee  
The Steering Committee is comprised of thought leaders in the areas of Urea Cycle Disorders. 
The Committee will have the following responsibilities:  
x Provide advice and guidance on the Registry study design and protocol;  
x Provide advice and guidance on the variables to be captured on the Case Report Form 
for the Registry;  
x Provide guidance on site selection into the Registry;  
x Review data results and provide insights on the interpretation of the data on a semi-
annual basis;  
x Provide input on the planning and organization of abstracts and manuscripts;  
x Draft and review abstracts and manuscripts;  
x Review abstracts and papers for submission to scientific journals and conferences;  
x Present data at scientific conferences.  
Details of roles and responsibilities of the Steering Committee will be defined in the Charter for 
Steering Committee.  
11.9. 
Coordination  
The Sponsor has the right to terminate the Registry at any time. All tangible property provided to 
Registry patients, Investigators, and their organizations in connection with this Registry shall be 
and remain the exclusive property of the Sponsor. All data, reports, or other information 
generated under this Registry (and any other results of such data, reports, or other information) 
shall be and remain the exclusive property of the Sponsor or its successors in interest. In the 
event that the Sponsor or any successors in interest terminates its financial support of this 
Registry the Sponsor would work to, following the guidance of the Steering Committee, entrust 
the data from the Registry to a non-profit organization (such as the National Urea Cycle 

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Foundation). Registry data will be maintained over the lifetime of the Registry, but not greater 
than ten years. At the end of the Study, a de-identified dataset will be transferred to the Sponsor.  

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12. 
REFERENCES 
1. Seminara J, Tuchman M, Krivitzky L, Krischer J, Lee HS, Lemons C, et al. Establishing 
a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Mol 
Genet Metab. 2010;100 Suppl 1:S97-105. Epub 2010 Feb 10. 
2. Summar ML. Urea Cycle Disorders Overview. In: Pagon RA, Bird TD, Dolan CR, 
Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, 
Seattle; 1993-. 2003 Apr 29. 
3. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle 
disorders. J Inherit Metab Dis. 2007 Nov;30(6):865-79. 
4. Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, et al., 
Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. 
Cross-sectional multicenter study of patients with urea cycle disorders in the United 
States. Mol Genet Metab. 2008 Aug;94(4):397-402. 
5. Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML. 
Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. 
Pediatr Res. 2009 Jul;66(1):96-101. 
6. Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and 
mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of 
acute hyperammonaemic episodes. Acta Paediatr. 2008 Oct;97(10):1420-5. 
7. AMMONUL® (sodium phenylacetate and sodium benzoate) injection, for intravenous 
use. Label approved 30-Jun-2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020645s008lbl.pdf 
8. BUPHENYL® (sodium phenylbutyrate) Tablets BUPHENYL® (sodium phenylbutyrate) 
Powder. Label approved 31-Mar-2009. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020572s016,020573s015lbl.p
df 
9. Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase 
deficiency: a retrospective analysis. J Pediatr. 1999;134:268-72. 
10. McBride KL, Miller G, Carter S, Karpen S, Goss J, Lee B. Developmental outcomes with 
early orthotopic liver transplantation for infants with neonatal-onset urea cycle defects 
and a female patient with late-onset ornithine transcarbamylase deficiency. Pediatrics 
2004;114;e523-6. 
11. Singh RH. Nutritional management of patients with urea cycle disorders. J Inherit Metab 
Dis. 2007;30:880-7. 
12. RAVICTI™ (glycerol phenylbutyrate) Liquid Full Prescribing Information and 
Medication Guide. South San Francisco, CA: Hyperion Therapeutics Inc.; February 2013 
13. McGuire BM, Zupanets I, Lowe ME, Syplyviy V, Monteleone J, Gargosky S, Nash C, 
Dickenson K, Martinez A, Mokhtarani M, Scharschmidt BF. Pharmacology and safety of 

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a novel ammonia lowering agent in healthy adults and adults with cirrhosis. Hepatology 
2010; 51:2077-85. 
14. Lee B, Rhead W, Diaz GA, Scharschmidt BF, Mian A, Shchelochkov O, Marier JF, 
Beliveau M, Mauney J, Dickinson K, Martinez A, Gargosky S, Mokhtarani M, Berry SA. 
Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in 
patients with urea cycle disorders: Safety, pharmacokinetics and ammonia control. Mol 
Genet Metab. 2010; 100:221–8. 
15. Lichter-Konecki U, Diaz GA, Merritt II JL, Feigenbaum A, Jomphe C, Marier JF, 
Beliveau M, Mauney J, Dickinson K, Martinez A, Mokhtarani M, Scharschmidt B, 
Rhead W. Ammonia (NH3) control in children with urea cycle disorders (UCDs): 
Comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Mol Genet Metab 
2011; Online publication date: 25-MAY-2011; DOI information: 
10.1016/j.ymgme.2011.04.013. 
16. Protocol HPN-100-012. Study of the safety, pharmacokinetics and efficacy of HPN-100, 
in pediatric subjects with urea cycle disorders (UCDs). 
http://clinicaltrials.gov/ct2/show/NCT01347073?term=hpn-100&rank=4 
17. Protocol HPN-100-011.To Evaluate the Safety of Long-term Use of HPN-100 in the 
Management of Urea Cycle Disorders (UCDs). 
http://clinicaltrials.gov/ct2/show/NCT01257737?term=hpn-100&rank=5 
18. Harrison PL, Oakland T. Adaptive behavior assessment system (2nd ed.).San Antonio: 
Harcourt Assessment; 2003. 
19. Gioia GA, Isquith PK, Guy SC, Kenworthy L. Behavior rating inventory of executive 
function. Lutz, FL: Psychological Assessment; 2000 (original version), 2003 (preschool 
version), 2005 (adult version). 
 

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13. 
APPENDIXES 

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APPENDIX A. SCHEDULE OF ASSESSMENTS 
Schedule for the UCD Registry: 
 
Baseline/ 
Enrollment 
Day 7 to 30 
Annual Visits 
Years 1 to 10) 
Standard 
Visits 
Informed consent 
X 
 
 
 
Demography 
X 
 
 
 
UCD medical history 
X 
 
 
 
UCD status and treatment: 
 
 
 
 
Ammonia-scavenging medications 
X 
X 
X 
X 
Prescribed protein and caloriesa 
X 
 
X 
X 
Ammonia levelsb 
X 
X 
X 
X 
Amino acid panel 
X 
X 
X 
X 
Hyperammonemic crises 
X 
X 
X 
X 
Reasons for change in, or 
discontinuation of, ammonia-
scavenging medications 
 
X 
X 
X 
Data points of interestc 
X 
 
X 
X 
Concomitant medications of interestd 
X 
 
X 
X 
Height  
X 
 
X 
X 
Weight 
X 
 
X 
X 
Development assessmente 
X 
 
X 
 
Neuropsychological tests:f 
 
 
 
 
ABAS-II: All ages 
X 
 
X 
 
BRIEF: Age 4 and older 
X 
 
X 
 
Serious adverse events (SAEs) 
 
Xg 
Xg 
X 
Additional data points when available 
 
 
 
 
Plasma and urine PK  
X 
X 
X 
X 
Actual dietary protein intake at 
predefined intervals 
X 
X 
X 
X 
Note: Standard visits are visits that occur between annual visits as part of standard care of the patients. These visits 
will be recorded as unscheduled visits, and indicated data will be collected, if available. 
a: 
Prescribed dietary protein and calorie intake will be recorded at the Baseline visit and thereafter, if there is a 
change in prescribed diet. 
b: The time of the last dose and meal must be recorded whenever single blood samples for ammonia are drawn. 
c: 
Data points of interest are defined in Appendix B and refer to select data points collected for the 12 months 
preceding enrollment and during the study. 
d: Concomitant medications of interest include arginine, citrulline, and amino acid supplements. 
e: 
Please see Appendix D. For pediatric patients only; may be performed ≤1 month before or after enrollment  
f: Please see Appendix C. May be performed ≤6 months before, or ≤2 months after enrollment. 
g: SAEs are to be reported as described in Section 6.2.2.3 and the Registry Reference Manual. 
 
 

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APPENDIX B. DATA POINTS OF INTEREST 
The data points of interest attempt to capture signs and symptoms that are commonly associated 
with uncontrolled UCD or have been reported as common side effects of UCD medication.  
Assessed by Investigator 
 
Yes 
No 
NA 
Attention-deficit / hyperactivity disorder (ADHD) 
 
 
 
Learning disability 
 
 
 
Cerebral palsy 
 
 
 
Mental retardation  
 
 
 
Hypertension 
 
 
 
G-tube or nasogastric tube 
 
 
 
Menstrual cycle disorder (specify below) 
 
 
 
Other developmental disabilities (specify below) 
 
 
 
 
Cancer diagnosis  (specify below) 
 
 
 
Type of cancer:______________                                                     Date of diagnosis: ____________ 
Is there a family history of similar cancer? If yes, please specify.  
_____________________________________________________________________________________________ 
 
Nitrogen scavenging agents patient is receiving at the time of assessment (please check): 
□ None □  BUPHENYL □  RAVICTI   □  AMMUNOL   □  Carbaglu  □  Other (specify): __________ 
Assessed by Investigator and/or 
Reported by Caregiver/Parents 
No 
Rarely 
Once a month 
Sometimes 
Almost Once 
a week 
Frequently 
2-3 times a 
week 
Always 
Almost daily 
NA 
Body odor 
 
 
 
 
 
 
GASTROINTESTINAL 
 
 
 
 
 
 
Nausea upon or after taking 
nitrogen scavenging agent  
 
 
 
 
 
 
Vomiting upon or after taking 
nitrogen scavenging agent 
 
 
 
 
 
 
Refusal to eat due to taste or smell 
of nitrogen scavenging agent 
 
 
 
 
 
 
Decreased appetite  
 
 
 
 
 
 
Recurrent abdominal pain 
 
 
 
 
 
 
Burning sensation in mouth or 
throat 
 
 
 
 
 
 
Irritability/agitation/excessive 
crying 
 
 
 
 
 
 
Heartburn 
 
 
 
 
 
 

 
 
 
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NEUROLOGICAL 
 
 
 
 
 
 
Lethargy or sleepiness   
 
 
 
 
 
 
Chronic or recurrent headache  
 
 
 
 
 
 
For Patients with Gastrostomy or Nasogastric Tubes 
Does the patient use his/her 
gastrostomy or nasogastric tube 
for nitrogen scavenging agent 
administration? 
 
 
 
 
 
 
Does the patient use his/her 
gastrostomy or nasogastric tube 
for food administration? 
 
 
 
 
 
 
Does the patient use his/her 
gastrostomy or nasogastric tube 
for administration of dietary 
supplements (e.g. arginine, 
citrulline, amino acids)? 
 
 
 
 
 
 
NA: Unable to assess 

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APPENDIX C. NEUROPSYCHOLOGICAL TESTS 
Adaptive Behavior Assessment System-Second Edition (ABAS-II)18  
The ABAS-II will be completed annually for all ages, using the appropriate form for each age 
category. No teacher forms will be used. The forms may be completed during office visits or at 
home. See the Registry Reference Manual for complete instructions. 
The ABAS-II measures adaptive skills for individuals ages birth to 89 years. There are 5 rating 
forms, for evaluation of various age ranges by parents, teachers, informants and the individual 
himself or herself. The forms include the Parent/Primary Caregiver Form (ages 0-5 years); Parent 
Form (ages 5-21 years); Teacher/Daycare Provider Form (Ages 2-5 years); Teacher Form (ages 
5-21 years) and the Adult Form (ages16-89, which can be completed by the adult or an 
informant). The number of items ranges from 193 to 241 items, and the form can be completed 
in approximately 20 minutes. 
The following Skill Areas are assessed in the Parent Form: Communication, Community Use, 
Functional Academics, Home Living, Health and Safety, Leisure, Self-Care, Self-Direction, 
Social and Work. A scaled score of 10 + 3 represents the mean. The following four Composite 
Scores are derived from the sum of the scaled scores: General Adaptive Composite (GAC), 
Conceptual, Social and Practical. These Composite Scores have a mean of 100 and a standard 
deviation of 15. 
The ABAS-II standardization samples included 1350 respondents for the infant-preschool 
Parent/Primary Caregiver Form, 1670 respondents for the Parent Form, and 900 respondents for 
the Adult Self-Report Form. Reliability coefficients were generally .90 for all scales and all 
forms. Test-retest reliability coefficients were also about .90. Inter-rater correlations were 
extremely high (generally above .80 for each scale on each form).  In terms of validity, 
correlations between the ABAS-II and the Vineland Adaptive Behavior Scales (VABS) were 
moderate to high, with a correlation of .70 between the ABAS-II GAC and the Vineland 
Adaptive Behavior Composite. The correlation between the ABAS-II GAC and the BASC 
Adaptive Skills Composite is .80.   
The ABAS also provides an estimate of IQ. The correlation is .61 between the ABAS-II (Parent 
Form) GAC and the Wechsler Preschool and Primary Scale of Intelligence-Third Edition 
(WPPSI-III), and .41 between the ABAS-II (Parent Form) GAC and the Wechsler Intelligence 
Scale for Children-Fourth Edition (WISC-IV). For individuals aged 7-21 years, the correlation 
between the ABAS (Parent Form) GAC and IQ on the Wechsler Abbreviated Scale of 
Intelligence (WASI) is .42. 
The Behavior Rating Inventory of Executive Function (BRIEF)19 
The BRIEF will be completed annually for ages 4 and above, using the appropriate form for each 
age category.  
The BRIEF provides theoretically and empirically derived clinical scales that measure aspects of 
executive function. The clinical scales form broader indices of behavior and cognition and an 
overall score, the Global Executive Composite. Two additional scales (Inconsistency and 
Negativity) provide a measure of validity of responses. Parent response forms are available for 

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Preschool and School-Aged Children. A self-report form and an informant response form are 
available for adults, permitting a uniform measure across all ages. All forms were standardized 
on normative samples representing a broad variety of race/ethnicity, age and geographical 
population density. 
Rater responses are scored on a 1-3 scale, with 1 corresponding to Never (N), 2 corresponding to 
Sometimes (S) and 3 corresponding to Often (O). The sum of the raw score for each scale is 
converted to a T score.  Percentile scores and Confidence Intervals are provided in age specific 
tables. A T score of 50 +/- 10 represents the mean of the T-score distribution, and a score of 65 
represents 1.5 standard deviations above the mean, which is the recommended threshold for an 
“abnormally elevated” score and is considered “clinically significant”. The questionnaire is 
completed within 10-15 minutes. 
The Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) is designed 
for children aged 2 years, 0 months through 5 years 11 months. To be completed by parents 
(guardians) or teachers, this questionnaire contains 63 items within five scales: Inhibit, Shift, 
Emotional Control, Working Memory and Plan/Organization. The clinical scales form broad 
indexes of Inhibitory Self-Control (ISCI), Flexibility (FI) and Emergent Metacognition (EMI) 
and an overall composite score, the Global Executive Composite (GEC).  
The BRIEF-P was standardized on a normative sample of 460 children. The test was determined 
to have adequate internal consistency, with alpha =.95 for the Global Executive Composite score 
and > 90 for each of the clinical scales and indexes. Test-retest stability was .90 for the GEC 
over an average interval of 4.5 weeks. In terms of validity, the BRIEF-P Working Memory scale 
and the Plan/Organize scale were highly correlated with an ADHD questionnaire  (r = .88, .86, 
p<.001). Greater than 70% of children with diagnoses of ADHD and autism spectrum disorder 
received “clinically significant” T Scores (>65), while less than 7% of children in the control 
group received scores in this range. A score of <8 on the Inconsistency Scale and a score of <4 
on the Negativity Scale indicate validity of responses. 
The Behavior Rating Inventory of Executive Function (BRIEF) for school-age children (ages 5- 
18 years) contains 86 items within 8 scales: Inhibit, Shift, Emotional Control, Initiate, Working 
Memory, Plan/Organize, Organization of Materials and Monitor. These scales form two indexes, 
Behavioral Regulation and Metacognition and the overall General Executive Composite. The 
BRIEF was standardized on a normative sample of 1,419 children.   
A score of  >6  on the Inconsistency Scale and a score of >5 on the Negativity Scale possibly 
invalidate the responses (or indicate severe executive function deficits, as might occur in severe 
traumatic brain injury or autism).  
Internal consistency was between .80 and .98 on all scales and indexes. Test-retest reliability was 
above .80 over a two-week period for the Behavioral Regulation Index, the Metacognition Index, 
and the overall General Executive Composite. In terms of validity, the Behavioral Regulation 
index correlated .70 with the ADHD Rating Scale (Hyperactivity/Impulsivity).  Scale scores on 
the BRIEF correlated significantly with other measures of general behavioral functioning but 
were generally unrelated to scores on tests of emotional functioning.     
The Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Self-Report 
and Informant Report are designed for adults, ages 18 to 90 years, with a minimum fifth-grade 
reading level. The BRIEF-A has 75 items comprising 9 clinical scales: Inhibit, Shift, Emotional 

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Control, Self-Monitor, Initiate, Working Memory, Plan/Organize, Task Monitor, Organization of 
Materials. Three validity scales are used: Negativity, Infrequency and Inconsistency. The clinical 
scales form two indexes: Behavioral Regulation and Metacognition. In addition, an overall 
summary score, the Global Executive Composite (GEC) is calculated. 
Scores > 6 on the Negativity Scale, >3 on the Infrequency Scale and >8 on the Inconsistency 
Scale are considered elevated and indicate a need to determine if the responses are valid. 
The BRIEF-A was standardized on a normative sample obtained throughout the US via Internet 
sampling methodology. A total of 1196 adults completed the self-report form, and 1215 adults 
completed the informant form. Gender accounted for less than 2% of the variance in any scale.  
Age-related differences were found on all self-report form scales except for the Self-Monitor 
Scale, with younger adults reporting greater difficulties. Therefore, separate norms are provided 
for 8 age categories. 
Alpha coefficients for internal consistency were above .80 on all scales, with somewhat higher 
scores of the Informant Report than for the Self-Report forms. Test-retest stability over an 
average of 4 weeks was adequate for all scales, and correlations with neuropsychological tests of 
executive functioning were as high as .87 for the Informant Form; all were above .50 for the 
General Executive Composite. 

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APPENDIX D. DEVELOPMENTAL MILESTONES  
Age 
Developmentally Delayed? 
2 Months 
□ Yes                           □ No  
3 Months 
□ Yes                           □ No  
4 Months 
□ Yes                           □ No  
6 Months 
□ Yes                           □ No  
7 Months 
□ Yes                           □ No  
9 Months 
□ Yes                           □ No  
12 Months 
□ Yes                           □ No  
18 Months 
□ Yes                           □ No  
2 Years 
□ Yes                           □ No  
3 Years 
□ Yes                           □ No 
4 Years 
□ Yes                           □ No 
5 Years 
□ Yes                           □ No 
The following list is proposed as general guidelines for assessment of developmental milestones. 
The data will be captured if available. Generally age-appropriate milestones for reference 
only 
Age 
Normal Developmental Behavior  
2 Months 
Smiles at the sound of your voice and follows you with their eyes as you move around a 
room 
3 Months 
Raises head and chest when lying on stomach 
Grasps objects  
Smiles at other people 
4 Months 
Babbles, laughs, and tries to imitate sounds; holds head steady 
6 Months 
Rolls from back to stomach and stomach to back  
Moves objects from hand to hand 
7 Months 
Responds to own name  
Finds partially hidden objects 
9 Months 
Sits without support, crawls, babbles "mama" and "dada" 
12 Months 
Walks with or without support 
Says at least one word 
Enjoys imitating people 
18 Months 
Walks independently, drinks from a cup, says at least 15 words, points to body parts 
2 Years 
Runs and jumps 
Speaks in two-word sentences 
Follows simple instructions 
Begins make-believe play 
3 Years 
Climbs well 
Speaks in multiword sentences 
Sorts objects by shape and color 

 
 
 
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4 Years 
Gets along with people outside the family 
Draws circles and squares 
Rides a tricycle 
5 Years 
Tells name and address 
Jumps, hops, and skips 
Gets dressed 
Counts 10 or more objects 
Source : http://children.webmd.com/features/is-your-baby-on-track