Conditions: Urea Cycle Disorders
Keywords: Urea Cycle Disorders GT4P HPN-100 Sodium Phenylbutyrate (NaPBA) Glyceryl tri-(4-phenylbutyrate) Phenylbutyrate Hyperion BUPHENYL hyperammonemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 88
Healthy volunteers: no

Brief summary:
This was an open-label, long-term safety study of HPN-100 (RAVICTI; glycerol phenylbutyrate) in participants with a urea cycle disorder (UCD) who completed the safety extensions of HPN-100-005 (NCT00947544; HPN-100-005SE), HPN-100-006 (NCT00947297; HPN-100-007), or HPN-100-012 (NCT01347073; HPN-100-012SE). The initial studies were 1- to 2-week crossover studies, and their associated safety extensions were 12-month, open-label studies. All participants who completed the initial studies were eligible to enroll in the associated safety extension studies, and new participants were also permitted to enroll directly into the safety extension studies.

Detailed description:
The duration of treatment in this study was open-ended. Participants were to return for clinic visits as prescribed by the investigator, and were to be seen at a minimum of every 6 months. At each clinic visit, participants were queried about any adverse events (AEs) or hyperammonemic crises (HACs) that occurred since the last visit. Physical and neurological examinations were performed, and blood samples were collected for the analysis of ammonia, amino acid panels, and routine clinical laboratory safety tests. Participants underwent neuropsychological testing at baseline, every 12 months thereafter, and at the final study visit.

Study acquired from Horizon in 2024.

Arms:
arm 1: Participants continued HPN-100 treatment after completion of HPN-100-005SE, HPN-100-007, or HPN-100-012SE.

Interventions: intervention 1: HPN-100
Intervention descriptions: intervention 1: Participants received individualized doses of HPN-100 orally, three times daily (TID) with meals. The initial dose was the same dose administered at the end of the HPN-100-005SE, HPN-100-007, or HPN-100-012SE studies. Dose adjustments (including frequency adjustments) were permitted as judged clinically appropriate by the investigator based on assessment of ammonia-scavenging needs (e.g., severity of the UCD defect, dietary protein intake, and urinary phenylacetylglutamine \[PAGN\] excretion). The maximum recommended dose of HPN-100 in participants weighing less than 20 kg was 0.53 mL/kg/day (equivalent to 600 mg/kg/day of NaPBA), and was 11.48 mL/m²/day in heavier subjects (equivalent to 13g/m²/day of NaPBA). The maximum HPN-100 dose recommended per protocol was 17.4 mL/day, which is equivalent to 20 g/day of NaPBA.

Protocol document:
Prot_000.pdf: 
Horizon Therapeutics, Inc. 
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Protocol HPN-100-011 
Clinical Study Protocol 
 
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Page 1 of 49 
  
 
 
 
 
 
 
IND NUMBER: 
73,480 
STUDY NUMBER: 
HPN-100-011 
INVESTIGATIONAL 
DRUG: 
HPN-100 
STUDY TITLE: 
Long Term Use of HPN-100 in Urea Cycle Disorders  
 
 
SPONSOR: 
Horizon Therapeutics, Inc. 
520 Lake Cook Road, Suite 520 
Deerfield, IL 60015 
 
 
Version: 
4.0 (Canada), Amendment 03, Administrative Change 1 
Date: 
October 21, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
THIS CONFIDENTIAL INFORMATION IS ABOUT AN INVESTIGATIONAL DRUG PROVIDED FOR THE EXCLUSIVE USE OF 
INVESTIGATORS OF THIS DRUG AND IS SUBJECT TO RECALL AT ANY TIME. THE INFORMATION IN THIS DOCUMENT MAY 
NOT BE DISCLOSED UNLESS SUCH DISCLOSURE IS LEGALLY REQUIRED. SUBJECT TO THE FOREGOING, THIS 
INFORMATION MAY BE DISCLOSED ONLY TO THOSE PERSONS INVOLVED IN THE STUDY WHO HAVE NEED TO KNOW, 
WITH THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS INFORMATION. THESE RESTRICTIONS ON DISCLOSURE WILL 
APPLY EQUALLY TO ALL FUTURE ORAL OR WRITTEN INFORMATION SUPPLIED TO YOU BY HORIZON THERAPEUTICS, INC. 
WHICH IS DESIGNATED AS “PRIVILEGED” OR “CONFIDENTIAL.” 
 






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INVESTIGATOR SIGNATURE PAGE 
Protocol Number: 
HPN-100-011 
Version 4, Amendment 03, Administrative Change 1 
Protocol Title: 
Long-Term Use of HPN-100 in Urea Cycle Disorders 
 
Horizon 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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STUDY PERSONNEL CONTACT INFORMATION 
Name  
 
Title Senior Medical Director, Clinical Development 
Organization Address Horizon Pharma 
Telephone 
 
Fax 
 
E-mail 
 
 
Name  
 
Title Executive Director, Clinical Compliance and Operations 
Organization Address Horizon Pharma 
Telephone 
 
Fax 
 
E-mail 
 
 
Name  Sponsor Contact for Serious Adverse Event Reporting 
Organization Address 
 
Telephone 
 
Fax 
 
E-mail 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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SYNOPSIS 
Title of Study  
Long-Term Use of HPN-100 in Urea Cycle Disorders 
Protocol No. 
HPN-100-011 
Objective 
To evaluate the safety of long-term use of HPN-100 in the management of 
urea cycle disorders (UCDs) 
Study Drug 
HPN-100 [(glyceryl tri-(4-phenylbutyrate)] (investigational product) 
Treatment Arms 
All subjects will receive open-label HPN-100. 
Study Population 
Subjects with a diagnosis of UCD who completed Study HPN-100-005, 
HPN-100-007, or HPN-100-012 may be eligible to enroll. 
Study Design 
This is a long-term safety study of HPN-100 in UCD subjects.  
Subjects will be assessed regularly for safety and control of their venous 
ammonia. Hyperammonemic crisis events will be characterized with respect 
to contributing factors such as intercurrent illness, diet, and noncompliance 
with medication. 
Safety Assessments 
Assessments will include safety laboratory tests, amino acid panel, and 
venous ammonia. Adverse events (AEs) will be recorded on an ongoing 
basis.  
Primary Endpoint 
Rate of adverse events 
Secondary Endpoints 
• 
Venous ammonia levels 
• 
Number and causes of hyperammonemic crises 
• 
Neuropsychological testing 
Sample Size and 
Statistical 
Considerations 
No formal statistical hypothesis testing will be performed. 
Inclusion Criteria 
• 
Male or female subjects who completed protocol HPN-100-005, HPN-
100-007, or HPN-100-012 
• 
Signed informed consent by subject and/or subject’s legally authorized 
representative  
• 
Negative pregnancy test for all females of childbearing potential 
Exclusion Criteria 
• 
Any clinical or laboratory abnormality or medical condition that, at the 
discretion of the investigator, may put the subject at increased risk by 
participating in this study 
• 
Known hypersensitivity to phenylacetate (PAA) or phenylbutyrate (PBA) 
• 
Liver transplant, including hepatocellular transplant  
• 
Pregnant, breastfeeding or lactating females  


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Investigational 
Product, Dosage and 
Mode of 
Administration 
HPN-100 [glyceryl tri-(4-phenylbutyrate)] will be administered orally three 
times daily (TID) with meals.  
Subjects who have completed Study HPN-100-005, HPN-100-007, or HPN-
100-012 will continue to receive open-label HPN-100, initially at the same 
dose which they were receiving at the time they completed study HPN-100-
005, HPN-100-007, or HPN-100-012. 
 
The investigator may subsequently adjust the dose for any subject if judged 
clinically appropriate [the dose should not exceed the equivalent of 20 grams 
(g) of NaPBA (~17.4 milliliters (mL) total daily dose of HPN-100)]. 
Duration of Study 
Until HPN-100 is available through the Health Canada Special Access 
Program 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
STUDY PERSONNEL CONTACT INFORMATION ...................................................................4 
SYNOPSIS ......................................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................11 
1. 
BACKGROUND INFORMATION ...........................................................................13 
1.1. 
Medical Introduction and Background .......................................................................13 
1.2. 
Summary of Potential Risks and Benefits ..................................................................14 
1.3. 
Study Rationale ...........................................................................................................18 
1.4. 
Conduct of Trial and Compliance with GCP ..............................................................18 
1.5. 
Study Population .........................................................................................................19 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................20 
2.1. 
Primary Endpoint ........................................................................................................20 
2.2. 
Secondary Endpoints ..................................................................................................20 
3. 
OVERALL STUDY DESIGN AND PLAN ...............................................................21 
3.1. 
Description ..................................................................................................................21 
3.2. 
Dose Selection ............................................................................................................21 
3.3. 
Duration of the Study ..................................................................................................21 
3.4. 
Management of Episodes of Hyperammonemia .........................................................21 
3.4.1. 
Hyperammonemic Crisis ............................................................................................22 
3.4.1.1. 
Management of Hyperammonemic Crisis and Withdrawal of Subjects ....................22 
3.4.2. 
Symptoms Suggestive of Chronic Hyperammonemia ................................................22 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................23 
4.1. 
Subject Inclusion Criteria ...........................................................................................23 
4.2. 
Subject Exclusion Criteria ..........................................................................................23 
4.3. 
Subject Withdrawal Criteria .......................................................................................23 
5. 
TREATMENT OF SUBJECTS ..................................................................................24 
5.1. 
Description of Study Drug ..........................................................................................24 
5.2. 
Study Drug Dosage and Administration .....................................................................24 
5.2.1. 
Preparation ..................................................................................................................24 


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5.2.2. 
Dose and Administration ............................................................................................24 
5.3. 
Study Drug Materials and Management .....................................................................24 
5.3.1. 
Study Drug Packaging and Labeling ..........................................................................24 
5.3.2. 
Study Drug Storage .....................................................................................................25 
5.3.3. 
Study Drug Dispensing and Disposal .........................................................................25 
5.4. 
Concomitant Medications ...........................................................................................25 
5.4.1. 
Prohibited Medications ...............................................................................................25 
5.4.2. 
Nutrition ......................................................................................................................25 
5.5. 
Randomization and Blinding ......................................................................................25 
6. 
STUDY PROCEDURES ............................................................................................26 
6.1. 
Study Visits .................................................................................................................26 
6.1.1. 
Baseline Visit (Month 0) ............................................................................................26 
6.1.2. 
Routine Clinic Visits (Every 6 Months) .....................................................................27 
6.1.3. 
Unscheduled Visits .....................................................................................................27 
6.1.4. 
Annual (12 Month) / End of Study Visit ....................................................................28 
6.2. 
Early Termination Procedures ....................................................................................29 
7. 
ASSESSMENT OF EFFICACY ................................................................................30 
8. 
ASSESSMENT OF SAFETY .....................................................................................31 
8.1. 
Adverse Events ...........................................................................................................31 
8.1.1. 
Definition of Adverse Event .......................................................................................31 
8.1.2. 
Definition of Serious Adverse Event ..........................................................................32 
8.1.3. 
Assessment of Severity ...............................................................................................32 
8.1.4. 
Assessment of Relationship to Study Drug ................................................................33 
8.1.5. 
Recording Adverse Events .........................................................................................34 
8.1.6. 
Procedures for Reporting Adverse Events ..................................................................34 
8.1.7. 
Post-Study Reporting for Subjects with Adverse Events ...........................................34 
8.2. 
Laboratory Assessments .............................................................................................34 
8.3. 
Vital Signs ..................................................................................................................35 
8.4. 
Unblinding of Treatment Assignment ........................................................................35 
9. 
OTHER ASSESSMENTS ..........................................................................................36 
9.1. 
Neuropsychological Battery .......................................................................................36 
10. 
STATISTICS ..............................................................................................................37 


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10.1. 
Sample Size and Power ..............................................................................................37 
10.2. 
Endpoints ....................................................................................................................37 
10.3. 
Methods of Analysis ...................................................................................................37 
10.3.1. 
Analysis Populations ..................................................................................................37 
10.3.2. 
Baseline and Demographic Variables .........................................................................37 
10.3.3. 
Safety Variables ..........................................................................................................37 
10.3.4. 
Efficacy Variables ......................................................................................................38 
10.3.5. 
Other Variables ...........................................................................................................38 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................39 
11.1. 
Study Monitoring ........................................................................................................39 
11.2. 
Audits and Inspections ................................................................................................39 
11.3. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................39 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................40 
13. 
ETHICS ......................................................................................................................41 
13.1. 
Ethics Review .............................................................................................................41 
13.2. 
Ethical Conduct of the Study ......................................................................................41 
13.3. 
Written Informed Consent ..........................................................................................41 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................42 
14.1. 
Inspection of Records .................................................................................................42 
14.2. 
Retention of Records ..................................................................................................42 
15. 
REFERENCES ...........................................................................................................43 
16. 
APPENDICES ............................................................................................................44 
APPENDIX A. SCHEDULE OF STUDY ASSESSMENTS .....................................................45 
APPENDIX B. NEUROPSYCHOLOGICAL BATTERY.........................................................46 
APPENDIX C. PROTOCOL REVISION HISTORY ..............................................................467 
  
LIST OF TABLES AND FIGURES 
Table 1: 
Comparison of Pharmacokinetic Parameters at Steady State – NaPBA vs. 
HPN-100 in UCD Subjects .........................................................................................17 
Figure 1: 
Alternative-Pathway Therapy for Nitrogen Disposal .................................................14 
Figure 2: 
Comparison of Adult and Pediatric Ammonia Values (TNAUC) For 
Individual Subjects Following Seven Days of Dosing with Either NaPBA or 
HPN-100 .....................................................................................................................16 


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List of Abbreviations and Definitions of Terms 
Abbreviation or specialist term 
Explanation 
Ae 
Amount excreted over 24 hours 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARG 
Arginase 
ASL 
Argininosuccinate lyase 
ASS 
Argininosuccinate synthetase 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the concentration from time 0 (pre-dose) to 24 hours 
BRIEF 
Behavior rating inventory of executive function 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CBCL 
Child behavior checklist 
Cmaxss 
Maximum plasma concentration at steady state 
Cminss 
Minimum plasma concentration at steady state 
CPS 
Carbamyl phosphate synthetase 1 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
CVLT 
California verbal learning test 
ECG 
Electrocardiogram 
CRF 
Case report form 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HPN-100 
Glyceryl tri-(4-phenylbutyrate), GT4P 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
MRI 
Magnetic resonance imaging 
NAGS 
N-acetylglutamate synthetase 
NaPBA 
Sodium phenylbutyrate 


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Abbreviation or specialist term 
Explanation 
OTC 
Ornithine transcarbamylase 
PAA 
Phenylacetate 
PAGN 
Phenylacetylglutamine 
PBA 
Phenylbutyrate 
PK 
Pharmacokinetic 
PP 
Per protocol 
SAE 
Serious adverse event 
SD 
Standard deviation 
SOP 
Standard operating procedure 
TID 
Three times daily 
TNAUC 
Time-normalized area under the curve 
UCD 
Urea cycle disorder 
ULN 
Upper limit of normal 
US 
United States 
WASI 
Wechsler abbreviated scale of intelligence 


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1. 
BACKGROUND INFORMATION 
1.1. 
Medical Introduction and Background 
Urea cycle disorders (UCDs) are inborn errors of metabolism that can result from decreased or 
absent activity of any of the following enzymes: carbamyl phosphate synthetase (CPS), 
N-acetylglutamate synthetase (NAGS), ornithine transcarbamylase (OTC), argininosuccinate 
synthetase (ASS), argininosuccinate lyase (ASL), or arginase (ARG). These disorders prevent 
the conversion of waste nitrogen into urea and result in the accumulation of toxic levels of 
ammonia in the blood and brain of affected patients (Brusilow 1996).  
The age of onset of UCDs is typically in the neonatal period, but onset can occur at any age, 
depending on the severity of the disorder. Patients with severe enzyme deficiencies, resulting in 
complete inactivity of one of the urea cycle enzymes, typically develop symptoms within the 
first week of life, while patients with mild to moderate enzyme deficiencies may become 
symptomatic as children, and those with mild deficiencies may become symptomatic as adults. 
The urea cycle is the major route for metabolism of waste nitrogen in the body. The urea cycle is 
normally very efficient, and waste nitrogen, in the form of ammonia and other metabolites, does 
not accumulate in the absence of urea cycle dysfunction or general hepatic dysfunction. 
Ammonia is a normal metabolic product of amino acid catabolism, which occurs in both the liver 
and the brain. In the urea cycle, which is completed in the liver, ammonia is converted to urea, 
eliminating 2 moles of waste nitrogen from ammonia per mole of urea generated. 
Therapeutic strategies for patients with UCDs are aimed at both reducing the requirement for 
ureagenesis and exploiting pathways for the synthesis and excretion of other waste nitrogen 
products that may serve as substitutes for urea. Approaches include dietary protein restriction, 
arginine or citrulline supplementation, which can enhance waste nitrogen excretion for certain 
UCDs, and administration of nitrogen-scavenging drugs. Nitrogen-scavenging drugs for UCDs 
include sodium phenylbutyrate (NaPBA) tablets or powder for the chronic management of 
UCDs, and intravenous sodium phenylacetate together with sodium benzoate (10%/10%) 
(marketed in the United States [US] as AMMONUL®), which is an acute parenterally 
administered treatment for hyperammonemia in patients with UCDs. 
Patients with UCDs who experience hyperammonemia despite dietary nitrogen restriction plus 
dietary supplementation with arginine or citrulline typically require administration of the 
ammonia-scavenging agent NaPBA. Patients with UCDs who are treated with NaPBA may still 
experience episodes of hyperammonemic encephalopathy requiring hospitalization and 
immediate aggressive medical intervention. Orthotopic liver transplantation may also be 
considered for patients with severe disease that manifests itself in the neonatal period. 
NaPBA tablets and powder have been approved for marketing in the US since 1996 (Trade 
name: BUPHENYL®) and in the European Union (EU) since 1999 (Trade name: 
AMMONAPS®) as adjunctive therapy in the long-term management of patients with UCDs 
involving deficiencies of CPS, OTC, or ASS. Some patients with UCDs are still treated with oral 
sodium benzoate (Gorker 2005); however, sodium benzoate is not approved by the US Food and 


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Drug Administration (FDA), nor the European Medicines Agency (EMA), and is thought to be 
less effective than NaPBA, because each mole of the active metabolite of NaPBA, phenylacetate 
(PAA), scavenges 2 moles of ammonia (same nitrogen-scavenging capacity as urea), while one 
mole of benzoate scavenges only one mole of ammonia. This reflects the fact that glutamine, 
which conjugates with PAA to form PAGN, contains two nitrogens, whereas glycine, which 
conjugates with benzoate to form hippuric acid, contains only one nitrogen. 
Figure 1 illustrates how phenylbutyrate (PBA) (via PAA) and benzoate provide an alternative 
pathway for nitrogen disposal in patients without a fully functioning urea cycle. Following oral 
administration, PBA undergoes ß-oxidation to the active metabolite PAA, which is then 
conjugated with glutamine in the liver and kidney and excreted as phenylacetylglutamine 
(PAGN) (in higher primates and humans) (James 1972). Two moles of nitrogen are removed per 
mole of PAA when it combines with glutamine to form PAGN, which is then excreted by both 
renal glomerular filtration and tubular secretion. The nitrogen content of PAGN per mole is 
identical to that of urea (both contain 2 moles of nitrogen). 
Figure 1: 
Alternative-Pathway Therapy for Nitrogen Disposal 
 
Source:    Modified from Summar 2001. 
1.2. 
Summary of Potential Risks and Benefits 
HPN-100, a prodrug of PBA and a pre-prodrug of the active compound PAA, is under 
development as an alternative therapy to NaPBA in patients with UCDs. HPN-100 is expected to 
provide similar or superior nitrogen-scavenging ability, while eliminating the current issues of 
bad taste, odor, sodium content, and pill burden. 
Three clinical studies have been completed to date: UP 1204-001 in healthy subjects, 
UP 1204-002 in healthy volunteers and in subjects with liver impairment, and UP 1204-003 in 
adult subjects with UCDs. 


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UP 1204-001 was a phase 1, randomized, cross-over, open-label study of HPN-100 in 24 healthy 
male subjects administered oral NaPBA and oral HPN-100 (equivalent to 3 g/m2 of PBA per 
dose for both study drugs). There were no deaths or serious adverse events (SAEs). More 
adverse events (AEs) occurred with NaPBA (21 AEs in 10 subjects) than with HPN-100 (6 AEs 
in 2 subjects). Adverse events reported with NaPBA treatment included gastrointestinal (nausea, 
vomiting, dysgeusia, epigastric discomfort, and flatulence) and neurological AEs (dizziness, 
headache, euphoric mood, and visual acuity reduced). None of the AEs reported after HPN-100 
treatment (upper abdominal pain, nausea, vomiting, increased blood creatinine kinase, and 
contusion) were considered related to HPN-100. There were no clinically significant changes or 
apparent trends with treatment in laboratory values, vital signs, electrocardiogram (ECG) results, 
or physical examination findings. 
UP 1204-002 was a phase 1, open-label study of HPN-100 in subjects with hepatic impairment 
with cirrhosis (n=24) and in age- and gender-matched control subjects with normal hepatic 
function (n=8). Overall, AEs were reported in 26/32 subjects. There were no SAEs, no severe 
AEs, and no AEs leading to withdrawal. The most frequent individual AEs were increased body 
temperature, which was reported in 10 subjects, and decreased platelet count, which was reported 
in 5 subjects. Upper abdominal pain, nausea, and dyspepsia were all reported in 3 or more 
subjects, and headache was reported in 7 subjects. The majority of AEs were mild in severity, 
and there were no severe AEs. Adverse events observed in cirrhotic subjects were generally 
consistent with liver disease. In healthy volunteers (n=8), reported AEs included epigastric 
discomfort and headache in 2 subjects each, and diarrhea, blood glucose increased, alanine 
aminotransferase (ALT) increased, alkaline phosphatase increased, C-reactive protein increased, 
eosinophil count increased, and platelet count decreased in 1 subject each. The principal findings 
of protocols UP 1204-001 and UP 1204-002 have been published (McGuire 2010).  
UP 1204-003 was a phase 2, open-label, fixed sequence, switch-over study of the safety, 
tolerability, and pharmacokinetics (PK) of HPN-100 compared to NaPBA in adult subjects with 
UCDs (Lee 2010). The study was conducted at 4 US centers and enrolled 14 adult UCD patients, 
10 of whom completed the study. All subjects who received at least one dose of HPN-100 
completed the study. Upon enrollment, subjects received NaPBA for 7 days and were then 
admitted to a study unit for overnight observation and 24-hour PK, venous ammonia 
measurements, amino acids, and urine collections. Subjects were then converted to the PBA 
equimolar dose of HPN-100, either in a single step or in multiple steps depending on the total 
dose of NaPBA (9 out of 10 subjects converted in a single step). Subjects stayed on the 100% 
HPN-100 dose for 7 days and were then re-admitted to the study unit for repeated 24-hour PK, 
venous ammonia, amino acids, and urine collections. 
The results of UP 1204-003 demonstrate that, when administered at doses which are the PBA 
molar equivalent of NaPBA, HPN-100 is well tolerated and exhibits a similar safety profile to 
NaPBA. A total of 48 AEs were reported in 9 of the 10 subjects. The overall safety profile was 
similar for the two drugs; 21 AEs were reported in 7 subjects during 100% NaPBA treatment, 
and 15 AEs were reported in 5 subjects during 100% HPN-100 treatment. There were two SAEs 
related to hyperammonemia (Subjects 03-001 and 05-001); both occurred during 100% NaPBA 
treatment (one SAE was prior to 100% HPN-100 treatment, and one was after the subject 
completed 100% HPN-100 treatment and switched back to NaPBA). No SAEs occurred during 




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The mean peak venous ammonia value during HPN-100 treatment was 29% lower than that 
observed with NaPBA (56.3 vs. 79.1 µmol/L in adults and 47.77 vs. 55.66 µmol/L in paediatric 
subjects; not statistically significant). The overall mean TNAUC for venous ammonia was above 
the upper limit of normal during NaPBA treatment (38.4 µmol/L in adults and 33.1 µmol/L in 
pediatrics), but was within the normal range after switching to HPN-100 (26.1 μmol/L in adults 
and 25.0 μmol/L in pediatric subjects). While these differences in venous ammonia between 
HPN-100 and NaPBA did not achieve statistical significance, these results collectively suggest 
that HPN-100 may offer more effective ammonia control than NaPBA. 
Table 1 summarizes the PK parameters obtained from the adult (UP 1204-003) and pediatric 
(HPN-100-005) studies.  The PK results for HPN-100 are reasonably similar for adults and 
children after treatment with HPN-100.  The ‘outlier’ in the pediatric data set is PBA-AUC 
following treatment with NaPBA (739 vs. 236 μg∙h/mL in adults and pediatric patients, 
respectively), which is both more highly variable and lower than PBA following HPN-100 in 
pediatric subjects.  By contrast, PBA levels following treatment with HPN-100 were similar (540 
vs. 631 μg∙h/mL in adults and pediatric patients, respectively), as were blood levels of PAA and 
PAGN. 
Table 1: 
Comparison of Pharmacokinetic Parameters at Steady State – NaPBA vs. 
HPN-100 in UCD Subjects 
 
Arithmetic Mean (CV%) 
PK Parameter 
NaPBA 
HPN-100 
Adults 
UP 1204-003 
(N=10) 
Peds 
HPN-100-005 
(N=11) 
Adults 
UP 1204-003 
(N=10) 
Peds 
HPN-100-005 
(N=11) 
PBA in Plasma 
 
 
 
AUC0-24 (μg∙h/mL) 
739 (49.1) 
236 (105.2) 
540 (60.2) 
631 (44.9) 
Cmaxss (μg/mL) 
141 (44.3) 
37.4 (101.6) 
70.1 (64.7) 
95.6 (42.0) 
Cminss (μg/mL) 
0.588 (255) 
0.366 (171.3) 
2.87 (265) 
1.50 (99.8) 
PAA in Plasma 
 
 
AUC0-24 (μg∙h/mL) 
595.6 (123.9) 
773 (73.3) 
574.6 (168.9) 
964 (63.6) 
Cmaxss (μg/mL) 
53.0 (94.7) 
75.1 (64.4) 
40.5 (147.6) 
90.5 (69.1) 
Cminss (μg/mL) 
3.56 (194.4) 
0.674 (130.5) 
7.06 (310.7) 
2.99 (122.1) 
PAGN in Plasma 
 
 
AUC0-24 (μg∙h/mL) 
1133 (31.1) 
1015 (44.7) 
1098 (44.2) 
1378 (40.2) 
Cmaxss (μg/mL) 
83.3 (25.8) 
74.8 (37.3) 
71.9 (56.0) 
105 (33.5) 
Cminss (μg/mL) 
16.8 (86.1) 
4.63 (66.4) 
12.1 (134.4) 
13.1 (64.9) 
PAGN in Urine 
 
 
 
 
U-PAGN24-hour Excr (μg) 
12 153 473 (48.2) 
12868446 (51.6) 
10 784 747 (25.9) 
13147199 (54.4) 
Fe 0-24(%) 
56.2 (13.5) 
65.9 (31.9) 
57.5 (12.8) 
68.0 (23.4) 


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AUC0-24 = area under the concentration from time 0 (pre-dose) to 24 hours; Cmaxss = maximum plasma 
concentration at steady state; Cminss = minimum plasma concentration at steady state; CV = coefficient of 
variation; Ae = amount excreted over 24 hours 
1.3. 
Study Rationale 
There is extensive clinical experience with NaPBA, which has been shown to be safe and 
effective in improving long-term survival in patients with UCDs (i.e., reducing the incidence of 
deaths due to hyperammonemic encephalopathy) when administered at the recommended dose 
levels.  
Compliance with NaPBA is difficult due to a 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 half life of the active metabolite PAA, the BUPHENYL package insert 
recommends 3–6 times/day dosing. Some pediatric patients with severe deficiency states require 
nasogastric or gastrostomy tubes to ensure adequate compliance with the complex treatment 
regimens (Maestri 1999, McBride 2004, Singh 2007). All of these factors render NaPBA very 
difficult to take, and compliance is suboptimal even for UCD patients with the most severe 
deficiency states, whose alternative is life-threatening hyperammonemia. 
HPN-100 [glyceryl tri-(4-phenylbutyrate)], is a nitrogen-scavenging agent with improved PK 
characteristics and palatability that is expected to improve the ease of administration and provide 
a significant quality-of-life benefit to UCD patients. In contrast to NaPBA which is a salt, HPN-
100 is a triglyceride, which delivers 3 moles of PBA per each mole of HPN-100 and is a nearly 
odorless and tasteless, colorless to pale yellow organic oil. HPN-100 contains no sodium, is 
expected to improve the ease and comfort of administration of medication, and provides a 
substantially reduced pill burden due to the concentrated nature of the drug. These advantages 
would represent a significant advance in the management of UCD patients and may result in 
improved compliance and outcomes. 
The findings from UP 1204-003 were largely corroborated by the findings from Protocol HPN-
100-005 in pediatric subjects. Twenty-four hour ammonia profiles were very similar, including 
the directionally lower values on HPN-100 as compared with NaPBA. HPN-100 safety was 
satisfactory in both adult and pediatrics subjects, and the PK profiles of HPN-100 were similar. 
The present protocol is a treatment protocol to allow continued use of HPN-100 for the treatment 
of UCD subjects who complete 12 months of treatment in Study HPN-100-005, HPN-100-007, 
or HPN-100-012. Under this protocol, long-term safety will continue to be assessed. 
1.4. 
Conduct of Trial and Compliance with GCP 
This study will be conducted in compliance with the protocol, in accordance with the Guidance 
for Good Clinical Practice (GCP) and the International Conference on Harmonisation (ICH) E6, 
and in accordance with applicable regulatory requirements. 


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1.5. 
Study Population 
Subjects with a diagnosis of UCD who completed Study HPN-100-005, HPN-100-007, or HPN-
100-012 may be eligible to enroll. 


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2. 
TRIAL OBJECTIVES AND ENDPOINTS 
The purpose of this protocol is to provide study subjects completing Protocols HPN-100-005, 
HPN-100-007, or HPN-100-012 continued access to HPN-100 in the context of a protocol 
designed to collect safety information with extended treatment. 
The objective of this study is to evaluate the long-term safety of HPN-100 and its control of 
venous ammonia in the management of UCDs.   
2.1. 
Primary Endpoint 
The primary endpoint is the rate of adverse events. 
2.2. 
Secondary Endpoints 
The secondary endpoints are the following: 
• Venous ammonia levels 
• Number and causes of hyperammonemic crises 
• Neuropsychological testing 
 


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3. 
OVERALL STUDY DESIGN AND PLAN 
3.1. 
Description 
This is a long-term safety study of HPN-100 in UCD subjects. Subjects will be assessed 
regularly for safety. Unscheduled visits (clinic visits/hospitalization/emergency room visits) will 
be assessed and hyperammonemic crisis events will be characterized with respect to contributing 
factors. 
Please refer to Section 4.3 for subject withdrawal criteria.  
3.2. 
Dose Selection 
As in Study HPN-100-005, HPN-100-007, and HPN-100-012 the dose of NaPBA and thus HPN-
100 is chosen based on the severity of the enzyme deficiency, on the content of the subject’s diet, 
and on the intake of amino acids or other supplements, and thus will vary among subjects.  
Subjects who have completed Study HPN-100-005, HPN-100-007, or HPN-100-012 will initially 
receive open-label HPN-100 at the same dose that they were receiving when they completed 
Study HPN-100-005, HPN-100-007, or HPN-100-012.  
The investigator may subsequently adjust the dose for any subject if judged clinically appropriate 
[the dose should not exceed the equivalent of 20 g/day of NaPBA (~17.4 mL total daily dose of 
HPN-100)]. 
Dose adjustments will be calculated by the investigator based on a clinical assessment of the 
subject’s ammonia-scavenging needs (e.g., severity of the UCD defect, dietary protein intake, 
and urinary PAGN excretion).  
3.3. 
Duration of the Study 
Subjects will stay on this study until HPN-100 is available through the Health Canada Special 
Access Program. 
3.4. 
Management of Episodes of Hyperammonemia 
Throughout this Treatment Protocol, occurrence of hyperammonemic crises will be captured. 
The following must be captured at a minimum on the appropriate case report forms (CRFs): 
• Precipitating factors (e.g., infection, intercurrent illness, stress, change in diet, 
noncompliance with HPN-100, noncompliance with other UCD medication) 
• If due to noncompliance, reasons for noncompliance  
• Ammonia level at hospital admission 
• Signs and symptoms suggestive of hyperammonemia 


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3.4.1. 
Hyperammonemic Crisis  
Hyperammonemic crisis is defined as follows: 
• Clinical symptoms associated with ammonia of ≥ 100 µmol/L  
Symptoms suggestive of an acute hyperammonemic crisis may include the following: 
• Vomiting 
• Nausea 
• Headache 
• Protein intolerance 
3.4.1.1. 
Management of Hyperammonemic Crisis and Withdrawal of Subjects 
Intercurrent episodes of hyperammonemia may be treated with rescue medication, with or 
without hemodialysis, at the investigator’s discretion. Any hospitalization for hyperammonemia 
should be considered an SAE. If sodium phenylacetate/sodium benzoate injection 10%/10% 
(AMMONUL®) is used as rescue medication for intercurrent hyperammonemia and if study 
medication is suspended during such treatment, study medication should be reintroduced as soon 
as practical. The sodium phenylacetate/sodium benzoate 10%/10% infusion should be continued 
for a minimum of 2 hours after reintroducing HPN-100. 
3.4.2. 
Symptoms Suggestive of Chronic Hyperammonemia 
Presence of at least two of the following clinical criteria would constitute evidence of chronic 
hyperammonemia: 
• Recurrent vomiting  
• Protein intolerance (becoming physically ill with high protein intake on multiple 
occasions leading to a self-imposed low-protein diet) 
• Episodic lethargy  
• Psychosis (episodic) 
• Abnormal neurological examination (hypotonia, spasticity, hyperreflexia, and/or 
clonus)  
• Brain edema (evidence on magnetic resonance imaging [MRI] or computed 
tomography [CT] scan) 
• Chronic migraine headaches  
New or worsening manifestations of chronic hyperammonemia, as compared with baseline, may 
be treated with an HPN-100 dose adjustment or the use of rescue medications such as 
AMMONUL®. 


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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1. 
Subject Inclusion Criteria 
• Male and female subjects who completed HPN-100-005, HPN-100-007, or HPN-100-
012 
• Signed informed consent by subject and/or subject’s legally authorized representative 
• Negative pregnancy test for all females of childbearing potential 
4.2. 
Subject Exclusion Criteria 
• Any clinical or laboratory abnormality or medical condition that, at the discretion of 
the investigator, may put the subject at increased risk when participating 
• Known hypersensitivity to PAA or PBA  
• Liver transplant, including hepatocellular transplant  
• Pregnant, breastfeeding or lactating females 
4.3. 
Subject Withdrawal Criteria 
Subjects may be withdrawn for any of the following reasons: 
• Voluntary withdrawal  
• At the discretion of the investigator if it is in the best interest of the subject 
• Lost to follow-up 
Please refer to Section 6.2 for procedures in case of early termination.  


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5. 
TREATMENT OF SUBJECTS 
5.1. 
Description of Study Drug 
HPN-100 [glyceryl tri-(4-phenylbutyrate)] is a precursor of PBA. PBA is released from 
HPN-100 in the gastrointestinal tract and acts as a nitrogen-scavenging agent in the body. PBA is 
a precursor of the active agent PAA, which combines with glutamine and ammonia to form 
PAGN, which is excreted in urine. 
The chemical name for HPN-100 is glyceryl tri-(4-phenylbutyrate). The empirical formula is 
C33H38O6 and the molecular weight is 530.67. 
It is a colorless to pale yellow, nearly odorless and tasteless oil that is administered neat 
(undiluted) orally or via gastrostomy tube. The density is 1.1033 g/L. 
HPN-100 contains no inactive ingredients. 
Each mL of HPN-100 delivers 1.02 g of PBA. 
5.2. 
Study Drug Dosage and Administration 
5.2.1. 
Preparation 
No special preparation is needed for HPN-100, which is administered neat (undiluted). Each mL 
of HPN-100 equals 1.1 g glyceryl tri-(4-phenylbutyrate) and delivers 1.02 g of PBA. 
Food grade flavors (lemon, lime, orange and tangerine oil) may be mixed in accordance with the 
pharmacy manual by the Pharmacist. 
5.2.2. 
Dose and Administration 
HPN-100 will be administered orally three times daily (TID) with meals. Please refer to section 
3.2 for complete information on dose selection and adjustment.  
The maximum recommended dose of HPN-100 in subjects weighing less than 20 kg is 
0.53 mL/kg/day (equivalent to 600 mg/kg/day of NaPBA), and is 11.48 mL/m2/day in heavier 
subjects (equivalent to 13g/m2/day of NaPBA). The maximum HPN-100 dose should be 
17.4 mL/day, which is equivalent to 20 g/day of NaPBA. 
5.3. 
Study Drug Materials and Management 
5.3.1. 
Study Drug Packaging and Labeling 
HPN-100 will be supplied in glass bottles with teflon screw-caps, and labeled with study 
identification information. Disposable oral syringes and Adapta Caps™ will be provided for 
measuring and administering HPN-100.  
Food grade flavors may also be provided for use by the Pharmacist, if requested by a subject.  


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5.3.2. 
Study Drug Storage 
HPN-100 is capped with nitrogen and stored at room temperature (15 to 30°C [59 to 86°F]). 
After opening, keep the bottle tightly closed after each use. Please reference the Pharmacy 
Manual for detailed information on study drug packaging, labeling and storage.  
5.3.3. 
Study Drug Dispensing and Disposal 
HPN-100 will be supplied by the Sponsor or designee.   
HPN-100 will be either dispensed to the subject through the Investigator or designee at each site 
or by a centralized pharmacy per Investigator order. The maximum supply of HPN-100 for a 
single shipment will be a 3 to 6-month supply. 
Subjects are NOT allowed to dispose of empty containers.  
See Pharmacy Manual for complete instructions. 
5.4. 
Concomitant Medications 
Medications being used at the time of study initiation may be continued with the permission of 
the investigator. All concomitant medications, including dose adjustments, and their indications 
must be recorded on the CRF.  
5.4.1. 
Prohibited Medications 
The following prohibited medications may not be used during the study:  
• Drugs known to cause hyperammonemia, such as valproate 
• Drugs known to significantly affect renal clearance, such as probenecid 
If, in the opinion of the treating physician, any of these medications are needed for treatment of a 
study participant, the investigator, in conjunction with the medical monitor, should discuss the 
feasibility of early termination. 
5.4.2. 
Nutrition 
All subjects should adhere to the diet (e.g. low protein, amino acid supplements) prescribed for 
them by the investigator. The diet chosen for each individual depends on age and residual 
enzyme activity and should not be altered for this study. At the discretion of the investigator, 
changes in dietary protein may be prescribed as necessary.  Changes in prescribed protein and/or 
calories will be recorded on the CRF. 
5.5. 
Randomization and Blinding 
This is a non-randomized, open-label study.   


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6. 
STUDY PROCEDURES 
The study Schedule of Study Assessments is provided in Appendix A.   
All Study Visits should occur in the morning and, if possible, fasted (before breakfast). 
6.1. 
Study Visits 
6.1.1. 
Baseline Visit (Month 0) 
For subjects who completed HPN-100-005, HPN-100-007, or HPN-100-012, and with the 
exception of the SF-36 or SF-15 questionnaire, the Month 0 visit of this study may be combined 
with the Month 12/Termination visit of the HPN-100-005, HPN-100-007, or HPN-100-012 study 
if conducted on the same day or within 14 days of the termination of either study. Common 
assessments between these visits (including neuropsychological battery) do not have to be 
repeated. However, these data must be recorded on both the Month 12 CRF for HPN-100-005, 
HPN-100-007, or HPN-100-012 and the Month 0 CRF for HPN-100-011. 
• Obtain informed consent from subject 
• Physical and neurological Exam 
• Record medical history 
• Record concomitant medications 
• Measure height and weight 
• Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
• Collect blood for safety laboratory assessments (see Section 8.2 for a list of tests) 
• Perform urine pregnancy test 
• Collect single blood sample for venous ammonia level assessment. Record time of 
blood sample and last dose 
• Collect blood for amino acid panel 
• Administer neuropsychological battery (Appendix B) 
• Assess conformance to inclusion/exclusion criteria 
• Record AEs 
• Dispense HPN-100 


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6.1.2. 
Routine Clinic Visits (Every 6 Months) 
Subjects should visit the clinic as prescribed by the Investigator, but at a minimum a visit must 
occur every 6 months until the HPN-100 is available to the subject through the Health Canada 
Special Access Program or the subject terminates HPN-100 for other reasons. At each clinic visit 
the following will be recorded: 
• Inquiry about a hyperammonemic crisis since the last visit. Record necessary 
information per Study Manual 
• Record concomitant medications (including any HPN-100 dose adjustment.  If dose 
adjustment is made, record reason) 
• Physical and neurological Exam  
• Measure height and weight 
• Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
• Collect single blood sample for venous ammonia level assessment.  
• Collect blood for safety laboratory assessments and amino acid panel (see 
Section 8.2) 
− Note: if labs were drawn within 30 days of study visit (e.g., as part of another 
study or standard of care), only the research labs not drawn need to be 
administered. 
• Perform urine pregnancy test 
− Note: Animal reproductive studies are in progress.  It is not known whether HPN-
100 can cause fetal harm when administered to a pregnant woman or can affect 
reproduction capacity.  Should a subject become pregnant while taking HPN-100, 
continued administration should be at the discretion of the Investigator in 
consultation with the study subject, taking into account the risk/benefit of 
continued administration, and with prior approval from the Sponsor. 
• Record prescribed protein and calories 
• Record AEs 
• Dispense HPN-100 
6.1.3. 
Unscheduled Visits 
Should a subject have an unscheduled visit (e.g., unscheduled clinic visit, emergency room visit, 
or hospitalization) the following will be recorded: 
• Record Reason for the visit (e.g., hyperammonemic crisis, vomiting, lethargy, 
seizure, fever, diarrhea, dehydration, anorexia, or other)  
− If the visit meets the definition of a SAE, complete a SAE report form, see 
Section 8). 


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− If the visit is due to a hyperammonemic crisis, complete the hyperammonemic 
event CRF. 
• Record concomitant medications (including any HPN-100 dose adjustment.  If dose 
adjustment is made, record reason) 
• Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
• Collect single blood sample for venous ammonia level assessment 
• Collect blood for safety laboratory assessments and amino acid panel  
• Perform urine pregnancy test 
− Note: Animal reproductive studies are in progress.  It is not known whether HPN-
100 can cause fetal harm when administered to a pregnant woman or can affect 
reproduction capacity.  Should a subject become pregnant while taking HPN-100, 
continued administration should be at the discretion of the Investigator in 
consultation with the study subject, taking into account the risk/benefit of 
continued administration, and with prior approval from the Sponsor. 
• Record prescribed protein and calories 
• Record AEs 
6.1.4. 
Annual (12 Month) / End of Study Visit 
Subjects will visit the clinic a minimum of every 6 months until HPN-100 is available through 
the Health Canada Special Access Program.  Assessments for every 12 months or the final visit 
are the same as the 6 month visit, with the exception of performing the neuropsychological 
battery, as follows: 
• Inquiry about a hyperammonemic crisis since the last visit. Record necessary 
information per Study (Reference) Manual 
• Record concomitant medications (including any HPN-100 dose adjustment.  If dose 
adjustment is made, record reason) 
• Physical and neurological exam  
• Measure height and weight 
• Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
• Collect single blood sample for venous ammonia level assessment 
• Collect blood for safety laboratory assessments and amino acid panel (see 
Section 8.2) 
− Note: if labs were drawn within 30 days of study visit (e.g., as part of another 
study or standard of care), only the research labs not drawn need to be 
administered. 
• Perform urine pregnancy test 


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− Note: Animal reproductive studies are in progress.  It is not known whether HPN-
100 can cause fetal harm when administered to a pregnant woman or can affect 
reproduction capacity.  Should a subject become pregnant while taking HPN-100, 
continued administration should be at the discretion of the Investigator in 
consultation with the study subject, taking into account the risk/benefit of 
continued administration, and with prior approval from the Sponsor. 
• Administer neuropsychological battery (Appendix B) 
• Record prescribed protein and calories 
• Record AEs 
• Discharge subject on available UCD medication  
6.2. 
Early Termination Procedures 
Subjects who discontinue treatment with HPN-100 will have end of study procedures performed 
as early termination assessments (see Section 6.1.3).  


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7. 
ASSESSMENT OF EFFICACY 
No formal assessment of efficacy will be performed.  Blood samples will be collected for 
assessment of venous ammonia levels at office visits in accordance with the Schedule of Study 
Assessments (Appendix A) and the Laboratory Manual. 


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8. 
ASSESSMENT OF SAFETY 
Safety laboratory tests, amino acid panel, and vital signs will be evaluated as described in the 
Schedule of Study Assessments (Appendix A). Adverse events and concomitant medications will 
be recorded on an ongoing basis. 
8.1. 
Adverse Events 
8.1.1. 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of the medicinal product, whether or not considered related to the 
medicinal product. 
AEs will be recorded in this study from the signing of the informed consent for this study 
through 7 days after the last dose of study medication.  
Adverse events include the following: 
• Any diagnosis, sign, symptom, or abnormal laboratory value not present, detected, or 
complained of at the baseline assessment of the prior study (HPN-100-005, HPN-100-
007, or HPN-100-012) 
• Any diagnosis, sign, symptom, or abnormal laboratory value noted at baseline that 
increases in severity or frequency during the study 
Hyperammonemia should be considered an AE if it results in a hyperammonemic crisis as 
defined in section 3.4.1. The investigator will be asked to assess the precipitating event, if known 
and record all pertinent information on specially-designed CRF for hyperammonemic crisis. 
Note that hyperammonemic crises can be considered expected complications of the underlying 
disease for many UCD patients. 
Other laboratory values that are outside the laboratory reference range should be reported as AEs 
if considered clinically significant by the investigator. 
Diseases or diagnoses present at entry into the prior study are regarded as concomitant diseases 
and will be documented in the medical history. Any clinically significant exacerbations of such 
conditions should be recorded as AEs in the current study. 
AEs that emerged during the prior study and are on-going at the transition into this study should 
be recorded as AEs on the AE CRF for this study. 
Diseases or diagnoses emerging during the study period are considered AEs and will be 
documented and reported accordingly. 
The term AE does not imply a causal relationship to the study medication. 


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All subjects experiencing AEs, including abnormal laboratory values, whether or not associated 
with use of the study medication, must be monitored until the condition returns to normal, 
returns to the subject’s baseline, or until the investigator determines the AE has reached a stable 
outcome.  
The sponsor will notify all investigators involved in the clinical investigation of important safety 
information regarding the study treatment as required by the applicable regulations. 
Adverse events are divided into the categories “serious” and “non-serious.” This determines the 
procedure that must be used to report/document the AE. 
8.1.2. 
Definition of Serious Adverse Event 
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes: 
• Death 
• Life-threatening 
• Persistent or significant disability/incapacity 
• Hospitalization or prolongation of an existing hospitalization 
• Congenital anomaly/birth defect 
• Important Medical Events 
− Important medical events are defined as those that may not result in death, be life-
threatening, or require hospitalization but may be considered SAEs when, based 
upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the other outcomes 
listed above. 
Adverse events that do not result in any of these outcomes are considered non-serious. 
Hyperammonemic episodes will be considered SAEs when they meet the criteria for an SAE as 
described above. Hyperammonemia that does not result in a serious outcome should not be 
considered an AE. If a hyperammonemic episode occurs, the investigator will be asked to assess 
the precipitating event, if known, on a specially-designed CRF. 
8.1.3. 
Assessment of Severity 
All adverse events, both serious and non-serious, will be assessed for severity using the CTCAE 
v3.0. The CTCAE scale includes unique clinical descriptions of adverse events that are 
categorized by anatomy and/or pathophysiology. The CTCAE v3.0 scale displays Grades 1 
through 5 with unique clinical descriptions of severity for each AE (including abnormal 
laboratory values) based on this general guideline: 
• Grade 1 
 
Mild AE 
• Grade 2 
 
Moderate AE 
• Grade 3 
 
Severe AE 


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• Grade 4 
 
Life-threatening or disabling AE 
• Grade 5 
 
AE resulting in death 
Not all grades are appropriate for all AEs; therefore, some AEs are listed with fewer than 
5 options for grade selection. In particular, Grade 5 (Death) is not appropriate for some AEs and 
therefore will not be an option for those AEs. 
For any AEs not covered by the CTCAE, the following criteria should be used: 
• Mild: Does not interfere with routine activities 
• Moderate: Interferes with routine activities 
• Severe: Impossible to perform routine activities 
• Life-threatening: Subject was at immediate risk of death from the event at the time it 
occurred, or the AE caused permanent disability 
• Fatal: AE with outcome of death 
8.1.4. 
Assessment of Relationship to Study Drug 
The principal investigator must review each AE and make the determination of relationship to 
study drug (i.e. whether or not the study drug possibly or probably caused the AE) using the 
following definitions: 
• Not Related: The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or injury; does not follow a 
known response pattern to the study drug; and/or no temporal relationship exists with 
the study drug. For AEs considered not related to study drug, the investigator will be 
asked to choose one of the following: 
− Not related (noncompliance with medication) 
− Not related (noncompliance with diet) 
− Not related (intercurrent illness) 
− Not related (symptoms of primary disease) 
− Not related (use of concomitant medication)  
− Not related (other) 
• Possibly Related: There is a reasonable temporal relationship between the event and 
the administration of the study drug, and the event cannot be readily explained by the 
subject’s medical condition, other therapies, or injury, and may not follow a known 
response pattern to the study drug. 
• Probably Related: The event follows a reasonable temporal sequence from 
administration of the medication and is part of a known or suspected response pattern 
to the medication, and a plausible alternative etiology cannot be identified.  




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• Hematology: complete blood count (CBC) with differential and platelet count  
• Coagulation: prothrombin time and international normalized ratio (INR) 
• Chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), 
creatinine, and glucose 
• Liver function tests: ALT, aspartate aminotransferase (AST), albumin, total bilirubin, 
and alkaline phosphatase 
• Amino acid panel: ornithine, aspartic acid, serine, threonine, glutamic acid, 
asparagine, proline, glutamine, alanine, glycine, valine, citrulline, methionine, 
cystine, leucine, isoleucine, phenylalanine, tyrosine, lysine, tryptophan, arginine, and 
taurine.  
Annually, ~51 mL of venous blood for safety laboratory assessments and amino acid panel will 
be drawn.  Please note that plasma ammonia only will be processed and analyzed by the 
investigative site laboratory while all other safety laboratory samples and amino acid panel 
samples will be processed and analyzed by a central laboratory per their respective standard 
operating procedures (SOPs). 
Urine pregnancy tests will be performed in women of childbearing potential. 
8.3. 
Vital Signs 
Blood pressure, respiratory rate, temperature, and pulse will be measured according to the 
Schedule of Study Assessments (Appendix A). 
8.4. 
Unblinding of Treatment Assignment 
Not applicable; this is an open-label study. 


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9. 
OTHER ASSESSMENTS 
9.1. 
Neuropsychological Battery 
Neuropsychological testing will be administered once a year, according to the Schedule of Study 
Assessments (Appendix A). 
These tests must be administered by a properly trained medical professional. The tests are 
described briefly in Appendix B.  


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10. 
STATISTICS 
10.1. 
Sample Size and Power 
No formal sample size or power calculations are proposed, as this is a long-term safety study. 
10.2. 
Endpoints 
The primary endpoint is the rate of adverse events. 
Secondary endpoints include the following: 
• Venous ammonia levels 
• Number and causes of hyperammonemic events 
• Neuropsychological testing 
10.3. 
Methods of Analysis 
Data will be summarized using descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], median, minimum, and maximum) for continuous variables, and frequency and 
percentages for categorical variables. Any statistical hypothesis testing that is performed will be 
exploratory in nature. 
10.3.1. 
Analysis Populations 
The following populations will be considered in the analysis of data for this study: 
Safety population: All subjects who receive any amount of study medication will be included 
in the safety population. This is the primary population for all analyses performed for this 
study.  
10.3.2. 
Baseline and Demographic Variables 
Demographic data including age, race, and gender will be summarized using descriptive 
statistics. Baseline variables including medical history, vital signs, laboratory data, and other 
baseline disease characteristics will be summarized using descriptive statistics. Summaries will 
be provided for the safety population.  
10.3.3. 
Safety Variables 
Safety assessments will include adverse events, vital signs, and clinical laboratory 
measurements. 
The number and percentage of subjects who discontinued the study prematurely will be 
summarized. The reasons for early study termination will also be presented. 
The number and percentage of subjects experiencing AEs will be summarized by system organ 
class and preferred term. Summaries by maximum severity and relationship to study treatment 


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will also be provided. Serious AEs and AEs leading to discontinuation of study treatment will be 
presented by system organ class and preferred term. 
Liver function tests and additional selected laboratory tests will be summarized by study visit. 
Laboratory tests will be classified relative to the normal reference range (normal, low, or high) 
and will be summarized by visit.  
Vital signs, including blood pressure, respiratory rate, temperature, and pulse, will be 
summarized by visit.  
Concomitant medications will be summarized and/or included in the data listings. 
10.3.4. 
Efficacy Variables 
Venous ammonia levels and changes from baseline will be summarized with descriptive 
statistics. The percentage of venous ammonia values above the upper limit of normal (ULN) will 
also be summarized. 
The number of hyperammonemic crises and their causes will be summarized descriptively. 
10.3.5. 
Other Variables 
Neuropsychological testing results will be summarized for each item and scale. 


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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Required information will be entered into the appropriate CRFs, which will be maintained in 
order and up-to-date so they reflect the latest information on the subject’s study file. All records 
are to be kept in conformance with applicable guidelines and SOPs. 
When the study 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. 
11.1. 
Study Monitoring 
The sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the investigator for the purpose of inspecting the facilities, and upon request, inspecting 
the various records of the trial. The sponsor’s clinical monitor is responsible for inspecting the 
CRFs throughout the study to verify source records; adherence to the protocol; completeness, 
accuracy, and consistency of data; and adherence to Good Clinical Practices. The monitor should 
have access to subject medical records and other study-related records needed to verify entries on 
the CRFs. 
The investigator agrees to cooperate with the monitor.  
11.2. 
Audits and Inspections 
The sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the investigator for the purpose of inspecting the facilities, and upon request, inspecting 
the various records of the trial. This study may be selected for audit by representatives of the 
sponsor’s Clinical Quality Assurance department or designee. Inspection of the site facilities 
(i.e., participant areas, drug storage areas, record storage areas, etc.) and review of study-related 
records may occur to evaluate the trial conduct and compliance with the protocol, ICH GCP, and 
applicable regulatory requirements. 
11.3. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 
The protocol, informed consent form, assent form, recruiting advertisements (if any), and subject 
instructions will be reviewed and approved by a properly constituted IRB/IEC that is in 
compliance with the requirements of ICH GCP and local and country requirements and is 
responsible for reviewing clinical studies. A copy of the letter indicating approval will be 
provided to the sponsor prior to study initiation. 
No amendments to this protocol will be permitted without approval from the study sponsor. 
These communications will be documented in writing. 
The investigator and appropriate representatives from the sponsor will sign the protocol to 
document their willingness to adhere to this protocol and to conduct the study in accordance with 
Good Clinical Practices. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Data will be entered into a password-protected database in accordance with the Study Operations 
Manual. After resolution of any discrepancies and a combination of manual and automated data-
review procedures, the final data sets will be subject to a quality assurance audit. 
When the database is declared to be complete and accurate, it will be locked. Any changes to the 
database after that time can only be made by written notice, as approved by the sponsor. 
The investigator will be responsible for ensuring the accuracy, completeness, and timeliness of 
the data reported to the sponsor in the CRFs and in all required reports. Data reported on the 
CRFs, which are derived from source documents, should be consistent with source documents or 
the discrepancies should be explained.  
Corrections to the CRFs will be made in accordance with the Study Operations Manual. 
Corrections to paper forms will be made by a single line stroke through the error and insertion of 
the correction above or beside the error. The change must be initialed and dated by the 
investigator or a member of the study staff authorized by the investigator on the Delegation of 
Responsibilities form. No erasures, correction fluid, or correction tape may be used. 
To ensure the quality of the clinical data across all participants and sites, a clinical data-
management review will be performed on all subject data. During this review, subject data will 
be checked for consistency, omissions, and any apparent discrepancies. In addition, the data will 
be reviewed for adherence to protocol and GCPs. To resolve any questions arising from the 
clinical data-review process, data queries will be sent to the site for completion. 
The principal investigator will sign and date the indicated places on the CRF. This signature will 
indicate that the principal investigator inspected or reviewed the data on the CRF and the data 
queries, and that the investigator agreed with the content. 


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13. 
ETHICS 
13.1. 
Ethics Review 
The protocol, informed consent form, recruiting advertisements (if any), and subject instructions 
will be reviewed and approved by a properly constituted IRB/IEC before any subject is enrolled 
at each study site. 
13.2. 
Ethical Conduct of the Study 
This study will be performed with adherence to the principles of Good Clinical Practices as 
required by applicable country and local regulations and by the ICH E6 Guidance for Industry: 
Good Clinical Practice Consolidated Guidance, April 1996, and in accordance with the ethical 
principles of the Declaration of Helsinki and its amendments. 
13.3. 
Written Informed Consent 
In accordance with ICH GCPs, written informed consent must be obtained prior to a subject’s 
participation in the study.  


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14. 
DATA HANDLING AND RECORDKEEPING 
The investigator must ensure that all participants’ confidentiality will be maintained and that 
their identities are protected from unauthorized parties. On CRFs or other documents that are 
submitted to the sponsor, participants should be identified by an identification code and not by 
their names. 
14.1. 
Inspection of Records 
All records are to be kept in conformance with applicable guidelines and SOPs. 
14.2. 
Retention of Records 
When the study 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. 


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15. 
REFERENCES 
Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv 
Pediatr. 1996; 43:127-70. 
Gorker I, Tuzun U. Autistic-like findings associated with a urea cycle disorder in a 4-year-old 
girl. J Psychiatry Neurosci 2005;30:133-5. 
James MO, Smith RL, Williams RT, Reidenberg M. The conjugation of phenylacetic acid in 
man, sub-human primates and some non-primates species. Proc R Soc Lond B Biol Sci. 1972; 
Jul 25;182(66):25-35. 
Maestri NE, g D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: a 
retrospective analysis.  
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 
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. 
McGuire BM, Zupanets I; Lowe ME, Syplyviy V, Monteleone J, Gargosky S, Dickenson K, 
Martinez A, Mokhtarani M, Scharschmidt BF, Pharmacology and safety of a novel ammonia 
lowering agents in healthy adults and adults with cirrhosis.  Hepatology 2010; 51:2077-85 
Singh RH. Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis 
2007; 30:880-7. 
Summar M., Tuchman M. Proceedings of a consensus conference for the management of patients 
with urea cycle disorders. J Pediatr 2001;138:S6-10. 


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16. 
APPENDICES 
 


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APPENDIX A. SCHEDULE OF STUDY ASSESSMENTS 
Month 
0 
Month 
Every 3 
months 
Every 6 
months 
Unscheduled 
Visits 
Every 12 months/ 
Termination 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Inclusion / Exclusion 
X 
 
 
 
 
Physical and Neurological Exam 
X 
 
X 
 
X 
Concomitant Medications 
X 
 
X 
X 
X 
Height and Weight  
X 
 
X 
 
X 
Vital Signs  
X 
 
X 
X 
X 
Safety Labs 
X 
 
X 
X 
X 
Urine Pregnancy Test  
X 
 
X 
X 
X 
Venous Ammonia 
X 
 
X 
X 
X 
Amino Acid 
X 
 
X 
X 
X 
Record prescribed dietary protein and calories 
X 
 
X 
X 
X 
Neuropsychological Battery 
X 
 
 
 
X 
Adverse Events 
X 
 
X 
X 
X 
Study Drugs 
 
 
 
 
Dispense HPN-100  
X 
X 
 
 
 
Resume Off-study Treatment 
 
 
 
 
X 
• Visit window is +/- 30 days. 
• Month 0 visit of this study may be combined with the Month 12 visit for subjects who completed HPN-100- 005, HPN-100-007, or HPN-100-012. Common assessments 
between these visits do not have to be repeated; however, these data must be recorded on both Month 0 of this study and the Month 12 CRF for HPN-100-005, HPN-100-007, 
and HPN-100-012. 
• Routine Study Visits must occur every 6 months. 
• Unscheduled Visits may occur due to a hospitalization, a visit to the emergency room, or at the discretion of the investigator between routine study visits.  In each case the 
reason for the unscheduled visit should be document (e.g., hyperammonemic crisis, vomiting, lethargy, seizure, fever, diarrhea, dehydration, anorexia, or other). 
• Subjects who exit the protocol will have the same procedures as the Month 12 visit.  
• Subjects must follow their prescribed diet and at the discretion of the investigator, changes in dietary protein may be prescribed as necessary throughout the study. Changes in 
dietary protein and calories (increases or decreases) should be record at each visit (scheduled or unscheduled) along with reason for the change. 
• Vital signs include blood pressure, respiratory rate, temperature, and pulse.   
• Neuropsychological battery (Appendix B) will be administered once every 12 months. 
 


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APPENDIX B. NEUROPSYCHOLOGICAL BATTERY 
These tests must be administered by a properly trained medical professional. 
Neuropsychological Battery Tests for Adults 
Wechsler Abbreviated Scale of Intelligence (WASI): Assesses general test of intelligence (IQ) 
Grooved Pegboard: This test is used to test motor and visual skills through manual dexterity in 
adults, adolescents, and children. It consists of 25 holes with randomly positioned slots. This test 
requires complex visual-motor coordination; for example, pegs with a key on one side must be 
rotated to match the hole before they can be inserted. The time during which the task is completed 
is recorded.  
The California Verbal Learning Test (CVLT): The California Verbal Learning Test (CVLT) 
assesses verbal memory abilities through testing immediate and delayed recall. Several lists of 
words are read to the subject. These lists contain sixteen common words, each of which belongs to 
one of four categories such as fruits, herbs, etc. The subject is then asked to recall as many of these 
items as possible. There is a short delay of 20 minutes, during which the subject is given other 
tasks to perform, and then the tester again asks the subject to recall the first list. The number of 
correct answers is recorded for both immediate and delayed recall tasks. 
Digit Span: The digit span test is a common measure of attention and short-term memory. The 
subject is given a list of digits and then asked to recall them in correct sequential order. The 
number of correct digits is recorded.  
Neuropsychological Battery Tests for Pediatrics 
Wechsler Abbreviated Scale of Intelligence (WASI): This test is a general assessment of 
intelligence (IQ). 
The Child Behavior Checklist (CBCL): (Thomas M. Achenbach, PhD, Leslie A. Rescorla, PhD) 
CBCL is a device by which parents rate a child’s problem behaviors and competencies. This 
instrument can either be self-administered or administered through an interview. The CBCL can 
also be used to measure a child’s change in behavior over time or following a treatment. The first 
section of this questionnaire consists of 20 competence items and the second section consists of 
120 items on behavior or emotional problems during the past 6 months. Teacher Report Forms and 
Youth Self-Report Forms are available. Two versions of this instrument exist: one for children 
aged 1 1/2 to 5 years and another for ages 6 to 18 years.  
Behavior Rating Inventory of Executive Function® (BRIEF®): (Gerard A. Gioia, PhD, 
Kimberly Andrews Espy, PhD, Peter K. Isquith, PhD)  The BRIEF is designed to assess executive 
functioning in children and adolescents ages 5 to 18 years. It consists of 2 rating forms, a parent 
questionnaire and a teacher questionnaire, which require only 10 to 15 minutes to administer and 
15 to 20 minutes to score. Suited for both home and school settings, the BRIEF is useful in 
evaluating children with a wide spectrum of developmental and acquired neurological conditions.   


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APPENDIX C. PROTOCOL REVISION HISTORY 
 
Protocol HPN-100-011 version 1.0 (dated 24 September 2010) was amended in the following 
sections: 
Protocol Section 
Revised Text 
Reason for Change 
Section 1.2 
 
Removed footnote of “*n=9” 
The footnote was listed in 
error.  The sample sizes are 
listed at the top of each 
column. 
various 
Revised various sections throughout the 
document to allow subjects who complete 
Study HPN-100-012 entry into Study 
HPN-100-011. 
Patients who complete Study 
HPN-100-012 are eligible for 
continued access to HPN-100 
via Study HPN-100-011. 
Section 5.3.3.   
Study Drug 
Dispensing and 
Disposal 
The maximum supply of HPN-100 for a 
single shipment will be a 3 to 6-month 
supply. 
 
Some patients travel by 
airplane to study sites and are 
unable to visit the clinic 
every 3 months. 
Section 6.1.4  
Annual (12 
Month)/End of 
Study Visit 
Inquiry about a hyperammonemic crisis 
since the last visit. Record necessary 
information per Study (Reference) 
Manual 
 
Study Manual was renamed 
Study (Reference) Manual 
 
Protocol HPN-100-011 version 2.0 (dated 21 August 2012) was amended in the following 
sections: 
Protocol Section 
Revised Text 
Reason for Change 
various 
Revised various sections throughout the 
document to allow subjects to stay on this 
study until HPN-100 is available through 
the Health Canada Special Access 
Program 
After HPN-100 
commercialization in US, 
patients will have access to 
HPN-100 through the Health 
Canada Special Access 
Program.  


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Protocol HPN-100-011 Amendment 3 Version 4.0 (Canada only - dated 12 February 2013) 
was amended in the following sections: 
Protocol HPN-100-011 version 3.0 (Amendment 2, dated 21August 2012) was revised with the 
following rationale:  
 
Rationale: To allow subjects to continue on this study until HPN-100 is available through the 
Health Canada Special Access Program. 
A detailed revision history of the protocol is provided below. 
Deletions are marked with a strikethrough, and insertions are shown in bold text.  The 
rationale for the changes in the protocol sections outlined below is as follows: 
Protocol Section: Synopsis (relevant section outlined) 
 
SYNOPSIS  
 
Mode of 
Administration 
Subjects who have completed Study HPN-100-005, HPN-100-007, or 
HPN- 100-012 will continue to receive open-label HPN-100, initially 
at the same dose which they were receiving at the time they 
completed study HPN-100- 005, HPN-100-007 or HPN-100-012. 
The investigator may subsequently adjust the dose for any subject if 
judged clinically appropriate [the dose should not exceed the 
equivalent of 20 grams (g) of NaPBA (~17.4 milliliters (mL) total 
daily dose of HPN-100)]. 
Duration of Study 
Until HPN-100 is commercially available in the US through the 
Health Canada Special Access Program 
 
Protocol Section 3.3: Duration of the Study 
3.3.         Duration of the Study 
Subjects will stay on this study until HPN-100 is commercially available through the Health 
Canada Special Access Program in the US 
 
Protocol Section 6.1.2: Routine Clinic Visit (Every 6 Months) 
6.1.1.  Routine Clinic Visit (Every 6 Months) 
Subjects should visit the clinic as prescribed by the Investigator, but at a minimum a visit 
must occur every 6 months until the HPN-100 is commercially available to the subject 
through the Health Canada Special Access Program or the subject terminates HPN-100 
for other reasons. At each clinic visit the following will be recorded: 
 
 


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Protocol Section 6.1.4: Annual (12 Month) / End of Study Visit 
6.1.4. Annual (12 Month) / End of Study Visit 
Subjects will visit the clinic a minimum of every 6 months until HPN-100 is commercially 
available through the Health Canada Special Access Program in the US.  
Assessments for every 12 months or the final visit are the same as the 6 month visit, with the 
exception of performing the neuropsychological battery, as follows: 
• Inquiry about a hyperammonemic crisis since the last visit. Record necessary 
information per Study (Reference) Manual 
•  Record concomitant medications (including any HPN-100 dose adjustment. If 
dose adjustment is made, record reason) 
• Physical and neurological exam 
• Measure height and weight 
• Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
• Collect single blood sample for venous ammonia level assessment 
• Collect blood for safety laboratory assessments and amino acid panel 
(see Section 8.2) 
− Note: if labs were drawn within 30 days of study visit (e.g., as part of 
another study or standard of care), only the research labs not drawn need to 
be administered. 
• Perform urine pregnancy test 
Note: Animal reproductive studies are in progress. It is not known whether 
HPN-100 can cause fetal harm when administered to a pregnant woman or can 
affect reproduction capacity.  Should a subject become pregnant while taking 
HPN-100, continued administration should be at the discretion of the 
Investigator in consultation with the study subject; taking into account the 
risk/benefit of continued administration and with prior approval from the 
Sponsor. 
• Administer neuropsychological battery (Appendix B) 
• Record prescribed protein and calories 
• Record AEs 
• Discharge subject on commercially available UCD medication 
 

SAP_001.pdf: 
Horizon Therapeutics 
Confidential 
Protocol: HPN-100-011 
TPBS001 Version 1 
Effective Date: 22nd September 2009 
Final Version 2 
Page 1 of 14 
18Nov2015 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
PROTOCOL NUMBER: HPN-100-011 
 
LONG TERM USE OF HPN-100 IN UREA CYCLE DISORDERS 
 
 
 
Author(s): 
Document Status: 
Final Version 2 
Version Dates: 
Draft 1 Version 1: 07 September 2012 
Draft 2 Version 1: 24 October 2012 
Final Version 1: 15 February 2013 
Final Version 2: 18Nov2015 
Pages: 
14 
CIL: 
30218 
 
 
Prepared by 
Chiltern 
 
Prepared for 
Horizon Therapeutics, Inc. 
520 Lake Cook Road 
Deerfield, IL 60015 


Horizon Therapeutics 
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Protocol: HPN-100-011 
TPBS001 Version 1 
Effective Date: 22nd September 2009 
Final Version 2 
Page 2 of 14 
18Nov2015 
 
 
 
 
Contents 
ABBREVIATIONS ......................................................................................................................3 
1 
INTRODUCTION ................................................................................................................4 
2 
STUDY OBJECTIVES .................................................................................................... 5 
2.1 
ENDPOINTS ....................................................................................................................5 
3 
STUDY DESIGN .............................................................................................................. 6 
3.1 
DISCUSSION OF STUDY DESIGN ...................................................................................6 
3.2 
STUDY SCHEDULE ...................................................................................................... 6 
3.3 
CONCOMITANT MEDICATIONS AND DIET ......................................................................6 
3.4 
STUDY ANALYSIS POPULATION ....................................................................................7 
3.5 
WITHDRAWN SUBJECTS ................................................................................................7 
3.6 
RANDOMIZATION AND BLINDING ................................................................................. 7 
3.7 
SAMPLE SIZE .............................................................................................................. 7 
4 
STATISTICAL METHODOLOGY ................................................................................. 8 
4.1 
PLANNED ANALYSES .....................................................................................................8 
4.2 
INTERIM ANALYSIS ...................................................................................................... 8 
4.3 
SIGNIFICANCE LEVELS ................................................................................................ 8 
4.4 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS ......................................................8 
4.5 
SAFETY ANALYSIS .........................................................................................................8 
4.5.1 Adverse events ...........................................................................................................9 
4.5.2 Laboratory and amino acid data ............................................................................ 9 
4.5.3 Vital signs ............................................................................................................. 10 
4.5.4 Hyperammonemic events ....................................................................................... 10 
4.6 
EXPLORATORY EFFICACY ANALYSES ........................................................................ 10 
4.6.1 Standardization and Normalization of the Ammonia Level Data ......................... 10 
4.6.2 Analysis of Ammonia Data ................................................................................... 11 
4.7 
DISPOSITION OF PATIENTS ....................................................................................... 11 
4.8 
CONCOMITANT MEDICATION ...................................................................................... 11 
4.9 
EXPOSURE TO HPN-100 ........................................................................................... 12 
4.10 NEUROPSYCHOLOGICAL TESTING ............................................................................ 12 
4.11 PROTOCOL VIOLATIONS OR DEVIATIONS .................................................................. 13 
4.12 DEVIATIONS FROM SAP ........................................................................................... 13 
4.13 CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ................ 13 
5 
TABLES AND LISTINGS ............................................................................................. 14 
5.1 
FORMAT ...................................................................................................................... 14 
5.2 
CONVENTIONS ............................................................................................................ 14 


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Final Version 2 
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Abbreviations 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BRIEF 
Behavior Rating Inventory of Executive Function 
BSA 
Body Surface Area 
CVLT-II 
California Verbal Learning Test 
CBC 
Complete Blood Count 
CBCL 
Child Behavior Checklist 
CI 
Confidence Interval 
CRF 
Case Report Form 
g 
Gram 
HPN-100 
Glyceryl tri-(4-phenylbutyrate), GT4P 
kg 
Kilogram 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
m2 
Square meter 
mg 
milligram 
Min 
Minimum 
mL 
millilitre 
NP 
Neuropsychological 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
UCD 
Urea Cycle Disorder 
ULN 
Upper Limit of Normal 
WASI 
Wechsler Abbreviated Scale of Intelligence 


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1 Introduction 
This document presents the statistical analysis plan (SAP) for Horizon Therapeutics, 
Inc. (Horizon) formerly Hyperion Therapeutics, Inc. (Hyperion), Protocol HPN-100-011: 
Long Term Use of HPN-100 in Urea Cycle Disorders. 
 
This analysis plan is based on protocol Version 4.0 Final (Amendment 3), Version 2.0 
Final (Amendment 1), Version 3.0 (Canada) Amendment 2, 4.0 Final (Amendment 3), 
and 4.0 (Canada) Amendment 03, Administrative Change 1. 
The SAP provides the description of the final data analysis. 


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2 Study Objectives 
The purpose of this protocol is to provide study subjects completing Protocols HPN- 
100-005, HPN-100-007, or HPN-100-012 continued access to HPN-100 in the context 
of a protocol designed to collect safety information with extended treatment. 
The objective of this study is to evaluate the long-term safety of HPN-100 and its 
control of venous ammonia in the management of UCDs. 
 
2.1 Endpoints 
The primary endpoint is the rate of adverse events. 
The secondary endpoints are the following: 
• Venous ammonia levels 
• Number and causes of hyperammonemic crises 
• Neuropsychological testing 


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3 Study Design 
3.1 Discussion of Study Design 
This is a long-term safety study of HPN-100 in UCD subjects. Subjects will be assessed 
regularly for safety. Unscheduled visits (clinic visits/hospitalization/emergency room 
visits) will be assessed and hyperammonemic crisis events will be characterized with 
respect to contributing factors. 
As in Studies HPN-100-005, HPN-100-007, and HPN-100-012, the dose of NaPBA 
and thus HPN-100 is chosen based on the severity of the enzyme deficiency, on the 
content of the subject’s diet, and on the intake of amino acids or other supplements. 
The dose will therefore vary among subjects. 
Subjects who have completed Study HPN-100-005, HPN-100-007, or HPN-100-012 
will initially receive open-label HPN-100 at the same dose that they were receiving 
when they completed Study HPN-100-005, HPN-100-007, or HPN-100-012. 
The investigator may subsequently adjust the dose for any subject if judged clinically 
appropriate [the dose should not exceed the equivalent of 20 g/day of NaPBA (~17.4 
mL total daily dose of HPN-100)]. 
Subjects will stay on this study until the subjects can be transitioned to commercially 
available HPN-100 or until alternate approved treatment is available. 
 
3.2 Study Schedule 
For subjects who completed HPN-100-005, HPN-100-007, or HPN-100-012 and with 
the exception of the SF-36 or SF-15 questionnaire, the Month 0 visit of this study may 
be combined with the Month 12/Termination visit of the HPN-100-005, HPN-100-007, 
or HPN-100-012 study if conducted on the same day or within 14 days of the 
termination of either study. Common assessments between these visits (including 
neuropsychological battery) do not have to be repeated. However, these data must be 
recorded on both the Month 12 CRF for HPN-100-005, HPN-100-007, or HPN-100- 
012 and the Month 0 CRF for HPN-100-011. 
Subjects should visit the clinic as prescribed by the Investigator, but at a minimum a 
visit must occur every 6 months until HPN-100 is commercially available to the subject 
or the subject terminates HPN-100 for other reasons. 
Data will also be recorded for unscheduled visits (e.g., unscheduled clinic visit, 
emergency room visit, or hospitalization). 
Assessments for every 12 months or the final visit are the same as the 6 month visits, 
with the exception of performing neuropsychological battery tests. 
Full details of the study schedules can be found in the study protocol. Details will not 
be duplicated within the SAP. 
 
3.3 Concomitant Medications and Diet 
Medications being used at the time of study initiation may be continued with the 
permission of the investigator. All concomitant medications, including dose 
adjustments, and their indications must be recorded on the CRF. 
The following prohibited medications may not be used during the study: 


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• Drugs known to cause hyperammonemia, such as valproate 
• Drugs known to significantly affect renal clearance, such as probenecid 
All subjects should adhere to the diet (e.g. low protein, amino acid supplements) 
prescribed for them by the investigator. The diet chosen for each individual depends 
on age and residual enzyme activity and should not be altered for this study. At the 
discretion of the investigator, changes in dietary protein may be prescribed as 
necessary. Changes in prescribed protein and/or calories will be recorded on the CRF. 
 
3.4 Study Analysis Population 
Only one analysis population will be evaluated for this study, the safety population. 
All subjects who receive any amount of study medication will be included in the safety 
population. This is the primary population for all analyses performed for this study. 
 
3.5 Withdrawn Subjects 
Subjects may be withdrawn for any of the following reasons: 
• Voluntary withdrawal 
• At the discretion of the investigator if it is in the best interest of the subject 
• Lost to follow-up 
Subjects who exit the study will not be replaced. 
 
3.6 Randomization and Blinding 
Not applicable – This is a non-randomized and open-label study. 
 
3.7 Sample Size 
No formal sample size or power calculations were performed for this long-term safety 
study. Subjects who completed protocols HPN-100-005, HPN-100-007, or HPN-100- 
012 will be eligible for enrollment in this study. 


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4 Statistical Methodology 
4.1 Planned Analyses 
Summary statistics [number of subjects (n), mean, standard deviation (SD), median, 
minimum and maximum] will be presented for continuous variables. Frequencies and 
percentages will be presented for categorical variables. Unless otherwise noted, 
percentages will be calculated using the total subjects per treatment group in the 
appropriate population and/or subgroup. 
All summary tables will include separate statistics for adults (>=18 years) and pediatric 
patients (<=17 years). Totals for all patients will also be presented. 
Final analyses will occur upon data cutoff from the last monitoring visit (paper case 
report forms) at the single remaining open site in 2015. This data cut will initiate a full 
analysis. Any additional data collected after this data cut-off will be summarized in a 
CSR addendum. 
4.2 Interim Analysis 
All Canadian patients enrolled in HPN-100-011 will continue to be followed under the 
protocol schedule of assessments until commercial access, or access through Health 
Canada Special Access Program or alternate treatment is available to them. 
All US patients will be terminated from the study after 30June2013. All data from US 
patients will be cleaned and locked upon completion of the final US patient. Data from 
these patients will be analyzed according to the plans detailed within this SAP. 
4.3 Significance Levels 
If statistical significance testing is performed, it will be performed for exploratory 
purposes only. Tests will be evaluated at the two-sided 0.05 level of significance and/or 
using two-sided CIs. No adjustments for multiple testing will be made for this study. 
4.4 Baseline and Demographic Characteristics 
Demographic data including age, race, ethnicity, and gender as well as UCD history 
will be summarized using descriptive statistics. UCD history data will be obtained from 
the original study (HPN-100-005, HPN-100-007, or HPN-100-012) databases. 
Baseline variables including medical history, physical and neurological examinations, 
vital signs, laboratory data, and other baseline disease characteristics will be 
summarized using descriptive statistics. 
Unless otherwise noted, baseline will be defined as the last non-missing value prior to 
the first dose of study treatment as part of protocol HPN-100-011. Additional analyses 
may be performed using the baseline value from the original study (HPN-100-005, 
HPN-100-007, or HPN-100-012). 
 
4.5 Safety Analysis 
The primary objective of this study is to evaluate the safety and tolerability of HPN- 
100. Safety will be evaluated in the safety population using adverse event reporting, 
laboratory tests, vital signs, hyperammonemic events, and concomitant medications. 


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4.5.1 Adverse events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). If a patient experiences multiple events that map to a single 
preferred term, the greatest severity and most conservative relationship will be 
assigned for the applicable summaries. 
A treatment-emergent AE is an AE that begins (or a pre-existing condition that 
worsens) after receiving the study medication as part of HPN-100-011. Where an AE 
start date is partially or fully missing, and it is unclear as to whether the AE is treatment 
emergent, it will be assumed that it is. 
Treatment-emergent AEs will be summarized by system organ classification, preferred 
term, and treatment. Treatment-emergent serious adverse events (SAEs) will also be 
summarized by system organ classification, preferred term, and treatment. A similar 
summary will also be prepared for AEs leading to discontinuation of study treatment. 
Treatment-emergent AEs will also be presented by maximum severity/intensity and by 
most conservative relationship to study medication. 
Adverse events will also be tabulated by total exposure to HPN-100 treatment during 
HPN-100-011 (0-3 months, >3-6 months, >6-9 months, >9-12 months, and >12- 
months exposure). 
The number and percentage of patients with at least one qualifying adverse event will 
be tabulated for all summaries. 
 
4.5.2 Laboratory and amino acid data 
Laboratory samples (blood and urine) were collected in accordance with the schedule 
of assessments, and at the investigator’s discretion. The safety laboratory 
assessments will be defined as: 
• Hematology: complete blood count (CBC) with differential and platelet count 
• Coagulation: prothrombin time and international normalized ratio (INR) 
• Chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), 
creatinine, and glucose 
• Liver function tests: ALT, aspartate aminotransferase (AST), albumin, total bilirubin, 
and alkaline phosphatase 
• Amino acid panel: ornithine, aspartic acid, serine, threonine, glutamic acid, 
asparagine, proline, glutamine, alanine, glycine, valine, citrulline, methionine, 
cystine, leucine, isoleucine, phenylalanine, tyrosine, lysine, tryptophan, arginine, 
and taurine. 
 
 
Laboratory test results and their changes from baseline will be summarized using 
descriptive statistics by study visit. Laboratory results will be classified relative to the 
normal reference range and will be summarized by study treatment and visit. A shift 
table showing the shift from baseline to each study visit, relative to the normal range, 
will be prepared. 
The amino acid data collected for each study period will be summarized similarly. 
Glutamine and glutamate results as well as the sum of glutamine and glutamate values 


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will be summarized in a separate table. Glutamine values will be plotted (mean ± 
standard error) by study visit. Branched chain amino acids will be summarized 
separately in a similar manner. 
 
4.5.3 Vital signs 
Results for systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
temperature will be summarized, along with the change from baseline, by treatment 
and visit. Body surface area (BSA) will be calculated as 
 
BSA(m2 ) = 
 
 
 
4.5.4 Hyperammonemic events 
The number of hyperammonemic (HA) crises and the number of subjects with at least 
one crisis will be summarized by study and age group (pediatric and adults). Peak 
observed ammonia during the crises will also be summarized. Precipitating factors and 
symptoms recorded as suggestive to hyperammonemia will be summarized. The 
duration of the crisis in hours will be calculated as stop date/time minus start date/time. 
If time is not known, then it will be assumed to be 12:00pm. A correlation analysis will 
be performed to determine if the ammonia value at admission is a determining factor 
on the length of the crisis. Spearman’s rank-order correlation will be used. 
HA crisis history data will be obtained from the databases of the original studies (HPN- 
100-005, HPN-100-007, or HPN-100-012) and summarized similarly. 
 
4.6 Exploratory Efficacy Analyses 
Blood samples will be collected for assessment of venous ammonia levels at office 
visits in accordance with the study protocol. Ammonia data will be summarized by 
study visit and relative to the baseline value in order to evaluate the long-term benefit 
of HPN-100 on controlling blood ammonia levels. 
 
All analyses of ammonia data collected as part of this protocol will be considered 
exploratory in nature and will be used as supportive to data collected under prior 
HPN-100 studies. 
 
Ammonia data will be presented using the normalized values described below as well 
as the raw or non-normalized results. 
 
4.6.1 Standardization and Normalization of the Ammonia Level Data 
Two units are used for the ammonia data, µmol/L and µg/dL. All data will be converted 
to SI unit (µmol/L) before the normalization, imputation and calculation of the AUC. 
The conversion formula is µg/dL * 0.5872 = µmol/L. 
The ammonia level data are obtained from different local laboratories and each 
laboratory may use a slightly different normal reference range. Therefore, the 
ammonia level data will be normalized to a standard laboratory reference range before 
weight (kg) × height (cm ) 
3600 


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performing any analysis of ammonia data. This normalization will be done by applying 
the scale normalization approach, using the following formula: 
 
s = x *(Us / Ux), 
 
where s is the normalized laboratory value, x is the original laboratory value, Ux is the 
upper limit of the normal reference range from the original laboratory, and Us is the 
upper limit of the normal reference range for the standard laboratory. For example, if 
a value of 10 was obtained from a local laboratory with a normal range of 5 – 25, and 
we want to normalize this value to a standard reference range, that was established to 
be 10 – 35, then by applying the above formula, we would obtain a normalized value 
of 14 as detailed below: 
 
s = 10 *(35 / 25) = 14 
These standardized and normalized values will be used in summaries of ammonia data. In 
addition to the normalized data, selected ammonia analyses may be repeated using raw/non- 
normalized results. 
 
 
4.6.2 Analysis of Ammonia Data 
Ammonia values will be summarized with descriptive statistics, along with the change 
from baseline for each study visit. 
Changes in average ammonia values from baseline to the average ammonia obtained 
during the entire study period will be analyzed. For this analysis, all available ammonia 
data obtained after beginning treatment under protocol HPN-100-011 will be averaged 
(including the values obtained while the subject was in hyperammonemic crisis) and 
compared to the baseline value. 
The percentage of abnormal ammonia values and ammonia values ≥ 2 times the ULN 
will be summarized by study visit. 
 
4.7 Disposition of Patients 
The number and percentage of patients receiving study treatment who completed or 
prematurely discontinued the study and the reasons for any premature discontinuation 
will be presented. In addition to study completion, the number of subjects who 
completed 3, 6, 9, 12 and >12 months of treatment with HPN-100 under this protocol 
will be summarized. 
 
4.8 Concomitant Medication 
Incidence of concomitant medications will be presented by therapeutic area and 
preferred drug name. Medications will be coded using the WHO Drug dictionary. 
Concomitant medications are all medications taken during the study period, including 
those started before but ongoing at first dose. 
Where a medication start date is partially or fully missing, and it is unclear as to whether 
the medication is prior or concomitant, it will be assumed that it is concomitant. 


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4.9 Exposure to HPN-100 
The number of patients treated with HPN-100 will be summarized. The dose of HPN- 
100 in mL/day, grams/day, grams/m2, and mg/kg will be summarized. Date of last dose 
of study drug will be derived from the last daily dose date and compared to last dose 
captured from the CRF when available. The total duration of HPN-100 treatment will 
also be summarized. Duration will be calculated as follows: 
Duration = Date of Last Dose – Date of First Dose +1. 
The duration of treatment will be summarized based on treatment under protocol HPN- 
100-011 as well as total treatment with HPN-100 based on data from the original 
studies the subjects participated in (HPN-100-005, 007, and 012). 
Data on dose modifications will be listed. 
 
4.10 Neuropsychological Testing 
Neuropsychological (NP) battery testing will be performed at study entry, every 12 
months (or early termination visit), and at the End of Study. For adults, the following 
tests will be performed: 
• Wechsler Abbreviated Scale of Intelligence (WASI) 
• Digit span 
• Grooved pegboard 
• California Verbal Learning Test (CVLT-II) 
For pediatric patients, the following tests will be performed: 
• Wechsler Abbreviated Scale of Intelligence (WASI) 
• Child Behavior Checklist (CBCL) 
• Behavior Rating Inventory of Executive Function (BRIEF) 
 
 
Results will be summarized and listed by subject. 
Tests are to be administered by a properly trained medical professional. Instructions 
to administer these tests, including individual test manuals and kits, will be provided in 
the Study Manual. 
For the WASI test, the vocabulary T score, matrix reasoning T score, and full scale IQ 
standard score will be summarized using descriptive statistics. 
For the CBCL form, the T-score for each item will be summarized. 
The T-score for each item will be summarized for the BRIEF tests. 
Change from baseline will be compared using paired t-tests for all NP tests. 
The Scaled Score for the Digit Span will be summarized. The Z scores for the dominant 
and non-dominant hands will be summarized for the Grooved Pegboard test. 
The T score for the CVLT-II List A Total 1-5 and the Z score for rows 1-6 will be 
summarized using descriptive statistics. 
Summaries for adult and pediatric patients will be produced separately. 


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4.11 Protocol Violations or Deviations 
Violations and deviations from the protocol will be documented on an ongoing basis by 
the study monitors and project managers throughout the study period. These 
violations/deviations will be included in the clinical study report. 
 
4.12 Deviations from SAP 
Any deviations from the final SAP will be described and justified in the final clinical 
study report. 
 
4.13 Changes in Conduct or Planned Analyses from the Protocol 
Paired t-tests for the neuropsychological tests were added to the SAP. 


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5 Tables and Listings 
All output will be produced using SAS version 9.1.3 or later. In general, outputs will be 
prepared in the following manner. 
 
5.1 Format 
At the top of each table/listing/figure, a number followed by the title will be presented. 
After the title line, optional sub-title or population information will be presented. 
Horizontal lines will appear before and after the column heading of the table/listing. 
Footnotes will be put under the main body of text. 
The sponsor name, protocol number, programmer ID, status of the output (i.e. draft or 
final), SAS program name, and the date and time of creation will be on the output. The 
page number will appear on the bottom right corner of each output (Page X of Y). 
Outputs will be prepared in landscape layout unless otherwise specified. All margins 
will be a minimum of 1 inch. In general, Courier New, 8 point font will be used for tables 
and listings. If necessary for formatting, an alternate font type or size may be used. 
 
5.2 Conventions 
Unless otherwise specified, in summary tables of continuous variables, the minimum 
and maximum values will be displayed to the same number of decimal places as the 
raw data, the mean and median will be presented to one extra decimal place compared 
to the raw data, and the standard deviation will be displayed to two extra decimal 
places compared to the raw data. Wherever possible, data will be decimal aligned. 
Unless otherwise specified, frequency tabulations will be presented by number and 
percentage, where the percentage is presented in brackets to 1 decimal place. 
P-values, if applicable, will be presented to 3 decimal places. If the p-value is less than 
0.001 then it will be presented as <0.001. If the rounded result is a value of 1.000, it 
will be displayed as >0.999. Any date information in the listing will use the date9. format 
(e.g., 01JAN2012). In the listing, a unit associated with a variable will be presented 
only once within parentheses either below or next to that variable in the heading 
portion. If a parameter has multiple units, each unit will be displayed only once, as 
applicable. 
Listings will be sorted by site, patient and visit, as appropriate. 
The mock ups and table of contents (Final Version 1 dated 15Feb2013) as part of this 
SAP provide the expected layout and titles of the tables, listings, and figures. Any 
changes to format, layout, titles, numbering, or any other minor deviation will not 
necessitate a revision to the SAP nor will it be considered a deviation from planned 
analyses. Only true differences in the analysis methods or data handling will 
necessitate such documentation.