A Randomised, Controlled, Open-Label Parallel Arm Study of Safety, PK and Ammonia Control of RAVICTI® (Glycerol Phenylbutyrate) Oral Liquid and Sodium Phenylbutyrate in Phenylbutyrate Treatment Naïve Patients With Urea Cycle Disorders
Phase: PHASE4
Conditions: Urea Cycle Disorder
Sponsor: Amgen

IND NUMBER:
073480
EudraCT NUMBER
2015-000075-27
STUDY NUMBER:
HPN-100-021
INVESTIGATIONAL DRUG:
RAVICTI® (glycerol phenylbutyrate) Oral Liquid
STUDY TITLE:
A Randomised, Controlled, Open-Label Parallel
Arm Study of the Safety, Pharmacokinetics and 
Ammonia Control of RAVICTI®(Glycerol 
Phenylbutyrate [GPB]) Oral Liquid and Sodium 
Phenylbutyrate (NaPBA) in Phenylbutyrate 
Treatment Naïve Patients with Urea Cycle 
Disorders (UCDs)
SPONSOR:
HorizonTherapeutics, LLC
1 Horizon Way
Deerfield, IL  60015
Amendment 11:
Amendment 10:   
Amendment 10:
Amendment 9:                                               
Amendment 8:                                                       
Version 12.023Sep2022
Version 11.0 Administrative Change#1
22April2022
Version 11.0   12November2019
Version 10.0 28August 2018
Version 9.0   15 June2018
Amendment 7:                                                        
Version 8.0   31 May 2017
Amendment 6:                                                         
Amendment 5:
Version 7.0   19 January 2017
Version 6.0   27 October 2016
Amendment 4:
Amendment 3:
Amendment 2:
Amendment 1: 
Version 5.0   22 June 2016
Version 4.0   23 September 2015
Version 3.0   07 August 2015
Version 2.0   17December 2014
Initial Version:
Version 1.0   23 July 2014
CONFIDENTIALITY STATEMENT
THIS CONFIDENTIAL INFORMATION IS ABOUT AN INVESTIGATIONAL DRUG PROVIDED FOR THE EXCLUSIVEUSE 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, WHICH IS DESI

Horizon Therapeutics, LLC CONFIDENTIAL                                                               Protocol HPN-100-021 
Clinical Study Protocol 
 
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INVESTIGATOR SIGNATURE PAGE 
 
 
 
Protocol Number: 
 
HPN-100-021 
Version: 
12.0, incorporating Amendment 11  
Protocol Title: 
 
A Randomised, Controlled, Open-Label Parallel Arm Study of the 
Safety, Pharmacokinetics and Ammonia Control of RAVICTI®  
(Glycerol Phenylbutyrate [GPB]) Oral Liquid and Sodium 
Phenylbutyrate (NaPBA) in Phenylbutyrate Treatment Naïve 
Patients with Urea Cycle Disorders (UCDs) 
Horizon Therapeutics, LLC 
 
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. 
 
 
 
 
 
 
Date 
 
 
 
 
 

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STUDY PERSONNEL CONTACT INFORMATION 
 
Name
Title
Organization
Telephone
E-mail
Name 
Title 
Organization 
Telephone 
Fax 
E-mail 
Name 
Title 
Organization 
Telephone 
Fax 
E-mail 
 
Name  Sponsor Contact for Emergency or Serious 
Adverse Event Reporting 
Organization 
Fax 
E-mail 
 
 CONTACT IN THE EVENT OF AN EMERGENCY 
Any death, life threatening event, or other Serious Adverse Event experienced by a subject 
during the course of the study, whether or not judged drug-related, must be reported within 24 
hours of knowledge of the event by entering the information into the electronic case report form 
(eCRF). If unable to access the eCRF, the event must be reported by submitting the completed 
Serious Adverse Event Form via email or fax to the contact numbers provided above. 
 
PPD
 
 
PPD
PPD
PPD

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SUMMARY OF CHANGES 
Protocol HPN-100-021 
Version 11.0 (22 April 2022) to Version 12.0 (23 September 2022) 
This amendment incorporates the following changes to the prior protocol: 
 Synopsis: Number of Subjects, Study Rationale: Updated to: 16 subjects  
 Synopsis; Sample Size and Statistical Considerations and Protocol Section 15.1:  A 
sample size of 16 subjects rather than 18 will be enrolled.  Approximately 12 subjects 
will complete the study 
 Administrative changes on pages 1, 2, 3, 4, 33, 43, 94, 95 
 Protocol Section 15.2 Interim Analysis:  updated to read:  There will be no formal interim 
analysis. 
 Protocol Section 20:  References; Lee 2015, corrected to Lee 2014 
Version 11.0 (12 November 2019) to Version 11.0 (22 April 2022) 
This amendment incorporates the following changes to the prior protocol: 
 
 Administrative changes on pages 1, 2, 4 of this protocol document 
 Section 7.1.5.1. Added the fax and email address for reporting SAE 
 
Version 10.0 (28 August 2018) to Version 11.0 (12 November 2019) 
This amendment incorporates the following changes to the prior protocol:  
                                      
 Administrative changes on pages 1 and 2 of this protocol document 
 Protocol Section 1, Prior studies with RAVICTI text replaced with the Benefit Risk 
Analysis from the EU PBRER (DL31Jan2019) section 18.2 
 Protocol list of abbreviations, VHP removed 
 Synopsis, Protocol Section 3.3, 5.2.2.1:  Clarifies the requirement to assign the initial 
dose of study drug according to the disease/treatment status on entry as set out in protocol 
section 3.3 
 Synopsis, Protocol Section 15.1:  Reduces the Number of Subjects to 18 
 Protocol section 15.4:  Removes age range for sub-groups, these will be defined in the 
Statistical Analysis Plan. 
 Synopsis, Protocol Section 4.1, 6, 9, 15.4,  Reduces age at entry to Birth 
 
Version 9.0 (15 June 2018) to Version 10.0 (28 August 2018) 

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This amendment incorporates the following changes to the prior protocol: 
 Synopsis Dosage and Regimen Transition Period, Protocol Sections 3.4, 5.2.2.3, 6.1.4:  
Provides a visit window of 2 days from End of Initial Treatment Period (EITP) visit to 
assignment to the next study period in order to evaluate ammonia and amino acid results 
from EITP, for subjects in Treatment Arm 1 
 Appendix A, Schedule of Assessments:  added footnote #22 to EITP visit 
 
Version 8.0 (31 May 2017) to Version 9.0 (15 June 2018) 
This amendment incorporates the following changes to the prior protocol: 
 Updated Horizon signature page in line with Horizon internal procedures 
 Synopsis  Study Procedures section, Protocol Sections 3.2.1, 6.1.3, 15.4.2, and Appendix 
A, Schedule of Assessments, updated to clarify the timing of randomisation ie.  
Following baseline assessments and confirmation of eligibility, up to and including Initial 
Treatment Period Day 1, subjects will be randomised 
 Amino Acid Panel for analysis at study visits has been updated 
 Treatment Success clarified to include: 
- specific timepoint (Hour 0) to assess glutamine levels 
-  specific timepoint (Hour 0) to assess amino acids 
-  specific Amino Acids which contribute to Treatment Success are listed: Essential amino 
acids and branch chain amino acids: threonine, phenylalanine, methionine, lysine, 
leucine, isoleucine, histidine, valine  
 Study Endpoints in Protocol Synopsis, Protocol section 2.2 and Protocol section 15.3 
have been revised for consistency. 
 Section 15.4.2  mITT population has been updated per SAP 
 Updated sponsor contact for SAE reporting 
 Section 7:  Updated SAE reporting process  
 Section 8: corrected order of priority for blood samples 
 Administrative Changes as appropriate 
 
Version 7.0 (19 January 2017) to Version 8.0 (31 May 2017) 
This amendment incorporates the following changes to the prior protocol: 
 Clarifies that NaPBA powder and NaPBA granules are the same product 
 Adds requirement to collect AST, ALT and total bilirubin at Unscheduled visits  
throughout the study when subjects experience hyperammonemia, HAC or PAA toxicity 

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and when PK sampling occurs at unscheduled visits due to signs and symptoms of HAC 
or PAA toxicity 
 Corrects the prior summary of changes, protocol version 4 to protocol version 5 to 
include: Removal of the requirement for the subject to complete the Clinical Global 
Impression scale 
Version 6.0 (27 October 2016) to Version 7.0 (19 January 2017) 
This amendment incorporates the following changes to the prior protocol: 
 Revises the inclusion criteria to allow subjects 
 of age and older 
 Updates the age range for measurement of head circumference 
 Updates the age range for administration of CBCL 
 Includes a recommendation for step-wise reduction of the dose of phenylbutyric acid 
(PBA) 
 Adds stopping rule relating to adverse clinical and laboratory parameters  
 Adds stopping rule relating to pregnancy 
 
 
 Adds an anticipated dropout rate and rationale for sample size calculations 
 
Version 5.0 (22 June 2016) to Version 6.0 (27 October 2016) 
This amendment incorporates the following changes to the prior protocol: 
 Corrects the prior summary of changes to include removal of the inclusion criterion of 
weight > 15 Kg 
 
the upper 
limit of normal (ULN) 
 Adds collection of plasma and urine for pharmacokinetic (PK) assessments whenever a 
subject presents at the study center with hyperammonemic crisis (HAC) or potential 
phenylacetic acid (PAA) toxicity and as feasible when subjects present at other health 
care facilities 
 Adds the signs and symptoms of PAA toxicity to section 1.2.1 
 Revises the dose adjustment algorithm in section 3.8 to: 
o  Add specificity regarding plasma ammonia > ULN when the subject is 
asymptomatic 
o Include the maximum daily doses of study drugs 
o Provide definitions of terms used in the algorithm 

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 Adds dietary protein adjustment guidelines to section 5.6 and capture of dietary changes 
to each relevant visit 
 Corrects typographical and formatting errors 
Version 4.0 (23 September 2015) to Version 5.0 (22 June 2016) 
This amendment incorporates the following changes to the prior protocol: 
 Changes the design for the initial dosing period from a crossover to a parallel arm 
 Adds information on the EMA approval of RAVICTI 
 Replaces Crossover Periods 1 and 2 with a single parallel arm Initial Treatment Period (4 
weeks) 
 Adds  a RAVICTI only Transition Period (1 week) 
 Adds a RAVICTI only Maintenance Period (8 weeks) 
 Changes the duration of the Safety Extension Period to 12 weeks 
 Removes the Optional Long Term Safety Extension Period 
 Removes pharmacokinetic (PK) analyses for sodium benzoate (NaBz) 
 Removes inclusion criterion of weight > 15 Kg 
 Limits analysis of serum phenylbutyric acid (PBA), phenylacetatic acid (PAA), and 
(phenylacetylglutamine) PAGN, as well as, urine PAGN to the End of Initial Treatment 
Period (EITP) visit 
 Modifies the definition of Treatment Success 
 Adjusts the PBA starting dose based on disease and treatment status at study entry 
 Adds a dose adjustment algorithm 
 Adds a process for product complaints 
 Changes the entity responsible for receiving SAE reports  
 Adds the maximum daily dose of study drug to all relevant sections 
 Adds a contact at 30 days post study to check for SAEs and pregnancy 
 
Protocol Version 4 was the first version approved via the Voluntary Harmonisation Procedure.  
Prior changes to the protocol are not addressed in this document. 
 

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for any other reason (palatability, dose volume, etc.) may enter the 
Transition Period on RAVICTI after they have completed the EITP visit. 
 
Transition Period 
Treatment Arm 1 subjects who achieved treatment success should proceed 
directly to the Maintenance Period. All others will receive RAVICTI in the 
Transition Period.  For subjects in Treatment Arm 1, where Ammonia 
or Amino Acid panel (glutamine, threonine, phenylalanine, 
methionine, lysine, leucine, isoleucine, histidine, valine) results are 
not available on the day of EITP visit; the investigator will contact 
the subject (phone/email) within 2 days, to adjust the dose of 
RAVICTI if necessary, and to confirm whether the subject should 
proceed to the Transition Period or Maintenance Period 1.  
Treatment Arm 1 treatment failures will have their RAVICTI dose or diet 
adjusted, if indicated to achieve ammonia control. See the Dose Adjustment 
Algorithm in section 3.8. 
Treatment Arm 2 subjects who achieved treatment success will begin 
RAVICTI at a dose equivalent to the NaPBA dose they were receiving at 
the end of the Initial Treatment Period. The following formula should be 
used to calculate equivalent dose: 
RAVICTI dose (mL) = NaPBA tablet dose (g) x 0.86 
RAVICTI dose (mL) = NaPBA powder/granulesdose (g) x 0.81 
Treatment Arm 2 treatment failures will begin RAVICTI at a dose that 
delivers an adjusted PBA dose, if indicated to achieve ammonia control. 
Alternatively, they may begin RAVICTI at a dose equivalent to their 
NaPBA ending dose and have diet adjusted, if indicated. See the Dose 
Adjustment Algorithm in section 3.8. 
Dose Adjustment  
During the Transition Period, the dose of RAVICTI can be adjusted at the 
discretion of the Investigator. See the Dose Adjustment Algorithm in 
Section 3.8 for guidelines on changes and related plasma ammonia 
assessment intervals. 
All subjects with adequate ammonia control (at minimum morning/fasting 
plasma ammonia < ULN at the ETPD7 visit), in the opinion of the 
Investigator, may proceed to the Maintenance Period. 
Maintenance Period 
Subjects will receive RAVICTI in the Maintenance Period.  All subjects 
will continue at the dose of RAVICTI they were receiving at the end of the 
prior study period.  
Dose Adjustment  
During the Maintenance Period, the dose of RAVICTI can be adjusted at 
the discretion of the Investigator. See the Dose Adjustment Algorithm in 

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Section 3.8for guidelines on changes and related plasma ammonia 
assessment intervals. 
Safety Extension 
After the completion of the Maintenance Period, subjects will receive 
RAVICTI in the Safety Extension. All subjects will enter the Safety 
Extension at the dose of RAVICTI they were receiving at the end of the 
Maintenance Period.   
Dose Adjustment 
During the Transition Period, the dose of RAVICTI can be adjusted at the 
discretion of the Investigator. See the Dose Adjustment Algorithm in 
Section 3.8 for guidelines on changes and related plasma ammonia 
assessment intervals. 
For subjects who were taking NaBz at study entry, NaBz may be resumed 
during the Safety Extension Period at the discretion of the Investigator, 
provided that the dose of NaBz is never greater than the equivalent of the 
dose of RAVICTI that the subject is taking. Please see protocol Section 
5.2.2.2 for dose equivalents of RAVICTI. 
Subjects with Gastrostomy Tubes (G-Tubes) or Nasogastric Tubes (NG 
Tubes): 
Subjects who enter the study with a G-tube or NG tube who cannot tolerate 
the study drug via oral administration may remain in the study and continue 
receiving the study drug through a G-tube or NG tube. Oral administration 
should be attempted on Day 1 of the Initial Treatment Period (unless the 
subject has swallowing difficulty).  If oral administration is not successful, 
the reason for failure will be captured in the eCRF. 

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TABLE OF CONTENTS 
 
PROTOCOL SIGNATURE PAGE 
.................................................................................................2 
INVESTIGATOR SIGNATURE PAGE 
.........................................................................................3 
STUDY PERSONNEL CONTACT INFORMATION 
...............................................................
....4 
SUMMARY OF CHANGES 
..........................................................................................................5 
SYNOPSIS. 
.....................................................................................................................................9 
TABLE OF CONTENTS 
..............................................................................................................24 
LIST OF TABLES 
........................................................................................................................28 
LIST OF FIGURES 
...............................................................
........................................................29 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
................................................30 
1. 
BACKGROUND INFORMATION 
...........................................................................32 
1.1. 
Introduction and Background 
.....................................................................................32 
1.2. 
Summary of Potential Risks and Benefits 
...............................................................
...34 
1.2.1. 
PAA Toxicity 
.............................................................................................................36 
1.3. 
Study Rationale 
..........................................................................................................36 
1.4. 
Conduct of Trial and Compliance with Good Clinical Practice 
.................................36 
1.5. 
Study Population 
........................................................................................................36 
2. 
TRIAL OBJECTIVES AND ENDPOINTS 
...............................................................37 
2.1. 
Objective 
....................................................................................................................37 
2.2. 
Endpoints 
...............................................................
.....................................................37 
2.2.1. 
Efficacy 
......................................................................................................................37 
2.2.2. 
Safety and Tolerability ...............................................................................................37 
2.2.3. 
Clinical Outcome Assessments 
...................................................................................37 
2.3. 
Pharmacokinetics 
.......................................................................................................37 
3. 
DESIGN AND PLAN.................................................................................................39 
3.1. 
Description 
.................................................................................................................39 
3.2. 
STUDY SCHEDULE 
.................................................................................................41 
3.2.1. 
Randomisation: 
...............................................................
............................................42 
3.3. 
Initial Treatment Period - First Dose Initiation and Adjustment: 
...............................42 
3.4. 
Transition Period: ...............................................................
........................................43 

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3.5.
Maintenance Period:...................................................................................................44
3.6. 
Safety Extension: 
...............................................................
.........................................44 
3.7. 
Duration of the Study 
..................................................................................................44 
3.8. 
Dose Adjustment ........................................................................................................44 
3.8.1. 
Dose Adjustments 
......................................................................................................48 
3.9. 
Stopping Rules 
...........................................................................................................48 
3.9.1. 
Stopping Rules for Individual Subjects 
......................................................................48 
3.10. 
Hyperammonemic Crises 
............................................................................................48 
3.10.1. 
Management of Subjects with Hyperammonemic Crisis ...........................................49 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
..............................................50 
4.1. 
Subject Inclusion Criteria 
...........................................................................................50 
4.2. 
Subject Exclusion Criteria 
..........................................................................................50 
4.3. 
Subject Withdrawal Criteria 
.......................................................................................51 
4.4. 
Criteria for Premature Termination or Suspension of the Study 
................................51 
5. 
TREATMENT OF SUBJECTS 
..................................................................................52 
5.1. 
Description of Study drug 
...........................................................................................52 
5.1.1. 
RAVICTI (glycerol phenylbutyrate) Oral Liquid 
.......................................................52 
5.1.2. 
NaPBA (sodium phenylbutyrate) Tablet or Powder/Granules 
...................................52 
5.2. 
Study drug Dosage and Administration 
......................................................................52 
5.2.1. 
Preparation 
.................................................................................................................52 
5.2.2. 
Dose and Administration 
............................................................................................53 
5.3. 
Study Drug Materials and Management 
.....................................................................56 
5.3.1. 
Study Drug Packaging and Labeling 
..........................................................................56 
5.3.2. 
Study Drug Storage 
....................................................................................................57 
5.3.3. 
Study Drug Accountability 
.........................................................................................57 
5.3.4. 
Study Drug Handling and Disposal 
............................................................................57 
5.4. 
Treatment Compliance 
................................................................................................57 
5.5. 
Concomitant Medications 
...........................................................................................57 
5.6. 
Nutrition 
.....................................................................................................................58 
5.7. 
Randomisation and Blinding 
......................................................................................59 
6. 
STUDY PROCEDURES 
............................................................................................60 
6.1. 
Study Visits 
................................................................................................................60 
6.1.1. 
Screening Assessments (Performed within 30 days of Baseline) 
...............................60 

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6.1.2.
Baseline (Day -3 to -1)...............................................................................................60
6.1.3. 
Initial Treatment Period 
..............................................................................................61 
6.1.4. 
End of Initial Treatment Period (EITP - last day of the Initial Treatment 
Period/Start of the Transition or Maintenance Period  optional overnight 
stay) 
............................................................................................................................63 
6.1.5. 
Transition Period (7 days ± 2 days) 
............................................................................64 
6.1.6. 
Maintenance Period  (8 Weeks) 
..................................................................................65 
6.1.7. 
Safety Extension Period (12 Weeks) 
..........................................................................66 
6.1.8. 
End of Study Visit or Early Termination 
...................................................................67 
6.1.9. 
30 Day Follow-Up (+ 7 days) 
.....................................................................................68 
6.2. 
Early Termination Procedures 
....................................................................................68 
6.3. 
Assessment of Efficacy 
...............................................................................................68 
7. 
ASSESSMENT OF SAFETY 
.....................................................................................70 
7.1. 
Adverse Events (AEs) 
.................................................................................................70 
7.1.1. 
Definition of Adverse Event 
.......................................................................................70 
7.1.2. 
Definition of Serious Adverse Event 
..........................................................................71 
7.1.3. 
Assessment of Severity 
...............................................................................................72 
7.1.4. 
Recording Adverse Events .........................................................................................72 
7.1.5. 
Procedures for Reporting Serious Adverse Events and Product Complaints 
.............73 
7.1.6. 
Duration of Follow-up for Patients with Adverse Events ..........................................73 
7.1.7. 
Investigator Notification of Important New Safety Information 
................................74 
7.1.8. 
Pregnancy ...................................................................................................................74 
7.1.9. 
Assessment of Relationship to Study drug 
...............................................................
..74 
8. 
LABORATORY ASSESSMENTS 
............................................................................76 
9. 
VITAL SIGNS, HEIGHT, WEIGHT, AND HEAD CIRCUMFERENCE 
................78 
10. 
PHYSICAL EXAMINATION 
...................................................................................79 
11. 
CLINICAL GLOBAL IMPRESSION (CGI) SCALES 
.............................................80 
12. 
EQ-5D-5L 
...............................................................
....................................................81 
13. 
NEUROPSYCHOLOGICAL TESTING....................................................................82 
13.1. 
Child Behavior Checklist (CBCL)..............................................................................82 
13.2. 
Adult Behavior Checklist (ABCL) and Adult Self-Report (ASR) 
.............................82 
14. 
PK AND OTHER ASSESSMENTS ..........................................................................83 
14.1. 
Handling of Blood Samples for PK Analysis 
.............................................................83 
14.2. 
Handling of Urine Samples for PK Analysis 
..............................................................83 

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15.
STATISTICS..............................................................................................................85
15.1. 
Sample Size and Power ..............................................................................................85 
15.2. 
Interim Analysis 
.........................................................................................................85 
15.3. 
Endpoints and Analyses 
..............................................................................................85 
15.3.1. 
Efficacy 
......................................................................................................................85 
15.3.2. 
Safety and Tolerability Endpoints 
..............................................................................85 
15.3.3. 
Clinical Outcome Assessments 
...................................................................................86 
15.4. 
Methods of Analysis 
...................................................................................................86 
15.4.1. 
Significance Level and Adjustment for Multiplicity 
..................................................86 
15.4.2. 
Analysis Populations ..................................................................................................86 
15.4.3. 
Baseline Demographic Variables ...............................................................................87 
15.4.4. 
Subject Disposition 
....................................................................................................87 
15.4.5. 
Efficacy Variables ......................................................................................................87 
15.4.6. 
Safety Variables 
.........................................................................................................87 
15.4.7. 
Statistical Analysis of Efficacy Variables ..................................................................88 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................90 
16.1. 
Study Monitoring 
.......................................................................................................90 
16.2. 
Audits and Inspections 
................................................................................................90 
16.3. 
Institutional Review Board/Independent Ethics Committee 
......................................90 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................91 
18. 
ETHICS ...............................................................
.......................................................92 
18.1. 
Ethics Review 
...............................................................
..............................................92 
18.2. 
Ethical Conduct of the Study 
......................................................................................92 
18.3. 
Written Informed Consent 
..........................................................................................92 
19. 
DATA HANDLING AND RECORD KEEPING 
......................................................93 
19.1. 
Inspection of Records 
.................................................................................................93 
19.2. 
Retention of Records ..................................................................................................93 
20. 
REFERENCES 
...............................................................
............................................94 
21. 
APPENDICES 
...............................................................
.............................................97 
APPENDIX A. SCHEDULE OF ASSESSMENTS ...................................................................98 
APPENDIX B. HEDONIC SCALE TO ASSESS PALATABILITY 
......................................104 
APPENDIX C. CLINICAL GLOBAL IMPRESSION (CGI) 
..................................................105 
APPENDIX D. ASSESSMENT OF DRUG PREFERENCE 
...................................................106 

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LIST OF TABLES
Table 1: Prevalence of Urea Cycle Disorders in the EU and US...................................................32 
Table 2: Dose Adjustment Algorithm 
............................................................................................46 
Table 3: Dietary Protein Guidelines ..............................................................................................58 
 

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LIST OF FIGURES
Figure 1: Study Design: Schema....................................................................................................41 
Figure 2: Starting Dose Schema ....................................................................................................45 
 
 
 
 
 

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Abbreviation or Specialist Term Explanation 
IRB 
Institutional Review Board 
ITP 
Initial Treatment Period 
IV 
Intravenous 
mITT 
modified intent-to-treat 
MP 
Maintenance Period 
NaBz 
sodium benzoate 
NAGS 
n-acetylglutamate synthetase 
NaPAA 
sodium phenylacetate 
NaPBA 
sodium phenylbutyrate 
NG Tube 
Nasogastric Tube 
OTC 
ornithine transcarbamylase 
PAA 
phenylacetatic acid (also referred to as phenylacetate) 
PAGN 
phenylacetylglutamine 
PBA 
phenylbutyric acid (also referred to as phenylbutyrate) 
PK 
Pharmacokinetic 
RAVICTI 
RAVICTI® (glycerol phenylbutyrate) Oral Liquid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
Safety Extension 
SOP 
standard operating procedure 
TP 
Transition Period 
U-PAGN 
urinary phenylacetyl glutamine 
UCD 
urea cycle disorder 
ULN 
upper limit of normal 
US 
United States 

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1.
BACKGROUND INFORMATION
1.1. 
Introduction and Background 
Urea cycle disorders (UCDs) are inborn errors of metabolism caused by a deficiency in one of 
six enzymes or two mitochondrial transport proteins involved in the production of urea, resulting 
in accumulation of toxic levels of ammonia in the blood (hyperammonemia). UCD subtypes are 
summarized in Table 1 (Seminara 2010, Orphanet 2013), along with estimated prevalence in the 
European Union (EU) and the United States (US).  These are rare diseases, and a recently 
estimated overall incidence in the US of 1 in 35,000 live births (Summar 2013) likely applies to 
Europe as well (Dionisi-Vici 2002).  
Table 1: Prevalence of Urea Cycle Disorders in the EU and US 
Deficiency 
Abbreviation Inheritance 
Pattern 
Estimated Prevalence 
in EU 
Estimated 
Prevalence in US 
Ornithine 
transcarbamylase 
OTC 
X-linked 
1 in 69,904 
1:14,000 
Argininosuccinate 
synthetase 
ASS 
Autosomal 
recessive 
1 in 50,800 (mild type) 
1 in 189,740 (classic) 
1:57,000 
Carbamoyl phosphate 
synthetase 
CPS 
Autosomal 
recessive 
1 in 142,857 
1:62,000 
Argininosuccinate 
lyase 
ASL 
Autosomal 
recessive 
1 in 146,857 
1:70,000 
Arginase 
ARG 
Autosomal 
recessive 
1 in 363,000 to                        
1 in 2,349,717 
1:350,000 
N-acetylglutamate 
synthetase 
NAGS 
Autosomal 
recessive 
(unknown/very rare) 
(unknown/very rare) 
Ornithine translocase HHH 
Autosomal 
recessive 
Exceedingly rare1 
(unknown/very rare) 
Aspartate glutamate 
transporter 
CITRIN 
Autosomal 
recessive 
Exceedingly rare1 
(unknown/very rare) 
1These are exceedingly rare UCD subtypes for which precise incidence rates are not available, because they occur 
much less frequently than ASL (Dionisi-Vici 2002).  Source:  Horizon Therapeutics data on file.  
The severity and timing of UCD presentation vary according to the severity of the deficiency, 
which may range from minor to extreme depending on the specific enzyme or transporter 
deficiency, and the specific mutation in the relevant gene. UCD patients may present in the early 
neonatal period with a catastrophic illness, or at any point in childhood, or even adulthood, after 
a precipitating event such as infection, trauma, surgery, pregnancy/delivery, or change in diet 
(Ah Mew 2015). Acute hyperammonemic episodes at any age carry the risk of encephalopathy 
and resulting neurologic damage that is sometimes fatal, but even chronic, sub-critical 
hyperammonemia can result in impaired cognition (Gropman 2007). UCDs are therefore 
associated with a significant risk of neurological abnormalities and intellectual and 

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developmental disabilities over all ages(Tuchman 2008, Krivitzky 2009). UCD patients with 
neonatal-onset disease are especially likely to suffer cognitive impairment (Krivitzky 2009) and 
death (Summar 2008) compared with patients who present later in life. 
Management of acute hyperammonemic crises (HAC) may require haemodialysis and/or 
intravenous (IV) administration of sodium phenylacetate (NaPAA) and sodium benzoate (NaBz). 
Orthotopic liver transplantation may also be considered for patients with severe disease that 
manifests itself in the neonatal period. Long-term UCD management is directed toward 
prevention of hyperammonemia and may include the following treatment options: 
 Restriction of dietary protein  
 Arginine and/or citrulline supplementation, which can enhance waste nitrogen 
excretion for certain UCDs   
 Sodium benzoate   
 Oral nitrogen-binding drug therapy that provides an alternate path for waste nitrogen 
removal including sodium phenylbutyrate (NaPBA; marketed as AMMONAPS
® in 
the EU and as BUPHENYL
® in the US).  
Despite dietary and pharmacologic management, UCD patients still experience episodes of 
hyperammonemia, which leads to further risk of hyperammonemic encephalopathy requiring 
aggressive medical intervention and chronic hyperammonemia leading to cumulative 
neurocognitive impairment (Krivitzky 2009).  
The clinical trials leading to the 2013 US approval and 2015 EMA approval of RAVICTI 
(glycerol phenylbutyrate) Oral Liquid (RAVICTI, formerly known as HPN-100), which involved 
short-term comparison of ammonia control and pharmacokinetics (PK) during equivalent dosing 
of NaPBA and RAVICTI (Lee 2010, Lichter-Konecki 2011, Diaz 2013, Smith 2013, Berry 
2014) as well as long-term open label RAVICTI dosing (Diaz 2013, Berry 2014), have also 
provided new information pertaining to the utility of fasting ammonia (Lee 2014), urinary 
phenylacetylglutamine   (U-PAGN) (Mokhtarani 2012) and the ratio of phenylacetic acid (also 
referred to as phenylacetate; PAA) to PAGN (phenylacetylglutamine) in plasma (Mokhtarani 
2013) as dosing biomarkers.  
The development program of RAVICTI involved switching patients who were already on 
NaPBA to RAVICTI to establish the non-inferiority of RAVICTI to NaPBA in terms of 
ammonia control. As a consequence, no patients who were naïve to phenylbutyric acid (PBA) 
were enrolled in the controlled studies. In the long-term study, a very limited number of patients 
were enrolled who had been diagnosed with UCD that were not on NaPBA and started receiving 
RAVICTI. Therefore limited data is available on patients naïve to PBA being treated with 
RAVICTI. 
RAVICTI, a prodrug of PBA and a pre-prodrug of the active compound phenylacetatic acid 
(PAA), has been approved in the US and Europe for use as a nitrogen-binding agent for chronic 
management of adult and paediatric patients from birth  with UCDs who cannot be managed by 
dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with 
dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, 
arginine, citrulline, protein-free calorie supplements). The limitations of use are as follows: 

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 RAVICTI is not indicated for the treatment of acute hyperammonemia in patients 
with UCDs. 
 The safety and efficacy of RAVICTI for the treatment of Nacetylglutamate synthetase 
(NAGS) deficiency has not been established. 
The current US RAVICTI Package Insert contains the following contraindications: 
 Known hypersensitivity to PBA. Signs of hypersensitivity include wheezing, 
dyspnea, coughing, hypotension, flushing, nausea, and rash.  
1.2. 
Summary of Potential Risks and Benefits 
.The clinical development program of RAVICTI, which comprised four short term and three 
long term studies including more than 100 UCD patients in the total study population, showed 
significant and clinically relevant efficacy of RAVICTI. The slow gastrointestinal absorption of 
RAVICTI, which presumably reflects the time required for digestion of RAVICTI by pancreatic 
lipases, leads to sustained levels of the active metabolites PAA and PAGN and results in evenly 
sustained release during the day, thus providing optimal reserve capacity to bind nitrogen 
between doses. This is the key to improved ammonia control and reduction in hyperammonemic 
events in UCD patients. Among all patient subgroups, RAVICTI demonstrated similar ammonia 
control independent of gender, age (2-11, 12-
-OTC) 
or age at onset. These lower ammonia levels were also maintained over 12 months of dosing in 
both adult and pediatric studies. 
Furthermore, RAVICTI significantly reduces glutamine levels, which correlate with plasma 
ammonia levels and symptoms in UCD patients. Its intracellular accumulation in glial cells is 
believed to mediate cerebral edema [Butterworth et al., 2009, Maestri et al., 1992, Tuchman et 
al., 2008].  
Approximately 50% of the UCD population is comprised of children, where compliance with 
treatment and sustained disease control are essential to provide normal growth and development. 
RAVICTI is an odorless, nearly tasteless liquid that requires no preparation and contains no 
sugar. RAVICTI is a palatable alternative for children that may increase compliance in this 
patient population. RAVICTI is also suitable for patients with hypertension due to the absence of 
sodium.  
The clinical data in 49 pediatric patients treated with RAVICTI up to 12 months indicates a 
favorable safety profile and ammonia control. The rate of documented hyperammonemic events 
after switching to RAVICTI showed the greatest decrease among the youngest patients, so that 
the rate of such crises decreased from 1.44/patient to 0.63/patient during treatment with 
RAVICTI. The improvement in cognitive function and in common symptoms associated with 
UCD was sustained and clinically meaningful in the pediatric study population treated with 
RAVICTI.  
Due to its liquid formulation, RAVICTI can also be administered via nasogastric tube or 
gastrostomy tube in patients with neurological impairment due to the underlying UCD. Overall, 
RAVICTI was shown to be well tolerated. ADRs believed to be unique to RAVICTI, such as 
flatulence, abnormal skin odor, decreased appetite or diarrhea, have been transient and mild.  

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The incidences of AEs were similar across the population subgroups including gender, race or 
UCD subtype. No trend towards an increase in the incidence of any treatment associated AE 
under long-term exposure with RAVICTI was identified.  
Furthermore, the favorable benefit-risk profile is supported by the completion of long-term 
studies by 90% of patients and the fact that only two (2%) patients discontinued treatment due to 
experiencing ADRs in these long-term studies.  
The use of RAVICTI is limited to the chronic management of UCD, and is not indicated for 
treatment of acute hyperammonemia, which requires emergency actions, such as hemodialysis 
for rapid ammonia detoxification.  
Of note, in the EU and US the indication for RAVICTI was extended for the pediatric population 
from birth based on results from the study HPN-100-009.  
There is limited information in relation to chronic use in subjects with UCDs. In long-term open 
label safety study HPN-100-011, RAVICTI was effective in maintaining ammonia control in 
adult and pediatric UCD subjects for up to 24 months. In addition, long-term treatment with 
RAVICTI was well tolerated, and the safety profile was consistent with the experience from the 
12 months of safety extension studies. The 10-year USA registry (HPN-100-014) will provide 
further information on long-term safety in the post authorization setting.  
The clinical findings collectively suggest that the benefits of RAVICTI substantially outweigh its 
risks, which are adequately addressed in the labeling. Furthermore, RAVICTI offers clinically 
meaningful advantages for UCD patients based on its slow-release formulation and improved 
tolerability. The slow-release formulation of RAVICTI allows for a more evenly waste nitrogen 
removal throughout the day, which results in better blood ammonia control with fewer 
quality of life. 
 
Prior Clinical Studies with NaPBA: 
NaPBA tablets and powder/granules have been approved for marketing in the US since 1996 as 
an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies 
of CPS, OTC, or ASS.  It is also indicated in all patients with neonatal-onset deficiency (enzyme 
deficiency presenting in the first 28 days of life) and in patients with late-onset disease who have 
a history of hyperammonemic encephalopathy. NaPBA must be combined with dietary protein 
restriction and, in some cases, essential amino acid supplementation. NaPBA should not be used 
to manage acute hyperammonemia, which is a medical emergency. 
For NaPBA, the assessment of clinical AEs was derived from 206 patients treated with NaPBA 
over a period of 20 years by many investigators across the US. AEs (both clinical and laboratory) 
were not collected systematically in these patients, but were obtained from patient-visit reports 
by the 65 co-investigators. In female patients, the most common clinical AE reported was 
amenorrhea/menstrual dysfunction (occurring in 23% of the menstruating patients). Decreased 
appetite, body odour (probably caused by the metabolite PAA), and bad taste or taste aversion 
were reported in 4%, 3%, and 3% of patients, respectively. A variety of laboratory abnormalities 
were also reported as AEs including acidosis, alkalosis, hyperchloremia, hypophosphatemia, 
hypoalbuminemia, decreased total protein, increased alkaline phosphatase and increased liver 
transaminases, anemia, leukopenia, leukocytosis, and thrombocytopenia 

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1.2.1.
PAA Toxicity
The major metabolite of RAVICTI and NaPBA, PAA, is associated with neurotoxicity. Signs 
and symptoms of PAA neurotoxicity, including somnolence, fatigue, lightheadedness, headache, 
dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting 
neuropathy, were observed at plasma PAA concentrations 
patients who were administered  IV PAA. In this study, adverse events were reversible. Although 
these have not been seen in clinical trials involving UCD patients, high PAA levels should be 
suspected in patients with unexplained somnolence, confusion, nausea and lethargy who have 
normal or low ammonia. 
1.3. 
Study Rationale 
The 2013 US approval of RAVICTI for UCDs was based on clinical studies that included     
cross-over comparison of ammonia control in stable UCD patients during equivalent steady-state 
dosing of NaPBA or RAVICTI, followed by long-term RAVICTI dosing studies. Most UCD 
patients enrolled in these studies were already on a stable dose of NaPBA and this study, which 
is a Food and Drug Administration post-marketing requirement, is therefore designed to assess 
the safety, efficacy and tolerability of RAVICTI as compared to NaPBA in patients who have not 
been treated chronically and are presently not being treated with oral phenylbutyrates (PAA 
prodrugs).  This study is also an element of the RAVICTI Risk Management Plan filed with the 
EMA.  This clinical study, HPN-100-021, is the first controlled and randomised study of 
RAVICTI in UCD subjects who have not been previously exposed chronically to phenylbutyrate 
derivatives. 
1.4. 
Conduct of Trial and Compliance with Good Clinical Practice 
This study will be conducted in compliance with the protocol, in accordance with the 
International Conference on Harmonisation (ICH) E6, and according to applicable regulatory 
requirements. 
1.5. 
Study Population 
Subjects eligible for this study will have a suspected or confirmed UCD diagnosis of any subtype 
except NAGS deficiency. Subjects must not be treated with PAA prodrugs (RAVICTI, NaPBA, 
Pheburane, or locally compounded mixture containing PAA prodrug) at the time of enrollment or 
for more than 14 consecutive days during the year prior to enrollment. 
For patients who are on NaBz at the time of enrollment, the Investigator must determine if 
transition from NaBz treatment to the use of PAA prodrugs (RAVICTI or NaPBA) will benefit 
the patient.   

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2.
TRIAL OBJECTIVES ANDENDPOINTS
2.1. 
Objective 
The objective of this study is to assess the safety, tolerability, PK, and ammonia control of 
RAVICTI as compared to NaPBA, in UCD subjects not currently or previously chronically 
treated with PAA prodrugs. 
2.2. 
Endpoints 
2.2.1. 
Efficacy 
2.2.1.1. Initial Treatment Period 
 Rate of Treatment Success (Primary)  
(See Section 6.3 for definition of Treatment Success) 
 Drug discontinuation due to any reason 
 
2.2.1.2. Transition, Maintenance and Safety-Extension Periods 
 Annualized rate of HAC 
 Control of Plasma Ammonia 
2.2.2. 
Safety and Tolerability 
 Assessment of AEs 
 Standard clinical laboratory tests  
 Amino acid panel 
 Rate of drug discontinuation due to AEs 
2.2.3. 
Clinical Outcome Assessments 
 Palatability of study drug (Hedonic Scale) 
 Drug preference at TPD7 (questionnaire) (Treatment Arm 2 only) 
 Changes in clinical global impression (CGI) scales (Investigator) 
 Neuropsychological assessments:  Child Behavior Checklist (CBCL) or Adult 
Behavior Checklist (ABCL) or Adult Self Report (ASR) 
 EQ-5D-5L health status quality of life assessment 
2.3. 
Pharmacokinetics 
For all subjects at the EITP visit: 
 Plasma PK parameters of PBA, PAA and PAGN 
 Urinary excretion of PAGN  

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For any subject upon presentation at the study center (and as feasible at other health care 
facilities) with signs and symptoms of HAC or PAA toxicity: 
 Plasma PK parameters of PBA, PAA and phenylacetylglutamine (PAGN) 
 Urinary excretion of PAGN 

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3.
DESIGN AND PLAN
3.1. 
Description 
This is a randomised, controlled, open-label parallel arm study of RAVICTI compared to 
NaPBA in UCD patients who are not currently and have not been chronically treated with PAA 
prodrugs. Subjects will be randomised to one of two treatment arms in which they will begin by 
receiving either RAVICTI or NaPBA at a dose that corresponds to their disease and treatment 
status at entry as follows: 1) presenting with hyperammonemic crisis (HAC) requiring a dose at 
the high end of the recommended and approved range; 2) inadequately controlled with diet and 
supplements requiring a dose in the middle of the recommended and approved range; and 3) 
stable on NaBz or needing additional scavenging while on NaBz treatment, requiring transition 
from NaBz to PBA at an equivalent dose. At the discretion of the Investigator and considering 
the clinical status of the subject, the dose may be adjusted after initial dosing.  
The approved dose of RAVICTI is 5-12.4 g/m2/day (US RAVICTI package insert).  
The recommended dose of NaPBA per its package insert is 450-600 mg/kg/day in patients 
weighing <20 kg or 9.9-13 g/m2/day in larger patients. 
The study design includes a Baseline Period, Initial Treatment Period, Transition Period, 
Maintenance Period and a Safety Extension Period. Prior to entering the Initial Treatment Period, 
subjects will be randomised 2:1 to Treatment Arm 1 (N=20) or Treatment Arm 2 (N=10) as 
follows:  
Treatment Arm 1:     RAVICTI  
or  
Treatment Arm 2:     NaPBA  
See Figure 1 for a schema of the overall study design. 
Subjects will receive their assigned study drug treatment (either RAVICTI or NaPBA) in the 
Initial Treatment Period for a period of approximately 4 weeks. Subjects who have reached and 
maintained a stable dose for at least 7 consecutive days by the end of the Initial Treatment Period 
will complete 8-hour plasma ammonia, amino acid panel, glutamine, PK, and spot urine 
collections.   
Subjects on NaBz entering the Baseline Period will have their NaBz treatment titrated down and 
simultaneously replaced with the assigned study drug (RAVICTI or NaPBA).   
After the completion of the Initial Treatment Period of the study, a subject will be considered a 
Treatment Success for NaPBA or RAVICTI if the subject has not experienced an unprovoked 
HAC (i.e., a HAC that cannot be attributed to one or more specific precipitating factors such as 
infection, intercurrent illness, diet noncompliance, treatment noncompliance, etc.) on the 
assigned treatment and has met at least 2 of the following 3 criteria: 
 Has absolute values at the 3 time points (pre-dose, after dose at 4 hours and 8 hours) of 
plasma ammonia levels which do not exceed ULN at the End of the Initial Treatment Period 
 Has normal ( ULN) glutamine levels at the end of the Initial Treatment Period at time point  
      0 Hour 

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Has normal 
) essential amino acids including branched chain amino acid levels
(specifically,  threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, 
valine ) at the end of the Initial Treatment Period at time point 0 Hour.    
Following successful completion of the Initial Treatment Period, subjects achieving a stable 
phenylbutyrate dose will begin the Maintenance Period and be treated with RAVICTI for 8 
weeks.  Treatment Arm 1 subjects will continue at the stable dose of RAVICTI they were 
receiving at the end of the Initial Treatment Period. Treatment Arm 2 subjects will begin 
RAVICTI at a dose equivalent to the NaPBA dose they were receiving at the end of the Initial 
Treatment Period; RAVICTI dose (mL) = NaPBA tablet dose (g) x 0.86 or NaPBA 
powder/granules dose (g) x 0.81. 
Subjects will be monitored in the RAVICTI Maintenance Period for adequate plasma ammonia 
control and clinical stability.   
Following completion of the Maintenance Period, subjects will begin the Safety Extension and 
be treated with RAVICTI for 12 weeks.  All subjects will continue at the dose of RAVICTI they 
were receiving at the end of the Maintenance Period. Subjects will continue to be monitored 
during phone and onsite visits that will include plasma ammonia and amino acid assessments. 
For subjects who were taking NaBz at study entry, the NaBz treatment may be resumed during 
the Safety Extension Period at the discretion of the Investigator. The dose of NaBz cannot be 
greater than the PBA equivalent of the dose of RAVICTI that the subject is taking. 
After completion of the Safety Extension Period, subjects will complete their participation in the 
study. The investigator may prescribe RAVICTI where it is commercially available or may 
contact the administrator of the Managed Access Program (MAP) in countries where RAVICTI 
is not commercially available. 

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Figure1:StudyDesign: Schema
 
3.2. 
STUDY SCHEDULE 
The study schedule consists of the following: 
Baseline (3 Days):  
During the Baseline Period, subjects will: 
 Provide informed consent 
 Undergo screening procedures  

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3.2.1.
Randomisation: 
Following baseline assessments and confirmation of eligibility, up to and including Initial 
Treatment Period Day 1, subjects will be randomised, in an open-label fashion, to Treatment 
Arm 1 or Treatment Arm 2 as follows:  
 Treatment Arm 1 (N=20):  
RAVICTI 
 Treatment Arm 2 (N=10):  
NaPBA  
3.3. 
Initial Treatment Period - First Dose Initiation and Adjustment: 
After randomisation, subjects will receive either RAVICTI or NaPBA in the dose range 
corresponding to their disease/treatment status at entry: 
Status at Entry 
Arm 1  RAVICTI  
Starting Dose Range 
Arm 2  NaPBA 
Starting Dose Range 
Stable (ammonia < 50% ULN)  
after presenting with HAC  
acutely managed with 
Ammonul®/dialysis 
11.2 mL/m
2/day 
Subjects weighing < 20Kg  
 0.6 g/kg/day 
All others   
13 g/m
2/day 
Not adequately controlled with 
diet and nutritional supplements 
8 ± 1 mL/m
2/day 
Subjects weighing < 20Kg  
 0.53 g/kg/day 
All others   
11.5 ± 0.5 g/m
2/day 
On NaBz treatment 
Gradual transition to equivalent 
dose (RAVICTI dose (mL) = 
NaBz dose (g) x 0.50 See 
section 5.2.2.1 
Gradual transition to equivalent 
dose (NaPBA tablet dose (g) = 
NaBz dose (g) x 0.58 
NaPBA powder/granules dose 
(g) = NaBz dose (g) x 0.63 See 
section 5.2.2.1 
 After administration of the initial dose (per protocol required ml/ m
2/day or g/ m
2/day for first 
dose) of study drug, at the discretion of the Investigator, the dose may be adjusted after initiation 
of therapy.  See section 3.8 Patients taking NaBz at Baseline will have their NaBz treatment 
titrated down as the study drug dose is increased to achieve a complete transition from NaBz to 
study drug.     
The Initial Treatment Period is 4 weeks (+/- 8 days) in duration.  Subjects will visit weekly (+/- 2 
days as counted from the prior scheduled visit) during this period. Subjects should be treated for 
at least 7 consecutive days at a stable dose, and at 100% of the dose of study drug (no NaBz), 
before undergoing 8-hour ammonia, amino acid panel, PK and spot urine sample collections at 
EITP prior to entering the next study period.  
There will be an optional overnight hospital stay at the end of the Initial Treatment Period.  
Alternatively, subjects may be released from the clinic after completion of all EITP procedures.  

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Dose adjustments(changes in the total daily dose)in the Initial TreatmentPeriod will be 
followed by repeat fasting/morning ammonia testing within an appropriate interval. See the Dose 
Adjustment Algorithm in section 3.8. 
3.4. 
Transition Period: 
Treatment Arm 1 (RAVICTI) subjects who meet the criteria for treatment success at the end of 
the Initial Treatment Period may proceed directly to the Maintenance Period. Treatment Arm 1 
subjects who do not meet the criteria for treatment success and all Treatment Arm 2 subjects may 
enter the 7 day Transition Period if the investigator considers continued treatment with 
RAVICTI to be an appropriate course of therapy. The Transition Period is 7 days in duration 
based on prior RAVICTI studies that have demonstrated this is an adequate period of time to 
move from NaPBA to RAVICTI and/or to stabilize on RAVICTI following a dose change. All 
subjects entering the Transition Period will receive RAVICTI.  
 Treatment Arm 1 subjects entering Transition will have their RAVICTI dose adjusted, if 
indicated, by the laboratory results at the EITP visit. 
olled (at minimum, fasting/morning was 
within the ULN at the EITP visit), the subject may enter Transition at the same dose of 
RAVICTI that he/she was receiving at the end of the Initial Treatment period.  
For subjects in Treatment Arm 1, where Ammonia or Amino Acid panel (glutamine, 
threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, valine) results 
are not available on the day of EITP visit; the investigator will contact the subject 
(phone/email) within 2 days, to adjust the dose of RAVICTI if necessary, and to confirm 
whether the subject should proceed to the Transition Period or Maintenance Period 1. 
 Treatment Arm 2 (NaPBA) subjects who meet the criteria for treatment success at the end 
of the Initial Treatment Period will begin RAVICTI at a dose equivalent to the NaPBA 
dose they were receiving at the end of the Initial Treatment Period.  
 Treatment Arm 2 (NaPBA) subjects who do not meet the criteria for treatment success at 
the end of the Initial Treatment Period will begin RAVICTI at a dose appropriately 
higher than the NaPBA dose they were receiving at the end of the Initial Treatment 
Period, if indicated. See the Dose Adjustment Algorithm in section 3.8. If in the 
minimum, fasting/morning was within the ULN at the EITP visit), the subject may enter 
Transition on RAVICTI at a dose equivalent to the NaPBA dose they were receiving at 
the end of the Initial Treatment Period. 
All Treatment Arm 2 subjects must be observed in the clinic for at least 1 hour after their first 
dose of RAVICTI. 
Dose adjustments (changes in the total daily dose) in the Transition Period will be followed by 
repeat fasting/morning ammonia testing within an appropriate interval. See the Dose Adjustment 
Algorithm in section 3.8. All subjects in the Transition Period will have morning/fasting plasma 
ammonia reassessed at an appropriate interval, not later than 7 days after entering Transition. If 
ammonia is adequately controlled, subjects may proceed to the Maintenance Period after 7 (± 2) 
days. 

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3.5.
MaintenancePeriod:
After completion of the Initial Treatment Period or Transition Period, subjects will receive 
RAVICTI in the Maintenance Period.  All subjects will continue at the dose of RAVICTI they 
were receiving at the end of the prior period. Subjects will alternate between phone/email and 
clinic visits every 2 weeks in the Maintenance Period.    
Dose adjustments (changes in the total daily dose) in the Maintenance Period will be followed by 
repeat fasting/morning ammonia testing within an appropriate interval. See the Dose Adjustment 
Algorithm in section 3.8. 
3.6. 
Safety Extension:  
Following completion of Maintenance Period, subjects will receive RAVICTI in the Safety 
Extension for 12 weeks.  All subjects will enter the Safety Extension at the dose of RAVICTI 
they were receiving at the end of the Maintenance Period. During the Safety Extension Period, 
subjects will visit every 4 weeks.  
Dose adjustments in the Safety Extension Period will be followed by repeat fasting/morning 
ammonia testing within 3-5 days. 
For subjects taking NaBz at study entry who transitioned from NaBz treatment during the Initial 
Treatment Period, the NaBz treatment may be resumed during the Safety Extension Period at the 
discretion of the Investigator, provided that the dose of NaBz is never greater than the equivalent 
of the dose of RAVICTI that the subject is taking.  Please see protocol Section 5.2.2.2 for dose 
equivalents of RAVICTI. 
Completion of the Safety Extension is the end of the study for all subjects. Investigators may 
prescribe RAVICTI for study subjects thereafter in regions where it is commercially available. 
Where RAVICTI is not commercially available, Investigators may apply to the MAP.  
3.7. 
Duration of the Study 
The study duration is approximately 25 weeks including:   
 Baseline Period:  Up to 3 days prior to Randomisation 
 Initial Treatment Period:  4 weeks (± 8 days -weekly visits are ± 2 days) 
 Transition Period: 7 days (± 2 days - All Treatment Arm 2 and Treatment Arm 1 
treatment failures) 
 Maintenance Period:  8 weeks (q 4week visits ± 7 days/ alternating with q 4 week 
phone/email contacts ± 4 days)  
 Safety Extension Period:  12 weeks (q 4 week visits ± 7 days) 
3.8. 
Dose Adjustment 
Throughout the study, the dose of study drug (RAVICTI or NaPBA) can be adjusted at the 
discretion of the Investigator. Adjustments may be indicated due to poor tolerability, to 
accommodate tapering the NaBz dose for those on NaBz at baseline, or to achieve the desired 
treatment effect and plasma ammonia control.  The Dosing Adjustment Algorithm below 
provides guidance on dose adjustments. Whenever dose is adjusted, morning or fasting ammonia 

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is to be repeated at an appropriate interval, generallywithin 3-5daysbut as early as clinically 
warranted and in no case > 7 days. An amino acid panel may also be repeated at the discretion of 
the investigator.  
 
Figure 2: Starting Dose Schema 
 
 

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2 Stable means plasma ammonia < ULN and asymptomatic 
3 Impending HAC means confirmed rising or elevated ammonia warranting intervention to prevent HAC and close observation for symptoms of 
hyperammonemia 

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Dose adjustment may be based on the following PBA equivalents for RAVICTI and NaPBA:  
 Each gram of NaPBA in tablet form contains approximately 0.880 g of PBA. 
 Each gram of NaPBA in powder/granules form contains approximately 0.818 g of 
PBA. 
 Each milliliter (mL) of RAVICTI delivers 1.1 g of GPB and 1.02g of PBA.  
The maximum daily doses of RAVICTI and NaPBA as stated in the current prescribing 
information should not be exceeded at any point during the study. The maximum total daily 
doses are: 
 RAVICTI - 17.5 mL  
 NaPBA in patients weighing < 20 Kg  600 mg/Kg 
 
 13 g/m2 
3.8.1. 
Dose Adjustments 
Dose adjustments must be followed by repeat fasting/morning plasma ammonia assessment 
within an appropriate time frame based on the reason for the adjustment.  See the Dose 
Adjustment Algorithm in section 3.8. Amino acids may also be collected at 
 
discretion.  These laboratory assessments will be captured as Unscheduled Visits and should 
occur at the study site during the Initial Treatment and Transition Periods. Thereafter, they may 
be done at an appropriate laboratory more con
 
3.9. 
Stopping Rules 
3.9.1. 
Stopping Rules for Individual Subjects 
Subjects meeting any of the following criteria must stop receiving treatment (either RAVICTI or 
NaPBA) and be withdrawn from the study: 
 Clinically significant allergy or hypersensitivity reactions to study drug requiring 
medical intervention and leading to discontinuation of RAVICTI and/or NaPBA 
 Liver transplant, including hepatocellular transplant 
 AE of Grade 4 or greater severity according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) or life-threatening AE 
if not covered by CTCAE except for events that are objectively unrelated to drug 
treatment. These patients must have been followed through resolution of the AE or up 
to 30 days after the completion of the study, whichever came first.  
 Pregnancy at any time during the study. 
3.10. 
Hyperammonemic Crises  
A HAC is defined as signs and symptoms consistent with hyperammonemia (such as frequent 
vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) which are 

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associated with high plasmaammonia requiring medical intervention.  Episodes of HAC may be 
controlled through standard-of-care measures, including parenteral administration of 
NaPAA/NaBz and/or dialysis.  A complete assessment of presenting signs and symptoms must 
be performed.  In addition, all triggering factors of the HAC must be assessed and treated until 
resolution at the discretion of the Investigator.  All interventions to treat HAC will be recorded 
on the appropriate eCRF.   
The history and occurrence of hyperammonemia will be recorded and captured in the database 
throughout the study.  
The following must be captured at a minimum: 
 Precipitating factors (e.g., infection, intercurrent illness, change in diet, 
noncompliance with the study drug, noncompliance with other UCD medication) 
 If due to noncompliance, reasons for noncompliance  
 Ammonia level at hospital admission, peak and discharge 
 Glutamine levels at admission, peak, and discharge (if performed as part of standard 
of care) 
 Single samples of blood and urine should also be collected upon presentation at the 
study center (and as feasible at other health care facilities) for PK analysis 
 AST, ALT, total bilirubin 
 Signs and symptoms suggestive of hyperammonemia 
3.10.1. Management of Subjects with Hyperammonemic Crisis 
Initial Treatment, Transition, and Maintenance Periods:   
If a HAC is experienced when subjects are receiving study drug during the Initial Treatment, 
Transition, or Maintenance Periods, medical management should be instituted and the study drug 
may be continued or temporarily stopped at the discretion of the Investigator and restarted after 
the subject is clinically stable. Subjects may continue in the study at the discretion of the 
Investigator.  However, the subject must be clinically stable and should be on a stable dose of the 
study drug (except if on NaPBA and transitioning early) for at least 7 consecutive days before 
undergoing the EITP procedures (8-hour PK, amino acid panel, and ammonia).   
Safety Extension Period:   
If a HAC is experienced during the Safety Extension, the study drug may be discontinued or 
temporarily stopped at the discretion of the Investigator and standard medical management 
should be instituted.  If stopped, study drug may be restarted after the subject is clinically stable 
and the presence of any factors contributing to the HAC have been identified and resolved. The 
dose of the study drug may be adjusted as needed. Temporary discontinuation of the study drug 
for this purpose will not constitute a withdrawal from the study and will be captured on the 
appropriate eCRF. 

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4.
SELECTION AND WITHDRAWAL OF SUBJECTS
4.1. 
Subject Inclusion Criteria 
Inclusion criteria are as follows: 
 Signed informed consent g
for those under 18 years of age or the age of consent by local regulation 
 Male and female subjects with a suspected or confirmed UCD diagnosis of any 
subtype, except NAGS deficiency  
 Suspected diagnosis is defined as having experienced an HAC or a documented 
high ammonia 
µmol/L (see Section 3.10 for HAC definition) 
 Confirmed diagnosis is determined via enzymatic, biochemical, or genetic testing 
 Requires nitrogen binding agents according to the judgment of the Investigator 
 Birth and older 
 All females of childbearing potential and all sexually active males must agree to use 
an acceptable method of contraception from signing the informed consent throughout 
the duration of the study and for 30 days after the last dose of study drug. Appropriate 
contraceptive methods include hormonal contraceptives (oral, injected, implanted, or 
transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double 
barrier methods. Abstinence is an acceptable form of birth control, though appropriate 
contraception must be used if the subject becomes sexually active.  
4.2. 
Subject Exclusion Criteria 
Exclusion criteria are as follows: 
 Subject has received chronic treatment with an oral phenylbutyrate (RAVICTI, 
NaPBA, Pheburane, or other) longer than 14 consecutive days within one year prior 
to enrollment 
 Temporary use of oral PBA for acute management of a hyperammonemic crisis in 
the past is acceptable. 
 Any concomitant illness (e.g. malabsorption or clinically significant liver or bowel 
Investigator  
 Have undergone liver transplantation, including hepatocellular transplant 
 Subjects on NaBz at Baseline will be excluded if they are viewed by the Investigator 
as being unable to undergo NaBz transition to a PAA prodrug during the Initial 
Treatment Period  
 Known hypersensitivity to PBA or any excipients of the NaPBA/PBA formulations 
 Pregnant or breast-feeding patients.  Women of childbearing potential must have a 
pregnancy test performed at the Baseline Visit prior to the start of study drug. 

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4.3.
Subject Withdrawal Criteria
Subjects may be withdrawn for any of the following reasons: 
 Voluntary withdrawal  
 Noncompliance as determined by the Investigator 
 At the discretion of the Investigator, if it is in the best interest of the subject 
 Having met any of the subject stopping rules (Section 3.9.1) 
 If pregnancy occurs at any time during the Initial Treatment Period in a subject 
receiving NaPBA (Section 7.1.8)  
 If lost to follow-up 
Please refer to Section 6.1.8 for additional details on the study procedures in the instance of 
Early Termination.  
4.4. 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless the following criteria are satisfied that require 
temporary suspension or early termination of the study. 
 New information regarding the safety or efficacy of the study drug indicates a change 
in the known risk/benefit profile for the compound, such that the risk/benefit is no 
longer acceptable for subjects participating in the study. 
 There is a significant violation of GCP that compromises the ability to achieve the 
primary study objectives or compromises subject safety. 
 

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5.
TREATMENT OF SUBJECTS
5.1. 
Description of Study drug 
5.1.1. 
RAVICTI (glycerol phenylbutyrate) Oral Liquid 
RAVICTI is a clear, colorless to pale yellow oral liquid. It is insoluble in water and most organic 
solvents, and it is soluble in dimethylsulfoxide and >65% acetonitrile.  
RAVICTI is a nitrogen-binding agent. It is a triglyceride containing 3 molecules of PBA linked 
to a glycerol backbone, the chemical name of which is benzenebutanoic acid, 1
', 1
' 
'-[1,2,3-
propanetriyl] ester. It has a molecular formula of C33H38O6 and a molecular weight of                
530.67 g/mol. 
RAVICTI contains no inactive ingredients.  
Each milliliter (mL) of RAVICTI delivers 1.1 g of GPB and 1.02g of PBA.  The density is       
1.1 g/mL. 
5.1.2. 
 NaPBA (sodium phenylbutyrate) Tablet or Powder/Granules 
NaPBA is a prodrug and is rapidly metabolized to PAA, the metabolically active compound that 
conjugates with glutamine via acetylation to form PAGN, which is excreted by the kidneys. 
NaPBA is an off-white crystalline substance, which is soluble in water. NaPBA is also freely 
soluble in methanol and practically insoluble in acetone and diethyl ether. It is known chemically 
as 4-phenylbutyric acid, sodium salt. It has a molecular formula of C
10H11O2Na and a molecular 
weight of 186 g/mol. 
Each gram of NaPBA in tablet form contains approximately 0.880 g of PBA. 
Each gram of NaPBA in powder/granules form contains approximately 0.818 g of PBA.  
5.2. 
Study drug Dosage and Administration 
5.2.1. 
Preparation 
No special preparation is needed for RAVICTI.  The dose should be drawn directly from the 
bottle and administered orally. It is recommended that subjects be fed immediately after dosing 
to ensure complete absorption of the drug.  
For infants and toddlers, RAVICTI should not be added to the feeding bottle or mixed with a 
large amount of formula or other liquids.  Due to its higher specific gravity, adding RAVICTI to 
formula in a bottle may cause it to settle to the bottom, thereby not allowing for adequate mixing 
or delivery of the full dose.  If needed, the dose can be added to small amount of formula in a 
small syringe, nipple or other age-appropriate dosing instrument and delivered orally followed 
by feeding. 
 
 

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For ease of administration, the individualdose can be rounded up to the nearest 0.1mL for 
RAVICTI. Each Individual dose can be rounded up to the nearest small spoon (spoons supplied 
with the drug) for NaPBA powder/granules, and to the nearest tablet for NaPBA tablet.  Subjects 
will be observed for at least 1 hour in the clinic after the initial dose of study drug. 
5.2.2.2. Titrating NaBz 
Subjects taking NaBz at Baseline will have their NaBz treatment titrated down and replaced 
completely by study drug (either NaPBA or RAVICTI) during the Initial Treatment Period.  
Assuming 70% conversion of RAVICTI to PBA and excretion of 2 moles of nitrogen in the form 
of PAGN per each mole of PBA delivered (compared to 70% conversion of NaBz to urinary 
hippuric acid scavenging 1 mole of nitrogen per mole of hippuric acid delivered as benzoate),   
0.5 mL of RAVICTI should replace 1 gram of NaBz. The following dose equivalents of 
RAVICTI and NaPBA should be considered when transitioning subjects from NaBz: 
 RAVICTI dose (mL) = NaBz dose (g) x 0.50 
 NaPBA tablet dose (g) = NaBz dose (g) x 0.58 
 NaPBA powder/granules dose (g) = NaBz dose (g) x 0.63  
A gradual transition from NaBz to PBA is suggested as follows: 
 Based on the dose equivalents above, calculate the target daily PBA dose based on the 
current NaBz dose.  
 Day 1  75% current NaBz dose and 25% target PBA dose 
 Day 2 - 50% current NaBz dose and 50% target PBA dose 
 Day 3 - 25% current NaBz dose and 75% target PBA dose 
 Day 4 - 25% current NaBz dose and 100% target PBA dose 
 Day 5 and ongoing -0 % current NaBz dose and 100% target PBA dose  
 
Throughout the transition, check plasma ammonia and amino acid panel as needed. Record all 
transition steps and laboratory results in the source and eCRF. 
Dose Adjustment in the Initial Treatment Period  
During the Initial Treatment Period, the dose of study drug (RAVICTI or NaPBA) can be 
adjusted at the discretion of the Investigator.  Adjustments may be indicated due to poor 
tolerability, to accommodate tapering the NaBz dose for those on NaBz at baseline, or to achieve 
the desired treatment effect and plasma ammonia control.   Dose adjustments will be 
individualized at the discretion of the Investigator and according to the needs of each subject and 
accounting for 
and ammonia 
control.  If the su
etabolic needs increase, the study drug dose may 
be increased accordingly.  No reduction in dose below the equivalent of 5 grams/m2/day of PBA 
is recommended; however it can be done if it is considered absolutely necessary by an 
Investigator. All dose adjustments will be followed by a repeat fasting/morning plasma ammonia 

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at an appropriate interval and no more than 7 daysfollowing the adjustment. All dose and diet 
adjustments will be captured in the eCRF. See the Dose Adjustment Algorithm in section 3.8. 
Subjects in Treatment Arm 1 who cannot tolerate RAVICTI due to AEs or any other reason in 
the Initial Treatment Period must be discontinued (complete early termination visit). The 8-hour 
ammonia, amino acid panel, PK, and spot urine collections should be completed if possible. 
Subjects in Treatment Arm 2  who cannot tolerate NaPBA during the Initial Treatment Period 
due to AEs or for any other reason (palatability, dose volume, etc.) may enter the Transition 
Period on RAVICTI after they have completed the 8-hour ammonia, amino acid panel, PK and 
spot urine sample collections at the EITP visit. 
Subjects who cannot achieve 7 consecutive days at a stable dose of RAVICTI or NaPBA 
(without NaBz) should complete the EITP visit.  
may proceed to the Transition Period. 
5.2.2.3. Transition Period 
Subjects in Treatment Arm 1 who were treatment successes at the EITP visit, should proceed to 
the Maintenance Period. Subjects in Treatment Arm 1 who were treatment failures at the EITP 
Visit may proceed to the Transition Period to optimize dose based on the Dose Adjustment 
Algorithm. For subjects in Treatment Arm 1, where Ammonia or Amino Acid panel (glutamine, 
threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, valine) results are not 
available on the day of EITP visit; the investigator will contact the subject (phone/email) within 
2 days, to adjust the dose of RAVICTI if necessary, and to confirm whether the subject should 
proceed to the Transition Period or Maintenance Period 1. 
All Treatment Arm 2 subjects should enter the Transition Period. Those who were treatment 
successes should receive the dose of RAVICTI equivalent to their NaPBA dose at the end of the 
Initial Treatment Period. Those who were treatment failures should receive a RAVICTI dose 
corresponding to an appropriate change in PBA. See the Dose Adjustment Algorithm in Section 
3.8. The following formula should be used to calculate equivalent dose: 
 RAVICTI dose (mL) = NaPBA tablet dose (g) x 0.86 
 RAVICTI dose (mL) = NaPBA powder/granules dose (g) x 0.81 
For ease of administration, the individual dose can be rounded up to the nearest 0.1 mL for 
RAVICTI.   
5.2.2.4. Maintenance Period  
At the end of the Initial Treatment Period or the Transition Period subjects will continue on the 
same dose of RAVICTI.  
The dose of RAVICTI may be adjusted during the Maintenance Period at the discretion of the 
Investigator. See the Dose Adjustment Algorithm in section 3.8. After any dose or diet 
adjustment in the Maintenance Period, subjects will return to the site (or a local laboratory) at an 
appropriate interval (unscheduled visit) for assessment of plasma ammonia and amino acids (if 
indicated). All dose and diet adjustments will be recorded in the eCRF. 

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5.2.2.5.
Safety ExtensionPeriod
Following completion of the Maintenance Period, subjects will receive RAVICTI in the Safety 
Extension at the same dose they received at the end of the Maintenance Period.   
During the Safety Extension Period, the dose of RAVICTI can be adjusted at the discretion of 
the Investigator.  See the Dose Adjustment Algorithm in section 3.8. 
After any dose or diet adjustment in the Safety Extension Period, subjects will return to the site 
(or a local laboratory) at an appropriate interval (unscheduled visit) for assessment of plasma 
ammonia and amino acids (if indicated). All dose and diet adjustments will be recorded in the 
eCRF. 
For subjects who were taking NaBz at study entry, the NaBz treatment may be resumed during 
the Safety Extension Period at the discretion of the Investigator.  The dose of NaBz cannot be 
greater than the equivalent dose of RAVICTI that the subject is taking. Please see protocol 
Section 5.2.2.2 for dose equivalents of RAVICTI. 
Subjects with Gastrostomy Tubes (G-Tubes) or Nasogastric Tubes (NG Tubes): 
While it is highly recommended that RAVICTI be administered orally, a G-tube or NG-tube may 
be used for RAVICTI or NaPBA administration for subjects unable to tolerate oral dosing.  
RAVICTI administered through a G-tube or NG-tube should be followed by one or two small 
flushes each of at least 10 mL of water or formula, administered through the same port as 
RAVICTI, as detailed in the Study Pharmacy Manual.   
A G-tube or NG-tube should only be used if the individual dose of RAVICTI is > 0.5 mL.  The 
individual dose of RAVICTI should be rounded up to the nearest 0.1 mL, for ease of 
administration.  
Subjects who enter the study with a G-tube or NG-tube who cannot tolerate the study drug via 
oral administration may remain in the study and continue receiving the study drug through a     
G-tube or NG-tube. Oral administration should be attempted on Day 1 of the Initial Treatment 
Period (unless the subject has known swallowing difficulty). If oral administration is not 
successful, the reason for failure will be captured in the eCRF. 
5.3. 
Study Drug Materials and Management 
5.3.1. 
Study Drug Packaging and Labeling 
NaPBA tablets will be supplied in 250 cc bottles containing 250 NaPBA tablets. The bottles are 
equipped with child-resistant caps. Each tablet is off-white, oval, 
 and 
contains 500 mg of NaPBA.  Doses in tablet form should be rounded up to the full tablet. 
NaPBA powder/granules will be supplied in 500 cc bottles, with 266 g of powder/granules, 
containing 250 g of NaPBA. The bottles are equipped with child-resistant caps. 
RAVICTI will be supplied in 1 ounce glass bottles with child resistant screw caps.  Disposable 
oral syringes will be provided for measuring and administering RAVICTI.   
Bottles will be labeled with study identification information and other pertinent information 
(contents, storage information, regulatory text, etc.) as necessary. 

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5.3.2.
Study DrugStorage
The storage conditions for NaPBA tablets and powder/granules are 15°  30°C (59°  86°F).  
RAVICTI storage conditions are 20°  25°C [68°  77°F] with excursions permitted to            
15°  30°C (59°  86°F). After opening, keep the bottle tightly closed after each use.  
5.3.3. 
Study Drug Accountability 
The Sponsor or designee will supply RAVICTI and NaPBA for this study. These medications 
will be dispensed to the Investigator or designee at each site. The site will maintain the following 
records: receipt of shipments, dispensing to subjects, and return of empty, partially used, and 
unopened bottles, conditions of storage. Study medication should not be returned to the Sponsor 
or designee before the study monitor has checked the drug accountability records with the site 
personnel. These records will be made available to study monitor for the purpose of accounting 
for RAVICTI and NaPBA. 
Study drug will be assigned and dispensed per the Study Pharmacy Manual and Schedule of 
Assessments (Appendix A:  Schedule of Assessments). Subjects will return any empty bottles 
and/or unused or partially used study drug at each visit and at Early Termination or End of 
Study. 
5.3.4. 
Study Drug Handling and Disposal 
At the completion of the study, all unused study medication, including partially used and 
unopened bottles, will be returned to the S
designee or disposed of at the site as 
applicable (see Study Pharmacy Manual for complete instructions). Subjects are not allowed to 
dispose of any study drug containers (empty or full) and must return empty or partially used 
bottles to the study clinic. 
Please reference the Study Pharmacy Manual for more detailed information on study drug 
packaging, labeling, and storage. 
5.4. 
Treatment Compliance 
Assessment of drug compliance will be made during the study based on study drug 
accountability records and/or by subject or parent/legal guardian interviews. 
5.5. 
Concomitant Medications 
Medications used at the time of study initiation may be continued at the discretion of the 
Investigator.   
The use of corticosteroids, valproic acid, or haloperidol may increase plasma ammonia levels. 
Therefore, ammonia levels should be monitored closely, as deemed appropriate by the 
Investigator, if the subject is on one of these medications.  
Probenecid may inhibit the renal excretion of metabolites of RAVICTI, including PAGN and 
PAA, and therefore this factor should be considered when assessing PK results. 
Information about administered medications at Baseline and during the study will be collected on 
source documents and the appropriate CRFs.  All concomitant medications used for any duration 
to treat an AE will be collected on source documents and the appropriate eCRFs.  The 

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6.
STUDY PROCEDURES
The schedule of assessments for subjects is provided in Appendix A-Schedule of Assessments. 
6.1. 
Study Visits 
6.1.1. 
Screening Assessments (Performed within 30 days of Baseline) 
Subjects will be screened for the study and will complete the following procedures:   
 Provide written informed consent either from the subject or the 
parent/legal 
guardian, as appropriate 
 Assessment by the Investigator that they have met the inclusion/exclusion criteria 
6.1.2. 
Baseline (Day -3 to -1)  
The following procedures should be completed at Baseline: 
 Perform physical and neurological exam 
 Record medical and UCD history   
UCD history includes the following information which may be recorded within            
2 weeks of study entry, if necessary: 
 UCD subtype, if established 
 Date and method of UCD diagnosis, including newborn screening and prenatal 
diagnosis 
 Family history of UCD 
 Ammonia values for all HAC in the preceding 12 months or, depending on age, 
for as long as available up to 12 months.  For each HAC, the peak ammonia level 
will be collected.  Additional data, such as presenting symptoms, triggering 
factors, and glutamine levels (if available) will be collected for all historical HAC. 
 All episodes of hospitalizations due to UCD in the 12 months prior to enrollment, 
including reasons for hospitalization, ammonia levels (if available), and dates of 
admission and discharge 
 Medication(s) and dietary supplements (including arginine and citrulline) used for 
management of UCD 
 Insertion, removal and/or use of G-tube or NG-tube along with dates and reasons 
for their use for the 12 months prior to enrollment 
 Family history of neoplasm and malignancy  
 Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
 Measure height, weight and calculate BSA using the following equation: 
BSA (m²) = ([Height(cm) x Weight(kg)]/ 3600 )½  
 Measure head circumference (Birth  -10 years of age only) 

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 Collect blood for safety laboratory assessments (Chemistry and Haematology) 
 Perform urine pregnancy test for female subjects with childbearing capability 
 Record concomitant medications 
 Record AEs that occurred after signing the Informed Consent  
 Perform CBCL (for subjects 18months  to 18 years of age) or ABCL/ASR (for 
subjects 19 to 65 years of age) 
 Record insertion, removal and/or use of G or NG tube 
 Evaluate CGISeverity (Investigator) 
 Administer and collect  EQ-5D-5L (for  12 years of age) 
NOTE:  Baseline Period may last up to 3 days to complete all of the required assessments 
 
6.1.3. 
Initial Treatment Period 
Following baseline assessments and confirmation of eligibility, up to and including Initial 
Treatment Period Day 1 subject will complete: 
 Randomisation to one of two treatment arms: 
Treatment Arm 1:   
RAVICTI in the Initial Treatment Period (approximately 28 days) 
or 
Treatment Arm 2: 
NaPBA in the Initial Treatment Period (approximately 28 days) 
 
6.1.3.1. Day 1 
The following procedures should be completed at Day 1: 
 Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
 Collect single blood sample for fasting (or first morning for those who cannot fast) 
ammonia level assessment and amino acid panel prior to first dose 
 Record 
 
 
with the diet prescribed prior to study entry 
 Record the reason for any change to the prescribed diet 
 Dispense study drug according to the randomised assignment. Study drug dose should 
be calculated as described in section 3.8 
  
 During the Initial Treatment Period, the dose of study drug (RAVICTI or NaPBA) 
can be adjusted at the discretion of the Investigator. See the Dose Adjustment 

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Algorithm in section 3.8for recommendations on dose change increments and 
follow-up assessment 
 No reduction in dose below the equivalent of 5 grams of PBA/m2 is 
recommended; however this can be undertaken if it is considered absolutely 
necessary by the Investigator. 
 The total daily dose of study drug should not exceed the limits stated in the 
current prescribing information (see section 3.8) 
 Initiate First Dose in the Initial Treatment Period  (with a meal)  
 Subjects will be observed in the clinic for a minimum of 1 hour following the first 
dose of study drug administered in the Initial Treatment Period 
 Record concomitant medications 
 Record AEs 
6.1.3.2. Days 2-6 
After release from the clinic on Day 1, subjects are not scheduled to return to the clinic until the 
ITP 1 visit (approximately day 7).  During Days 2-6, laboratory results from Baseline and/or Day 
1 visits are to be evaluated as they become available.  Dose adjustments, based on laboratory 
results, can be made as necessary on an outpatient basis during this period.  However, 
unscheduled visits may occur as necessary for proper follow up during Days 2-6 at the discretion 
of the Investigator.   
6.1.3.3. Initial Treatment Period Visits 1, 2, and 3 (Weekly)  
Subjects will report to the study unit in the morning at ITP 1, 2, and 3 visits (weekly +/- 2 days) 
and undergo the required study assessments and procedures as noted below: 
 Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
 Physical and Neurological Exam 
 Collect blood for safety laboratory assessments (Chemistry and Haematology) 
 Collect blood samples for fasting/morning amino acid panel and plasma ammonia 
prior to dosing 
 Record the 
 
 Record the reason for any change to the prescribed diet  
 
 
 Record insertion, removal and/or use of G or NG-tube along  
 Record concomitant medications 
 Record AEs 
 Collect all unused study drug and empty bottles  
 Assess study drug compliance 

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 Record any changes to prescribed study drug dose and the reason for change 
 Dispense study drug 
6.1.4. 
End of Initial Treatment Period (EITP - last day of the Initial Treatment 
Period/Start of the Transition or Maintenance Period  optional overnight stay)   
Subjects will visit the study unit in the morning at the EITP visit (approximately Day 28 ± 8 
days) and undergo 8-hour blood sampling and spot urine collections and complete the required 
study assessments as noted below: 
 Perform physical and neurological exam 
 Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
 Measure height, weight and calculate BSA using the following equation: 
BSA (m²) = ([Height(cm) x Weight(kg)]/ 3600 )½  
 Measure head circumference (Birth  -10 years of age at study entry only) 
 Collect blood for safety laboratory assessments (Chemistry and Haematology) 
 Collect blood samples for amino acid panel (at Hour 0 and 8 only), ammonia level 
and PK at the following time points: 
 Hour 0 (just before the first main meal prior to dosing after an overnight fasting or 
after 4-6 hours without high calorie and protein intake: i.e., 08:00 [8:00 am]) 
 Hour 4 (lunch: i.e., 12:00 [12:00 pm] prior to dosing) 
 Hour 8 (approximately 2-4 hours after lunch or after the second main meal: i.e., 
approximately 16:00 [4:00 pm] prior to dosing) 
 Collect spot urine samples at the following timepoints: 
 Hour 0 (just before the first main meal prior to dosing after an overnight fasting or 
after 4-6 hours without high calorie and protein intake: i.e., 08:00 [8:00 am]) 
 Hour 8 (approximately 2-4 hours after lunch or the after second main meal: i.e., 
approximately 16:00 [4:00 pm] prior to dosing) 
Spot urine is defined as a single aliquot of urine from a void at a particular time 
point. 
 Perform urine pregnancy test for female subjects with childbearing capability 
 Record actual protein and calorie intake during this visit, including all meals, snacks 
and supplements 
 
 
 Record the reason for any change to the prescribed diet  
 
 NOTE:  The 
prescribed dietary intake of protein and calories, should be stable (unchanged) for at 
least 7 days prior to the EITP visit 
 

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 Record insertion, removal and/or use of G or NG-tube  
 Record any changes to prescribed study drug dose and the reason for change 
 Record concomitant medications 
 Record AEs 
 Collect all unused study drug and empty bottles 
 Administer and collect EQ-5D-5L 
 
 Perform palatability assessment for all subjects (Appendix B:  Hedonic Scale to 
Assess Palatability)  
 Dispense study drug for the Transition or Maintenance period. Arm 2 subjects will 
remain in the clinic for at least 1 hour following their first dose of RAVICTI (for 
Subjects in treatment Arm 2, the first dose of RAVICTI will be taken on the evening 
of the EITP visit after the 8-hour ammonia, amino acid panel, PK and spot urine 
samples have been collected) 
For subjects in Treatment Arm 1, where Ammonia or Amino Acid panel (glutamine, 
threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, valine) 
results are not available on the day of EITP visit; the investigator will contact the 
subject (phone/email)  within 2 days, to adjust the dose of RAVICTI if necessary, and 
to confirm whether the subject should proceed to  End of  Transition Period Visit or 
Maintenance Period Visit 1. 
 
6.1.5. 
Transition Period (7 days ± 2 days) 
The Transition Period is 7 days in duration for all Treatment Arm 2 subjects and Treatment Arm 
1 subjects who were treatment failures.  
 If the dose of RAVICTI was adjusted to deliver a different amount of PBA than the 
subject was receiving during the final week of the Initial Treatment Period, the subject 
must return at an appropriate interval (see the Dose Adjustment Algorithm in section 3.8) 
for fasting/morning plasma ammonia and, if indicated, amino acid panel. 
6.1.5.1. End of Transition Day 7 (± 2 days) 
 Subjects will return to the clinic for: 
 Fasting/morning plasma ammonia and amino acid panel prior to dosing 
 Collect blood for safety laboratory assessments (Chemistry and Haematology) 
 Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
 
 
 Record the reason for any change to the prescribed diet 
 Record t
 

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 Record insertion, removal and/or use of G tube or NG tube along with dates and reasons 
for their use 
 Record concomitant medications 
 Record AEs 
 Collect all unused study drug and empty bottles  
 Assess study drug compliance 
 Record any changes to prescribed study drug dose and the reason for change 
 Dispense study drug 
 Perform palatability assessment for Arm 2 subjects (Appendix B:  Hedonic Scale to 
Assess Palatability)  
 Assess Drug Preference for Arm 2 subjects (Appendix D: Drug Preference Assessment) 
6.1.6. 
 Maintenance Period  (8 Weeks) 
Visits will occur every 2 weeks and alternate between onsite and phone/email contacts. 
6.1.6.1.  Maintenance Period Visits 1 (Week 2) and 3 (Week 6) (± 4 days) 
Subjects or caregivers will be contacted by phone or email to: 
 Record AEs 
 Assess compliance with study drug 
 Assess compliance with prescribed diet 
 Record Concomitant Medications 
6.1.6.2 Maintenance Period Visits 2 (Week 4) and 4 (Week 8) (± 7 days) 
Subjects will report to the study unit in the morning at Maintenance Period visits 2 and 4 and 
undergo the required study assessments and procedures as noted below: 
 Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
 Physical and Neurological Exam 
 Perform urine pregnancy test for female subjects with childbearing capability 
 Measure height, weight and calculate BSA using the following equation: 
BSA (m²) = ([Height (cm) x Weight (kg)]/ 3600 )½  
 Measure head circumference (Birth  -10 years of age at study entry only) 
 Collect blood for safety laboratory assessments (Chemistry and Haematology) 
 Collect blood samples for fasting/morning amino acid panel and plasma ammonia 
prior to dosing 
 
ician 

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 Record the reason for any change to the prescribed diet  
 
 
 Record insertion, removal and/or use of G-tube or NG-tube along with dates and 
reasons for their use 
 Record concomitant medications 
 Administer and collect EQ-5D-5L 
  Maintenance Period visit 4 
only 
 Administer and collect CBCL/ABCL/ASR  Maintenance Period visit 4 only 
 CGI Severity and Improvement (Investigator)  Maintenance Period visit 4 only 
 Record AEs 
  Collect all unused study drug and empty bottles.  
 Assess study drug compliance. 
 Record any changes to prescribed study drug dose and the reason for change 
 Dispense study drug 
6.1.7. 
Safety Extension Period (12 Weeks)  
Monthly Visits scheduled during the Safety Extension Period are intended to assess safety and 
ammonia control.  Additional visits may be scheduled at the discretion of the Investigator and the 
data will be captured as unscheduled visits.  For subjects taking NaBz at study entry who 
transitioned from NaBz treatment during the Initial Treatment Period, NaBz may be resumed 
during the Safety Extension Period at the discretion of the Investigator.  The dose of NaBz 
cannot be greater than the equivalent of the dose of RAVICTI that the subject is taking.  Please 
see protocol Section 5.2.2.2 for dose equivalents of RAVICTI.  
6.1.7.1. Safety Extension visits 1 and 2 (at 4 week intervals ± 7 days) 
 At Safety Extension Visits 1 and 2, the following will be performed: 
 Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
 Measure height for subjects with BSA <1.3 m2 
 Measure weight - calculate BSA using the following equation: 
BSA (m²) = ([Height(cm) x Weight(kg)]/ 3600 )½  
 Measure head circumference (for those who were Birth-10 years of age at study 
entry) 
 Collect blood for safety laboratory assessments (Chemistry and Haematology) 
 Collect single blood sample for fasting ammonia level assessment and amino acid 
panel prior to dosing 
 Perform urine pregnancy test for female subjects with childbearing capability 

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 Record the reason for any change to the prescribed diet  
 
  
 Record concomitant medications 
 Record AEs 
 Record insertion, removal and/or use of G or NG-tube  
 Collect all unused study drug and empty bottles  
 Assess study drug compliance 
 Record any changes to prescribed study drug dose and the reason for change  
 Dispense RAVICTI  
6.1.8. 
End of Study Visit or Early Termination 
At the end of the Safety Extension Period or at Early Termination, subjects will undergo the 
assessments outlined below:  
 Perform physical and neurological exam  
 Measure vital signs: blood pressure, respiratory rate, temperature, and pulse 
 Measure height  
 Measure weight 
 Measure head circumference ( for those who were Birth  -10 years of age at study 
entry) 
 Collect blood for safety laboratory assessments (Chemistry and Haematology) 
 Collect single blood sample for fasting/morning ammonia level assessment and amino 
acid panel prior to dosing  
 Perform urine pregnancy test for female subjects with childbearing capability 
 
 
 Record the reason for any change to the prescribed diet 
 
 Record concomitant 
medications 
 Record AEs 
 Collect all unused study drugs and empty bottles 
 Record date and time of last dose of study drug 
 Record any changes to prescribed study drug dose and the reason for change  
 Assess study drug compliance 
 Record insertion, removal and/or use of G or NG-tube  

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 Perform CBCL (for subjects 18months to 18 years of age) or ABCL/ASR (for 
subjects 19 to 65 years of age) 
 Administer and collect CGI Severity and Improvement (Investigator) 
 Record reason for termination 
 Perform EQ-5D-5L 
 
6.1.9. 
30 Day Follow-Up (+ 7 days) 
Subjects or guardians/caregivers (as appropriate) will be contacted (phone, email, or visit) for the 
following assessments: 
 Record and report to sponsor any SAEs that have started or become serious since the 
final study visit 
 Record and report to sponsor 
occurred since the final study visit 
 If SAEs or pregnancy have occurred, schedule follow-up visits or communications to 
obtain records and complete data collection and reporting as described in section 7 
6.2. 
Early Termination Procedures 
Subjects who discontinue treatment will complete end of study procedures designated as early 
termination assessments (see Section 6.1.8 End of Study Visit). 
6.3. 
Assessment of Efficacy 
Upon completion of the EITP visit, a subject will be considered a Treatment Success for the 
assigned treatment arm if the subject has not experienced an unprovoked HAC (i.e., a HAC that 
cannot be attributed to one or more specific precipitating factors such as infection, intercurrent 
illness, diet noncompliance, treatment noncompliance, etc.) on the assigned treatment and has 
met at least 2 of the following 3 criteria: 
 Has absolute values at the 3 time points (pre-dose, after dose at 4 hours and 8 
hours)  of plasma ammonia levels which do not exceed ULN at the End of Initial 
Treatment Period visit 
 Has normal (  ULN) glutamine levels at the End of Initial Treatment Period visit 
at time point 0 Hour 
 Has normal 
 essential amino acids including branched chain amino acid 
levels (threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, 
valine)  at the End of Initial Treatment Period visit at time point 0 Hour 
During the Initial Treatment Period, blood samples will be collected for assessment of plasma 
ammonia levels in accordance with the schedule of assessments (Appendix A:  Schedule of 
Assessments) and as indicated based on dose and/or diet adjustments. Serial samples for the 
measurement of ammonia level will be collected over an 8-hour period at the End of Initial 
Treatment Period visit (approximately Day 28). All plasma ammonias and amino acid panels 
obtained will be recorded in the eCRF. 

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During the Transition, Maintenance,and Safety Extensionperiods,plasma ammonia samples 
will be collected at study visits and as indicated based on dose and/or diet adjustments. These 
will be assessed as a measure of 
s ammonia control. All plasma ammonias and amino 
acid panels obtained will be recorded in the eCRF. In addition, HACs will be captured and 
characterized throughout the study.  
Global clinical impression of change based on the Investigators assessment will be undertaken 
as an exploratory measure of the effects of treatment on the perceived improvement or worsening 
of the condition. 

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7.
ASSESSMENT OF SAFETY
7.1. 
Adverse Events (AEs) 
7.1.1. 
Definition of Adverse Event 
As defined by the ICH, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product, whether or not the event is 
considered related to the investigational product. An AE is therefore any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of the investigational product. 
-serious and serious AEs unless otherwise specified. 
7.1.1.1. Examples of an AE 
 Conditions newly detected or diagnosed after the signing of the informed consent, 
including conditions that may have been present but undetected prior to the start of 
the study. 
 Conditions known to have been present prior to the start of the study that worsen after 
the signing of the informed consent. 
 Signs, symptoms, or the clinical sequelae of a suspected drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication (overdose per se should not be 
reported as an AE). 
7.1.1.2. Issues Not Considered AEs 
 Conditions present at the start of the study should be recorded as medical history; 
 Medical or surgical procedures (e.g., endoscopy, appendectomy); a condition that 
leads to a procedure is an AE if it qualifies according to the definitions above; 
 Situations where an untoward medical occurrence did not occur (e.g., social, 
diagnostic, elective, or convenience admission to a hospital); 
 Fluctuations of pre-existing disease(s) or condition(s) present or detected at the start 
of the study that do not represent a clinically significant change from Baseline; 
 Abnormal laboratory or test findings that are not assessed by the Investigator as a 
clinically significant change from Baseline; 
Hyperammonemia should be considered an AE if clinically significant unless the Investigator 
determines that the abnormal result was due to an inaccurate test.  If a HAC occurs, the 
Investigator will be asked to assess for a precipitating event, if known.   
AE
-
that must be used to report/document the AE. 

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7.1.2.
Definition of Serious Adverse Event
A serious adverse event (SAE) is any AE that: 
a. Results in death 
b. Is life threatening 
which the subject was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe, prolonged, 
or untreated. 
c. Requires hospitalization or prolongation of existing hospitalization  
NOTE: Hospitalization signifies that the subject has been admitted to the hospital as 
an inpatient for any length of time. Emergency room treatment does not qualify for 
this category, but may be appropriately included in category f (see below). 
Complications that occur during hospitalization are usually AEs. If a complication 
prolongs hospitalization or fulfills any other serious criterion, the event will be 
the medical monitor. 
Hospitalization will not be considered an AE in itself. It will be considered an 
outcome of an AE. Therefore, if there is no associated AE, there is no SAE. For 
example, hospitalization for elective treatment of a pre-existing condition that did not 
worsen from Baseline will not be considered an AE. 
d. Results in disability/incapacity 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may 
temporarily interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether 
reporting as serious is appropriate in other situations; specifically, important medical 
events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such events are invasive cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or development 
of drug dependency or drug abuse. If in doubt as to whether or not an event qualifies 
 
AEs that do not result in any of these outcomes are considered non-serious. 

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Hyperammonemic episodes will be considered SAEs when they meet the criteria for an SAE as 
described above. 
7.1.3. 
Assessment of Severity 
All AEs, both serious and non-serious, will be assessed for severity using the Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03. The CTCAE v4.03 scale displays 
Grades 1 through 5 with unique clinical descriptions of severity for each AE (including abnormal 
laboratory values) based on this general guideline.  
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. 
AEs that do not have a corresponding CTCAE term will be assessed according to their impact on 
 
 Grade 1 (Mild)  Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
 Grade 2 (Moderate)  Moderate; minimal, local or non-invasive intervention 
indicated; limiting age-appropriate activities of daily living (ADL) 
 Grade 3 (Severe)  Severe or medically significant but not immediately                           
life-threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL  
 Grade 4 (Life Threatening)  Life-threatening consequences; urgent intervention 
indicated  
 Grade 5 (Fatal)  Death related to AE 
Notes:  
 Severity is a category for rating the intensity of an event in relation to other events of 
the same type, and both non-serious AEs and SAEs can be assessed as severe.  An 
event will be defined as serious when it meets one of the outcomes described in 
Section 7.1.2
 
 
-
definition than t
-
CTCAE Grade 4 in severity and still not meet the SAE definition of                               
-
 
7.1.4. 
Recording Adverse Events 
Adverse event collection begins from the signature of the informed consent. Subjects/or 
caregivers will be questioned about AEs at each study visit, including at the Day 1 visit prior to 
study drug
ve/has 
you/your child been feeling s
eCRF 
and documented in the source record after the signing of the informed consent. 

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Non-serious AEs will be recorded through the last study visit. All SAEs that occur at any time 
beginning from the time informed consent is given until 30 days after the last dose of study 
medication should be recorded.   
7.1.5. 
Procedures for Reporting Serious Adverse Events and Product Complaints 
7.1.5.1. Serious Adverse Events  
An SAE is reported  by entering the information in the eCRF within 24 hours of becoming aware 
that a subject has experienced an SAE. If unable to access the eCRF, the event must be reported by 
submitting the completed SAE form by fax or email within 24 hours of the Investigator becoming 
aware of the event.        
The event must be documented in source documentation as well as on the eCRF.  
See the Study Reference Manual for complete instructions.  
After receipt of the initial report, the information will be reviewed and the Investigator may be 
contacted with requests for additional information or for data clarification. 
Follow-up will be obtained via fax and e-mail as necessary until the event has resolved or 
attained a stable outcome.  Horizon is responsible for the preparation of MedWatch 3500 
A/CIOMS I forms and analysis of similar events for individual occurrences (to be submitted as 
Investigational New Drug [IND] safety letters to the FDA and investigators according to 21 CFR 
312.32 by Horizon) and  suspected unexpected serious adverse reactions [SUSARs] according to 
Clinical Trial Directive 2001/20/EC and respective national legislation (to be submitted to 
European health authorities, IECs, and Investigators by Horizon). 
7.1.5.2. Product Complaints  
A product complaint process will be described in the Study Reference Manual. Any product 
complaint must be reported to the sponsor using this process. 
7.1.6. 
Duration of Follow-up for Patients with Adverse Events 
Once the study-defined non-serious AE and SAE reporting periods have passed (see Section 
7.1.4), reporting is required only if an Investigator becomes aware of an SAE that he or she 
considers related to the study treatment.  
After the initial recording of an AE, the Investigator should proactively follow the subject. Any 
non-serious AEs that are still ongoing at the end of the study should be reviewed to determine if 
further follow-up is required. The Investigator will document on the AE eCRF any/all ongoing 
non-serious AEs that will not be followed further after the subject exits the study. If in doubt, the 
PPD
   
All SAEs should be followed until resolution, until the condition stabilizes, or until the subject is 
lost to follow-up. Once the SAE is resolved, the corresponding AE eCRF page should be 
updated. 

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7.1.7.
Investigator Notification of Important New Safety Information
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.  
Investigators will notify their Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) of all such notifications as required by the IRB/IEC. 
7.1.8. 
Pregnancy  
Pregnancy, per se, will not be considered an AE in this study. However, a urine or serum 
pregnancy test should be performed if any female patient or partner of a male patient suspects 
that she has become pregnant during the time period of the study or within 30 days after the end 
of the study. If the test is positive, the pregnancy should be immediately reported to the 
Investigator and sponsor.   
Because NaPBA is contraindicated for use during pregnancy and the effects of RAVICTI have 
not been determined the subject must be withdrawn from the study. 
Complete pregnancy information, including the outcome of the pregnancy, should be collected in 
the source documents on the female patient or partner of a male patient (if she is willing). In the 
absence of complications, follow-up after delivery will be no longer than 8 weeks.  Any 
stillbirths or premature terminations of pregnancies, whether elective, therapeutic, or 
spontaneous, should be reported on the pregnancy outcome form. Any pregnancy complications, 
including an elective termination for medical reasons, should be reported as an AE 
A spontaneous abortion should always be considered a SAE, as should any congenital defects in 
the newborn. Any SAE occurring as a result of a post-study pregnancy and considered 
reasonably related to the investigational product by the Investigator should be reported to the 
sponsor. 
7.1.9. 
Assessment of Relationship to Study drug 
The Principal Investigator must review each AE and make a determination of relationship to 
study drug (i.e., whether the study drug caused the AE) using the following definitions: 
 Not Related:  
erlying 
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.  
 Possibly Related:  
There is a reasonable temporal relationship between the event and the administration 
of the study drug
condition, other therapies, or injury; may not follow a known response pattern to the 
study drug. 
 Probably Related:  
The event follows a reasonable temporal sequence from administration of the study 
drug 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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The assessment of causality will be based on the information available, and may be changed 
upon receipt of additional information.  The reference safety information is contained within the 
following documents for each respective study drug: 
 RAVICTI: Investigator Brochure 
 AMMONAPS: Summary of Product Characteristics (SmPC) 
 BUPHENYL: Package Insert 

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8.
LABORATORY ASSESSMENTS
Blood samples will be collected for assessment of subject safety at clinic visits in accordance 
with the schedule of assessments (Appendix A: Schedule of Assessments).  
Safety laboratory assessments will include:  
 Haematology: complete blood count (CBC) with differential and platelet count 
 Chemistry: sodium, potassium, calcium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), albumin, total bilirubin, and alkaline phosphatase 
Safety laboratory assessments will be sent to the central laboratory.  Safety laboratory 
assessments may be sent to the local laboratory in exceptional circumstances if deemed 
necessary by the study investigator. 
Ammonia assessments: 
 Blood samples to measure ammonia levels  
Ammonia samples will be analysed at the local laboratory. 
Amino Acid assessments 
 Required Amino acid panel will include the following essential, non-essential and branched chain 
amino acid tests:   threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, 
valine, glutamine  
 As available and required when the site has validated testing and reportable results are 
available:  citrulline, arginine and ornithine 
 As available when the site has validated testing and reportable results are available:  aspartic acid, 
serine, glutamic acid, asparagine, proline, alanine, glycine, cystine, tyrosine, taurine, 
phosphoserine, phosphoethanolamine, alpha-aminobutyric acid, 1-methylhistidine, 3-
methylhistidine, and argininosuccinate 
 Amino acid assessments will be analysed at the local laboratory 
 
Sampling Limitations: 
Local IRB and institutional guidelines on pediatric patients involved in clinical trials must be 
followed regarding the maximum blood volume withdrawal allowed.   
Per recommendation Rec (2006) 4 of the Committee of Ministers to Member States on Research 
on Biological Materials of Human Origin (2006) the study-related blood loss should not exceed 
3% of the total blood volume during a period of four weeks and should not exceed 1% at any 
single time. The total volume of blood is estimated at 80 to 90 mL/kg body weight; 3% is 2.4 mL 
blood per Kg body weight.  
Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited 
 for studies that represent no more than minimal risk to 

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paediatric subjects, the amount of blood drawn may not exceed the lesser of 50 mL or 3 mL/kg 
in an 8-week period.   
Protocol-specified blood sampling should in no case exceed appropriate ethical and regulatory 
guidelines and institutional requirements and in all cases the risk/benefit assessment of subjects 
participating in clinical trials must be considered. 
In cases where the blood limits are approached or met, or in cases where an insufficient amount 
of blood is drawn from the subject to run all protocol-required tests, blood samples should be 
collected for the following tests in order of priority:  
1. Ammonia  
2. Amino Acid panel 
3. Safety labs (chemistry/hematology) 
4. PK  
Safety labs will be evaluated as part of medical management.  The duration of ammonia 
conditions, 
 
It is the investigator/sites responsibility to track blood volumes. 
 
Urine pregnancy tests will be performed in women of childbearing potential. 

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9.
VITAL SIGNS, HEIGHT, WEIGHT, AND HEAD 
CIRCUMFERENCE 
Blood pressure, respiratory rate, temperature, and pulse as well as height and weight will be 
measured according to the schedule of assessments (Appendix A: Schedule of Assessments).  
Measure length for infants who cannot yet stand. Height measurements must be made with the 
use of a stadiometer.  Head circumference will be measured in children who are Birth  -10 years 
of age at study entry. 

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10.
PHYSICAL EXAMINATION
Physical examinations will be performed using the normal study site procedures according to the 
schedule of assessments.  (Appendix A: Schedule of Assessments). 

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11.
CLINICAL GLOBAL IMPRESSION (CGI) SCALES
The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the 
clinician to rate the severity of the patient
's illness at the time of assessment, relative to the 
clinician
's past experience with patients who have the same diagnosis. Considering total clinical 
experience, a patient is assessed on severity of illness at the time of rating relative to Baseline.  
 1 normal, not at all ill  
 2 borderline ill  
 3 mildly ill 
 4 moderately ill 
 5 markedly ill 
 6 severely ill 
 7 extremely ill 
The Clinical Global Impression  Improvement scale (CGI-I) is a 7 point scale that requires 
the I
relative to a 
Baseline state at the beginning of the intervention and rated as:  
 1 very much improved  
 2 much improved 
 3 minimally improved 
 4 no change  
 5 minimally worse 
 6 much worse 
 7 very much worse 

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12.
EQ-5D-5L
EQ-5D-5L (http://www.euroqol.org/home.html) is a standardized measure of health status 
developed by the EuroQoL Group in order to provide a simple, generic measure of health for 
clinical and economic appraisal. Applicable to a wide range of health conditions and treatments, 
it provides a simple descriptive profile and a single index value for health status that can be used 
in the clinical and economic evaluation of health care as well as in population health surveys.  
The EQ-5D-5L is designed for self-completion by subjects or caregivers (Euroqol 1990) of 
12  years. 
EQ-5D-5L will be administered according to the schedule of assessments (Appendix A:  
Schedule of Assessments). 

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13.
NEUROPSYCHOLOGICAL TESTING
13.1. 
Child Behavior Checklist (CBCL)  
 
m behaviors and competencies. 
This instrument can either be self-administered or administered through an interview.  
There are two versions of the checklist. The preschool checklist (CBCL/1½-5) is intended for use 
with children aged 18 months to 5 years. The school-age version (CBCL/6-18) is for children 
aged 6 to 18 years. It is an important measure for children
's emotional, behavioral and social 
aspects of life and is used as a diagnostic tool for a variety of behavioral and emotional 
problems. 
Validated CBCL questionnaires are available in English, Czech, French, Flemish, German, 
Italian, and Spanish. They will be administered only for subjects whose parents/caregivers 
readily understand one of these languages. 
13.2. 
Adult Behavior Checklist (ABCL) and Adult Self-Report (ASR) 
functioning and problems.  It is completed by an observer who knows the individual well, such 
as a spouse, partner, family member, or friend.  It is intended for use with adults aged 19 to            
59 years. Alternatively, the ASR is a similar questionnaire that may be completed by those 
subjects able to self-complete the form.   
Validated ABCL/and ASR questionnaires are available in US English. They will be administered 
only for subjects and caregivers who readily understand English. 
The ABCL and ASR, like the CBCL, is used as a diagnostic tool for a variety of behavioral and 
emotional problems.  
During administration of the CBCL and ABCL/ASR, a trained professional will explain the 
questionnaires to the subject and family and answer any questions they may have.  The CBCL 
and ABCL/ASR will be administered according to the schedule of assessments (Appendix A:  
Schedule of Assessments). 

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14.
PKAND OTHER ASSESSMENTS
Samples for assessment of RAVICTI (glycerol phenylbutyrate) Oral Liquid and NaPBA 
metabolites will be collected at the EITP visit.  The specific PK parameters to be analyzed will 
be as follows:   
For all subjects: 
 Plasma levels of PBA, PAA and PAGN 
 Urinary excretion of PAGN  
The time of sample collection, last meal prior to each sample collection, and all study 
medications doses should be recorded. 
The blood volume required for PK is 0.5 mL at each time point.   
For this protocol, Hour 0 samples should be collected just before the first main meal and dose 
after an overnight fasting or after 4 hours without high calorie and protein intake.  Water or low 
calorie juice is allowed before Hour 0. However, for subjects who are unable to fast, the PK 
samples should still be collected with Hour 0 occurring just before the first dose and meal of the 
day. 
Single samples of blood and urine should also be collected upon presentation at the study center 
(and as feasible at other health care facilities) with signs and symptoms of HAC or PAA toxicity. 
14.1. 
Handling of Blood Samples for PK Analysis 
 At each designated time point, the requisite amount of blood will be drawn, processed, frozen, 
and prepared for shipment to the designated central laboratory 
 Hour 0 (just before the first main meal and dose after an overnight fasting or after 4 
hours without high calorie and protein intake: i.e., 08:00 [8:00 am]) 
 Hour 4 (prior to lunch and second dose: i.e., 12:00 [12:00 pm] prior to dosing)  
 Hour 8 (approximately 2-4 hours after lunch or the after second main meal: i.e. 
approximately 16:00 [4:00 pm] prior to dosing) 
 Upon presentation at the study center (and as feasible at other health care facilities) 
with signs and symptoms of HAC or PAA toxicity 
Detailed instructions regarding PK blood sample timing and handling are provided in the 
Laboratory Manual. 
14.2. 
Handling of Urine Samples for PK Analysis 
Urine will be collected for the time intervals designated in the schedule of assessments 
(Appendix A: Schedule of Assessments) including upon presentation at the study center (and as 
feasible at other health care facilities) with signs and symptoms of HAC or PAA toxicity. The 
urine samples will be handled in accordance with the instructions provided in the Laboratory 
Manual. 
 
 

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The 8 hour spot urinecollections areintended to capture metabolites excreted over 8hours from 
the full daily dose of the study drug.  
 Hour 0 (just before the first main meal and dose after an overnight fasting or after 4 
hours without high calorie and protein intake: i.e., 08:00 [8:00 am]) 
 Hour 8 (approximately 2-4 hours after lunch or after the second main meal: i.e., 
approximately 16:00 [4:00 pm] prior to dosing) 
Spot urine is defined as a single aliquot of urine from a void at a particular time point. The 
timing of spot urine samples for each collection must be recorded in the eCRF.  

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15.
STATISTICS
15.1. 
Sample Size and Power 
Approximately 16 subjects will be enrolled in this study.  This is a safety, efficacy and 
tolerability study and no formal sample size calculation has been performed. The sample size of 
16 patients was chosen considering the number of patients with this orphan disease and the 
criteria of the study. Sixteen subjects meeting the entry criteria will be enrolled and expected to 
complete the initial treatment period (including assessment of the primary endpoint) The study is 
expected to have approximately 30% drop out rate after the initial treatment period, due to liver 
transplant or other reasons and therefore approximately 12 subjects will complete the study. The 
rate of treatment success will be presented for each treatment arm with appropriate statistical 
tests performed.  Descriptive statistics for all endpoints will be presented. Further details of 
statistical analysis will be provided in the Statistical Analysis Plan (SAP). 
15.2. 
Interim Analysis 
No formal interim analysis is planned for this study. 
15.3. 
Endpoints and Analyses 
15.3.1. Efficacy 
15.3.1.1. Initial Treatment Period Endpoints (RAVICTI vs NaPBA)  
The efficacy endpoints that will be evaluated during the Initial Treatment Period are: 
 Rate of Treatment Success (Primary)  
 Drug discontinuation due to any reason 
15.3.1.2. Transition, Maintenance, and Safety Extension Periods (RAVICTI) 
The efficacy endpoints that will be evaluated during the Transition, Maintenance, and Safety 
Extension Periods are: 
 Control of plasma ammonia 
 Annualized rate of HAC 
15.3.2. Safety and Tolerability Endpoints 
The endpoints that will be evaluated for safety and tolerability are: 
 Assessment of AEs 
 Standard clinical laboratory tests 
 Amino acid panel 
 Rate of drug discontinuation due to AEs 

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15.3.3.
Clinical Outcome Assessments
 Subject preference for study drug (Arm 2 after exposure to both RAVICTI and 
NaPBA) 
 Palatability of study drug (Hedonic Scale) 
 Changes in CGI scales (Investigator) 
 Neuropsychological assessments:  CBCL or ABCL or ASR 
 EQ-5D-5L health status quality of life assessment 
15.4. 
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. Statistical hypothesis testing will be performed for selected 
endpoints. Significance levels (p-values) and confidence intervals (CIs) will be calculated using 
appropriate statistical methods.  
Data will also be summarized by age group for the primary endpoint, treatment success. 
The primary endpoint will also be stratified by NaBz, provided that there are least 2 non-NaBz 
subjects in each treatment group. 
 
A formal SAP that will provide details of all analyses and presentation of study data will be 
prepared prior to database lock.  
15.4.1. Significance Level and Adjustment for Multiplicity 
Analyses will be performed at the two-sided 0.05 level. There will be no adjustment for 
multiplicity. Details will be provided in the SAP. 
15.4.2. Analysis Populations 
The following populations will be considered in the analysis of data for this study.  Assignment 
or exclusion of subjects from the analysis populations will be performed: 
 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 safety 
analyses performed for this study. Subjects will be included based on medication 
received. 
 Modified intention-to-treat (mITT) population: The mITT population will include all 
subjects from either treatment group with 1) no major eligibility violations, 2) who 
have received at least one dose of study drug and 3) have a data point post 
randomisation. Subjects will be included in the mITT based on the treatment subjects 
are randomised to. This will be the primary population for efficacy.    
 Pharmacokinetic population (PK): The PK population includes all subjects who have 
at least one dose of study drug and have a valid PK measurement. This will be used 
for all PK analyses 

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15.4.3.
BaselineDemographic 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.  If the analysis populations differ, selected variables will 
also be summarized separately for each of the analysis populations (safety, mITT).  Listings will 
include all randomised subjects. 
15.4.4. Subject Disposition 
The number and percentage of subjects who discontinued the study prematurely will be 
summarized. The reasons for early study termination will also be presented. 
15.4.5. Efficacy Variables 
The primary efficacy endpoint is the rate of Treatment Success, as defined in Section 6.3.    
Additionally, 8-hour AUC, the peak (Cmax) and mean levels of venous ammonia will be 
summarized by treatment.  Plasma ammonia levels will be summarized using descriptive 
statistics at each time point on Day 1, and at the end of the Initial Treatment Period, and by 
treatment. 
Since ammonia data will be collected through local laboratories that may have different normal 
ranges, all ammonia analyses will be performed using ammonia results standardized to a 
common unit (µmol/L) and normalized to a common ULN per age group.  Details will be 
provided in the SAP. 
During the Transition, Maintenance and Safety Extension Periods, descriptive statistics of blood 
ammonia at each scheduled onsite visit will be presented. 
Frequency of HACs during the Maintenance and Safety Extension Periods will be presented 
along with the year prior to enrollment period. 
Plasma PBA, PAA, and PAGN and urinary excretion of PAGN (the terminal metabolite of PBA) 
will also be analyzed. Data will be summarized for the EITP visit by time point using descriptive 
statistics. 
15.4.6. Safety Variables 
Safety will be evaluated in the safety population via AEs, vital signs, and clinical laboratory 
measurements. 
All summaries of AEs will include treatment-emergent AEs (TEAEs), defined as events with an 
onset date on or after the first dose of study medication. Events will be summarized by treatment 
received according to the most recent dose of study drug received prior to the onset of the event. 
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 
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 
treatment and study visit. Laboratory tests will be classified relative to the normal reference 
range (normal, low, or high) and will be summarized by study treatment and visit.  

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Vital signs, including blood pressure, respiratory rate, temperature, and pulse, will be 
summarized by study treatment and visit.  
Concomitant medications will be summarized and/or included in the data listings. 
Neuropsychological testing results (CBCL and ABCL/ASR) will be summarized and/or listed. 
Data for the Initial Treatment Period will be presented separately from data for the Transition,  
Maintenance, and Safety Extension Periods. 
15.4.6.1. Statistical Analysis of Safety Variables  
Safety data will be presented descriptively. No formal analyses will be conducted. 
15.4.7. Statistical Analysis of Efficacy Variables 
-tests and                     
non-parametric tests (Wilcoxon) for analysis of continuous endpoints.  Data will be log 
transformed as appropriate (e.g., AUCs). If appropriate analyses will also be performed based on 
whether subjects were receiving NaBz at baseline. Details will be included in the SAP.    
15.4.7.1. Analysis of Treatment Success and Ammonia8-hour AUC at the End of 
Initial Treatment Period Visit 
The primary endpoint is the rate of treatment success by treatment at the end of the Initial 
Treatment Period of the study.  The two treatment groups will also be compared using the two-
sample t-test and the nonparametric Wilcoxon rank-sum test.  Further details will be provided in 
the SAP.  
The mITT population will be used for the primary analysis of the primary efficacy endpoint.  
Evaluable subjects are defined as those subjects with calculable ammonia AUC at the End of the 
Initial Treatment Period visit. If subjects have missing data at the 4 hour timepoint for 
calculation of the ammonia 8 hour AUC but have values available at the 0 and 8 hour timepoints, 
then AUC will be calculated using the available values, which is equivalent to linear 
interpolation of the missing value.  If the subjects are missing ammonia measurement for either 0 
hour or the 8 hour timepoint or both timepoints (0 hour and 8 hour) then the AUC will not be 
calculated and the subjects will not be used in the analysis of the AUC.   
15.4.7.2. Other Efficacy Analyses During the Initial Treatment Period 
Plasma ammonia levels and changes from Baseline will be summarized by sampling time point 
with descriptive statistics. Treatments will be compared using two-sample t-tests and Wilcoxon 
rank-sum tests. 
15.4.7.3. Analysis of PK Parameters During the Initial Treatment Period 
Descriptive statistics for all plasma metabolites (PBA, PAA and PAGN) and urinary metabolites 
(PAGN) from all spot urine samples during the 8-hour period including minimum and maximum 
concentrations and at various time points will be presented. There will be no PK parameters 
calculated. Further information will be provided in the SAP.  

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15.4.7.4. Analysis During the Transition, Maintenance,and Safety Extension
Periods 
The number and percentage of abnormal ammo
2 times the ULN 
will be summarized by visit. The average plasma ammonia levels and change from Baseline 
values during the Transition, Maintenance, and Safety Extension Periods will also be 
summarized.   
The frequency of HAC episodes will be summarized and compared with the frequency of HAC 
episodes during the 1 year pre-enrollment period. 
Descriptive statistics for CBCL/ABCL/ASR and EQ-5D-5L assessment instruments during the 
Maintenance and Safety Extension Periods by time point will be presented. 
A summary of Treatment Arm 2 (randomised to NaPBA for the Initial Treatment Period and 
then received RAVICTI in the Transition Period) subject
 will be provided. 

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16.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
Required information will be entered into the appropriate eCRFs, which are to be maintained in 
order and current so they reflect the latest information in 
source records. All records 
are to be kept in conformance with applicable guidelines and standard operating procedures 
(SOPs). When the study is completed, the Investigator must retain the essential documents for as 
long as needed to comply with regulatory and sponsor requirements. The Investigator will notify 
the sponsor prior to moving or destroying any of the study documents. 
16.1. 
Study Monitoring 
The sponsor representative is responsible for contacting and visiting the Investigator for the 
purpose of inspecting the facilities, and upon request, inspecting the various records of the trial. 
eCRFs throughout the study to 
verify: selected data against source records; adherence to the protocol; completeness, accuracy, 
and consistency of data; and to monitor adherence to GCPs. The monitor must have access to 
subject medical records and other study-related records needed to verify entries on the eCRFs. In 
addition, the sponsor representative may contact the site via email, phone, teleconference, or web 
conference or online meeting to review study progress. 
The Investigator agrees to cooperate with the monitor.  
16.2. 
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 
(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. 
16.3. 
Institutional Review Board/Independent Ethics Committee  
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 
GCPs. 

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17.
QUALITY CONTROL AND QUALITY ASSURANCE
Data will be entered into a password-protected EDC database in accordance with the Study 
Reference Manual and/or eCRF Completion Guidelines.  
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, legibility (of the 
source records), and timeliness of the data reported to the sponsor in the eCRFs and in all 
required reports. Data reported on the eCRFs, which are derived from source documents, should 
be consistent with source documents or the discrepancies should be explained. 
Corrections to the eCRFs will be made in accordance with the Study Reference Manual and/or 
eCRF Completion Guidelines .  
To ensure the quality of the clinical data across all participants and sites, a clinical                             
data-management review will be performed. 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 directed to the site for completion. 
The Principal Investigator will sign and date the indicated places on the eCRF. This signature 
will indicate that the Principal Investigator inspected or reviewed the data on the eCRF and the 
data queries, and that the Investigator agreed with the content. 

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18.
ETHICS
18.1. 
Ethics Review 
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 before any subject 
is enrolled at each study site. 
18.2. 
Ethical Conduct of the Study 
This study will be performed with adherence to the principles of GCP as required by applicable 
country and local regulations and by the ICH E6 Guidance for Industry: GCP Consolidated 
Guidance, April 1996, and in accordance with the ethical principles of the Declaration of 
Helsinki and its amendments. 
18.3. 
Written Informed Consent 
In accordance with ICH GCPs, written informed consent by the subject or the 
parent/legal guardian for those under 18 years of age or the local age of consent must be obtained 
 

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19.
DATA HANDLING AND RECORDKEEPING
The I
their identities are protected from unauthorized parties. On eCRFs or other documents that are 
submitted to the sponsor, participants should be identified by an identification code and not by 
their names. 
19.1. 
Inspection of Records 
All records are to be kept in conformance with applicable guidelines and SOPs. 
19.2. 
Retention of Records 
When the study is completed, the Investigator must retain the essential documents for as long as 
needed to comply with regulatory and sponsor requirements. The Investigator will notify the 
sponsor prior to moving or destroying any of the study documents. 

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20.
REFERENCES
In-text Reference 
Reference List 
Ah Mew 2015 
Ah Mew N, Lanpher B, Gropman  A, et al, . Urea cycle disorders overview. 
GeneReviews [Internet]. April 29, 2003 Revised April 9, 2015. Available at: 
http://www.ncbi.nlm.nih.gov/books/NBK1217/. Accessed on June 17, 2016 
Berry 2014 
Berry SA, Lichter-Konecki U, Diaz GA, et al.  Glycerol phenylbutyrate 
treatment in children with urea cycle disorders: pooled analysis of short and 
long-term ammonia control and outcomes. Mol Genet Metab. 2014;112:17-24. 
Chen 1996 
 
Chen AW, Resurreccion AVA, Paguio LP. Age appropriate hedonic scales to 
measure food preferences of young children. J Sens Stud. 1996;11:141-163. 
Diaz 2013 
 
Diaz GA, Krivitzky LS, Mokhtarani M, et al. Ammonia control and 
neurocognitive outcome among urea cycle disorder patients treated with glycerol 
phenylbutyrate. Hepatology. 2013;57:2171-2179. 
Dionisi-Vici 2002 
Dionisi-Vici C, Rizzo C, Burlina AB, et al. Inborn errors of metabolism in the 
Italian pediatric population: a national retrospective survey. J Pediatr. 
2002;140:321-327. 
EuroQol Group 1990 EuroQoL Group. EuroQol--a new facility for the measurement of health-
related quality of life. Health Policy. 1990;16:199-208. 
Gropman 2007 
Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle 
disorders. J Inherit Metab Dis. 2007;30:865-879. 
Guy 1976 
Guy W. ECDEU assessment manual for psychopharmacology. Rockville, MD: 
U.S. Department of Health, Education, and Welfare, Public Health Service; 
Alcohol, Drug Abuse, and Mental Health Administration, NIMH; 
Psychopharmacology Research Branch; Division of Extramural Research 
Programs; 1976:218222. 
Guy 2000 
Guy W. Clinical Global Impressions (CGI) Scale. Washington, DC: APA; 2000. 
Modified From: Rush J, et al. Psychiatric Measures. 
Krivitzky 2009 
Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML. 
Intellectual, adaptive, and behavioral functioning in children with urea cycle 
disorders. Pediatr Res. 2009;66:96-101. 
Lee 2010 
 
Lee B, Rhead W, Diaz GA, et al. 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;100:221228. 
Lee 2014 
 
B Lee, GA Diaz, W Rhead, U Lichter-Konecki A Feigenbaum, SA Berry, C Le 
Mons, JA Bartley, N Longo, SC Nagamani, W Berquist, R Gallagher, D 
Bartholomew, CO Harding, MS Korson, SE McCandless, W Smith, S 
Cederbaum, D Wong, JL Merritt, II, A Schulze, G Vockley, D Kronn, R Zori, M 
Summar, DA Milikien, M Marino, DF Coakley, M Mokhtarani, BF 
Scharschmidt. Blood ammonia and glutamine as predictors of hyperammonemic 
crises in urea cycle disorder patients. Genetics in Medicine (2015) 17,561568 
doi:10.1038/gim.2014.148 

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21.
APPENDICES
A. Schedule of Assessments 
B. Hedonic Scale to Assess Palatability 
C. Clinical Global Impression (CGI) 
D. Assessment of Drug Preference 
  
 

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APPENDIX A. 
SCHEDULE OF ASSESSMENTS 
 
Screen 
Baseline 
(Days-3 
thru -1) 
Initial 
Treatment 
Period 
End 
Treat
ment/ 
Start 
Next 
Period 
Transi- 
tion 
Period 
(7 days) 
Maintenance Period11 
End 
Mainte
nance/ 
Start 
Safety 
Safety Extension11, 
14 
Added 
Visits 
Post 
Study 
Visit 
 
 
Day 1 ITP 1, 
2, & 3 
(Weekly) 
EITP 
(ITP Wk 4 
-End of 
Initial 
Treatment 
Period)4, 22 
ETPD
7 
(Transit 
Day 7) 
MP111 
(Maint 
Wk 2)  
Phone/ 
email 
MP2 
(Maint 
Wk 4) 
MP3 
(Maint 
Wk 6) 
Phone/ 
email 
MP4 
(Maint 
Wk 8) 
SE1-2 
(Safety 
Wks 4 & 
8) 
EOS 
(Safety Wk 
12 or Early 
Termination) 
Unsched 
Visit 11, 15 
30 Days 
Post 
EOS 
Phone/email 
Visit Windows 
 
 
 
± 2 
days17 
± 2 
days17 
± 2 
days 
± 4 
days 
± 7 
days 
± 4 
days 
± 7 days 
± 7 
days 
± 7 days 
NA 
+ 7 days 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclu
sion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical/Neurol
ogical Exam 
 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
Medical and 
UCD History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation21 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Height1,Weight 
and Head 
Circumference 
(Birth to 10 
years old) 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
Chemistry 
/Haematology
 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 

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Screen 
Baseline 
(Days-3 
thru -1) 
Initial 
Treatment 
Period 
End 
Treat
ment/ 
Start 
Next 
Period 
Transi- 
tion 
Period 
(7 days) 
Maintenance Period11 
End 
Mainte
nance/ 
Start 
Safety 
Safety Extension11, 
14 
Added 
Visits 
Post 
Study 
Visit 
 
 
Day 1 ITP 1, 
2, & 3 
(Weekly) 
EITP 
(ITP Wk 4 
-End of 
Initial 
Treatment 
Period)4, 22 
ETPD
7 
(Transit 
Day 7) 
MP111 
(Maint 
Wk 2)  
Phone/ 
email 
MP2 
(Maint 
Wk 4) 
MP3 
(Maint 
Wk 6) 
Phone/ 
email 
MP4 
(Maint 
Wk 8) 
SE1-2 
(Safety 
Wks 4 & 
8) 
EOS 
(Safety Wk 
12 or Early 
Termination) 
Unsched 
Visit 11, 15 
30 Days 
Post 
EOS 
Phone/email 
Visit Windows 
 
 
 
± 2 
days17 
± 2 
days17 
± 2 
days 
± 4 
days 
± 7 
days 
± 4 
days 
± 7 days 
± 7 
days 
± 7 days 
NA 
+ 7 days 
8-Hour Amino 
Acid Panel 2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Fasting Amino 
Acid Panel 3, 15 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
8-Hour 
Ammonia 2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
8-Hour PK 2, 10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Spot Blood PK 
 
 
 
 
 
 
 
 
 
 
 
 
X19 
 
AST, ALT, 
Total Bilirubin 
 
 
 
 
 
 
 
 
 
 
 
 
X
20 
 
Fasting 
Ammonia 3, 15 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
8-Hour Spot 
Urine 2, 12 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Spot Urine 
PK12 
 
 
 
 
 
 
 
 
 
 
 
 
X
19 
 
Urine 
Pregnancy Test 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 

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Screen 
Baseline 
(Days-3 
thru -1) 
Initial 
Treatment 
Period 
End 
Treat
ment/ 
Start 
Next 
Period 
Transi- 
tion 
Period 
(7 days) 
Maintenance Period11 
End 
Mainte
nance/ 
Start 
Safety 
Safety Extension11, 
14 
Added 
Visits 
Post 
Study 
Visit 
 
 
Day 1 ITP 1, 
2, & 3 
(Weekly) 
EITP 
(ITP Wk 4 
-End of 
Initial 
Treatment 
Period)4, 22 
ETPD
7 
(Transit 
Day 7) 
MP111 
(Maint 
Wk 2)  
Phone/ 
email 
MP2 
(Maint 
Wk 4) 
MP3 
(Maint 
Wk 6) 
Phone/ 
email 
MP4 
(Maint 
Wk 8) 
SE1-2 
(Safety 
Wks 4 & 
8) 
EOS 
(Safety Wk 
12 or Early 
Termination) 
Unsched 
Visit 11, 15 
30 Days 
Post 
EOS 
Phone/email 
Visit Windows 
 
 
 
± 2 
days17 
± 2 
days17 
± 2 
days 
± 4 
days 
± 7 
days 
± 4 
days 
± 7 days 
± 7 
days 
± 7 days 
NA 
+ 7 days 
Diet 
Prescription by 
Investigator or 
Dietician 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Assess 
Compliance 
with Diet 
Prescription 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Actual Protein 
and Calorie 
Intake (in-
clinic) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Assess G or NG 
tube use
9 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Drug 
Preference 
Assessment 
 
 
 
 
 
X
8 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
(AEs) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

HorizonTherapeutics, LLCCONFIDENTIAL      
Protocol HPN-100-021
Clinical Study Protocol
Version 12.0 |Amendment 11, 
 
Page 101 of 106 
 
 
Screen 
Baseline 
(Days-3 
thru -1) 
Initial 
Treatment 
Period 
End 
Treat
ment/ 
Start 
Next 
Period 
Transi- 
tion 
Period 
(7 days) 
Maintenance Period11 
End 
Mainte
nance/ 
Start 
Safety 
Safety Extension11, 
14 
Added 
Visits 
Post 
Study 
Visit 
 
 
Day 1 ITP 1, 
2, & 3 
(Weekly) 
EITP 
(ITP Wk 4 
-End of 
Initial 
Treatment 
Period)4, 22 
ETPD
7 
(Transit 
Day 7) 
MP111 
(Maint 
Wk 2)  
Phone/ 
email 
MP2 
(Maint 
Wk 4) 
MP3 
(Maint 
Wk 6) 
Phone/ 
email 
MP4 
(Maint 
Wk 8) 
SE1-2 
(Safety 
Wks 4 & 
8) 
EOS 
(Safety Wk 
12 or Early 
Termination) 
Unsched 
Visit 11, 15 
30 Days 
Post 
EOS 
Phone/email 
Visit Windows 
 
 
 
± 2 
days17 
± 2 
days17 
± 2 
days 
± 4 
days 
± 7 
days 
± 4 
days 
± 7 days 
± 7 
days 
± 7 days 
NA 
+ 7 days 
Dispense/ 
Collect Study 
Drug 
(Compliance 
check) 
 
 
X 
X 
X 
X 
X16 
X 
X
16 
X 
X 
X 
 
 
 
Initial Dose and 
Observation 5 
 
 
 
 
X 
 
 
 
X13 
 
 
 
 
 
 
 
 
 
CBCL or 
ABCL/ASR 6 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
CGI-Severity 7 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
CGI-
Improvement
 7 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
EQ-5D-5L 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
 
Hedonic Scale  
 
 
 
 
X
 
X8 
 
 
 
 
 
 
 
 
Date and Time 
Last Dose 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Reason for 
Termination 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 

HorizonTherapeutics, LLCCONFIDENTIAL      
Protocol HPN-100-021
Clinical Study Protocol
Version 12.0 |Amendment 11, 
 
Page 102 of 106 
 
 
Screen 
Baseline 
(Days-3 
thru -1) 
Initial 
Treatment 
Period 
End 
Treat
ment/ 
Start 
Next 
Period 
Transi- 
tion 
Period 
(7 days) 
Maintenance Period11 
End 
Mainte
nance/ 
Start 
Safety 
Safety Extension11, 
14 
Added 
Visits 
Post 
Study 
Visit 
 
 
Day 1 ITP 1, 
2, & 3 
(Weekly) 
EITP 
(ITP Wk 4 
-End of 
Initial 
Treatment 
Period)4, 22 
ETPD
7 
(Transit 
Day 7) 
MP111 
(Maint 
Wk 2)  
Phone/ 
email 
MP2 
(Maint 
Wk 4) 
MP3 
(Maint 
Wk 6) 
Phone/ 
email 
MP4 
(Maint 
Wk 8) 
SE1-2 
(Safety 
Wks 4 & 
8) 
EOS 
(Safety Wk 
12 or Early 
Termination) 
Unsched 
Visit 11, 15 
30 Days 
Post 
EOS 
Phone/email 
Visit Windows 
 
 
 
± 2 
days17 
± 2 
days17 
± 2 
days 
± 4 
days 
± 7 
days 
± 4 
days 
± 7 days 
± 7 
days 
± 7 days 
NA 
+ 7 days 
SAE / 
Pregnancy Post 
EOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
X18 
 
1. Height will be measured at Baseline for all subjects. At the EITP visit, and throughout the Maintenance and Safety Extension Period, height will be measured 
only for those subjects with BSA < 1.3 m2. Height measurement should be made with the use of a stadiometer.  
2. For the 8-hour amino acid (Hour 0 and Hour 8 only), blood and spot urine (Hour 0 and Hour 8 only) and ammonia and PK assessments samples will be 
collected relative to the first morning dose as follows: 
 Hour 0 (just before the first main meal and dose after an overnight fast or 4-6 hours without high calorie and protein intake; i.e., 08:00 [8:00 am] for 
those who can tolerate fasting) 
 Hour 4 (just before lunch and prior to dosing; i.e., 12:00 [12:00 pm])  
 Hour 8 (~2 4 hours after lunch or the second main meal; i.e., approximately16:00 [4:00 pm] prior to dosing) 
3. Collect single sample prior to morning dose (just before the first main meal and dose after an overnight fast or 4-6 hours without high calorie and protein 
intake; i.e., 08:00 [8:00 am] for those who can tolerate fasting) 
4.  An optional overnight stay may be utilized for subject convenience or Investigator discretion, based on dosing requirements of the subject and/or the 
travel requirements to the site. 
5. Subjects will be observed for at least 1 hour following the first dose in the Initial Treatment Period, and subjects in treatment Arm 2 also at the EITP visit after 
the first dose of RAVICTI. 
6. CBCL is administered to subjects 18 months  to 18 years of age, while the ABCL/ASR is administered to subjects 19 to 59 years of age. For subjects on NaBz 
at baseline, they should remain on NaBz for their baseline assessments. 
7. CGI Scoring: See Appendix C of the protocol 

HorizonTherapeutics, LLCCONFIDENTIAL      
Protocol HPN-100-021
Clinical Study Protocol
Version 12.0 |Amendment 11, 
 
Page 103 of 106 
 
8. Arm 2 only 
9. Assessment of G or NG tube use only for subjects with G or NG tubes 
10. Plasma PK analysis for PBA, PAA, and PAGN. 
11. Biochemical markers (plasma ammonia and if indicated blood amino acid panel) should be drawn and considered for any dose adjustments at least every 7 
days until stable during the Initial Treatment Period . During Transition, Maintenance, and Safety Periods, biochemical markers should be assessed after dose 
and diet changes at appropriate intervals (see Dose Adjustment Algorithm in section 3.8) not > 7 days after each dose/diet adjustment.  This can occur at 
unscheduled visits throughout the study as needed.  
12. Urine PK analysis for PAGN 
13. For subjects in Treatment Arm 2, the first dose of RAVICTI will be taken on the evening of the EITP visit after 8-hour ammonia, amino acid panel, PK, and 
spot urine samples have been collected (i.e., approximately 16:00 [4:00 pm]).   
14. During the Safety Extension Period, additional visits and assessments may be scheduled at the discretion of the Investigator. 
15. Blood sample(s) can be non-fasting, for subjects who cannot fast and in situations where fasting cannot be accomplished, such as HAC and neurological AE 
grade >2 and at the Investigators discretion. For every ammonia and amino acid panel, the fasting status (fasting/non-fasting) of the subject at the time of the 
blood collection will be recorded. 
16.  Compliance check only. 
17. As counted from the prior scheduled visit. 
18. The 30 day post end of study check for SAEs and pregnancy may be done via remote contact (phone, email, etc.) or visit if it coincides with standard of care.  
19. To be collected upon presentation at the study center (and as feasible at other health care facilities) with signs and symptoms of HAC or PAA toxicity. 
20. To be collected on any day that a PK sample is collected and upon presentation at the study center  (and as feasible at other health care facilities) with signs 
and symptoms of hyperammonemia, HAC or PAA toxicity. 
21. Randomisation to be completed following baseline assessments and confirmation of eligibility, up to and including Initial Treatment Period Day 1.For subjects 
in  Treatment Arm 1, where Ammonia or Amino Acid panel (glutamine, threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, valine) 
results are not available on the day of EITP visit; the investigator will contact the subject (phone/email) within 2 days of the visit, to adjust the dose of 
RAVICTI if necessary, and to confirm whether the subject should proceed to the Transition Period or Maintenance Period 1. 
 
 

Horizon Therapeutics, LLC CONFIDENTIAL                                                               Protocol HPN-100-021 
Clinical Study Protocol 
 
Version 12.0 |Amendment 11,  
 
Page 104 of 106 
 
APPENDIX B. 
HEDONIC SCALE TO ASSESS PALATABILITY  
Hedonic scale is a validated scale developed to test palatability of food (Peryam 1957, Chen 
1996) and has been extensively used to assess palatability of flavored medications (Matsui 
2007). Subjects (or parents or caregivers) are asked to rate the palatability of RAVICTI (glycerol 
phenylbutyrate) Oral Liquid and NaPBA 
following hedonic scale during the study periods indicated below.   
 
 
Likes very much 
Likes 
moderately 
Neither likes or 
dislikes 
Dislikes 
moderately 
Dislikes very 
much 
 
Hedonic scale is performed at the following time points during the Initial Treatment and 
Transition Periods:   
Initial Treatment Period 
1. EITP visit for all subjects  
Transition Period 
2. Transition Day 7 visit for Treatment Arm 2 subjects only 
 
 
 
 

Horizon Therapeutics, LLC CONFIDENTIAL                                                               Protocol HPN-100-021 
Clinical Study Protocol 
 
Version 12.0 |Amendment 11,  
 
Page 105 of 106 
 
APPENDIXC.CLINICAL GLOBAL IMPRESSION (CGI) 
The Clinical Global Impression  Severity scale (CGIS) is a 7point scale that requires the 
clinician to rate the severity of the patient
's illness at the time of assessment, relative to the 
clinician
's past experience with patients who have the same diagnosis (Guy 1976, Guy 2000). 
Considering total clinical experience, a patient is assessed on severity of illness at the time of 
rating relative to Baseline.  
 1 normal, not at all ill  
 2 borderline ill  
 3 mildly ill 
 4 moderately ill 
 5 markedly ill 
 6 severely ill 
 7 extremely ill 
The Clinical Global Impression  Improvement scale (CGII) is a 7 point scale that requires 
the Investigator 
relative to a 
Baseline state at the beginning of the intervention and rated as:  
 1 very much improved  
 2 much improved 
 3 minimally improved 
 4 no change  
 5 minimally worse 
 6 much worse 
 7 very much worse 
 
 

Horizon Therapeutics, LLC CONFIDENTIAL                                                               Protocol HPN-100-021 
Clinical Study Protocol 
 
Version 12.0 |Amendment 11,  
 
Page 106 of 106 
 
APPENDIXD.ASSESSMENT OF DRUG PREFERENCE
Assessment of Drug Preference: 
1. Which drug do you prefer?* (Circle 
one) 
AMMONAPS®   or 
BUPHENYL® 
(sodium phenylbutyrate) 
 
RAVICTI®  
(glycerol phenylbutyrate) 
Oral Liquid 
2. Why do you prefer this drug*?  Mark all that apply. 
- [  ] taste 
- [  ] volume (amount of drug that must be given) 
- [  ] side effect profile (please specify) 
 
 
- [  ] ease of administration (please describe what is easier about your choice) 
 
 
- [  ] other (please specify) 
 
 
 
 
*Subject should be queried directly.  However for young children, the parent/legal guardian can report on 
behalf of the child if more appropriate.