Clinical trial NCT02214160
Conditions: Carnitine Palmitoyltransferase (CPT I or CPT II) Deficiency Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency Long-chain 3-hydroxy-acyl-CoA Dehydrogenase (LCHAD) Deficiency Trifunctional Protein (TFP) Deficiency Carnitine-acylcarnitine Translocase (CACT) Deficiency
Keywords: Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) carnitine palmitoyltransferase (CPT I or CPT II) deficiency very long chain acyl-CoA dehydrogenase (VLCAD) deficiency long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency trifunctional protein (TFP) deficiency carnitine-acylcarnitine translocase (CACT) deficiency Triheptanoin UX007 C7
Sponsor: Ultragenyx Pharmaceutical Inc
Start date: 2014-12-09; Completion date: 2020-12-03
Enrollment: 94 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the long-term safety and efficacy of UX007 in participants with LC-FAOD. The secondary objectives of this study are to evaluate the effect of UX007 on energy metabolism in LC-FAOD and evaluate the impact of UX007 on clinical events associated with LC-FAOD.

Detailed description:

Arms: arm 1: Participants previously treated with UX007 or treatment-naive participants will begin or continue treatment with daily open-label UX007 while maintaining their other dietary restrictions.
Interventions: intervention 1: UX007
Intervention descriptions: intervention 1: Administered orally (PO) with food or by gastrostomy tube, at the target dose range of 25-35% of total calories.

Protocol documents:
Prot_000.pdf: 
TITLE PAGE 
An Open-label Long-Term Safety and Efficacy Extension Study in Subjects with 
Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Previously Enrolled in UX007 
or Triheptanoin Studies 
Protocol Number: UX007-CL202 
Original Protocol: 14 July 2014 
Amendment 1: 16 April 2015 
Amendment 2: 21 December 2015 
Amendment 3: 12 April 2016 
Amendment 4: 16 September 2016 
Amendment 5: 02 October 2017 
Amendment 6:  01 October 2019 
Investigational Product: 
UX007 (triheptanoin) 
Indication: 
Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) 
IND Number: 
117053 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA 94949 
Sponsor’s Responsible 
Medical Officer: 
 
Senior Medical Director, Clinical Sciences 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA USA 94949 
 
This study is to be performed in compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. 
Confidentiality Statement:  This document and the information it contains is confidential and proprietary 
and is the property of Ultragenyx Pharmaceutical Inc. (Ultragenyx).  Unauthorized disclosure, reproduction, 
transmission, or use of this document or information is strictly prohibited.  By accepting this document, the 
recipient agrees that the information it contains will not be disclosed without written authorization from 
Ultragenyx, except to the extent required to satisfy Institutional Review Board /Ethics Committee procedures, to 
obtain written informed consent from potential subjects, or as required by law. 


Protocol Number:  UX007-CL202  
Amendment 1:  16 Apr 2015 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007-CL202 Amendment 1 
16 April 2015 
 
 
The Protocol UX007-CL202 (dated 14 July 2014) has been modified by Amendment 1 to 
incorporate a number of changes based on additional information acquired since the 
beginning of the study.  The major changes to the protocol impacting the conduct of the 
study are summarized below.  Additional changes have also been made to provide supportive 
information and rationale for the proposed changes (along with minor edits for consistency 
and clarity) but are not detailed in this summary. 
1. Sponsor’s Responsible Medical Officer and associated Medical Monitor contact 
information (title page and Section 10) have been updated to: 
 
2. A study schematic was added to the synopsis and the body of the protocol. 
Rationale: A study schematic will assist the reader in visualizing the course of the 
study.  
 
3. Inclusion Criterion 2 (synopsis and Section 7.3.1) was updated to allow inclusion of 
patients who have failed conventional therapy and who have documented severe 
unmet need. Similar changes were made to Sections 7.1, 7.3, and 7.6.5 
Rationale: This change was made to allow inclusion of patients with severe unmet 
need not previously eligible for this study. 
 
4. Inclusion Criterion 7 (synopsis and Section 7.3.1) was updated to provide additional 
detail as to the acceptable methods of contraception required for inclusion into this 
study. A similar change was made in Section 7.5.4.6. 
 
Rationale:  This change was made to clarify the contraception language. 
 
5. Added Exclusion Criterion Number 2 indicating that patients qualifying for any other 
clinical trial designed to progressively evaluate the safety and efficacy of triheptanoin 
in LC-FAOD are not eligible for this study. 
Rationale:  This change was made for clarification. 


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6. Exclusion criterion Number 4 in the synopsis and Section 7.3.2 was updated to 
exclude breastfeeding mothers from participation in this study. 
Rationale: This change was made for clarification and to ensure that breastfeeding 
mothers are not enrolled into the study.  
7. Stopping Rules in Section 7.3.3.1 were updated to state that Regulatory Authorities, 
as well as Institutional Review Boards (IRBs) and Ethics Committees (ECs), will be 
informed should unexpected and possibly, probably, or definitely drug-related SAEs 
occur and/or if the study is paused or stopped. Language was also added stating that, 
if paused or stopped, the trial will only be restarted following approval by Regulatory 
Authorities.  
 
Rationale: This change was made to clearly convey that Regulatory Authorities will 
be contacted if any of the above occurs during the course of this study. 
 
8. The Peabody Developmental Motor Scales (PDMS) and the Clinical Global 
Impression (CGI) scales were removed as efficacy variables in the study. 
Rationale: The PDMS was removed because gross motor function does not appear to 
be a problem for younger FAOD patients. The CGI scales were removed because pre-
treatment assessments for comparison are not available for this pool of patients. 
Removal of these assessments will also alleviate patient burden. 
9. A visit window of ±1 week was added to the phone visits in the schedule of events.  
Rationale: This change was made to reduce site and patient burden. 
10. The definitions for AE relatedness were updated in Section 8.5.3. 
Rationale: This change was made to standardize the definitions across protocols. 
11. Text was added to Section 8.5.1 noting that hospitalizations planned prior to study 
enrollment (e.g. for elective surgeries) are not considered SAEs. Hospitalizations that 
occur for pre-existing conditions that are scheduled after study enrollment are 
considered SAEs. 
Rationale: This change was made for clarification. 
12. Sections 8.5.1, 8.5.4, 8.5.5, and 8.5.6 were updated to define the sponsor’s 
responsibilities with regard to reporting SAEs/SUSARs. 
Rationale: These changes were made in accordance with European Directive 
2001/20/EC.  


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007-CL202 Amendment 2 
21 Dec 2015 
 
 
The Protocol UX007-CL202 (dated 16 April 2015) has been modified by Amendment 2 to 
incorporate a number of changes based on additional information acquired since Amendment 
1.  The major changes to the protocol impacting the conduct of the study are summarized 
below.  Additional changes have also been made to provide supportive information and 
rationale for the proposed changes (along with minor edits for consistency and clarity) but 
are not detailed in this summary. 
1. Updated the medical director contact from 
, MD to 
, 
DO. This change affected Sections 8.5.7, 10, and the cover page.  
 
2. Changed the term “Screening” to “Baseline” in Exclusion Criterion Number 4. 
Similar changes were made to Sections 7.5.4.9 and 8.1.1. 
Rationale: This change was made to clarify an earlier oversight.  
 
3. Deleted the sentence: “For subjects completing the UX007-CL201 study, the last 
evaluable ECHO will serve as Baseline for this study” in Footnote 7 of Table 2.1 and 
in Section 7.5.2.4. 
Rationale: Since the last echocardiogram (ECHO) in the UX007-CL201 study is 
performed at week 24, nearly a year will have transpired and subjects will be due for 
a repeat ECHO (UX007-CL202 requires an ECHO be performed annually). 
  
4. Additional detail was added to Table 2.1 (Footnote 6) regarding the performance of 
the 12MWT. 
 
Rationale: This change was made for clarity and patient convenience. 
 
5. Added pancreatic lipase inhibitors and removed oral salicylates from the list of 
prohibited medications.  
Rationale: Pancreatic lipase inhibitors were added as prohibited medications 
because in vitro studies have shown that pancreatic lipases hydrolyze triheptanoin; 
therefore inhibitors of pancreatic lipases (e.g. orlistat) should be avoided while 
taking UX007. Salicylates are not routinely prescribed in children because of concern 


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for potential association with Reye’s syndrome; however, they may be used at the 
physician’s discretion. They may also be recommended as low dose daily treatment 
for adult subjects with risk for cardiovascular disease or those at risk for colon 
cancer. 
6. Updated text in Sections 7.5.4 (Safety Measures & General Assessments) and 7.5.4.8 
(Adverse Events).  
Rationale: This change was made for clarification. 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007-CL202 Amendment 3 
12 April 2016 
 
 
The Protocol UX007-CL202 (Version 2 dated 21 December 2015) has been modified by 
Amendment 3 to incorporate a change based on Regulatory feedback.  The change to the 
protocol impacting the conduct of the study is summarized below.   
1. The protocol was updated to clarify the total duration of the study. Specifically, the phrase 
“whichever occurs first” was included indicating that patients will be treated with “UX007 
for up to 3 years or until market approval, whichever occurs first.” This change affects the 
synopsis (Rationale, Study Design and Methodology, and Duration of Treatment), Section 5, 
Section 5.4, Section 7.1, and Section 7.4.4. 
Rationale: This change was made per guidance from Regulatory Authorities and for 
clarification.  
 
 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007-CL202 Amendment 4 
16 September 2016 
 
 
The Protocol UX007-CL202 (Version 3 dated 12 April 2016) has been modified by 
Amendment 4 to incorporate changes based on information obtained since the previous 
amendment.  The changes to the protocol impacting the conduct of the study are summarized 
below.  Additional minor changes have also been made for consistency and clarity but are not 
included in this summary.  
1. 
The length of study participation was increased to 5 years (60 months; end of 
treatment visit). This change affected multiple sections of the protocol including the 
schedule of events (Table 2.1) and Section 7.1 (Overall Study Design and Plan). 
Rationale: This change was made to ensure subjects are eligible to continue receiving 
study medication under the auspices of this clinical trial for 5 years or until market 
approval, whichever occurs first.  
2. The following statement was added to Sections 7.1 (Overall Study Design and Plan) 
and 7.4.4 (Selection of Doses and Study Duration): Subjects who switch from medium 
chain triglycerides (MCTs) to UX007 may transition at the same dose and then titrate, 
as appropriate. 
Rationale: This change was made to ensure a safe transition for those subjects 
formerly on MCT therapy. 
3. Inclusion Criterion #2 (Section 7.3.1, and corresponding information throughout) was 
updated to specifically include treatment-naïve (i.e., naïve to both UX007 and 
food-grade triheptanoin) patients. 
Rationale: Text was updated to provide clarification. This is not a change to the study 
eligibility. 
4. 
Inclusion Criterion #6 (Section 7.3.1, and corresponding information in 
Section 7.5.4.6 [Pregnancy Testing]) regarding pregnancy testing and contraception 
was updated as follows: 
• Females of childbearing potential must have a negative urine pregnancy test at 
Baseline and be willing to have additional pregnancy tests during the study. 
Females considered not of childbearing potential include those who have not 
experienced menarche, are post-menopausal (defined as having no menses for 


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at least 12 months without an alternative medical cause), or are permanently 
sterile due to total hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy. 
• Participants of child-bearing potential or fertile males with partners of 
child-bearing potential who are sexually active must consent to use a highly-
effective method of contraception as determined by the investigator from the 
period following the signing of the informed consent through 30 days after last 
dose of study drug. 
• Examples of highly effective contraception methods were added to 
Section 7.5.4.6. 
Rationale: The change provides clarification of study requirements. 
 
5. The 12-Minute Walk Test (12MWT) efficacy assessment was removed from the 
protocol (e.g., from Section 7.5.2 [Clinical Efficacy Measures] and the schedule of 
events [Table 2.1]). 
 
Rationale: Continuing to use the 12MWT assessment in this open-label, single-arm 
extension is unlikely to yield informative data. Removal of this assessment will reduce 
the burden to subjects and investigational sites participating in the study. 
 
6. The Pediatric Evaluation of Disability Inventory – Computer Adaptive Test 
(PEDI-CAT efficacy assessment was removed from the protocol (e.g., Section 7.5.2 
[Clinical Efficacy Measures] and the schedule of events [Table 2.1]). 
Rationale: Continuing to use the PEDI-CAT assessment in this open-label, single-
arm extension is unlikely to yield informative data. Removal of these assessments will 
reduce the burden to subjects and investigational sites participating in the study. 
 
7. A Safety Follow-up Phone Call was added to the schedule of events (Table 2.1) and 
relevant sections of the protocol (e.g., Sections 7.4.4 [Selection of Doses and Study 
Duration] and 7.5.1 [Schedule of Events]). 
 
Rationale: This change was made to align language with other Ultragenyx protocols 
based on requests from Regulatory Authorities to standardize how adverse event 
information is collected 30 days following the last dose of study drug. 
 
8. Text was added to clarify that the end of study is the last subject’s Safety Follow-up 
Phone Call. This change affected multiple sections of the protocol including 
Sections 7.1 (Overall Study Design and Plan) and 7.5.1 (Schedule of Events), and the 
schedule of events (Table 2.1). 
 
Rationale: This change was made to align language with other Ultragenyx protocols 
based on requests from Regulatory Authorities to clarify the end of study. 


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9. The statement in Section 7.4.5.1 (Prohibited Medications) was edited to be clearer: 
MCT oil and metabolic formulas containing significant contributions from MCT oil, 
including coconut oil, must not be used after the first dose of study medication. 
Rationale: This change was made for clarity. 
10. Section 7.5.2.3 (LC-FAOD Major Events) was updated to state that if events occur 
that represent a substantive change in the nature or an increase in frequency from a 
subject’s prior medical history, the event should be reported as an adverse event (AE). 
Rationale: This change was made to ensure that major LC-FAOD events are 
captured as AEs. 
11. Subject-reported fatigue, exercise tolerance, muscle pain, and activity level efficacy 
recording was removed from the protocol (e.g., from Section 7.5.2 [Clinical Efficacy 
Measures] and the schedule of events [Table 2.1]). 
Rationale: Continuing to record subject-reported symptoms of muscle weakness and 
fatigue in this open-label, single-arm extension is unlikely to yield informative data. 
Removal of this assessment will reduce the burden to subjects participating in the 
study. Note: New or worsened events of fatigue and muscle pain will still be collected 
as adverse events as described under Section 8.5 (Reporting and Follow-up of 
Adverse Events). 
12. Section 7.5.4.2 (Growth and Weight Evaluations) was updated to state that height, 
weight, and head circumference (if applicable) data will be used to evaluate subject 
growth using published normative data, when available. 
Rationale: This change was made to clarify how the growth and weight evaluations 
will be assessed. 
13. Section 8.4.3 (Record Retention) has been updated to state that all study records must 
be retained for at least 25 years after the end of the clinical trial or in accordance with 
national law and to clarify the responsibilities of the Investigator, Institution, and 
Ultragenyx with regard to record retention. 
 
Rationale: This administrative change to mandate retention of records for at least 
25 years has been made to reflect upcoming changes to EU clinical trial regulations 
and current regulations by other health authorities.  Record retention responsibility 
text was updated to clarify that it is not the explicit responsibility of Ultragenyx to 
assist with records retention. 
 
14. Updated language in Section 8.5.4 (Adverse Event Reporting). 
Rationale: This change was made so the language would be aligned with the most 
current Ultragenyx protocol template. 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007-CL202 Amendment 5 
02 October 2017 
 
 
The Protocol UX007-CL202 (Amendment 4 dated 16 September 2016) has been modified by 
Amendment 5 to provide pharmacokinetic assessments and modify dosing allowances.  
Primary and secondary endpoints have also been specified. The changes to the protocol 
impacting the conduct of the study are summarized below. Additional minor changes have 
also been made for consistency and clarity but are not included in this summary.  
1. 
Pharmacokinetic (PK) measurements were added to evaluate UX007 and UX007 
metabolites in a subset of subjects at select sites (minimum of 12 subjects) in 
Section 7.5.4, the Schedule of Events in Table 2.1, and Section 7.6.4. PK analysis was 
also added as a study objective in Section 6. 
Rationale: A PK sub-study was added to characterize the steady-state PK of UX007 
and UX007 metabolites in subjects with LC-FAOD. 
2. 
Section 7.1 was modified to include dosing greater than the target range of 25-35% at 
the Investigator’s discretion. 
Rationale: Dosing greater than the upper level of the target range has been included 
to allow subjects who enroll with a baseline UX007/triheptanoin dose greater than 
35% to maintain that dose on UX007-CL202. Investigators may also dose individual 
subjects above target range at their discretion; it is recommended that doses above 
35% are discussed with the Medical Monitor prior to administration. Anecdotal 
evidence from subjects on UX007-CL201 receiving MCT doses above 35% at 
Baseline and from subjects transitioning into UX007-CL202 with 
UX007/triheptanoin doses above 35% from Investigator-Sponsored Trials or 
Compassionate Use support that higher oil doses are safe and tolerable. 
3. 
Section 7.5.5.4 was modified to specify that the genitourinary component of the 
physical exam will be performed as age-appropriate at the Investigator’s discretion. 
Rationale: This modification was added to clarify that the genitourinary examination 
scope should be performed at the Investigator's discretion based on clinical judgement 
and/or safety need. 
4. 
Primary, secondary, and exploratory endpoints were added within the synopsis and 
Section 7.6.2.  Additional information on endpoint analysis was provided within 
Section 7.6.3. 


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Rationale: To adhere to clinical trial disclosure requirements, primary and secondary 
endpoints were clarified based on the study objectives outlined in Section 6.  
Exploratory endpoints were identified to characterize the potential effect of UX007 
treatment on functional disability and cognitive development, clinical biomarkers, 
and growth measurements, as outlined in Section 7.5.2.1, Section 7.5.3, and 
Section 7.5.5.2, respectively, as well as PK data for the UX007 metabolites as added 
to Section 7.5.4.   
 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007-CL202 Amendment 6 
01 October 2019 
 
 
The Protocol UX007-CL202 (Amendment 5 dated 02 October 2017) has been modified by 
Amendment 6 to extend the study duration and potential subject enrollment. 
Additional language was added to clarify the echocardiogram and lymphatic examination 
assessments. Modifications were also made to the exclusion criteria and to the study stopping 
rules. The changes to the protocol impacting the conduct of the study are summarized below. 
Additional minor changes have also been made for consistency and clarity but are not 
included in this summary.  
1. 
The study duration (Section 7.1 and throughout) has been extended from 5 years to 
up to 7 years or until commercial availability of UX007 in any region, whichever 
occurs first. The study duration has been extended to allow subjects to continue to 
receive study drug until UX007 is commercially available. An End of Study Visit was 
added in the case of commercial availability.   
2. 
The planned number of subjects (Section 7.3, Section 7.6.6, and throughout) was 
increased from approximately 100 subjects to approximately 150 subjects as the 
study continues to enroll subjects from investigator sponsored trials (ISTs) and 
UX007-naive subjects. 
3. 
Exclusion criterion #3 was modified in the synopsis and in Section 7.3.2 to allow 
exclusion of subjects who may be at increased risk of hypersensitivity adverse effects 
per the judgment of the Investigator.  
4. 
Inclusion criterion #2 was modified in the synopsis and in Section 7.3.1 from “severe 
unmet need” to “clear unmet need” to more accurately reflect the clinical presentation 
of LC-FAOD in the study population. 
5. 
Additional clarifying language was added to Section 7.5.2.2 and the Schedule of 
Events (Table 2.1) to allow for echocardiogram assessments performed as routine 
care within 30 days prior to the scheduled clinic visits.  
6. 
Additional clarifying language regarding the lymphatic portion of the physical 
examination was added to Section 7.5.5.4 to ensure that the exam scope is 
age-appropriate and at the Investigator’s discretion based on clinical judgement. 
7. 
Additional text was added to Section 7.3.3.1 to clarify the SAE severity (Grade 3 or 
higher) to be considered by the Investigator for the study stopping rules.  
 


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2 SYNOPSIS 
TITLE OF STUDY: 
An Open-label Long-Term Safety and Efficacy Extension Study in Subjects with Long-Chain Fatty 
Acid Oxidation Disorders (LC-FAOD) Previously Enrolled in UX007 or Triheptanoin Studies 
PROTOCOL NUMBER: 
UX007-CL202 
STUDY SITES: 
Approximately 10 sites globally 
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE: 
Long-chain fatty acid oxidation disorders (LC-FAOD) are caused by defects in the metabolic 
pathway that converts fatty acids into energy, leading to deficiencies in energy metabolism. 
The metabolic deficiency can deplete energy sources, resulting in serious clinical manifestations 
including hypotonia, rhabdomyolysis, liver dysfunction andhypoglycemia, and cardiomyopathy. 
These LC-FAOD major events are not sufficiently controlled in many patients by current standard of 
care, usually consisting of avoidance of fasting, low-fat/high-carbohydrate diet, dietary medium chain 
triglycerides (MCT oil), and/or carnitine supplementation. MCT oil, an even chain fatty acid, can 
provide medium chain fatty acids that bypass the specific LC-FAOD pathway defects but may not 
restore energy metabolism fully. In addition to supplying medium chain fatty acids, UX007 
(triheptanoin), a specialized medium odd-chain (C7) triglyceride, also replaces deficient mitochondrial 
tricarboxylic acid (TCA) cycle intermediates via the generation of 3-carbon intermediates, thereby 
improving energy metabolism. 
Triheptanoin has been studied in many types of LC-FAOD for approximately 20 years. Published 
reports describe profound clinical responses to triheptanoin, including improved physical capacity and 
a reduction of frequency and severity of major LC-FAOD events (rhabdomyolysis, hypoglycemia, 
liver function and hepatomegaly, and cardiomyopathy). Numerous LC-FAOD patients have 
participated, or are actively participating in multiple clinical studies or treatment programs with 
UX007/triheptanoin conducted by various sponsors and investigational sites.   
This open-label long-term safety and efficacy study will provide an opportunity for LC-FAOD 
patients to be treated with UX007 for up to 7 years or until commercial availability of UX007 in any 
region, whichever occurs first, under a single standardized protocol. The subjects may have 
participated in other studies or treatment programs with UX007/triheptanoin or be treatment naïve and 
have clear unmet need but would be consolidated into one program for long-term triheptanoin 
treatment and consistent safety monitoring. The study is designed to obtain long-term safety 
information and evaluate maintenance of efficacy in a diverse LC-FAOD population. 


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OBJECTIVES: 
The primary objective of the study is to: 
• 
Evaluate the long-term safety and efficacy of UX007 in LC-FAOD subjects 
The secondary objectives of the study are to: 
• 
Evaluate the effect of UX007 on energy metabolism in LC-FAOD 
• 
Evaluate impact of UX007 on clinical events associated with  LC-FAOD  
The objective of the pharmacokinetic sub-study is to: 
• 
Characterize the steady-state pharmacokinetics (PK) of UX007 and UX007 metabolites in subjects 
with LC-FAOD 
ENDPOINTS: 
 
Efficacy Endpoints 
The primary efficacy endpoint:   
• 
The annualized LC-FAOD major events rate inclusive of skeletal myopathy (rhabdomyolysis), 
hepatic (hypoglycemia) and cardiomyopathy events.  
 
The secondary efficacy endpoints:  
• 
Energy metabolism in LC-FAOD on the basis of the following endpoints: 
o Ventricle size  
o Ejection fraction (EF) 
o Shortening fraction (SF)  
• 
Clinical events associated with  LC-FAOD on the basis of the following endpoints 
o Annualized duration rate of all MCEs 
o Annualized event rate of rhabdomyolysis MCEs 
o Annualized duration rate of rhabdomyolysis MCEs 
o Annualized event rate of cardiomyopathy MCEs 
o Annualized duration rate of cardiomyopathy MCEs 
o Annualized event rate of hypoglycemic MCEs 
o Annualized duration rate of hypoglycemic MCEs 
 
Exploratory endpoints include the following: 
• 
Functional disability and cognitive development (instrument selection based on age) endpoints:  
o SF-10 physical health component summary (PCS) score  
o SF-10 mental health component summary (MCS) score  
o SF-12 physical health component summary (PCS) score  
o SF-12 mental health component summary (MCS) score  
• Clinical biomarkers endpoints: 
o Serum creatine kinase 
o Fasting serum glucose  
o Alanine aminotransferase (ALT) 
o Aspartate transaminase (AST) 
o Gamma glutamyl transpeptidase (GGT)  
• 
Growth measurement endpoints: 


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o Height  
o Weight 
o Head circumference, if applicable (subjects ≤ 36 months of age) 
PK endpoints 
• Plasma levels of UX007 
• Plasma levels of UX007 metabolites, including heptanoate, beta-hydroxypentanoate (BHP), and 
beta-hydroxybutyrate (BHB) 
 
Safety Endpoints 
Safety events will be collected as adverse events (AE) or serious adverse events (SAE).  The analyses 
of safety will include all subjects who receive at least one dose of study drug.   
The safety endpoints in this study are: 
• Incidence and severity of treatment emergent AEs  (primary safety endpoint) 
• Vital signs  
• Incidence of laboratory abnormalities  
• Concomitant medications 
STUDY DESIGN AND METHODOLOGY: 
The study is an interventional, open-label, long-term safety and efficacy extension study of UX007 
treatment in approximately 150 LC-FAOD subjects who have participated in prior clinical studies or 
treatment programs with UX007/triheptanoin or are treatment naïve (i.e., naïve to both UX007 and 
food-grade triheptanoin), have failed conventional therapy, and have clear unmet need.  UX007 dosing 
will be targeted at 25-35% of total caloric intake. If a subject has been receiving a lower dose of 
UX007/triheptanoin, the individual may continue treatment at the current dose.  If however, the 
subject has symptomatic disease or clinical signs of exercise limitation while on UX007 doses below 
the target range, the Investigator should consider titrating the dose to 25-35% of total caloric intake. 
UX007 doses above 35% of total caloric intake may be considered as needed at the discretion of the 
Investigator on an individual basis; it is recommended that doses above 35% are discussed with the 
Medical Monitor prior to administration. If a subject has been off UX007/triheptanoin treatment for 
> 1 month or is treatment naïve, the dose will be titrated according to the Study Drug Administration 
Guidelines. Subjects who switch from MCT to UX007 may transition at the same dose and then titrate, 
as appropriate. The subjects will be followed to evaluate the long-term safety and continued effects of 
UX007 for up to 7 years or until commercial availability of UX007 in any region, whichever occurs 
first. A Safety Follow-up Phone Call will be conducted 30-35 days after last dose of study drug.  The 
end of study is defined as the last day that protocol-specified assessments (including telephone 
contact) are conducted for the last subject in the study. 
If UX007 becomes commercially available during the study, each subject will return for an End of 
Study Visit; this will be recorded as study completion rather than early termination. For subjects not 
immediately continuing UX007 through another mechanism (ie, commercial product, IST, or 
compassionate use), a Safety Follow-up Phone Call will be conducted 30-35 days after last dose of 
investigational study drug.  
The continued effects of UX007 treatment on clinical and physiologic disease of the skeletal muscle, 
the liver and the heart will be assessed. Creatine kinase (CK) will be measured as a biomarker of 
skeletal myopathy. The metabolic effects on the liver and energy homeostasis will be assessed by 


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Protocol Number:  UX007-CL202 
Amendment 6: 01 October 2019 
 
 
Proprietary and Confidential 
Page 7 
treatment programs; or patients who are treatment naïve (i.e., naïve to both UX007 and food-grade 
triheptanoin), have failed conventional therapy and, in the opinion of the Investigator and Sponsor, 
have documented clear unmet need, may also be eligible at the discretion of the Sponsor. 
3. Confirmed diagnosis of LC-FAOD including:  carnitine palmitoyltransferase (CPT I or CPT II) 
deficiency, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxy-
acyl-CoA dehydrogenase (LCHAD) deficiency, trifunctional protein (TFP) deficiency, or 
carnitine-acylcarnitine translocase (CACT) deficiency. Information on diagnosis will be obtained 
from medical records and should include confirmed diagnosis by results of acylcarnitine profiles, 
fatty acid oxidation probe studies in cultured fibroblasts, and/or mutation analysis. 
4. Willing and able to complete all aspects of the study through the end of the study, including visits 
and tests, documentation of symptoms and diet, and administration of study medications. If a 
minor, have a caregiver(s) willing and able to assist in all applicable study requirements. 
5. Provide written informed consent (subjects aged ≥ 18 years), or provide written assent 
(where appropriate) and have a legally authorized representative willing and able to provide 
written informed consent, after the nature of the study has been explained and prior to any 
research-related procedures.  
6. Females of child-bearing potential must have a negative urine pregnancy test at Baseline and be 
willing to have additional pregnancy tests during the study. Females considered not of 
child-bearing potential include those who have not experienced menarche, are post-menopausal 
(defined as having no menses for at least 12 months without an alternative medical cause), or are 
permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 
7. Participants of child‐bearing potential or fertile males with partners of child-bearing potential who 
are sexually active must consent to use a highly effective method of contraception as determined 
by the Investigator from the period following the signing of the informed consent through 30 days 
after last dose of study drug. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short- or medium-
chain FAOD, ketone body metabolism defect, propionic acidemia or methylmalonic acidemia 
2. Patient qualifies for any other clinical trial designed to progressively evaluate the safety and 
efficacy of triheptanoin in LC-FAOD 
3. Any known hypersensitivity to triheptanoin that, in the judgment of the Investigator, places the 
subject at increased risk for adverse effects 
4. Pregnant and/or breastfeeding an infant at Baseline or planning to become pregnant (self or 
partner) at any time during the study  
5. Have any co-morbid conditions, including unstable major organ-system disease(s) that in the 
opinion of the Investigator, places the subject at increased risk of complications, interferes with 
study participation or compliance, or confounds study objectives or unwilling to discontinue 
prohibited medications. 


Protocol Number:  UX007-CL202 
Amendment 6: 01 October 2019 
 
 
Proprietary and Confidential 
Page 8 
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION: 
UX007 is colorless to light yellow oil packaged in 1L round, translucent high-density polyethylene 
(HDPE) bottles. UX007 will be administered orally (PO) with food or by gastronomy tube; usually 
four times per day: breakfast, lunch, dinner, and before bed, at the target dose range of 25-35% of total 
calories. The dose may be divided into smaller more frequent doses with food as needed. The dose 
may be mixed with small amounts of food or drink (including formula) as indicated in the 
administration guideline. If a subject has been receiving a lower dose of triheptanoin, the individual 
may continue treatment at the current dose provided there is no evidence of symptomatic disease or 
clinical signs of exercise limitation. UX007 doses above 35% of total caloric intake may be considered 
as needed at the discretion of the Investigator on an individual basis; and it is recommended that doses 
above 35% are discussed with the Medical Monitor prior to administration. If a subject has been off 
UX007/triheptanoin treatment for > 1 month or is treatment naïve, the dose will be titrated according 
to the Study Drug Administration Guidelines. Subjects who switch from MCT to UX007 may 
transition at the same dose and then titrate, as appropriate. 
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION: 
The study is designed as an open-label interventional trial. Therefore, no reference therapy or placebo 
will be administered. 
DURATION OF TREATMENT: 
Subjects may receive UX007 treatment for up to 7 years (84 months) during the study or until 
commercial availability of UX007 in any region, whichever occurs first. The end of study is defined as 
the last day that protocol-specified assessments (including telephone contact) are conducted for the 
last subject in the study. 
CRITERIA FOR EVALUATION: 
The concept for evaluation is to study the long-term safety and continued effects of UX007 on energy 
metabolism and clinical events associated with LC-FAOD. Biologic and clinical assessments will be 
conducted throughout the 84 month Treatment Extension Period. The occurrence of major LC-FAOD 
clinical events will be captured and compared to available data prior to initiation of UX007 treatment.  
Dosing compliance and diet will be regularly monitored along with a standard panel of safety 
assessments. 
Clinical Efficacy Variables: 
Functional disability and cognitive development (instrument selection based on age):  
 
Medical Outcomes Study 10-Item Short Form (SF-10) OR Medical Outcomes Study 
12-Item Short Form (SF-12)  
• 
Cardiomyopathy and cardiac function measured by ECHO; includes ventricle size, ejection 
fraction and shortening fraction 
• 
LC-FAOD major events inclusive of skeletal myopathy (rhabdomyolysis), hepatic (hypoglycemia) 
and cardiac disease (cardiomyopathy) events. Defined as any visit to the ER/acute care, 
hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at 
home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an 
intercurrent illness complicated by LC-FAOD. The event type, levels of relevant laboratory 


Protocol Number:  UX007-CL202 
Amendment 6: 01 October 2019 
 
 
Proprietary and Confidential 
Page 9 
parameters (including CK, glucose, and BNP/troponin), the number of days hospitalized and in 
ICU, and the type and number of days of treatment and intervention will be recorded. 
Biomarkers & LC-FAOD Laboratory Measures:  
• 
Biomarkers of clinical manifestations:   
 Skeletal myopathy:  CK 
 Hepatic disease:  fasting serum glucose and liver enzymes (ALT, AST, GGT) 
• Laboratory measures of LC-FAOD disease activity, including total and free plasma carnitine, 
plasma acylcarnitines, and urine organic acids 
Pharmacokinetics of UX007 and Metabolites 
• 
Plasma levels of UX007 
• 
Plasma levels of UX007 metabolites, including heptanoate, beta-hydroxypentanoate (BHP), and 
beta-hydroxybutyrate (BHB) 
Safety & General Assessments: 
Safety events will be collected as adverse events (AE) or serious adverse events (SAE).  Study 
assessments to evaluate safety include:  
• 
Clinical laboratory tests 
• 
Vital signs 
• 
Physical examination 
• 
Concomitant medications  
• 
Growth rate, height and weight:  The amount and rate of growth in pediatric and adolescent 
subjects will be measured using standard methods and compared to baseline height and weight, 
and head circumference, if applicable (subjects ≤ 36 months of age), and to normal growth rates 
and published LC-FAOD growth rates, if available.  
STATISTICAL METHODS: 
A full description of the planned analyses will be provided in a Statistical Analysis Plan. 
The primary efficacy endpoint, ie annualized MCE event rate, will be calculated using all MCE events 
collected post-UX007 treatment through the end of study. The primary analysis of the annualized 
MCE rate is descriptive statistics using mean, standard deviation (SD), median, quartiles, minimum, 
and maximum values. Two-sided 95% confidence interval will also be provided when appropriate. 
Annualized event rates for MCE by event type (ie, rhabdomyolysis, cardiomyopathy and 
hypoglycemic events) will be calculated and summarized in a similar fashion as with the primary 
efficacy endpoint. 
In addition, for subjects who have historical event rate data collected, comparisons of pre- and 
post-UX007 treatment annualized event rates for overall MCE events will be conducted. In addition, 
intra-patient comparisons of pre- and post-UX007 treatment for MCE events by event type might be 
considered if sample size permits.  


Protocol Number:  UX007-CL202 
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Page 10 
Summary statistics will be produced for all exploratory endpoints using all available assessments. 
For continuous variables, the number of observations and the mean, standard deviation (SD), median, 
quartiles, minimum, and maximum values were tabulated by endpoint. For categorical variables, the 
counts and proportions of each value were tabulated. Two-sided 95% confidence interval will also be 
provided when appropriate. Efficacy data collected for age-specific assessments (e.g. SF-10/12) will 
be summarized for subjects in that age group only.  Other age-specific summaries may be provided for 
measures collected across all age groups.  
PK Analyses 
Summary statistics of plasma concentration will be provided for UX007 and metabolites. PK 
parameters such as area under the plasma concentration-time curve (AUC), time to maximum plasma 
concentration (Tmax), maximum plasma concentration (Cmax), and trough plasma concentration 
(Ctrough) will be estimated for participating subjects. 
Safety Analyses 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
The incidence and frequency of AEs will be summarized by System Organ Class (SOC), Preferred 
Term (PT), severity, and relationship to UX007 treatment, if possible. A by-subject listing will be 
provided for those subjects who experience a SAE, including death, or experience an AE associated 
with early withdrawal from the study or study drug treatment. 
Clinical laboratory data will be summarized by the type of laboratory test. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (i.e. outside reference 
ranges) and/or clinically significant abnormalities will be presented for each measurement.   


Protocol Number:  UX007-CL202  
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Page 11 
Table 2.1:  Schedule of Events 
 
Baseline1 
Treatment Extension2 
Year 1 
Treatment Extension2 
Years 2-7 
Early-
Term/End of 
Study3 
Safety 
Follow-up 
(30-35 days)13 
MONTH 
0 
0.5 
3 
6 
9 
12 
15, 21, 27, 33, 
39, 45, 51, 57, 
63, 69, 75, 81 
18, 
30, 42, 
54, 66, 
78 
24, 
36, 48, 
60, 72, 
84 
 
 
TYPE 
Clinic 
Phone 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Clinic 
Clinic 
Phone 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
Medical & Triheptanoin 
Treatment History4 
X 
 
 
 
 
 
 
 
 
 
 
Growth5 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
SF10/12 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Echocardiogram 
(ECHO)6 
X 
 
 
 
 
X 
 
 
X 
X 
 
LC-FAOD Major 
Events Assessment 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LC-FAOD Biomarkers 
& Laboratory Measures8 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Vital Signs9 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Physical Examination 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Clinical Laboratory 
Tests 10 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Urine Pregnancy Test 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol Number:  UX007-CL202  
Amendment 6: 01 October 2019 
 
 
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Page 12 
 
Baseline1 
Treatment Extension2 
Year 1 
Treatment Extension2 
Years 2-7 
Early-
Term/End of 
Study3 
Safety 
Follow-up 
(30-35 days)13 
MONTH 
0 
0.5 
3 
6 
9 
12 
15, 21, 27, 33, 
39, 45, 51, 57, 
63, 69, 75, 81 
18, 
30, 42, 
54, 66, 
78 
24, 
36, 48, 
60, 72, 
84 
 
 
TYPE 
Clinic 
Phone 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Clinic 
Clinic 
Phone 
Dietary Assessment and 
Diet diary11 
 
 
 
X 
 
X 
 
X 
X 
X 
 
UX007 Treatment & 
Compliance12 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
X12 
 
Plasma UX007 and 
Metabolites14 
 
 
 
X14 
 
X14 
 
X14 
X14 
 
 
Standardized Meal14 
 
 
 
X14 
 
X14 
 
X14 
X14 
 
 
 
1 
The Baseline visit may occur in conjunction with the last scheduled visit from study UX007-CL201.  Assessments conducted at the last UX007-CL201 visit 
will be used for Baseline data to avoid duplication. Minor subjects who turn 18, should provide consent at their next visit. 
2 
Clinic Visits will occur at 6 month intervals (± 2 weeks). The window for phone visits is ± 1 week. 
3 
Early Termination Visit should take place within 4 weeks of treatment discontinuation, if possible. The End of Study Visit will take place following 
commercial availability of UX007 in any region; if the End of Study Visit occurs within 2 weeks of a previous clinic visit, only the following assessments 
will occur: growth, vital signs, physical examination, urine pregnancy testing, AEs, concomitant medications, and UX007 compliance. 
4 
Medical history including major medical illness, diagnoses and surgeries will be collected for all subjects not previously enrolled in UX007-CL201.  
LC-FAOD maintenance treatment history, including triheptanoin treatment history, and relevant concomitant medications will be recorded (start date, stop 
date, dose, dose regimen). Any available sibling history of LC-FAOD will be noted.   
5 
Growth measurements include height and weight for all subjects, as well as head circumference for subjects aged ≤ 36 months.  
6 
ECHO will be performed at Baseline and annually thereafter at indicated clinic visits (or if performed as routine care within 30 days prior to the Baseline or 
indicated clinic visits) or Early Termination if not performed within 6 months prior to termination.  Additional tests may be performed during Treatment 
Extension Period if any abnormalities are detected or if medically indicated.   
7 
Major LC-FAOD events include skeletal myopathy (rhabdomyolysis), hepatic (hypoglycemia) and cardiac disease (cardiomyopathy) events, and are defined 
as any visit to the ER/acute care, hospitalization, emergency intervention (ie any unscheduled administration of therapeutics at home or in the clinic), or any 
similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD.  The event type, levels of relevant laboratory 
parameters (including CK, glucose, and BNP/troponin), the number of days hospitalized and days in ICU, and the type and number of days of treatment and 
intervention will be recorded. 


Protocol Number:  UX007-CL202  
Amendment 6: 01 October 2019 
 
 
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Page 13 
8 
Biomarkers of clinical manifestations include skeletal myopathy (CK) and hepatic disease (fasting serum glucose and liver enzymes [ALT, AST, GGT]). 
Laboratory measures of LC-FAOD disease activity include total and free plasma carnitine, plasma acylcarnitines, and urine organic acids.   
9 
Vital sign measurements consist of seated systolic/diastolic BP measured in millimeters of mercury (mm Hg), HR (beats per minute), respiration rate 
(breaths per minute), and temperature in degrees Celsius (°C).  Obtain at the beginning of each visit before any additional assessments are completed. 
10 
Clinical Laboratory Tests include standard serum chemistry, hematology, and urinalysis. These panels may overlap with LC-FAOD-specific biomarkers 
(including glucose and liver enzymes) which are called out separately in the table.   
11 
Subjects and/or caregivers are required to maintain record of daily diet in a diary for 3 days prior to each clinic visit after consenting to participate in the 
trial. The daily diet should be representative of typical consumption for the subject. The diet diary will be reviewed with the site staff upon each indicated 
visit.  
12 
Treatment with UX007 will begin after any necessary washout period for prohibited medications. UX007 dosing will be targeted at 25-35% of total caloric 
intake.  If a subject has been receiving a lower dose, the individual may be titrated to a UX007 dose up to 25-35% of total caloric intake, while ensuring 
tolerability. However, a subject may remain at a lower dose if higher doses are not tolerated or at a higher dose at the discretion of the Investigator.  UX007 
will not be dispensed at the Month 84 (end-of-treatment visit), End of Study, Early Termination visits (as applicable). 
13 
Safety Follow-up Phone Call to be conducted 30-35 days after last dose of investigational study drug.  Following commercial availability of UX007, a 
Safety Follow-up Phone Call will be conducted 30-35 days after last dose of investigational study drug for subjects not immediately continuing UX007 
through another mechanism (ie, commercial product, IST, or compassionate use). The site personnel will initiate this safety follow-up telephone call to 
collect information on any ongoing or new AEs, serious adverse events (SAEs), and concomitant medications, as appropriate.  Appropriate follow-up should 
continue until all safety concerns, in the Investigator’s opinion, are resolved. 
14 
PK measurements will occur at select sites in a subset of subjects at two consecutively scheduled clinic visits (eg Month 18 and Month 24), excluding the 
Baseline Visit. Participating subjects (minimum of 12 subjects) will be fed a standardized meal containing one of their divided daily doses of UX007.  Blood 
for plasma UX007 and metabolites will be collected pre-dose (within 15 minutes prior to start of meal) and at 30, 90, 120, and 240 minutes [± 5 minutes] 
after finishing the meal. For each sample collection, the meal start/stop times, calories consumed, UX007 dosing, and sampling times will be recorded. 


Protocol Number:  UX007-CL202  
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Page 14 
3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................3 
3 TABLE OF CONTENTS ...................................................................................................14 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................17 
5 INTRODUCTION .............................................................................................................20 
5.1 Overview of Long-chain Fatty Acid Oxidation Disorders ........................................21 
5.2 Brief Overview of UX007 (Triheptanoin) Development ..........................................21 
5.2.1 
Brief Description of the Investigational Product .........................................22 
5.2.2 
Nonclinical Studies ......................................................................................24 
5.2.3 
Previous Clinical Studies .............................................................................25 
5.3 Summary of Overall Risks and Potential Benefits ....................................................26 
5.4 Study Rationale .........................................................................................................27 
6 STUDY OBJECTIVES ......................................................................................................29 
7 INVESTIGATIONAL PLAN ............................................................................................30 
7.1 Overall Study Design and Plan .................................................................................30 
7.2 Discussion of Study Design, Including Choice of Control Group ............................31 
7.3 Selection of Study Population ...................................................................................32 
7.3.1 
Inclusion Criteria .........................................................................................32 
7.3.2 
Exclusion Criteria ........................................................................................33 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................34 
7.4 Treatments .................................................................................................................35 
7.4.1 
Reference Therapy ......................................................................................35 
7.4.2 
Investigational Product ................................................................................35 
7.4.3 
Identity of Investigational Product ..............................................................35 
7.4.4 
Selection of Doses and Study Duration .......................................................36 
7.4.5 
Prior and Concomitant Therapy ..................................................................37 


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7.4.6 
Treatment Compliance ................................................................................38 
7.5 Study Procedures and Assessments ..........................................................................38 
7.5.1 
Schedule of Events ......................................................................................38 
7.5.2 
Clinical Efficacy Measures .........................................................................39 
7.5.3 
Biomarkers & LC-FAOD Laboratory Measures .........................................41 
7.5.4 
Pharmacokinetics of UX007 and Metabolites .............................................42 
7.5.5 
Safety Measures & General Assessments ...................................................42 
7.5.6 
Appropriateness of Measures ......................................................................46 
7.6 Statistical Methods and Determination of Sample Size ............................................46 
7.6.1 
Analysis Populations ...................................................................................46 
7.6.2 
Endpoints .....................................................................................................47 
7.6.3 
Efficacy Analyses ........................................................................................49 
7.6.4 
Pharmacokinetic (PK) Analyses: .................................................................49 
7.6.5 
Safety Analyses ...........................................................................................49 
7.6.6 
Determination of Sample Size .....................................................................50 
8 STUDY CONDUCT ..........................................................................................................51 
8.1 Ethics .........................................................................................................................51 
8.1.1 
Institutional Review Board or Ethics Committee ........................................51 
8.1.2 
Ethical Conduct of Study ............................................................................51 
8.1.3 
Subject Information and Consent ................................................................51 
8.2 Investigators and Study Administrative Structure ....................................................52 
8.3 Investigational Product Accountability .....................................................................52 
8.4 Data Handling and Record Keeping .........................................................................53 
8.4.1 
Case Report Forms and Source Documents ................................................53 
8.4.2 
Data Quality Assurance ...............................................................................53 
8.4.3 
Record Retention .........................................................................................54 
8.5 Reporting and Follow-up of Adverse Events ............................................................54 


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8.5.1 
Definition of Adverse Events ......................................................................54 
8.5.2 
Severity of Adverse Events .........................................................................55 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................56 
8.5.4 
Adverse Event Reporting ............................................................................56 
8.5.5 
Communication Plan ...................................................................................58 
8.5.6 
Safety Contact Information .........................................................................59 
8.6 Financing and Insurance ...........................................................................................59 
8.7 Publication Policy .....................................................................................................59 
9 REFERENCES ..................................................................................................................60 
10 SIGNATURE PAGE .........................................................................................................63 
 
List of Tables 
Table 2.1:  Schedule of Events ................................................................................................11 
Table 7.5.3.1:  Biomarkers and LC-FAOD-related Laboratory Measures ..............................42 
Table 7.5.5.5.1:  Clinical Laboratory Assessments .................................................................44 
 
List of Figures 
Figure 2.1:  UX007-CL202 Study Schema ................................................................................6 
Figure 5.2.1.1.1:  Mechanism of Action ..................................................................................23 
Figure 7.1.1:  UX007-CL202 Study Schema ...........................................................................31 
 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
APBD 
adult polyglucosan body disease 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
BNP 
B-type natriuretic peptide 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CACT 
carnitine-acylcarnitine translocase 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CPT 
carnitine palmitoyltransferase 
CRF 
Case Report Form 
ECHO 
echocardiogram 
EC 
Ethics Committee 
EDC 
electronic data capture 
EF 
ejection fraction 
ER 
emergency department/room 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAOD 
fatty acid oxidation disorders 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
GMP 
Good Manufacturing Practice 
GSD II 
glycogen storage disease type II 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICU 
intensive care unit 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IUD 
intrauterine device 


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IUS 
intrauterine system 
LC-FAOD 
long-chain fatty acid oxidation disorders 
LCHAD 
L-3-hydroxy-Acyl-CoA dehydrogenase 
LDH 
lactate dehydrogenase 
MADD 
multiple acyl-CoA dehydrogenase deficiency 
MCAD 
medium-chain acyl-CoA dehydrogenase deficiency 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCS 
Mental Component Summary 
MCT 
medium chain triglyceride 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NADH 
nicotinamide adenine dinucleotide hydrogen (reduced form) 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
No observed adverse effect level 
PCS 
Physical Component Summary 
PK 
pharmacokinetic 
PO 
oral, by mouth 
PT 
Preferred Term 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SF 
shortening fraction 
SF-10 
Medical Outcomes Study 10-Item Short Form for Children 
SF-12 
Medical Outcomes Study 12-Item Short Form 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious  adverse reaction 
TCA 
tricarboxylic acid 
TFP 
trifunctional protein 
US 
United States 
UX007 
Investigational Product/study drug, triheptanoin 
VLCAD 
very long chain acyl-CoA dehydrogenase 
WBC 
white blood cell 


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Definition of Terms 
Investigational Product is defined as, “A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use” (from International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use [ICH] Harmonised Tripartite Guideline E6: Guideline for Good Clinical Practice).  
The terms “Investigational Product” and “study drug” may be used interchangeably in the 
protocol. 


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5 INTRODUCTION 
Long-chain fatty acid oxidation disorders (LC-FAOD) are caused by enzyme deficiencies 
in the metabolic pathway that converts fatty acid into energy, leading to inadequate energy 
metabolism. LC-FAOD can result in serious and potentially life-threatening clinical 
manifestations, including rhabdomyolysis, hypotonia/weakness, hypoglycemia, and 
cardiomyopathy.  The clinical manifestations are usually managed through the avoidance of 
fasting, a low-fat/high-carbohydrate diet, supplementation with medium chain triglycerides 
(MCT oil) and/or carnitine supplementation. Despite treatment, many patients still suffer 
significant morbidity and mortality. The mortality rate can be above 50% for subjects 
diagnosed symptomatically and treated with the standard of care (Baruteau et al. 2012).   
Triheptanoin (UX007), a highly purified medium-odd-chain triglyceride consisting of 3 fatty 
acids with 7 carbons each, is intended as a substrate replacement therapy in patients with 
LC-FAOD and potentially other metabolic disorders to restore deficient intermediates in the 
mitochondria required for energy metabolism. Triheptanoin has been studied in many types 
of LC-FAOD and various other disorders. Some patients have been treated with triheptanoin 
for approximately 20 years with evidence of clinical benefit and no significant safety issues 
reported. Published reports suggest that LC-FAOD patients failing current therapy can 
exhibit profound positive clinical responses to triheptanoin (Roe et al. 2002); (Barone 2012); 
(Vockley et al. 2015); (Vockley et al. 2016); (Vockley et al. 2017); (Vockley et al. 2018). 
A retrospective medical record review study (UX007-CL001) has been conducted to 
formally assess the clinical outcome of triheptanoin treatment in 20 of 24 LC-FAOD patients 
who have been participating in an ongoing compassionate use program (IND-106011) for up 
to 13 years. The data suggest triheptanoin is effective in reducing serious and potentially life-
threatening energy crises as indicated by a 69% decrease in the number of hospitalization 
days during major medical events (Vockley et al. 2015). The results imply the possibility to 
reduce major medical events, and provide the basis for further evaluation of UX007 in 
prospective clinical studies to verify this effect on the clinical manifestations and major 
events of LC-FAOD disease. 
A completed Phase 2 clinical trial (UX007-CL201) evaluated the safety and effectiveness of 
UX007 in LC-FAOD patients who continued to suffer the effects of LC-FAOD disease 
despite current therapy. Following completion of a 24-week Treatment Period and 54-week 
Extension Period, subjects from UX007-CL201 were eligible to continue treatment in this 
extension study (UX007-CL202). Numerous LC-FAOD patients have also participated, or 
are actively participating in multiple clinical studies or compassionate use treatment 
programs with UX007/triheptanoin conducted by various sponsors and investigational sites. 
This open-label long-term safety extension study will provide an opportunity for these 
patients and treatment-naïve patients (i.e., naïve to both UX007 and food-grade triheptanoin) 
with clear unmet need to be treated with UX007 for up to 7 years or until commercial 
availability of UX007 in any region, whichever occurs first, under a single standardized 
protocol. The study is designed to obtain long-term safety information and evaluate 
maintenance of efficacy in a diverse LC-FAOD population. 


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5.1 
Overview of Long-chain Fatty Acid Oxidation Disorders 
Inherited autosomal recessive defects in the mitochondrial long-chain fatty acid oxidation 
pathways are collectively referred to as LC-FAOD. LC-FAOD are caused by defects in the 
mitochondrial β-oxidation pathways that convert fatty acids into energy, leading to 
deficiencies in energy metabolism. As a result, partial or incomplete oxidation of fatty acids 
leads to accumulation of high concentrations of fatty acids or other metabolic intermediates 
and an energy deficient state in most organs. The clinical manifestations of the various 
LC-FAOD frequently overlap and include rhabdomyolysis, hypoglycemia, hepatomegaly, 
cardiomyopathy, hypotonia and developmental delay, as well as sudden infant death 
(reviewed in(Roe et al. 2002). 
Clinical surveys suggest patients with LC-FAOD as a group have an overall premature 
mortality rate from birth of about 50% or higher when diagnosed symptomatically and 
treated (Baruteau et al. 2012).  Mortality may now have been reduced by newborn screening 
and early presymptomatic treatment, including diligent prevention of fasting combined with 
the use of low fat/high carbohydrate diets, carnitine supplementation in some cases, and 
MCT oil supplementation (Spiekerkoetter et al. 2009). MCT oil has medium even-chain fatty 
acids that can be metabolized by the separate set of medium-chain fatty acid oxidation 
enzymes that are distinct from those affected in LC-FAOD and should therefore bypass the 
LC-FAOD block. 
Despite improved mortality rates achieved with newborn screening, Spiekerkoetter and 
colleagues noted that patients on the best available treatment, including MCT oil with 
compliance of ≥ 80%, still had significant problems (Spiekerkoetter et al. 2009).  
Lindner and colleagues studied the outcome of expanded newborn screening on major 
decompensation events in different classes of disease diagnosed in South-West Germany 
(Lindner et al. 2011). The 16 patients (6 very long chain acyl-CoA dehydrogenase [VLCAD], 
5 L-3-hydroxy-Acyl-CoA dehydrogenase [LCHAD], 2 carnitine-acylcarnitine translocase 
[CACT] deficiency, 3 multiple acyl-CoA dehydrogenase [MADD]) in the group had a 25% 
rate of major decompenstion after only 2 years of follow-up. 
5.2 
Brief Overview of UX007 (Triheptanoin) Development 
A brief overview of existing information on UX007 (triheptanoin) is provided below; a 
comprehensive review of the data is contained in the Investigator’s Brochure (IB) provided 
by Ultragenyx Pharmaceutical Inc. (Ultragenyx), which should be reviewed prior to initiating 
the study.   


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5.2.1 Brief Description of the Investigational Product 
UX007 is a liquid, intended for oral (PO) administration. UX007 is highly purified 
triheptanoin, a triglyceride of 3 fatty acids with 7 carbons each. UX007 is manufactured by 
chemical synthesis from glycerol and heptanoic acid. The molecular formula and structure 
are as follows: 
Molecular Formula: C24H44O6  
Structure:  
 
Triheptanoin is metabolized to heptanoate, which in turn is further metabolized to 4- and 
5- carbon ketone bodies and the 3-carbon propionyl CoA (derived from the 5-carbon 
ketones).  Therefore, UX007 is designed as a pro-drug that is metabolized to heptanoate to 
provide substrate replacement as an odd-carbon medium-chain fatty acid for both fatty acid 
metabolism and anaplerosis (replacement of tricarboxylic acid [TCA] cycle intermediates) 
required for generation of energy. 
5.2.1.1 
Mechanism of Action 
The mechanism of action of UX007 in restoring energy metabolism is dependent on its 
medium chain length as well as its odd-carbon properties.  UX007 can be metabolized by 
LC-FAOD patients into free heptanoate which can traverse the mitochondrial membrane 
without the carnitine carrier. The free heptanoate from UX007 is then metabolized by a 
different set of medium chain fatty acid oxidation enzymes, bypassing the long chain 
oxidation enzymes that are deficient in LC-FAOD. The heptanoate is converted to both 
propionyl-CoA and acetyl-CoA required for energy metabolism (Figure 5.2.1.1.1).  
The restoration of energy metabolism is accomplished by two modalities: 1) the acetyl-CoA 
is condensed into citrate, the first step of the energy generating TCA cycle, and 2) the 
3-carbon unit in propionyl-CoA resupplies the TCA cycle intermediates that may be 
secondarily deficient in these patients. The production of propionyl-CoA is specific to 
odd-carbon fatty acids and is responsible for the anaplerotic properties of UX007, which are 
believed to be critical for restoring the energy deficiency state in LC-FAOD.   


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Figure 5.2.1.1.1:  Mechanism of Action 
 
Propionyl-CoA is a particularly efficient compound for restoring depleted TCA cycle 
intermediates due to the low succinyl-CoA concentration which can differ by 2-3 orders of 
magnitude compared to other compounds in TCA cycle intermediate pools. Propionyl-CoA is 
an anaplerotic substrate for all tissues, and is also gluconeogenic in the liver, kidney cortex, 
and brain (Kinman et al. 2006); (Gu et al. 2010); (Marin-Valencia et al. 2013). Production of 
anaplerotic propionyl-CoA stimulates acetyl-CoA oxidation, NADH production, and ATP 
regeneration, which should result in improved cardiac and skeletal muscle function.  
Although it is clear that even-carbon medium-chain triglycerides such as MCT oil can help 
LC-FAOD patients by bypassing defects, the additional effect of anaplerosis, and subsequent 
gluconeogenesis, is believed to be responsible for the further benefits observed in 
triheptanoin clinical programs. 
In addition to restoration of energy metabolism, UX007 reduces the production of toxic fatty 
acid intermediates by providing an external source of energy which is preferentially utilized 
over endogenous long-chain fatty acids, thus suppressing lipolysis. UX007 provides an 
efficient source of energy from fatty acids for muscles, potentially preserving glucose and 
glycogen stores during periods of fasting. This leads to a potentially more stable energy state 
whereby fasting and exercise episodes can be better tolerated due to both increased energy 
stores and also leads to better utilization of fats and ketone bodies as energy sources. 


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5.2.2 
Nonclinical Studies 
Studies of potential clinical significance and relevance to this protocol are summarized 
below. Additional details are provided in the UX007 IB. 
Nonclinical studies evaluating triheptanoin and its metabolites in mice and rats have been 
published and further support the safety of UX007. These studies provide data on the 
absorption, and metabolism of triheptanoin when administered intravenously and PO at doses 
up to 40% the recommended caloric intake. Triheptanoin is metabolized rapidly in the gut to 
form a series of energy containing metabolites, including heptanoate, C4- and C5-ketone 
bodies (Kinman et al. 2006), (Deng et al. 2009).   
Nonclinical studies in rats have demonstrated that triheptanoin is hydrolyzed to heptanoate 
and glycerol, which are efficiently absorbed by the liver (Kinman et al. 2006). A study in 
mice infused with intravenous 13C-heptanoate at 50% the caloric requirement demonstrated 
increased plasma 13C-enriched glucose levels over baseline plasma glucose levels, 
confirming that heptanoate is a substrate for gluconeogenesis in the liver (Marin-Valencia et 
al. 2013). Gu et al. also showed that triheptanoin infusion can generate glucose and also 
increase glycogen stores in liver (Gu et al. 2010). 
The acute oral toxicity of triheptanoin was performed in rats at four dose levels ranging from 
0.5 ml/kg (n= 2) to 5 ml/kg (n=5M/5F). There were no deaths or signs of toxicity at any time 
throughout the duration of the study and up to 7 days post dose (IND-59303).   
A 9 month oral toxicity study in rats was performed with an experimental oil containing 
64% triheptanoin to determine the effects of a diet containing triheptanoin on animal growth, 
lipid digestibility, clinical chemistry, and toxicity in liver, kidney, and small intestine (Ataide 
et al. 2009). After 9 months of consumption of a standard diet containing doses up to 1.14 g 
triheptanoin per kg of body weight per day, no toxic effects attributed to triheptanoin were 
found in rats. There was no significant difference in the clinical chemistries that would 
indicate hepatic damage or adverse effect on renal function compared to control animals fed 
a standard diet supplemented with soybean oil as the lipid source.  
A Good Laboratory Practice (GLP) 9-month chronic toxicology study in juvenile Yucatan 
Mini-Pigs has been completed. UX007 was well tolerated for 9-months with no evidence of 
toxicity in mini-pigs receiving up to 50% of their daily caloric intake from UX007. 
Systemic exposure to UX007 was evident from the dose-related increase in its primary 
metabolites (heptanoic acid and C5 ketone bodies). No accumulation was seen after 9 months 
of treatment. No gross or microscopic lesions were noted due to UX007 administration at any 
of the dose levels. Based on the lack of toxicity in these animals after 9 months of treatment, 
the no observed adverse effect level (NOAEL) for systemic toxicity following oral 
administration of UX007 to juvenile Yucatan minipigs was 50% of daily caloric intake. 


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5.2.3 
Previous Clinical Studies 
Over 500 subjects with various diseases have been treated with triheptanoin for up to 
approximately 20 years. The clinical experience supports the safety of triheptanoin when 
administered at approximately 35% of daily caloric intake in pediatric patients as young as 
neonates. 
Triheptanoin has been studied for over a decade in a large cohort of LC-FAOD patients  
(Roe et al. 2002), (Roe et al. 2006), (Roe et al. 2008), (Barone 2012). Patients with other 
disorders have also been treated with triheptanoin, including those with pyruvate carboxylase 
deficiency (Mochel et al. 2005), Huntington’s disease (Mochel et al. 2010), adult 
polyglucosan body disease (APBD, a form of glycogen storage disorder due to brancher 
enzyme deficiency; (Roe et al. 2010), and Pompe disease (also known as glycogen storage 
disease type II [GSD-II] or acid maltase deficiency; (Roe et al. 2006). Ultragenyx also 
evaluated UX007 as treatment for Glut1 deficiency syndrome (Glut1 DS). The use of UX007 
in the Glut1 DS indication is no longer under clinical development as the clinical studies did 
not meet their primary efficacy endpoints.  
Roe and colleagues described triheptanoin treatment of 3 subjects with VLCAD  
(Roe et al. 2002). Despite 2 - 5 years on standard of care including MCT oil as fat 
supplement, all subjects had numerous clinical problems. Within hours of initiating 
triheptanoin treatment, improvements in muscle pain and function were seen in all subjects. 
Within 1 week, both subjects with hepatomegaly had normal liver size. The subject with 
cardiomyopathy had a shortening fraction (SF) of 19% prior to treatment which improved to 
30% after 1 month on triheptanoin therapy.  
A cumulative summary of triheptanoin treatment was reported for 48 LC-FAOD patients by 
Roe and Mochel (Roe et al. 2006). Following initiation of triheptanoin, a large decrease in 
hepatomegaly/hypoglycemia in nearly all patients was observed. Substantial decreases in 
rhabdomyolysis event frequency, and a decrease in cardiac disease were also reported. 
Roe and colleagues described the impact of triheptanoin treatment in 7 patients with carnitine 
palmitoyltransferase type II (CPT II) deficiency (Roe et al. 2008). During the 18 month 
assessment period, there were no rhabdomyolysis events or hospitalizations, and all patients 
returned to normal physical activity within 2 months following initiation of triheptanoin.  
The treatment was well tolerated when triheptanoin was consumed over a 20-30 minute 
period (Roe et al. 2008).  
In total, 61 LC-FAOD patients have been treated with triheptanoin by Dr. Charles Roe and 
colleagues in a study sponsored by the Baylor Research Institute (IND-59303). A subset of 
subjects continued triheptanoin treatment for up to 10 years as part of a compassionate use 
program. These patients were transferred to the University of Pittsburgh Medical Center, 
under Dr. Jerry Vockley and their treatment continued (IND-106011). Some of these patients 
have been reported to exhibit profound clinical responses to triheptanoin including reduction 
of frequency and severity of rhabdomyolysis events, reduction or elimination of 


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hypoglycemia events, improved physical capacity, and resolution of cardiomyopathy (Roe et 
al. 2002); (Barone 2012). Anecdotal evidence suggests triheptanoin treatment is well 
tolerated and does not result in excess weight gain with proper management of caloric intake 
(Barone 2012).   
A retrospective medical record review study (UX007-CL001) was conducted for LC-FAOD 
subjects who have been treated with triheptanoin for 0.6 – 13 years under the aforementioned 
treatment program (Vockley et al. 2013). The study evaluated the impact of triheptanoin 
treatment on the rate and extent of hospitalizations in 20 of 24 patients who consented to be 
part of the study. A total of 120 individual charts were evaluated, which covered 241 years of 
patient data and included a total of 319 hospitalizations. The study compared the major 
medical event rate before and after initiation of triheptanoin treatment including the total 
number of hospitalizations and hospital days per year due to all causes, muscle rupture, 
hypoglycemia, or cardiomyopathy. Results demonstrated significant decreases in the number 
of hospitalization days during major medical events (69%; p < 0.05), and the mean number 
of hypoglycemia events per year (96%; p<0.01) after initiation of triheptanoin treatment 
(Vockley et al. 2015).  
In the Phase 2 study, UX007-CL201, the frequency and duration of major clinical events 
including rhabdomyolysis, hypoglycemia, and cardiomyopathy were consistently reduced 
during 78 weeks of UX007 treatment compared with the 78-week pre-UX007 period 
(Vockley et al. 2018), supported by the consistent results from the retrospective study 
CL001. In addition to total events, a clinically meaningful reduction in events leading to 
hospitalizations was observed, indicating an effect of UX007 on the most serious 
manifestations of LC-FAOD. Walking distance improved for the 12 Minute Walk Test 
(12MWT) in UX007-CL201, indicating that subjects maintained pace and exhibited 
increased stamina throughout the entire distance walked, consistent with an improvement in 
energy metabolism. In addition, both workload and duration improved during cycle 
ergometry testing following 24 weeks of UX007 treatment, with an observed 60% mean 
increase in workload over Baseline, suggesting the potential for improved exercise capacity 
following treatment with triheptanoin (Vockley et al. 2017). 
5.3 
Summary of Overall Risks and Potential Benefits 
UX007 is intended as a substrate replacement therapy to restore the full process of energy 
metabolism in patients with LC-FAOD. Triheptanoin was developed to address the needs of 
LC-FAOD patients who continued to have disease crises despite the best available treatment. 
The current standard of care for these patients is not sufficient to prevent all LC-FAOD 
manifestations, and is still associated with a high mortality rate (Baruteau et al. 2012).   
Over 500patients with various disorders, including LC-FAOD patients ranging from neonates 
to adults, have been treated with triheptanoin for up to approximately 20 years with evidence 
of clinical benefit and no significant safety issues reported. Published reports indicate that 
triheptanoin has improved a wide range of LC-FAOD symptoms in the subjects studied and 
some LC-FAOD patients failing current therapy can exhibit profound positive clinical 


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responses to triheptanoin, including a reduction of frequency and severity of rhabdomyolysis 
events, reduction or elimination of hypoglycemia events, improvements in liver function and 
hepatomegaly, improved physical capacity, and resolution of cardiomyopathy. 
Nonclinical studies evaluating triheptanoin and its metabolites in mice and rats have 
been published and further support the safety of triheptanoin in the LC-FAOD population. 
Data from pharmacokinetic and toxicity studies indicates that triheptanoin is well absorbed 
after oral dosing and is well-tolerated without overt toxicities at doses as high as 1.14 g/kg 
for 9 months. There were no signs of hepatic or renal injury. 
Data from nonclinical and clinical studies to date suggest triheptanoin does not pose any 
significant safety risks that can be identified at this time. Triheptanoin has been well tolerated 
in humans with no significant safety issues and toxicology or adverse pharmacology findings 
were not observed in triheptanoin-treated animals. Studies in animals and humans suggest 
triheptanoin consumed orally has side effects that are similar to those of orally consumed 
medium chain triglycerides.  
In clinical trials with UX007, the most common treatment-related treatment-emergent 
adverse events (TEAEs) were gastrointestinal (GI) in nature. Of these most frequently 
reported TEAEs were diarrhea and abdominal pain, which were mild or moderate in severity, 
and mostly occurred during up-titration of the initial dose of triheptanoin, and lasted a 
median duration of 3 days. Where it was deemed clinically necessary in the judgment of the 
Investigator, treatment-related GI events may be managed with UX007 dose reductions. 
The adverse drug reactions for triheptanoin in subjects with LC-FAOD are diarrhea, 
abdominal pain (including preferred terms of abdominal pain, abdominal pain upper, 
abdominal discomfort, abdominal distention, and gastrointestinal pain), vomiting and nausea. 
Overall the risk-benefit ratio of triheptanoin/UX007 appears to be favorable based on the 
safety record to date and the benefit observed in published observational studies, 
compassionate use programs, and Ultragenyx clinical trials. 
5.4 
Study Rationale 
LC-FAOD are caused by defects in the metabolic pathway that converts fatty acids into 
energy, leading to deficiencies in energy metabolism. The metabolic deficiency can deplete 
energy sources, resulting in serious clinical manifestations including hypotonia, 
rhabdomyolysis, liver dysfunction and hypoglycemia, and cardiomyopathy. These LC-FAOD 
major events are not sufficiently controlled in many patients by current standard of care, 
usually consisting of avoidance of fasting, low-fat/high-carbohydrate diet, dietary medium 
chain triglycerides (MCT oil), and/or carnitine supplementation. MCT oil, an even chain 
fatty acid, can provide medium chain fatty acids that bypass the specific LC-FAOD pathway 
defects but may not restore energy metabolism fully. In addition to supplying medium chain 
fatty acids, UX007 (triheptanoin), a specialized medium odd-chain (C7) triglyceride, also 
replaces deficient mitochondrial TCA cycle intermediates via the generation of 3-carbon 
intermediates, thereby improving energy metabolism. 


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At the time of protocol development, triheptanoin had been studied in many types of 
LC-FAOD for more than 13 years. Published reports describe profound clinical responses to 
triheptanoin, including improved physical capacity and a reduction of frequency and severity 
of major LC-FAOD events (rhabdomyolysis, hypoglycemia, liver function and 
hepatomegaly, and cardiomyopathy).  Numerous LC-FAOD patients have participated, or are 
actively participating in multiple clinical studies or treatment programs with 
UX007/triheptanoin conducted by various sponsors and investigational sites.   
This open-label long-term safety and efficacy extension study will provide an opportunity for 
LC-FAOD patients to be treated with UX007 for up to 7 years or until commercial 
availability of UX007 in any region, whichever occurs first, under a single standardized 
protocol. The subjects may have participated in other studies or treatment programs with 
UX007/triheptanoin or be treatment naïve and have clear unmet need but would be 
consolidated into one program for long-term maintenance and consistent safety monitoring. 
The study is designed to obtain long-term safety and efficacy information and evaluate 
maintenance of efficacy in a diverse LC-FAOD population. 


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6 STUDY OBJECTIVES 
The primary objective of the study is to: 
• Evaluate the long-term safety and efficacy of UX007 in LC-FAOD subjects 
The secondary objectives of the study are to: 
• Evaluate the effect of UX007 on energy metabolism in LC-FAOD 
• Evaluate impact of UX007 on clinical events associated with LC-FAOD  
The objective of the pharmacokinetic sub-study is to: 
• Characterize the steady-state pharmacokinetics (PK) of UX007 and UX007 metabolites 
in subjects with LC-FAOD. 


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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
The study is an interventional, open-label, long-term safety and efficacy extension study of 
UX007 or triheptanoin treatment in approximately 150 LC-FAOD subjects who have 
participated in prior clinical studies or treatment programs with UX007/triheptanoin, or 
who have failed conventional therapy and have documented clear unmet need (in the opinion 
of the Investigator and Sponsor). UX007 dosing will be targeted at 25-35% of total caloric 
intake. If a subject has been receiving a lower dose of UX007/triheptanoin, the individual 
may continue treatment at the current dose. If however, the subject has symptomatic disease 
or clinical signs of exercise limitation while on UX007 doses below the target range, the 
Investigator should consider titrating the dose to 25-35% of total caloric intake. UX007 
doses above 35% of total caloric intake may be considered as needed at the discretion of the 
Investigator on an individual basis; it is recommended that doses above 35% are discussed 
with the Medical Monitor prior to administration. If a subject has been off 
UX007/triheptanoin treatment for > 1 month or is treatment naïve, the dose will be titrated 
following Dose Administration Guidelines. Subjects who switch from MCT to UX007 may 
transition at the same dose and then titrate, as appropriate.  
The subjects will be followed to evaluate the long-term safety and continued effects of 
UX007 for up to 7 years or until commercial availability of UX007 in any region, whichever 
occurs first. A Safety Follow-up Phone Call will be conducted 30-35 days after last dose of 
study drug. The end of study is defined as the last day that protocol-specified assessments 
(including telephone contact) are conducted for the last subject in the study. 
If UX007 becomes commercially available during the study, each subject will return for an 
End of Study Clinic Visit; this will be recorded as study completion rather than an early 
termination. For subjects not immediately continuing UX007 through another mechanism 
(ie, commercial product, IST, or compassionate use), a Safety Follow-up Phone Call will be 
conducted 30-35 days after last dose of investigational study drug.  
The continued effects of UX007 treatment on clinical and physiologic disease of the skeletal 
muscle, the liver and the heart will be assessed. Creatine kinase (CK) will be measured as a 
biomarker of skeletal myopathy. The metabolic effects on the liver and energy homeostasis 
will be assessed by evaluating liver enzymes and serum glucose as biomarkers. Cardiac 
disease will be assessed by annual echocardiograms (ECHO).   
The impact of UX007 treatment on major clinical events will also be assessed throughout the 
study. Major events are defined as musculoskeletal, hepatic, and cardiac events caused by 
LC-FAOD, or intercurrent illness complicated by LC-FAOD, resulting in any hospitalization, 
ER visit, or emergency intervention (any unscheduled administration of therapeutics at home 
or in the clinic). In subjects for which prior medical events data have already been collected 
during a prior UX007 protocol the effect of UX007 treatment on major clinical events 
during this study will be compared with the subject’s available historical information for the 


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Given the acute-on-chronic nature of LC-FAOD, subjects will be eligible to continue 
maintenance UX007 treatment for up to 7 years (84 months) or until commercial availability 
of UX007 in any region, whichever occurs first. The treatment duration is intended to 
provide additional long-term safety information and provide sufficient insight on sustained 
clinical effects in LC-FAOD patients under a single study protocol. 
7.3 
Selection of Study Population 
The study will be conducted in approximately 150 subjects who have participated in clinical 
studies or compassionate use programs with UX007/triheptanoin, or who have failed 
conventional therapy and have documented clear unmet need (in the opinion of the 
Investigator and Sponsor). Most subjects in this study will have prior treatment exposure to 
UX007/triheptanoin, although it is possible to enroll treatment-naïve individuals if prior 
study participation involved assignment to a control treatment arm. 
The inclusion criteria are structured to enroll subjects with various types of LC-FAOD 
(CPT-I, CPT-II, VLCAD, LCHAD, TFP, or CACT deficiencies).   
Many LC-FAOD patients are seriously impacted by their disorder from birth. 
Triheptanoin has been administered previously to LC-FAOD patients, including newborns, 
infants, children, and adults. The experience reported in clinical studies and compassionate 
use programs suggests a favorable risk/benefit profile for the target study population. 
The Sponsor has taken all reasonable measures to ensure the protection and safety of this 
population. Appropriate pediatric expertise will be available at all trial sites, and efforts will 
be focused on minimizing risk, fear, pain and distress for this population during conduct of 
the study. 
7.3.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Male or female, 6 months of age or older 
2. Prior participation in a clinical study assessing UX007/triheptanoin treatment for 
LC-FAOD.  Study Sponsors/Collaborators include: Oregon Health & Science University, 
University of Pittsburgh, and Ultragenyx Pharmaceutical (ClinicalTrials.gov Identifiers: 
NCT01379625, NCT01461304, and NCT01886378). Patients who received 
UX007/triheptanoin treatment as part of other clinical studies; investigator sponsored 
trials (IST); expanded access/compassionate use treatment programs; or patients who are 
treatment naïve (i.e., naïve to both UX007 and food-grade triheptanoin), have failed 
conventional therapy and, in the opinion of the Investigator and Sponsor, have 
documented clear unmet need, may also be eligible at the discretion of the Sponsor. 
3. Confirmed diagnosis of LC-FAOD including:  carnitine palmitoyltransferase (CPT I or 
CPT II) deficiency, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, long 
chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency, trifunctional protein 
(TFP) deficiency, or carnitine-acylcarnitine translocase (CACT) deficiency. Information 


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on diagnosis will be obtained from medical records and should include confirmed 
diagnosis by results of acylcarnitine profiles, fatty acid oxidation probe studies in 
cultured fibroblasts, and/or mutation analysis. 
4. Willing and able to complete all aspects of the study through the end of the study, 
including visits and tests, documentation of symptoms and diet, and administration of 
study medications. If a minor, have a caregiver(s) willing and able to assist in all 
applicable study requirements. 
5. Provide written informed consent (subjects aged ≥ 18 years), or provide written assent 
(where appropriate) and have a legally authorized representative willing and able to 
provide written informed consent, after the nature of the study has been explained and 
prior to any research-related procedures.  
6. Females of child-bearing potential must have a negative urine pregnancy test at Baseline 
and be willing to have additional pregnancy tests during the study. Females considered 
not of child-bearing potential include those who have not experienced menarche, are 
post-menopausal (defined as having no menses for at least 12 months without an 
alternative medical cause), or are permanently sterile due to total hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy.  
7. Participants of child‐bearing potential or fertile males with partners of child-bearing 
potential who are sexually active must consent to use a highly effective method of 
contraception as determined by the Investigator from the period following the signing of 
the informed consent through 30 days after last dose of study drug. 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Diagnosis of MCAD deficiency, short- or medium-chain FAOD, ketone body metabolism 
defect, propionic acidemia or methylmalonic acidemia 
2. Patient qualifies for any other clinical trial designed to progressively evaluate the safety 
and efficacy of triheptanoin in LC-FAOD 
3. Any known hypersensitivity to triheptanoin that, in the judgment of the Investigator, 
places the subject at increased risk for adverse effects 
4. Pregnant and/or breastfeeding an infant at Baseline or planning to become pregnant 
(self or partner) at any time during the study   
5. Have any co-morbid conditions, including unstable major organ-system disease(s) that in 
the opinion of the Investigator, places the subject at increased risk of complications, 
interferes with study participation or compliance, or confounds study objectives, or 
unwilling to discontinue prohibited medications. 


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7.3.3 
Removal of Subjects from Therapy or Assessment 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason. The Principal Investigator and Ultragenyx also have the 
right to remove subjects from the study. Ultragenyx must be notified of all subject 
withdrawals as soon as possible. Ultragenyx also reserves the right to discontinue the study at 
any time for either clinical or administrative reasons and to discontinue participation of an 
individual subject or Investigator due to poor enrollment or noncompliance, as applicable. 
Subjects may be removed from the study for the following reasons: 
• Occurrence of an unacceptable adverse event (AE) 
• An illness that, in the judgment of the Principal Investigator or Ultragenyx, might place 
the subject at risk or invalidate the study  
• At the request of the subject, Investigator, or Ultragenyx, for administrative or other 
reasons 
• Protocol deviation or unreliable behavior 
If the reason for removal of a subject from the study is an AE, the AE and any related test or 
procedure results will be recorded in the source documents and transcribed onto the Case 
Report Form (CRF). Each clinically significant abnormal laboratory value or other clinically 
meaningful abnormality should be followed until the abnormality resolves or until a decision 
is made that it is not likely to resolve. If such abnormalities do not return to normal within 
30 days after the last dose given, their etiology should be identified and Ultragenyx should be 
notified. All unscheduled tests must be reported to Ultragenyx immediately. 
If a subject discontinues from the study prematurely, every reasonable effort should be made 
to perform the Early Termination Visit procedures within four weeks of discontinuation. 
A Safety Follow-up Phone Call will be conducted 30-35 days after last dose of 
investigational study drug, even if the Early Termination Visit does not occur. 
7.3.3.1 
Stopping Rules 
Individual subjects who experience a Grade 3 or higher SAE that is unexpected and possibly, 
probably, or definitely related to UX007 (Section 8.5.3) that represents a change in the nature 
or an increase in frequency of the serious event from their prior medical history will be 
assessed, by the Investigator, as to whether the subject will continue on the study.   
Commonly occurring LC-FAOD medical events include rhabdomyolysis, cardiomyopathy, 
hypoglycemia, and other events as described in the IB. If a subject experiences a major 
LC-FAOD medical event, which represents a change in the nature or an increase in 
frequency of the serious event from their prior medical history, the Investigator should 
determine whether the subject should be discontinued from the study. In these cases, the 


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subject visit schedule may need to be modified or assessments withheld to allow the subject 
to continue as deemed appropriate by the Investigator.   
Regulatory Authorities, as well as the IRBs/ECs, will be informed should unexpected and 
possibly, probably, or definitely drug-related SAEs occur, a full evaluation of the event will 
be performed in order to make a decision regarding what actions to take, including whether 
to recommend stopping the study. Regulatory Authorities, as well as IRBs/ECs, will be 
informed if the study is paused or stopped. If the Sponsor deems it appropriate to restart the 
trial following an internal safety review, this will be done only following approval by 
Regulatory Authorities.  
7.4 
Treatments 
7.4.1 
Reference Therapy 
The study design is open-label; all subjects will receive investigational product. No placebo 
or reference therapy will be administered in this study.   
7.4.2 
Investigational Product 
Subjects will begin or continue treatment with daily open-label UX007 while maintaining 
their other dietary restrictions. 
The UX007 investigational product, triheptanoin, will be administered orally (PO) with food 
or by gastronomy tube (usually four times per day: breakfast, lunch, dinner, and before bed), 
at the target dose range of 25-35% of total calories. The dose may be divided into smaller 
more frequent doses with food as needed. The dose may be mixed with small amounts of 
food or drink (including formula) as indicated in the Study Drug Administration Guidelines. 
If a subject has been receiving a lower dose of triheptanoin, the individual may continue 
treatment at the current dose provided there is no evidence of symptomatic disease or 
clinical signs of exercise limitation. If a subject has been off UX007/triheptanoin treatment 
for > 1 month or is treatment naïve, the dose will be titrated following the Study Drug 
Administration Guidelines. UX007 doses above 35% of total caloric intake may be 
considered as needed at the discretion of the Investigator on an individual basis; it is 
recommended that doses above 35% are discussed with the Medical Monitor prior to 
administration. 
7.4.3 
Identity of Investigational Product 
UX007 is a colorless to light yellow oil packaged in 1L round, translucent high-density 
polyethylene (HDPE) bottles. UX007 should be stored at room temperature. The study drug 
was manufactured, packaged, and labeled according to Good Manufacturing Practice (GMP) 
regulations. 


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7.4.4 
Selection of Doses and Study Duration 
The UX007 dose and regimen is selected based on the extensive information derived from 
over 13 years of clinical experience in LC-FAOD at the time of protocol development. 
These data show an age-dependent dose related to the relatively higher energy requirements 
for young children versus older children versus adults. The target dose is 25-35% of total 
calories by UX007, as tolerated, which is equivalent to approximately 2-4 g/kg in young 
children, decreasing to 1-2 g/kg for older children and adolescents, and 1 g/kg for adults. 
Since this treatment is a substrate replacement therapy and not an enzyme inhibitor or other 
type of drug class, dosing is individualized based on tolerability, metabolism, and energy 
needs. The following information provides support for the UX007 dose and regimen: 
• Clinical doses used in the compassionate use program and previous clinical studies  
(IND-59303); (Roe et al. 2006) 
• Barone and colleagues reported safety and efficacy of triheptanoin administered at 
1-2 g/kg/day to 22 LC-FAOD patients (aged 1.5 – 58 years) (Barone 2012). 
• Roe and colleagues reported safety and efficacy of triheptanoin administered at a dose 
level between 2.6 - 4.0 g/kg/day to 3 VLCAD patients (aged 2-8 years) (Roe et al. 2002) 
• Consultations with physicians and dietitians experienced in the administration of 
triheptanoin to LC-FAOD patients in clinical practice resulted in consensus on a dose of 
triheptanoin titrated to comprise 25 – 35% of daily caloric intake 
 
: personal communication). 
Based on these data, the target dose range for UX007 will be an estimated 25-35% of daily 
caloric intake.   
• If a subject has been receiving a lower dose of UX007/triheptanoin, the individual 
may continue treatment at the current dose. If however, the subject has symptomatic 
disease or clinical signs of exercise limitation while on UX007 doses below the target 
range, the Investigator should consider titrating the dose to 25-35% of total caloric 
intake.   
• If a subject has been receiving a dose of UX007/triheptanoin greater than 35% total 
caloric intake, the individual may continue treatment at the current dose at the 
Investigator’s discretion. Investigators may also dose individual subjects above target 
range as needed at their discretion; it is recommended that doses above 35% are 
discussed with the Medical Monitor prior to administration. 
• If a subject has been off UX007/triheptanoin treatment for > 1 month or is 
treatment naïve, the dose will be titrated following Study Drug Administration 
Guidelines. Subjects who switch from MCT to UX007 may transition at the same 
dose and then titrate as appropriate.  


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• Daily caloric intake will be established based on the most recent dietary analysis in 
the medical record, and collected periodically during the study.  
o For patients over 1 year old, if the most recent dietary analysis available is not 
within 6 months prior to study initiation, a Baseline diet diary will be 
completed after the initial visit and discussed with the dietitian within a 
month.  
o For patients under 1 year old, if the most recent dietary analysis available is 
not within 3 months prior to study initiation, a Baseline diet diary will be 
completed after the initial visit and discussed with the dietitian within a 
month. The dose may be recalculated by the study nutritionist as necessary for 
normal weight gain/growth based on the study diet diary analysis.  
Subject participation duration in this extension study will be up to 7 years (84 months) or 
until commercial availability of UX007 in any region, whichever occurs first. The total 
UX007 treatment duration per subject will vary depending on prior exposure from 
participation in clinical studies and compassionate use programs. The 7-year study duration 
will provide a continued treatment option and enable a long-term assessment of the safety 
and efficacy of UX007 in subjects with LC-FAOD under a single study protocol. The end of 
study is defined as the last day that protocol-specified assessments (including telephone 
contact) are conducted for the last subject in the study. 
7.4.5 
Prior and Concomitant Therapy 
7.4.5.1 
Prohibited Medications 
Subjects may not be enrolled if they are unwilling to discontinue use of a substance that may 
confound study objectives. The following medications are prohibited during the study and 
must be discontinued at minimum 1 week prior to the first dose: 
• Valproate products (e.g. Depacon, Depakote, Depakene, Stavzor, and their generics) 
• Pancreatic lipase inhibitors (e.g., Orlistat) due to possible inhibition of metabolism of 
triheptanoin  
The following medications are prohibited during the study and must be discontinued prior to 
the first dose: 
• MCT oil and metabolic formulas containing significant contributions from MCT oil, 
including coconut oil, must not be used after the first dose of study medication  


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7.4.5.2 
Permitted Medications 
Other than the medications specifically prohibited in this protocol, subjects may receive 
concomitant medications as required. Medications (investigational, prescription, over-the-
counter, and herbal) and nutritional supplements taken during the 30 days prior to the 
Baseline visit will be reviewed and recorded.   
7.4.6 
Treatment Compliance 
At the Baseline visit and each subsequent visit through Month 81, each subject will be 
dispensed an adequate supply of study drug to comprise 25-35% total daily caloric intake 
(or prescribed dose). Additional study drug will be shipped to the subject between clinic 
visits.  UX007 will not be dispensed at the Month 84 (end-of-treatment visit), End of Study, 
or Early Termination visits (as applicable). The subject will maintain a weekly diary to 
record adherence to prescribed treatment. The diary will be reviewed upon each indicated 
visit and an estimate of overall treatment compliance will be made by the site staff. Subjects 
will be instructed to return all used (empty study drug containers) study drug to the site at the 
next visit. Site personnel will maintain a record of all medication dispensed to each subject 
and returned to the site. 
7.5 
Study Procedures and Assessments 
The concept for evaluation is to study the long-term safety and continued effects of UX007 
on energy metabolism and clinical events associated with LC-FAOD. Biologic and clinical 
assessments will be conducted throughout the 84 month Treatment Extension Period. 
The occurrence of major LC-FAOD clinical events will be captured and compared to 
available data prior to initiation of UX007 treatment. Dosing compliance and diet will be 
regularly monitored along with a standard panel of safety assessments. 
7.5.1 
Schedule of Events 
The Baseline visit may occur in conjunction with the last scheduled visit from study 
UX007-CL201. Assessments conducted at the last UX007-CL201 visit will be used for 
Baseline data to avoid duplication. Following the signing of informed consent at the Baseline 
visit, subjects will complete required assessments and return for clinic visits at 6 month 
intervals (± 2 weeks) to assess long-term safety and efficacy. The study coordinator will 
telephone the subject/caregiver at specified intervals (± 1 week) for additional safety 
monitoring.  
A Safety Follow-up Phone Call will be conducted 30-35 days after last dose of study drug.  
The site personnel will initiate this safety follow-up telephone call to collect information on 
any ongoing or new AEs, SAEs, and concomitant medications. Appropriate follow-up should 
continue until all safety concerns, in the Investigator’s opinion, are resolved. The end of 
study is defined as the last day that protocol-specified assessments (including telephone 
contact) are conducted for the last subject in the study. 


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For subjects who discontinue prior to completing the study, every reasonable effort should be 
made to perform the Early Termination Visit procedures within four weeks of 
discontinuation. A Safety Follow-up Phone Call will be conducted 30-35 days after last dose 
of investigational study drug, even if the Early Termination Visit does not occur. 
If UX007 becomes commercially available during the study, each subject will return for an 
End of Study Clinic Visit; this will be recorded as study completion rather than an early 
termination. For subjects not immediately continuing UX007 through another mechanism 
(ie, commercial product, IST, or compassionate use), a Safety Follow-up Phone Call will be 
conducted 30-35 days after last dose of investigational study drug.  
The parameters to be assessed in Study UX007-CL202, along with timing of assessments, are 
provided in the Schedule of Events (Table 2.1). Where caregiver assessments are required, 
the same individual should complete the assessment for consistency or reporting when 
possible. Refer to the Study Reference Manual for additional details on specific assessments.   
7.5.2 
Clinical Efficacy Measures 
7.5.2.1 
 Functional Disability and Cognitive Development 
Functional disability often limits daily activities of living and health-related quality of life in 
patients with LC-FAOD. Individuals with LC-FAOD may also have delayed cognitive 
development. Functional disability and cognitive development will be assessed at clinic visits 
as specified in Table 2.1. Parameters will be evaluated using the following age appropriate 
validated health assessment questionnaires: 
• The Medical Outcomes Study 10-Item Short Form (SF-10) is a 10-item caregiver 
completed questionnaire designed to assess generic health-related quality of life in 
healthy and ill pediatric populations (Saris-Baglama et al. 2006). The 10 items were 
adapted from the Child Health Questionnaire and utilize a 4-week recall period. 
Responses are used to generate 2 component summary scores: physical component 
summary (PCS) and mental component summary (MCS). Higher global scores are 
associated with better quality of life. The SF-10 will be administered to caregivers of 
subjects aged 6 through 17 years. The SF-10 will be administered -at the Baseline visit 
and at 6 month intervals thereafter (or Early Termination).  


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• The Medical Outcomes Study 12-Item Short Form (SF-12) is a 12-item interview and 
self-administered questionnaire designed to assess generic health-related quality of life in 
healthy and ill adult populations (Ware et al. 1996). The 12 items in the SF-12 are a 
subset of the items in the SF-36 and measure physical functioning, role limitations due to 
physical health problems, bodily pain, general health, vitality (energy/fatigue), social 
functioning, role limitations due to emotional problems, and mental health. Responses are 
used to generate 2 component summary scores: physical health (PCS) and mental health 
(MCS). Higher global scores are associated with better quality of life. The standard 
version of the instrument with a 4-week recall period will be used in this study. 
The SF-12 will be administered to subjects 18 years of age and older. The SF-12 will be 
administered at the Baseline visit and at 6-month intervals thereafter (or Early 
Termination). 
7.5.2.2 
Cardiomyopathy and Cardiac Function 
ECHO will be performed at the Baseline Visit and annually thereafter at clinic visits 
indicated in Table 2.1 (or if performed as routine care within 30 days prior to the Baseline or 
indicated clinic visits) or Early Termination if not performed within 6 months prior to 
termination. Additional tests may be performed if any abnormalities are detected or if 
medically indicated.  
ECHO efficacy variables include ventricle size, ejection fraction (EF), and shortening 
fraction (SF), as described within the Study Reference Manual.  
7.5.2.3 
LC-FAOD Major Events 
Major LC-FAOD events include skeletal myopathy (rhabdomyolysis), hepatic 
(hypoglycemia) and cardiac disease (cardiomyopathy) events, and are defined as any visit to 
the ER/acute care, hospitalization, emergency intervention (i.e. any unscheduled 
administration of therapeutics at home or in the clinic), or any similar event whether caused 
primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The event 
type, levels of relevant laboratory parameters (including CK, glucose, and BNP/troponin), 
the number of days hospitalized and in ICU, and the type and number of days of treatment 
and intervention will be recorded. 
By definition, events requiring inpatient hospitalization or that cause persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, are 
classified as a serious adverse event (SAE) or serious suspected adverse reaction, and will be 
reported as described in Section 8.5. If the event represents a substantive change in the nature 
or an increase in frequency from a subject’s prior medical history, the event should be 
reported as an adverse event (AE) and the Investigator should evaluate whether the subject 
should be discontinued from the study.   


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In these cases, the subject visit schedules may need to be modified or assessments withheld 
to allow the subject to continue as deemed appropriate by the Investigator. Information on 
the incidence of major rhabdomyolysis events will be collected at each visit. 
7.5.3 
Biomarkers & LC-FAOD Laboratory Measures 
A panel of biomarkers will be assessed as clinical indicators of skeletal myopathy and 
hepatic disease. CK is a useful marker in the investigation of skeletal muscle disease.  
The presence of CK suggests that muscle cells somewhere in the patient are sufficiently 
energy deficient to over-contract and rupture, providing an ongoing chronic or non-acute 
total CK release. Chronic elevations of CK have been reported to indicate patients at risk for 
major rhabdomyolysis events, although no quantitative relationship has been established yet.   
Assessing glucose levels is central to the management of hypoglycemia associated with 
LC-FAOD. Samples for fasting serum glucose (as tolerated) will be collected on arrival to 
the clinic; the length of fast, the date and time of the last dose of study medication, and time 
of collection will be recorded on the CRF. Relevant liver enzymes, including alanine 
aminotransferase (ALT), aspartate transaminase (AST), and gamma glutamyl transpeptidase 
(GGT) will be evaluated as indicators of liver injury related to LC-FAOD.   
Biomarkers and relevant indicators of LC-FAOD are summarized in Table 7.5.3.1.  
Blood samples will be collected at each clinic visit to assess relevant biomarkers and 
laboratory measures of LC-FAOD. For each sample collection, the duration of fasting and 
time elapsed since last study drug administration will be recorded on the CRF.  
Where possible, assessment of certain parameters (i.e. glucose, ALT, AST, GGT) will be 
performed as part of the routine clinical laboratory test panel to avoid unnecessary 
duplication of testing (see Section 7.5.5.5). Refer to the Study Reference Manual for 
additional details. 


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Table 7.5.3.1:  Biomarkers and LC-FAOD-related Laboratory Measures 
Biomarkers of UX007 Effects 
LC-FAOD Laboratory Measures 
Skeletal myopathy biomarkers: 
serum creatine kinase (CK) 
Total and free plasma carnitine 
 
Hepatic disease biomarkers: 
serum glucose, serum liver 
enzymes (ALT, AST, GGT) 
Plasma acylcarnitines 
Urine organic acids 
7.5.4 
Pharmacokinetics of UX007 and Metabolites 
PK measurements will occur at select sites in a subset of subjects (minimum of 12 subjects) 
at their next two consecutively scheduled clinic visits (eg Month 18 and Month 24) 
excluding the Baseline Visit. Participating subjects will be fed a standardized meal 
containing one of their divided daily doses of UX007. Blood for plasma UX007 and 
metabolites will be collected pre-dose (within 15 minutes prior to start of meal) and at 30, 90, 
120, and 240 minutes after finishing the meal [± 5 minutes]. For each sample collection, the 
meal start/stop times, calories consumed, UX007 dosing, and sampling time will be recorded. 
Plasma UX007 and the following UX007 metabolites will be assessed: 
• Beta-hydroxypentanoate (BHP) 
• Beta-hydroxybutyrate (BHB) 
• Heptanoate 
7.5.5 
Safety Measures & General Assessments  
General assessments include medical history, concomitant medications, demographics, and 
growth. Safety will be evaluated by the incidence, frequency, severity and relatedness of 
AEs and SAEs, including clinically significant changes from baseline to scheduled 
timepoints in vital signs, weight, physical examination, and clinical laboratory evaluations.  
Pregnancy testing (or pregnancy of partner, if needed) will also be conducted as appropriate.  
Refer to the Study Reference Manual for additional details. 
7.5.5.1 
Medical History and Triheptanoin Treatment History 
Medical history will be obtained for all subjects not previously enrolled in UX007-CL201. 
General medical information includes subject demographics (date of birth, ethnicity, and sex) 
and a history of major medical illnesses, diagnoses, and surgeries. The review will also 
include an assessment of major medical conditions associated with LC-FAOD, including 
clinical or subclinical rhabdomyolysis, cardiomyopathy, hypoglycemia, and 
hypotonia/exercise intolerance. Any available sibling history of LC-FAOD will be noted 
including relationship and outcome.  


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LC-FAOD maintenance treatment history, including triheptanoin treatment history, and 
relevant concomitant medications will be recorded (start date, stop date, dose, dose regimen).  
Other LC-FAOD treatments include MCT oil (including coconut oil), carnitine supplements, 
other standard of care treatments, and all other relevant concomitant medications (e.g. 
diuretics, inotropes, seizure medications, supplements, etc.). Medications include 
prescription, over-the-counter, herbal and nutritional supplements. Any relevant concomitant 
therapy, including physical/occupational therapy will be recorded.   
7.5.5.2 
Growth and Weight Evaluations 
At each clinic visit, measurements of height and weight will be collected for each 
subject using a stadiometer and a scale. Head circumference will be obtained for subjects 
≤ 36 months of age. Height, weight, and head circumference (if applicable) data will be used 
to evaluate each subject’s growth using published normative data, when available. 
7.5.5.3 
Vital Signs 
Vital signs will include seated systolic and diastolic blood pressure (BP) measured in 
millimeters of mercury (mm Hg), heart rate (HR) in beats per minute, respiration rate in 
breaths per minute, and temperature in degrees Celsius (°C). Vital sign measurements will be 
performed at every clinic visit before any additional assessments are completed.   
7.5.5.4 
Physical Examination 
Complete physical examinations will be performed at the Baseline visit and at 6-month 
intervals (or Early Termination). Physical examinations will include assessments of general 
appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, 
respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. 
The lymphatic exam scope should be as per age-appropriate standard of care, at the 
Investigator’s discretion based on the clinical judgement and/or safety need. If a PI 
determines there is no clinical indication for a lymphatic exam, it is not necessary to perform. 
The genitourinary exam scope should be non-invasive and as per age-appropriate standard of 
care, at the Investigator's discretion based on the clinical judgement and/or safety need. If the 
PI determines there is no clinical indication for a genitourinary exam, it is not necessary to 
perform.  
7.5.5.5 
Clinical Laboratory Tests 
The clinical laboratory evaluations to be performed in this study are listed in Table 7.5.5.5.1 
Clinical laboratory testing will be performed at each visit. Blood samples obtained as part of 
scheduled visits will be obtained following ≥ 4 hours fasting, where possible. 


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Table 7.5.5.5.1:  Clinical Laboratory Assessments 
Chemistry 
Hematology 
Urinalysis 
Alanine aminotransferase (ALT) 1 
Hematocrit 
Appearance 
Alkaline phosphatase 
Hemoglobin 
Color 
Aspartate aminotransferase (AST) 1 
MCH concentration (MCHC) 
pH 
Bilirubin (total) 
Mean corpuscular hemoglobin (MCH) 
Specific gravity 
Blood urea nitrogen (BUN) 
Mean corpuscular volume (MCV) 
Ketones 
Chloride 
Platelet count 
Protein  
Cholesterol (total) 
Red blood cell (RBC) count 
Glucose  
Serum creatinine 
Reticulocyte count 
Bilirubin 
Gamma-glutamyl transpeptidase 
(GGT)1 
WBC differential 
Nitrite 
Serum glucose, fasting 1 
Neutrophil count (absolute and %) 
Urobilinogen 
Lactate dehydrogenase (LDH) 
Lymphocyte count (absolute and %) 
Blood 
Potassium 
Monocyte count (absolute and %) 
Creatinine 
Protein (albumin and total) 
Eosinophil count (absolute and %) 
 
Sodium 
Basophil count (absolute and %) 
Pregnancy test (if 
applicable) 
 
White blood cell (WBC) count 
 
 
 
*Special 
Assessment 
 
 
Serum pregnancy 
test (if a positive 
urine pregnancy 
test) 
1 
Analyte is also a biomarker of clinical efficacy 
Subjects who experience a SAE possibly or probably related to study drug or other AE of 
concern may, at the discretion of the Investigator (and/or Medical Monitor), have additional 
blood samples taken for safety laboratory tests. 
7.5.5.6 
Pregnancy Testing 
Female subjects of childbearing potential will have urine pregnancy tests as described in the 
Schedule of Events (Table 2.1). Females considered not of childbearing potential include 
those who have not experienced menarche, are post-menopausal (defined as having no 
menses for at least 12 months without an alternative medical cause); or are permanently 
sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 


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Female subjects with a positive pregnancy test at Baseline will not be enrolled in the study.  
Pregnancy in subject or partner must be reported (Section 8.5.4.3); pregnant subjects will be 
discontinued from the study. Additional pregnancy tests may be performed at any time in 
which pregnancy status is in question. A serum pregnancy test will be performed in the event 
of a positive or equivocal urine pregnancy test result, or can be performed if pregnancy test 
by urine is not feasible.   
Experience with UX007 (triheptanoin) in pregnant women is limited. The study drug may 
involve risks to a pregnant female or unborn baby which are currently unknown. 
Sexually active fertile males or females of child‐bearing potential must use highly effective 
contraception during heterosexual intercourse throughout the study period and for 30 days 
after stopping the study drug. Examples of highly effective methods (CTFG 2014) include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence (i.e., refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments, when this is in line with the preferred and 
usual lifestyle of the subject) 
7.5.5.7 
Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent through 
30 days following the last administration of study drug. Assessments of AEs will occur at 
each study visit (phone and clinic). At each visit subjects will be asked about any new or 
ongoing AEs since the previous visit. The determination, evaluation, reporting, and 
follow-up of AEs will be performed as outlined in Section 8.5.   
Clinically significant changes from Baseline in physical examination findings, vital signs, 
weight, and clinical laboratory parameters will be recorded as AEs or SAEs, if appropriate. 
7.5.5.8 
Concomitant Medications 
Concomitant medications will be reviewed and recorded in the subject’s CRF at each study 
visit (phone and clinic). Medications (investigational, prescription, over-the-counter, and 
herbal) and nutritional supplements taken during the 30 days prior to Baseline will be 
reviewed and recorded. At each subsequent visit, change in medications since the previous 
visit will be recorded. A discussion of concomitant medications is provided in Section 7.4.5. 


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7.5.5.9 
Dietary Assessment 
The initial 3-day diet history recorded will be reviewed by the site in order to establish daily 
caloric intake. Subjects and/or caregivers will maintain a record of the subject’s daily diet 
using a diary for 3 days prior to each clinic visit. The daily diet should be representative of 
typical consumption for the subject. The diet diary will be reviewed with the site staff upon 
each indicated visit. 
7.5.6 
Appropriateness of Measures 
The efficacy parameters to be evaluated in this study focus on the key disease areas 
impacted by LC-FAOD, including skeletal myopathy, hepatic disease, and cardiac disease.  
The clinical assessments in the study employ standard measures used in other diseases and 
conditions that impair muscle, liver, and heart function.   
Where possible, additional validated, age-appropriate, patient-reported outcomes were 
included to assess functional disability, cognitive development and health-related quality of 
life (i.e. SF-10/12). ECHO is a routine, non-invasive procedure inflicting minimal 
pain/distress for the subject, while providing relevant indicators of cardiac disease. 
Additional relevant biomarkers of LC-FAOD disease status will be assessed using blood 
samples. Where possible, timing of assessments has been coordinated with standard safety 
laboratory tests to minimize risk and discomfort and avoid unnecessary duplication of 
testing. 
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs, serum 
chemistry, concomitant medications, and other routine clinical and laboratory procedures.  
7.6 
Statistical Methods and Determination of Sample Size 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort will be made to ensure complete, accurate and timely data collection, 
and to avoid missing data. The detailed method for analyses along with procedures for 
accounting for missing, unused, and spurious data will be presented in the Statistical 
Analysis Plan (SAP); the information below is intended as a guide to planned analyses.  
7.6.1 
Analysis Populations 
All subjects with any post-dose efficacy assessment will be included in the efficacy analysis; 
the evaluable set only includes subjects who complete at least 80% of treatment doses and 
assessments. A complete treatment dose is defined as at least 25% of caloric intake from 
UX007.  


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Subjects with historical medical events collected will be analyzed separately for changes in 
the rates of medical events and hospitalization days.  Individual genetic disease types will be 
analyzed together in separate subset populations.  Subsets based on dominant clinical 
phenotype may also be analyzed. Subsets may also be defined based on prior study 
participation assessing UX007 treatment. Other analysis subset populations will be defined in 
the SAP.  
7.6.2 
Endpoints  
The primary efficacy endpoint:   
• The annualized LC-FAOD major events rate inclusive of skeletal myopathy 
(rhabdomyolysis), hepatic (hypoglycemia) and cardiomyopathy events.  
The secondary efficacy endpoints:  
• Energy metabolism in LC-FAOD on the basis of the following endpoints: 
o Ventricle size  
o Ejection fraction (EF) 
o Shortening fraction (SF)  
• Clinical events associated with  LC-FAOD on the basis of the following endpoints 
o Annualized duration rate of all MCEs 
o Annualized event rate of rhabdomyolysis MCEs 
o Annualized duration rate of rhabdomyolysis MCEs 
o Annualized event rate of cardiomyopathy MCEs 
o Annualized duration rate of cardiomyopathy MCEs 
o Annualized event rate of hypoglycemic MCEs 
o Annualized duration rate of hypoglycemic MCEs 
Exploratory endpoints include the following: 
• Functional disability and cognitive development (instrument selection based on age) 
endpoints:  
o SF-10 physical health component summary (PCS) score  


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o SF-10 mental health component summary (MCS) score  
o SF-12 physical health component summary (PCS) score  
o SF-12 mental health component summary (MCS) score  
• Clinical biomarkers endpoints: 
o Serum creatine kinase 
o Fasting serum glucose  
o Alanine aminotransferase (ALT) 
o Aspartate transaminase (AST) 
o Gamma glutamyl transpeptidase (GGT)  
• Growth measurements: 
o Height  
o Weight 
o Head circumference, if applicable (subjects ≤ 36 months of age) 
PK endpoints: 
o Plasma levels of UX007 
o Plasma levels of UX007 metabolites, including heptanoate, 
beta-hydroxypentanoate (BHP), and beta-hydroxybutyrate (BHB) 
Safety endpoints: 
Safety events will be collected as adverse events (AE) or serious adverse events (SAE).  
The analyses of safety will include all subjects who receive at least one dose of study drug.   
The safety endpoints in this study are: 
• Incidence and severity of treatment emergent AEs  (primary safety endpoint) 
• Vital signs  
• Incidence of laboratory abnormalities  
• Concomitant medications 


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7.6.3 
Efficacy Analyses 
The primary efficacy endpoint, ie, annualized MCE event rate, will be calculated using all 
MCE events collected post-UX007 treatment through the end of study. The primary analysis 
of the annualized MCE rate is descriptive statistics using mean, standard deviation (SD), 
median, quartiles, minimum, and maximum values. Two-sided 95% confidence interval will 
also be provided when appropriate. Annualized event rates for MCE by event type (ie, 
rhabdomyolysis, cardiomyopathy and hypoglycemic events) will be calculated and 
summarized in a similar fashion as with the primary efficacy endpoint. 
In addition, for subjects who have historical event rate data collected, comparisons of 
pre- and post-UX007 treatment annualized event rates for overall MCE events will be 
conducted. In addition, intra-patient comparisons of pre- and post-UX007 treatment for MCE 
events by event type might be considered if sample size permits.  
Summary statistics will be produced for all exploratory endpoints using all available 
assessments. For continuous variables, the number of observations and the mean, standard 
deviation (SD), median, quartiles, minimum, and maximum values were tabulated by 
endpoint. For categorical variables, the counts and proportions of each value were tabulated. 
Two-sided 95% confidence interval will also be provided when appropriate. Efficacy data 
collected for age-specific assessments (e.g. SF-10/12) will be summarized for subjects in that 
age group only. Other age-specific summaries may be provided for measures collected across 
all age groups.  
7.6.4 
Pharmacokinetic (PK) Analyses: 
Summary statistics of plasma concentration will be provided for UX007 and metabolites. 
PK parameters such as area under the plasma concentration-time curve (AUC), time to 
maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), and 
trough plasma concentration (Ctrough) will be estimated for participating subjects. 
7.6.5 
Safety Analyses 
For the safety analysis, the incidence and frequency of treatment-emergent AEs and SAEs 
will be evaluated. All AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence and frequency of AEs will be summarized by System 
Organ Class (SOC), Preferred Term (PT), relationship to study drug, and severity. 
A by-subject listing will be provided for those subjects who experience a SAE, including 
death, or experience an AE associated with early withdrawal from the study or study drug 
treatment. 
Clinical laboratory data will be summarized by the type of laboratory test. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (i.e., outside of 
reference ranges) and/or clinically significant abnormalities will be presented for each 
clinical laboratory measurement.   


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7.6.6 
Determination of Sample Size 
Approximately 150 subjects with a history of participation in a UX007/triheptanoin clinical 
study, or who have failed conventional therapy and have documented clear unmet need 
(in the opinion of the Investigator and Sponsor) may be enrolled for this study. The sample 
size is intended to provide the maximum amount of information regarding UX007 long-term 
safety, along with indicators of sustained efficacy and durability of response.   
A minimum of 12 subjects will participate in the PK sub-study at select sites. 


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8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 
Institutional Review Board or Ethics Committee 
The IRB/EC must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, "Institutional Review Boards." This protocol, any protocol amendments, and 
the associated informed consent forms (ICFs) must be submitted to the IRB/EC for review 
and must be approved before enrollment of any subject into the study. Study drug may not be 
shipped to the Investigator until Ultragenyx or its designee has received a copy of the letter 
or certificate of approval from the IRB/EC for the protocol and any protocol amendments, as 
applicable. 
All subject recruitment and/or advertising information must be submitted to the IRB/EC and 
Ultragenyx or its designee for review and approval prior to implementation. IRB/EC 
approval of any protocol amendments must be received before any of the changes outlined in 
the amendments are put into effect, except when the amendment has been enacted to protect 
subject safety. In such cases, the chair of the IRB/EC should be notified immediately and the 
amendment forwarded to the IRB/EC for review and approval. 
8.1.2 
Ethical Conduct of Study 
This protocol is written in accordance with the principles established by the 18th World 
Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and 
clarifications adopted by the General Assemblies. The Investigator will make every effort to 
assure the study described in this protocol is conducted in full conformance with those 
principles, current FDA regulations, ICH Good Clinical Practices (GCP) guidelines, and 
local ethical and regulatory requirements. Should a conflict arise, the Investigator will follow 
whichever law or guideline affords the greater protection to the individual subject.  
The Investigator will also make sure he or she is thoroughly familiar with the appropriate 
administration and potential risks of administration of the study drug, as described in this 
protocol and the IB, prior to the initiation of the study. 
8.1.3 
Subject Information and Consent 
Appropriate forms for documenting written informed consent will be provided by the 
Investigator and reviewed and approved by Ultragenyx or its designee before submission to 
the IRB/EC. Ultragenyx or its designee must receive a copy of the IRB/EC's approval of the 
ICF before the shipment of study drug to the study site. 
It is the Investigator's responsibility to obtain signed written informed consent from each 
potential study subject prior to the conduct of any study procedures. This written informed 
consent will be obtained after the methods, objectives, requirements, and potential risks of 
the study have been fully explained to each potential subject. The Investigator must explain 
to each subject that the subject is completely free to refuse to enter the study or to withdraw 


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from it at any time. Subjects under the age of 18 years (or 16 years, depending on the region) 
will provide written assent (if required), and his/her legally authorized representative (parent 
or legal guardian) will provide written informed consent for such subjects. Subjects who are 
minors should provide consent as soon as they turn 18.    
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements. Subjects will be given a copy of 
the signed ICF and will be provided any new information during the course of the study that 
might affect their continued participation in the study. The Investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject's questions must be answered to the subject's satisfaction. If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
Receipt of written informed consent will be documented in each potential subject’s CRF.  
The signed ICF will remain in each subject's study file and must be available to the study 
monitor(s) at all times. 
8.2 
Investigators and Study Administrative Structure 
Each Investigator must provide Ultragenyx and/or its designee a completed and signed Form 
FDA 1572 and a Financial Disclosure Form. All sub-investigators must be listed on Form 
FDA 1572 and Financial Disclosure Forms must be completed for all sub-investigators listed 
on Form FDA 1572. 
Ultragenyx and/or its designee will be responsible for managing and monitoring the clinical 
trial to ensure compliance with FDA and ICH GCP guidelines. Ultragenyx's trained 
designated representative (the monitor) will conduct regular visits to the clinical site, to 
perform source document verification. The monitor will verify the Investigator's ongoing 
qualifications, inspect clinical site facilities, and inspect study records, including proof of 
IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. 
8.3 
Investigational Product Accountability 
While at the clinical site, study drug must be stored in a secure limited access location at 
controlled temperature as described in the IB and according to product packaging.  
The storage facility must be available for inspection by the study monitor at any time during 
the study.  Subjects will be given instructions on the proper storage of study drug when 
initially dispensed and reminded of storage requirements at all subsequent visits. 
A drug accountability record must be maintained for all study drug received, dispensed, 
returned, and/or lost during the study. This record must be kept current and made available to 
the study monitor for inspection. Following the close-out of the study, all unused study drug 


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must be returned to Ultragenyx and/or its designee unless other instructions have been 
provided for final disposition of the study drug.  
8.4 
Data Handling and Record Keeping 
8.4.1 
Case Report Forms and Source Documents 
The Investigator is required to initiate and maintain, for each subject, an adequate and 
accurate case history that records all observations and other data related to the study for that 
subject. A validated electronic data capture (EDC) system will be used for entry of the data 
into electronic CRFs. Data must be recorded on CRFs approved by Ultragenyx or its 
designee. All information recorded on CRFs for this study must be consistent with the 
subject's source documentation. 
Initial data entry and any changes to the electronic CRF data will be made only by 
Ultragenyx-authorized users, and data entries and changes will be captured in an electronic 
audit trail. An explanation of any data change should be recorded in the CRF. All data 
entered in to the CRF must be verifiable; therefore, CRFs will be routinely checked for 
accuracy, completeness, and clarity and will be cross-checked for consistency with source 
documents, including laboratory test reports and other subject records by Ultragenyx or its 
designee. The Investigator must allow direct access to all source documents. 
8.4.2 
Data Quality Assurance 
Monitoring and auditing procedures developed by Ultragenyx and/or its designee will 
be implemented to ensure compliance with FDA and ICH GCP guidelines.  
Ultragenyx's designated representative (the monitor) will contact the Investigator and 
conduct regular visits to the study site. The monitor will be expected and allowed to verify 
the Investigator's qualifications, to inspect clinical site facilities, and to inspect study records, 
including proof of IRB/EC review, with the stipulation that subject confidentiality will be 
maintained in accordance with local and federal regulations, including HIPAA requirements.  
The monitor will also be responsible for confirming adherence to the study protocol, 
inspecting CRFs and source documents, and ensuring the integrity of the data. CRFs will be 
checked for accuracy, completeness, and clarity and will be cross-checked for consistency 
with source documents including progress notes, laboratory test reports and other subject 
records.  Instances of missing or uninterpretable data will be resolved in coordination with 
the Investigator. 
The monitor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications with the study site by 
e-mail, telephone, facsimile, and/or mail. The Investigator and all other site personnel agree 
to cooperate fully with the monitor and will work in good faith with the monitor to resolve 
any and all questions raised and any and all issues identified by the monitor. 


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The Investigator understands that regulatory authorities, the IRB/EC, and/or Ultragenyx or its 
designees have the right to access all CRFs, source documents, and other study 
documentation for on-site audit or inspection and will retain this right from the start of the 
study to at least two years after the last approval of a marketing application or for at least two 
years after clinical development of the study drug for the indication being studied has been 
discontinued. The Investigator is required to guaranty access to these documents and to 
cooperate with and support such audits and inspections. 
8.4.3 
Record Retention 
All study records must be retained for at least 25 years after the end of the clinical trial or in 
accordance with national law. Subject files and other source data must be kept for the 
maximum period of time permitted by the hospital, institution or private practice, but not less 
than 25 years. Ultragenyx must be notified should the Investigator/institution be unable to 
continue maintenance of subject files for the full 25 years. All study records must be stored 
in a secure and safe facility.  
8.5 
Reporting and Follow-up of Adverse Events 
8.5.1 
Definition of Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) products. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of expedited safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug. 
Life-threatening adverse event or life-threatening suspected adverse reaction is an adverse 
event or suspected adverse reaction that, in the view of either the Investigator or Sponsor, 
places the patient or subject at immediate risk of death. It does not include an adverse event 
or suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
A serious adverse event (SAE) or serious suspected adverse reaction is an adverse event or 
suspected adverse reaction that at any dose, in the view of either the Investigator or Sponsor, 
results in any of the following outcomes:  


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• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions) 
• A congenital anomaly/birth defect 
Note that hospitalizations planned prior to study enrollment (e.g. for elective surgeries) are 
not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs. 
Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
8.5.2 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the NCI CTCAE Version 4.0.  
The majority of AEs can be graded using this system. 
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions.  
• Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and are of a minor 
irritant type, causing no loss of time from normal activities. Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
• Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
• Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
• Life-threatening (Grade 4): Events that place the participant at immediate risk of death 
or are disabling. 
• Death (Grade 5): Events that result in death. 


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To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 
provided. The term "severe" is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache). This is not the same as 
"serious" which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning. Seriousness (not severity) serves as 
a guide for defining regulatory reporting obligations. 
8.5.3 
Relationship of Adverse Events to Study Drug 
The Investigator will assess the potential relationship of the AE to study drug using the 
following descriptions. 
Categories of attributions for “Unrelated” events: 
• Unrelated:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure. 
• Unlikely Related:  This category applies to an AE that is doubtfully related to the 
investigational agent/procedure.  
Categories of attributions for “Related” events: 
• Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. 
• Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure.  
• Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Unrelated or Unlikely Related 
will be considered Unrelated. 
8.5.4 
Adverse Event Reporting  
8.5.4.1 
General 
All AEs (i.e. any new or worsening in severity or frequency of a preexisting condition) with 
onset after the subject signs consent for study participation must be promptly documented on 
the CRF. The Investigator is responsible for evaluating all AEs, obtaining supporting 
documents, and ensuring documentation of the event is adequate. Details of the AE must 
include severity, relationship to study drug, duration, and outcome.  


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All AEs will be collected from the time the subject signs informed consent through 30 days 
following the last dose of study drug. In addition, the Investigator should report any AE that 
occurs after this time period that is believed to have a reasonable possibility of being 
associated with study drug.  
AEs ongoing at 30 days following the last dose of study drug should have a comment in the 
source document by the Investigator whether the event has recovered, recovered with 
sequelae, or stabilized. 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Ultragenyx or its designee must be notified of any SAE that occurs at any time during the 
reporting period within 24 hours of the Investigator, designee, or site personnel’s knowledge 
of the event. SAEs will be reported by completing and submitting SAE report forms to 
Ultragenyx or its designee.  
Follow-up SAE information must be submitted in a timely manner as additional information 
becomes available. All SAEs regardless of relationship to study drug must be followed to 
resolution or stabilization if improvement is not expected. 
All deaths, regardless of causality, occurring from the signing of the informed consent until 
30 days following the last dose of study drug are to be reported as SAEs to Ultragenyx or its 
designee within 24 hours of knowledge.  
8.5.4.3 
Pregnancy in Subject or Partner, and Requirements for Immediate 
Reporting 
Ultragenyx or its designee must be notified of the occurrence of any pregnancy in a subject 
or subject’s partner that occurs during the reporting period within 24 hours of the 
Investigator, designee, or site personnel’s knowledge of the event. Pregnancies will be 
reported by completing and submitting Pregnancy Notification forms to Ultragenyx or 
designee. Reported pregnancy of a subject or a subject’s partner, while participating in the 
study, will be monitored for the full duration and/or followed until the outcome of the 
pregnancy is known. In the event of a pregnancy in the partner of a subject, the Investigator 
should make every effort to obtain the female partner’s consent for release of protected 
health information. 
Ultragenyx or its designee must be notified of the outcome of the pregnancy within 24 hours 
of the Investigator, designee, or site personnel’s knowledge of the outcome. 
Pregnancy outcomes will be reported by completing and submitting Pregnancy Outcome 
forms to Ultragenyx or designee.  


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8.5.5 Communication Plan 
8.5.5.1 
Serious Adverse Drug Reaction Reporting 
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSAR) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), Ethics Committees, and Investigators as per local laws and 
regulations. Fatal and life-threatening SUSARs will be submitted no later than 7-calendar 
days of first knowledge of the event and follow-up information submitted within an 
additional eight (8) days. All other SUSARs will be submitted within 15-calendar days of 
first knowledge of the event.  
The Investigator will notify the IRBs/ECs of SAEs and urgent safety matters, in accordance 
with IRB/EC requirements and local laws and regulations. A copy of this notification must 
be provided to Ultragenyx or its designee.  
8.5.5.2 
Urgent Safety Matters and Non-SUSAR Reporting 
Principal Investigators are required to report any urgent safety matters to Ultragenyx or its 
designee within 24 hours. Ultragenyx or its designee will inform the Regulatory Authorities, 
ECs, and Investigators of any events (e.g. change to the safety profile of UX007, major 
safety findings) that may occur during the clinical trial that do not fall within the definition of 
a SUSAR but may affect the safety of subjects participating in the clinical trials, as required, 
in accordance with applicable laws and regulations. The reporting period for urgent safety 
issues is the period from the signing of the ICF through 30 days following the last dose of 
study drug. 
The Investigator will notify the IRBs/ECs of urgent safety matters, in accordance with 
IRB/EC requirements and local laws and regulations. A copy of this notification must be 
provided to Ultragenyx or its designee. 
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and ECs, as per local laws and regulations.  
8.5.5.3 
Pregnancy Reporting 
Reported pregnancy of a subject or a subject’s partner, while participating in the study, will 
be monitored for the full duration and/or followed until the outcome of the pregnancy is 
known. Any pregnancy-associated SAEs must be reported as per the SUSAR reporting 
process indicated in Section 8.5.5.1. 


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8.5.6 
Safety Contact Information 
Drug Safety 
Medical Monitor 
PrimeVigilance 
Fax: 
 
e-mail:
 
 
Telephone: 
 
Mobile: 
 
 
e-mail:  
 
8.6 
Financing and Insurance 
Financing and insurance for this clinical trial will be addressed in clinical trial agreements 
with the study site. 
8.7 
Publication Policy 
Any publication or presentation by the Investigator and/or the Institution based on data or 
results resulting from the Ultragenyx study shall only be done in strict accordance with the 
Publication section in the Clinical Trial Agreement executed between Ultragenyx and the 
Institution and/or the Investigator. 


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9 REFERENCES 
Ataide, TR, de Oliveira, SL, da Silva, FM, Vitorino, LGC, Tavares, MCN and Sant'Ana, 
AEG. 2009. "Toxicological analysis of the chronic consumption of diheptanoin and 
triheptanoin in rats." Int.J.Food Sci.Tech 44:484-92. 
Barone, A, DeWard, SJ., Payne, N. Goldstein, A., Vockley, J. . 2012. "Triheptanoin therapy 
for inherited disorders of fatty acid oxidation.  Poster presentation." Society for Inherited 
Metabolic Disorders Annual Meeting, Charlotte, NC, Mar 31 – Apr 3, 2012. 
Baruteau, J, Sachs, P, Broue, P, Brivet, M, Abdoul, H, Vianey-Saban, C and Ogier de, BH. 
2012. "Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation 
defects: a French pediatric study of 187 patients." J Inherit.Metab Dis. 
Deng, S, Zhang, GF, Kasumov, T, Roe, CR and Brunengraber, H. 2009. "Interrelations 
between C4 ketogenesis, C5 ketogenesis, and anaplerosis in the perfused rat liver." 
J.Biol.Chem. 284 (41):27799-807. 
Gu, L, Zhang, GF, Kombu, RS, Allen, F, Kutz, G, Brewer, WU, Roe, CR and Brunengraber, 
H. 2010. "Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. II. 
Effects on lipolysis, glucose production, and liver acyl-CoA profile." Am.J Physiol 
Endocrinol Metab 298 (2):E362-E71. 
IND-59303. Triheptanoin Therapy for Metabolic Disorders under Charles Roe MD, Baylor 
Research Institute. In  
IND-106011. "Triheptanoin Compassionate Use Protocol under Gerard Vockley MD PhD, 
School of Medicine University of Pittsburgh." 
Kinman, RP, Kasumov, T, Jobbins, KA, Thomas, KR, Adams, JE, Brunengraber, LN, Kutz, 
G, Brewer, WU, Roe, CR and Brunengraber, H. 2006. "Parenteral and enteral metabolism of 
anaplerotic triheptanoin in normal rats." Am.J.Physiol Endocrinol.Metab 291 (4):E860-E66. 
Lindner, M, Gramer, G, Haege, G, Fang-Hoffmann, J, Schwab, KO, Tacke, U, Trefz, FK, 
Mengel, E, Wendel, U, Leichsenring, M, Burgard, P and Hoffmann, GF. 2011. "Efficacy and 
outcome of expanded newborn screening for metabolic diseases--report of 10 years from 
South-West Germany." Orphanet J Rare Dis 6:44. 
Marin-Valencia, I, Good, LB, Ma, Q, Malloy, CR and Pascual, JM. 2013. "Heptanoate as a 
neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-
deficient (G1D) brain." J Cereb.Blood Flow Metab 33 (2):175-82. 
Mochel, F, DeLonlay, P, Touati, G, Brunengraber, H, Kinman, RP, Rabier, D, Roe, CR and 
Saudubray, JM. 2005. "Pyruvate carboxylase deficiency: clinical and biochemical response 
to anaplerotic diet therapy." Mol.Genet.Metab 84 (4):305-12. 


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Mochel, F, Duteil, S, Marelli, C, Jauffret, C, Barles, A, Holm, J, Sweetman, L, Benoist, JF, 
Rabier, D, Carlier, PG and Durr, A. 2010. "Dietary anaplerotic therapy improves peripheral 
tissue energy metabolism in patients with Huntington's disease." Eur.J.Hum.Genet. 18 
(9):1057-60. 
Roe, CR, Bottiglieri, T, Wallace, M, Arning, E and Martin, A. 2010. "Adult Polyglucosan 
Body Disease (APBD): Anaplerotic diet therapy (Triheptanoin) and demonstration of 
defective methylation pathways." Mol.Genet.Metab 101 (2-3):246-52. 
Roe, CR and Mochel, F. 2006. "Anaplerotic diet therapy in inherited metabolic disease: 
therapeutic potential." J.Inherit.Metab Dis. 29 (2-3):332-40. 
Roe, CR, Sweetman, L, Roe, DS, David, F and Brunengraber, H. 2002. "Treatment of 
cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an 
anaplerotic odd-chain triglyceride." J.Clin.Invest 110 (2):259-69. 
Roe, CR, Yang, BZ, Brunengraber, H, Roe, DS, Wallace, M and Garritson, BK. 2008. 
"Carnitine palmitoyltransferase II deficiency: successful anaplerotic diet therapy." Neurology 
71 (4):260-64. 
Saris-Baglama, RN, DeRosa, MA, Raczek, AE, Bjorner, JB and Ware, JE. 2006. 
"Development, validation, and norming of the SF-10 for Children Health Survey." Quality of 
Life Research 15 (S1):A-145. 
Spiekerkoetter, U, Lindner, M, Santer, R, Grotzke, M, Baumgartner, MR, Boehles, H, Das, 
A, Haase, C, Hennermann, JB, Karall, D, de, KH, Knerr, I, Koch, HG, Plecko, B, 
Roschinger, W, Schwab, KO, Scheible, D, Wijburg, FA, Zschocke, J, Mayatepek, E and 
Wendel, U. 2009. "Management and outcome in 75 individuals with long-chain fatty acid 
oxidation defects: results from a workshop." J.Inherit.Metab Dis. 32 (4):488-97. 
Vockley, J, Burton, B, Berry, GT, Longo, N, Phillips, J, Sanchez-Valle, A, Tanpaiboon, P, 
Grunewald, S, Murphy, E, Bowden, A, Chen, W, Chen, CY, Cataldo, J, Marsden, D and 
Kakkis, E. 2018. "Results from a 78-week, single-arm, open-label Phase 2 study to evaluate 
UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders 
(LC-FAOD)." J Inherit Metab Dis. 
Vockley, J, Burton, B, Berry, GT, Longo, N, Phillips, J, Sanchez-Valle, A, Tanpaiboon, P, 
Grunewald, S, Murphy, E, Humphrey, R, Mayhew, J, Bowden, A, Zhang, L, Cataldo, J, 
Marsden, DL and Kakkis, E. 2017. "UX007 for the treatment of long chain-fatty acid 
oxidation disorders: Safety and efficacy in children and adults following 24weeks of 
treatment." Mol Genet Metab. 


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 Vockley, J, Charrow, J, Ganesh, J, Eswara, M, Diaz, GA, McCracken, E, Conway, R, Enns, 
GM, Starr, J, Wang, R, Abdenur, JE, Sanchez-de-Toledo, J and Marsden, DL. 2016. 
"Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long 
chain-fatty acid oxidation disorders." Mol Genet Metab 119 (3):223-31. 
Vockley, J, DeWard, S, McCracken, E, Hsu, K, Skrinar, A, Kakkis, E and Roe, C. 2013. 
"The impact of triheptanoin treatment on the incidence of major medical events in patients 
with long-chain fatty acid oxidation defects (FAOD)." J Inherit Metab Dis 36 (Suppl 2):S94. 
Vockley, J, Marsden, D, McCracken, E, DeWard, S, Barone, A, Hsu, K and Kakkis, E. 2015. 
"Long-term major clinical outcomes in patients with long chain fatty acid oxidation disorders 
before and after transition to triheptanoin treatment-A retrospective chart review." Mol Genet 
Metab. 
Ware, J, Jr., Kosinski, M and Keller, SD. 1996. "A 12-Item Short-Form Health Survey: 
construction of scales and preliminary tests of reliability and validity." Med Care 34
(3):220-33.



SAP_001.pdf: 
Protocol Number: UX007-CL202-Amendment 6  
Statistical Analysis Plan  
21 Dec 2020, Version 2.0 
 
 
Proprietary and Confidential 
Page 1 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Title 
An Open-label Long-Term Safety and Efficacy Extension Study 
in Subjects with Long-Chain Fatty Acid Oxidation Disorders 
(LC-FAOD) Previously Enrolled in UX007 
Protocol: 
UX007-CL202-Amendment 6 
Investigational Product: UX007 
Phase: 
2 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA USA 94949 
Author: 
 
Manager, Biostatistics 
Date: 
21 Dec 2020 
Version Number: 
2.0 


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STATISTICAL ANALYSIS PLAN AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
21 December 2020
 
The Statistical Analysis Plan Version 1.0 dated 07 February 2019, for the UX007-CL202 
study has been modified and the major statistical analysis plan changes are summarized 
below.  These changes described in this amendment do not impact the primary method of 
analysis of the clinical endpoints. 
a. A data listing of completed and missing visits will be provided for Echocardiogram, 
SF-10 and SF-12v2/SF-10 by pre- and post- UX007 treatment period (Section 8.5). 
 
Rationale: These listings will provide information on the amount of missing data for 
ECHO, SF-10, and SF-12v2 endpoints by treatment group. 
 
b. Sensitivity analyses will be performed by removing identified outliers in pre- and 
post-UX007 treatment periods for:  
a. Triheptanoin-naive Cohort (Section 8.5.4.2) 
i. annualized event rate of MCEs and MCE hospitalizations 
ii. annualized duration of event rate of MCEs and MCE hospitalizations 
b. CL201 Rollover Cohort (Section 8.5.5.2) 
i. annualized event rate of MCEs and MCE hospitalizations 
ii. annualized duration of event rate of MCEs and MCE hospitalizations 
 
Rationale: Sensitivity analyses removing outliers will be performed to confirm the 
robustness of the primary MCE analysis findings. 
 
c. Sensitivity analysis will be performed by using an alternative definition of MCEs in 
pre- and post-UX007 treatment periods in  Triheptanoin-naïve (Section 8.5.4.3) and 
CL201-Rollover cohorts (Section 8.5.5.3)  combined and separately for: 
a. Rhabdomyolysis MCEs alternatively defined as a patient having CK value 
>=1000   
b. Hypoglycemia MCEs alternatively defined as a patient having glycemia < 
3.89 mmol   
 
c. Rationale: Sensitivity analyses with an alternative definition of 
Rhabdomyolysis and Hypoglycemia using clinical thresholds will be 
performed to confirm the robustness of the primary MCE analysis findings. 
The clinical assessment for an upper threshold of detecting hypoglycemia of 
glycemia <70 mg/dL (3.89 mmol) is recommended by the American Diabetes 
Association as a level for intervention required in diabetic patients.  The 
clinical assessment for a lower threshold for Rhabdomyolysis, CK value 
>=1000, was chosen to be 5 times the upper limit of normal.  
 


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d. The data listing of prescribed dosing will be updated to include the total daily 
prescribed dose in mg/kg/day (Section 8.4.1). 
 
Rationale:  The data listing will be updated to include the dose adjusted for body 
weight.  
 
e. Profile figures for individual subjects will be generated to display dietary parameters 
along with the occurrence of MCEs on the same plot, over the combined pre- and 
post- UX007 treatment period. Prescribed %DCI of the macronutrient intakes 
(UX007, MCT, other fat, carbohydrates, and protein) and total caloric intake (TCI) 
will be displayed over time (Section 8.4.1). 
 
Rationale: Profile figures will create a visual display demonstrating the consistency 
of dietary intake as well as allowing for comparisons of MCEs occurrences with 
subject’s dietary profiles over time. 
 
f. Data listings of 3-day average subject diet diary parameters which includes fat, 
carbohydrates, and protein measured in g/kg/day and %DCI will be provided for the 
CL201-Rollover and the Naïve Cohort (Section 8.4.1). 
 
Rationale: To provide for diet diary parameters adjusted for subject body weight. 
 
g. The duration of treatment will be summarized for pediatric subjects (<18 years). 
(Section 8.4.1). 
 
Rationale: Exposure in the pediatric population will be used to aid interpretation in 
any future analyses performed for the pediatric population.   
 
h. Modification of the overall summary of adverse events table will be made by 
replacing the row for Grade 3/4 treatment-emergent adverse events (TEAEs) with a 
row for Grade 3 TEAEs and a row for Grade 4 TEAEs. (Section 8.7.1) 
 
Rationale: More granularity for TEAEs of Grades 3 and 4 will be provided.  
 
i. Summary safety tables and listings will be provided (Section 8.7.1) showing:   
a. TEAEs leading to dose reduction  
b. TEAEs leading to treatment interruption 
 
Rationale: These tables and data listings will be prepared to facilitate an investigation 
of which TEAEs lead to dose reductions and which TEAEs lead to treatment 
interruptions.  
 
j. Summary safety tables of gastrointestinal adverse drug reactions (GI ADRs) will be 
provided in order to characterize the severity, outcome, and time course of the GI 


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ADR. Additionally, Kaplan-Meier curves for time to first GI ADR will be provided 
by cohort. (Section 8.7.1.1) 
 
Rationale: These summaries will provide information for an in-depth analysis of 
ADRs during Study UX007-CL202.  
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................11 
1 INTRODUCTION .............................................................................................................12 
2 STUDY OBJECTIVE(S) ...................................................................................................13 
2.1 Primary Objective(s) .................................................................................................13 
2.2 Secondary Objective(s) .............................................................................................13 
2.3 Pharmacokinetic Objectives ......................................................................................20 
3 STUDY DESIGN...............................................................................................................14 
3.1 Study Population .......................................................................................................14 
3.2 Dosage and Administration .......................................................................................15 
3.3 Study Duration ..........................................................................................................16 
3.4 Blinding and Randomization Methods .....................................................................16 
3.5 Stratification Factors .................................................................................................16 
3.6 Sample Size Considerations ......................................................................................16 
3.7 Interim Analysis ........................................................................................................16 
3.8 Data Monitoring Committee .....................................................................................16 
3.9 Discussion of Study Design, Including Choice of Control Group ............................16 
4 STUDY ENDPOINTS AND COVARIATES ...................................................................17 
4.1 Primary Efficacy Endpoint........................................................................................17 
4.2 Secondary Efficacy Endpoints ..................................................................................17 
4.3 Exploratory Endpoints ..............................................................................................18 
4.4 Safety Endpoints .......................................................................................................19 
4.5 Pharmacokinetics Endpoints .....................................................................................19 
4.6 Potential Covariate(s) ................................................................................................19 
5 DEFINITIONS ...................................................................................................................20 
5.1 MCE ..........................................................................................................................20 
5.2 Study Day 1 ...............................................................................................................20 
5.3 UX007 Treatment Day 1 ...........................................................................................20 


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5.4 Study Days ................................................................................................................20 
5.5 Subject Cohorts for Presentation...............................................................................20 
5.6 Baseline .....................................................................................................................21 
5.7 UX007 Treatment Baseline .......................................................................................21 
5.8 Visits .........................................................................................................................21 
5.9 Study Periods ............................................................................................................21 
5.9.1 
Study Period 1 (Main Study Period) ...........................................................21 
5.9.2 
Study Period 2 .............................................................................................22 
5.9.3 
Study Period 3 .............................................................................................22 
5.10 Annualized Event Rate..............................................................................................22 
5.11 Annualized Duration Rate .........................................................................................23 
5.12 Age at Enrollment .....................................................................................................23 
5.13 Age at First Dose of UX007/trihep ...........................................................................23 
5.14 Total Duration of UX007 Exposure ..........................................................................23 
5.15 % of Daily Caloric Intake Provided by Prescribed UX007 Dose .............................23 
5.16 Overall Average Prescribed UX007 Dose ................................................................24 
5.17 Overall UX007 dosing completion percentage .........................................................24 
5.18 SF-12 PCS and MCS.................................................................................................25 
5.19 SF-10 PCS and MCS.................................................................................................25 
5.20 Exposure-adjusted Adverse Event Incidence Rate ...................................................26 
5.21 Outlier .......................................................................................................................26 
6 ANALYSIS POPULATIONS ...........................................................................................27 
6.1 Full Analysis Set (FAS) ............................................................................................27 
6.2 Safety Analysis Set ...................................................................................................27 
6.3 Full Analysis Set-SF-10 ............................................................................................27 
6.4 Full Analysis Set-SF-12 ............................................................................................27 
6.5 PK Sub-study Set ......................................................................................................27 
7 DATA SCREENING AND ACCEPTANCE ....................................................................28 


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7.1 General Principles .....................................................................................................28 
7.2 Handling of Missing and Incomplete Data ...............................................................28 
7.2.1 
Missing Medical History Related Dates ......................................................28 
7.2.2 
Missing Birth Dates .....................................................................................28 
7.2.3 
Missing Date Imputation for Adverse Events and Concomitant 
Medications .................................................................................................29 
7.2.4 
Missing Data for Efficacy Endpoints ..........................................................30 
7.2.5 
Missing Causal Relationship to Investigational Product for Adverse 
Event ...........................................................................................................30 
7.2.6 
Visit Window ..............................................................................................30 
7.3 Testing/Validation Plan.............................................................................................30 
7.4 Software ....................................................................................................................30 
8 STATISTICAL METHODS OF ANALYSES ..................................................................31 
8.1 General Principles .....................................................................................................31 
8.1.1 
Repeated Measure Model: General Estimating Equations ..........................31 
8.2 Subject Accountability ..............................................................................................31 
8.3 Protocol Deviations ...................................................................................................31 
8.4 Investigational Product Administration ....................................................................32 
8.4.1 
UX007 Dosing,Exposure, and Diet .............................................................32 
8.4.2 
Treatment Compliance ................................................................................32 
8.4.3 
Demographic and Baseline Characteristics .................................................32 
8.4.4 
Prior and Concomitant Medication .............................................................33 
8.5 Efficacy Analysis ......................................................................................................33 
8.5.1 
Analysis of Primary Efficacy Endpoint .......................................................34 
8.5.2 
Analysis of Secondary Efficacy Endpoints .................................................34 
8.5.3 
Analysis of Exploratory Endpoint(s) ...........................................................35 
8.5.3.1 
SF-10/12 .......................................................................................35 
8.5.3.2 
Clinical biomarkers endpoints .....................................................35 


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8.5.3.3 
Growth measurements .................................................................35 
8.5.4 
Triheptanoin-Naïve Cohort:  Statistical Comparisons in Efficacy 
Endpoints ....................................................................................................36 
8.5.4.1 
Pre- and Post-UX007 Comparisons in MCE in 
Triheptanoin-Naïve Cohort ..........................................................36 
8.5.4.2 
Sensitivity Analyses for Triheptanoin-Naïve Cohort ..................37 
8.5.4.2.1 
Negative Binomial Regression in Triheptanoin-
naïve .............................................................................37 
8.5.4.2.2 
Removing Outliers in Triheptanoin-naïve ...................37 
8.5.4.2.3 
Alternative Clinical Definitions of MCEs in 
Triheptanoin-naïve Cohorts .........................................37 
8.5.4.3 
Analyses of Non-MCE Endpoints in Triheptanoin-naïve 
Cohort ..........................................................................................38 
8.5.5 
CL201-Rollover Cohort:  Integrated Analyses for efficacy 
endpoints .....................................................................................................38 
8.5.5.1 
Pre- and Post-UX007 MCEs in CL201-Rollover Cohort ............38 
8.5.5.2 
Sensitivity Analyses for CL201-Rollover Cohort........................39 
8.5.5.2.1 
Negative Binomial Regression in CL201-
Rollover Cohort ...........................................................39 
8.5.5.2.2 
Alternative Clinical Definitions of MCEs in 
CL201-Rollover Cohorts .............................................39 
8.5.5.3 
Analyses of Non-MCE endpoints in CL201-Rollover 
Cohorts .........................................................................................40 
8.6 Pharmacokinetics Analysis .......................................................................................40 
8.7 Safety Analysis .........................................................................................................40 
8.7.1 
Adverse Events ............................................................................................40 
8.7.1.1 
Gastrointestinal Adverse Drug Reactions ....................................42 
8.7.2 
Clinical Laboratory Parameters ...................................................................43 
8.7.2.1 
Biomarkers & LC-FAOD Laboratory Measures .........................43 
8.7.2.2 
Clinical Laboratory Tests .............................................................44 


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Page 9 
8.7.3 
Vital Signs ...................................................................................................45 
8.7.4 
Cardiac Safety – Echocardiograms .............................................................46 
8.7.5 
Physical Examination ..................................................................................46 
8.7.6 
Pregnancy Test ............................................................................................46 
9 LIST OF PLANNED TABLES, LISTINGS, AND FIGURES .........................................47 
10 REFERENCES ..................................................................................................................48 
11 APPENDICES ...................................................................................................................49 
11.1 Summary of Efficacy Endpoints and Analysis .........................................................49 
11.2 Reference Values/Severity Grades ............................................................................50 
11.3 MedDRA Search Strategy for GI TEAEs and Hepatobiliary TEAEs ......................51 
11.4 Visit Windows...........................................................................................................53 
11.5 Schedule of Events ....................................................................................................54 
 


Protocol Number: UX007-CL202-Amendment 6  
Statistical Analysis Plan  
21 Dec 2020, Version 2.0 
 
 
Proprietary and Confidential 
Page 10 
List of Tables 
Table 8.7.1:  Biomarkers and LC-FAOD-related Laboratory Measures .................................43 
Table 8.7.2:  Clinical Laboratory Assessments .......................................................................44 
Table 8.7.3:  Screen for Liver/Muscle Damage .......................................................................45 
Table 11.1.1:  Summary Table of UX007-CL202 Efficacy Endpoints and Analysis..............49 
Table 11.2.1:  CTCAE Severity Grades for Selected Laboratory Parameters .........................50 
Table 11.3.1: Hepatobiliary Disorders .....................................................................................51 
Table 11.4.1: Visit Time Windows ..........................................................................................53 
Table 11.5.1: Schedule of Events ............................................................................................54 
 
List of Figures 
Figure 3.1:  UX007-CL202 Study Schema ..............................................................................14 
Figure 5.9.3.1:  Diagram of Study Periods in CL202 ..............................................................22 
 


Protocol Number: UX007-CL202-Amendment 6  
Statistical Analysis Plan  
21 Dec 2020, Version 2.0 
 
 
Proprietary and Confidential 
Page 11 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate transaminase 
BHB 
beta-hydroxypentanoate 
BHP 
beta-hydroxybutyrate 
CDC 
Centers for Disease Control and Prevention 
CK 
creatinine kinase 
CTCAE 
common terminology criteria for adverse events 
ECHO 
echocardiogram 
ICF 
informed consent form 
LC-FAOD 
long-chain fatty acid oxidation disorders 
LLN 
lower limit of normal 
MCE 
major clinical event 
MCS 
mental health component summary score 
MedDRA 
Medical Dictionary for Regulatory Activity 
OHSU 
Oregon Health & Science University 
PCS 
physical health component summary score 
PDMS-2 
Peabody Developmental Motor Scales 2nd edition 
PEDI-CAT 
Pediatric Evaluation of Disability Inventory Computer Adaptive Test 
PK 
pharmacokinetics 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDTM 
study data tabulation model 
SF 
shortening fraction 
SF-10 
Medical Outcome Study 10-items Short Form for Children 
SF-12 
Medical Outcome Study 10-items Short Form 
SI 
Le Système International d’Unités (International System of Units) 
SMQ 
standardized MedDRA query 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 


Protocol Number: UX007-CL202-Amendment 6  
Statistical Analysis Plan  
21 Dec 2020, Version 2.0 
 
 
Proprietary and Confidential 
Page 12 
1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the UX007-CL202 original protocol and all 
amendments through Protocol Amendment 6 dated 01 October, 2019. This is the original 
version of SAP for this study. Changes from these guidelines must be substantiated by sound 
statistical reasoning and documented in the clinical study report (CSR). 
Should there be a difference between the SAP and the protocol with respect to data analysis, 
the SAP will take precedence over the protocol. 


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Protocol Number: UX007-CL202-Amendment 6  
Statistical Analysis Plan  
21 Dec 2020, Version 2.0 
 
 
Proprietary and Confidential 
Page 29 
7.2.3 
Missing Date Imputation for Adverse Events and Concomitant Medications 
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications.  Note that the imputed values outlined here may not 
always provide the most conservative date.   
Missing Start Dates 
• If the day is unknown, then: 
▪ If the month and year match the first dose of investigational product start date month 
and year in this study, then impute the day of the first dose date. 
▪ Otherwise, assign the first day of the month. 
• If the month is unknown, then: 
▪ If the year matches the year of the first dose of investigational product date in this 
study, then impute the month and day of the first dose date in this study. 
▪ Otherwise, assign ‘January’  
• If the year is unknown, then the date will not be imputed and will be assigned a missing 
value.  
If the imputed date is earlier than birth date, then birth date will be used. If the imputed start 
date is later than the end date, then the start date will be set as the same date as the end date. 
Missing Stop Dates (not applicable to ongoing) 
• If the day is unknown, then assign the last day of the month. 
• If the month is unknown, then assign ‘December.’ 
• If the year is unknown, then the date will not be imputed and will be assigned a missing 
value, and the event will be considered ongoing. If the AE has been recorded as 
resolved/recovered, all efforts should be made to obtain the date from the Investigator. 
• If the resulting end date is after the date of study completion / discontinuation/ data 
cutoff, set the imputed end date as close to the date of study completion / discontinuation/ 
data cutoff as possible without overwritten existing information. 
If the year is missing for the start date and the stop date (observed or imputed) is on or after 
the first dose or event is ongoing, the start date will be imputed as the first dose date. 


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Protocol Number: UX007-CL202-Amendment 6  
Statistical Analysis Plan  
21 Dec 2020, Version 2.0 
 
 
Proprietary and Confidential 
Page 35 
A data listing of missing visits will be provided for ECHO endpoint by treatment. 
 
8.5.3 
Analysis of Exploratory Endpoint(s) 
8.5.3.1 
SF-10/12 
For SF-10 and SF-12, analyses include summary statistics of baseline and change from the 
study baseline over time for each individual domain and the summary scores. The full 
analysis set-SF-10 will be used for statistical analyses of SF-10. The full analysis set-SF-12 
will be used for statistical analyses of SF-12. 
Individual subject listings will be provided for all SF-10/12 tests performed for all subjects in 
FAS. 
A data listing of missing visits will be provided for SF-10 and SF-12v2. 
8.5.3.2 
Clinical biomarkers endpoints 
Biomarker results and corresponding changes from baseline will be summarized 
descriptively by visit.   
8.5.3.3 
Growth measurements 
Height, weight, and head circumference measurements and the corresponding changes and 
percent changes from baseline will be summarized descriptively by visit and by age group 
with summary statistics. 
Z-score will be calculated for growth measurements including standing height (or sitting 
height if applicable) and weight for the male ≤18 years, or for the female ≤15 years.  
Z-scores and percentiles will be calculated using (CDC/NCHS) Clinical Growth Charts 
(Kuczmarski et al. 2000).  The plot of height over age with reference to CDC growth chart 
for each subject will be provided. Data used to produce the United States Growth Charts 
smoothed percentile curves will be downloaded from the official CDC/NCHS web site: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm 
The data files from the CDC/NCHS that are used for this analysis are summarized below. 
These files represent the different growth curves for children. LMS refers to the parameters 
in the CDC Growth Charts Percentile Data Files used to construct the growth curves; these 
are: the power in the Box-Cox transformation (L); the median (M); and the generalized 
coefficient of variation (S). 
The data files used are: 
• Length-for-age charts, birth to 36 months, LMS parameters and selected smoothed 
recumbent length percentiles in centimeters, by sex and age (LENAGEINF). 


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Statistical Analysis Plan  
21 Dec 2020, Version 2.0 
 
 
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An AE (classified by preferred term) will be considered a treatment emergent adverse event 
(TEAE) if it occurred on or after the first dose of UX007 and was not present prior to the first 
dose or worsening in severity or frequency of a preexisting condition. AEs that started in 
UX007-CL201 and continued into UX007-CL202 will not be considered UX007-CL202 
TEAE since the start date is prior to UX007-CL202 first dose. 
The following subject incidence of AEs will be summarized: 
• Summary of TEAEs  
• TEAEs by SOC and PT (preferred term)  
• Related TEAEs by SOC and PT  
• Serious TEAEs by SOC and PT  
• Serious Related TEAEs by SOC and PT  
• Grade 3 or 4 TEAEs by SOC and PT  
• Deaths by  SOC and PT  
• TEAEs leading to discontinuation of study treatment  by SOC and PT  
• TEAEs by PT  
• TEAEs leading to dose reduction by SOC and PT 
• TEAEs leading to treatment interruption by SOC and PT 
• TEAEs by PT  
• TEAEs in the GI SOC  
• Related TEAEs in the GI SOC 
• GI ADRs 
• GI ADRs leading to treatment discontinuation 
Hepatobiliary TEAEs  (see Appendix 11.4)For those AEs that occurred more than once 
during the study, the maximum severity or highest grade causality will be used to summarize 
the subject incidence. Exposure-adjusted adverse event incidence rates will also be presented 
at the preferred term level. 
The number and percent of subjects experiencing one or more TEAE by SOC and PT in 
order of descending frequency may be summarized by age, gender and subtype of FAOD 


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Statistical Analysis Plan  
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history depending on the sample size.  The planned age categories are ‘0-1 year’, 
‘>1-6 years’, ‘>6-18 years’ and ‘>18 years’ and some may be combined if their number of 
subjects is small. 
In the overall summary of adverse events table, there will be separate summaries for Grade3 
and Grade 4 TEAEs.  
Detailed subject listings for all AEs, serious TEAEs, AEs leading to the discontinuation of 
study, AEs leading to the discontinuation of treatment, and death TEAEs leading to dose 
reduction, and TEAEs leading to treatment interruption will also be generated.  
8.7.1.1 
Gastrointestinal Adverse Drug Reactions  
Summaries of gastrointestinal adverse drug reactions ( GI ADRs) will be prepared to within 
each cohort. GI ADRs include the following PTs: Diarrhea, Abdominal pain, Abdominal 
pain upper, Gastrointestinal pain, Abdominal discomfort, Abdominal distension, Vomiting, 
and Nausea.   
 
Summaries to characterize the severity and outcome of GI ADRs will include the following:  
1) incidence of subjects with at least one GI ADR, 
2) incidence of GI ADRs leading to treatment discontinuation,  
3) a frequency distribution of the number of GI ADRs per subject,  
4) descriptive statistics (n, mean, standard deviation, standard error, median and first and 
3rd quartiles) for the number of GI ADRs per subject,  
5) the frequency GI ADRs by severity and seriousness grade 
6) a frequency distribution of the outcome of the GI ADRs that were 
a) Recovered/Resolved 
b) Resolving/Recovering 
c) Recovered/Resolved with Sequelae 
d) Death 
e) Not Resolved  
 
Characterization of the time course of GI ADRs will be provided for: 
1) Time to first GI ADR with  
2) Frequency of GI ADRs by time categories 
3) Number of Subjects with GI ADR by time categories 
4) descriptive statistics by time categories for any GI ADR 
 
The frequency distributions will the following categories: <= 8 Weeks, > 8 Weeks to <= 24 
Weeks, > 24 Weeks to <= 48 Weeks, > 48 Weeks to <= 78 Weeks, > 78 Weeks to <= 102 
Weeks, > 102 Weeks to <= 126 Weeks, > 126 Weeks to <= 150 Weeks, > 198 Weeks to 
<= 222 Weeks, etc. 
 
The duration of a treatment-emergent GI ADR that was resolved is defined as AE end date 
minus AE start date plus 1 day. The duration of a treatment-emergent GI ADR for GI events 


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Statistical Analysis Plan  
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that are ongoing is defined as data cutoff date minus AE start date plus 1 day. The duration of 
treatment-emergent GI ADRs will be categorized as follows:  1 Day, 2 to <= 3 Days, 4 to <= 
7 Days, 8 to <= 14 Days, 15 to <= 28 Days, and > 28 Days. Descriptive statistics will be also 
be provided. 
 
Kaplan-Meier curves will be provided by cohort for time to first treatment-emergent GI ADR 
which is defined as AE start date minus the first UX007 dose date in UX007-CL202 plus 1 
day. For the Kaplan-Meier curves, subjects will be censored at the end of study date or the 
data cutoff date, whichever is earlier. Time to first GI ADR in a subject is determined by the 
first GI ADR with non-missing start date of the subject. For the Rollover cohort, only 
UX007-CL202 data will be used and time plotted will be in weeks since the start of UX007-
CL202. 
 
8.7.2 
Clinical Laboratory Parameters 
8.7.2.1 
Biomarkers & LC-FAOD Laboratory Measures 
Biomarkers and relevant indicators of LC-FAOD are summarized in Table 8.7.1.  
Blood samples will be collected at each clinic visit to assess relevant biomarkers and 
laboratory measures of LC-FAOD. 
Table 8.7.1:  Biomarkers and LC-FAOD-related Laboratory Measures 
Biomarkers of UX007 Effects 
LC-FAOD Laboratory Measures 
Skeletal myopathy biomarkers: 
serum creatine kinase (CK) 
Total and free plasma carnitine 
Hepatic disease biomarkers: 
serum glucose, serum liver enzymes (ALT, AST, GGT) 
Plasma acylcarnitines 
Urine organic acids 
 
Descriptive statistics for clinical laboratory values (in SI units) and changes from the baseline 
values at each scheduled visit will be presented for the following laboratory parameters: 
• Total and free plasma carnitine 
• Plasma acylcarnitines 
• Urine organic acids 
Shift tables pairing each subject’s baseline severity grade with the subject’s highest post-
baseline severity grade will be presented for the following parameters: 
• Fasting serum glucose 
• Triglycerides 


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Statistical Analysis Plan  
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• Creatine kinase (CK) 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST)  
• Gamma glutamyl transpeptidase (GGT) 
8.7.2.2 
Clinical Laboratory Tests 
Clinical laboratory values (in SI units) at each visit will be presented for the following 
laboratory parameters as listed in the following table: 
Table 8.7.2:  Clinical Laboratory Assessments 
Chemistry 
Hematology 
Urinalysis 
Alanine aminotransferase (ALT) 1  
Hematocrit  
Appearance  
Alkaline phosphatase  
Hemoglobin  
Color  
Aspartate aminotransferase (AST) 1  
MCH concentration (MCHC)  
pH  
Bilirubin (total)  
Mean corpuscular hemoglobin (MCH)  
Specific gravity  
Blood urea nitrogen (BUN)  
Mean corpuscular volume (MCV)  
Ketones  
Chloride  
Platelet count  
Protein  
Cholesterol (total)  
Red blood cell (RBC) count  
Glucose  
Serum creatinine  
Reticulocyte count  
Bilirubin  
Gamma-glutamyl transpeptidase (GGT)1 
WBC differential  
Nitrite  
Serum glucose, fasting 1  
Neutrophil count (absolute and %)  
Urobilinogen  
Lactate dehydrogenase (LDH)  
Lymphocyte count (absolute and %)  
Blood  
Potassium  
Monocyte count (absolute and %)  
Creatinine  
Protein (albumin and total)  
Eosinophil count (absolute and %)  
 
Sodium  
Basophil count (absolute and %)  
 
 
White blood cell (WBC) count  
 
 
The frequency and percentage of subjects who experience abnormal clinical laboratory 
results (i.e. outside of reference ranges) and/or clinically significant abnormalities will be 
presented. 


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All valid assessments will be converted into SI units.  In calculating change from baseline at 
each scheduled visit, only subjects with non-missing values at both baseline and the 
individual scheduled visit are included. All available data (i.e., scheduled and unscheduled 
assessments) are, however, used in identifying abnormalities in shift tables. Severity for the 
selected clinical laboratory parameters will be graded according to Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. CTCAE severity grades for selected 
laboratory parameters are listed in Appendix 11. 
Hy’s Law criteria will be applied against test results. Subjects with serum total bilirubin 
>2 x ULN and ALT or AST >3 x ULN will be identified and further reviewed to confirm 
there is no other reason to explain the lab increases before confirming Hy’s law status.  
Results will be presented in shift tables. For Hy’s Law, shift tables will be produced: 
• Hy’s Law negative at baseline, remaining Hy’s Law negative throughout the study 
• Hy’s Law negative at baseline, becoming Hy’s Law positive at any point during the study  
• Hy’s Law positive at baseline and Hy’s Law negative throughout the study 
• Hy’s Law positive at baseline and Hy’s Law positive at any point during the study  
A data listing of all subjects who are Hy’s Law positive will be produced. 
Potential liver / muscle damage will be assessed based on clinical laboratory test results (and 
to differentiate it from possible muscle degradation) based on AST, ALT, GGT and CK test 
results shown below. All results will be listed, and subjects identified with potential toxicity 
stemming from liver, muscle or both will be flagged. 
Table 8.7.3:  Screen for Liver/Muscle Damage 
AST and ALT 
GGT ≤1.5 x ULN 
GGT >1.5 x ULN 
CK ≤ULN 
CK >ULN 
CK ≤ULN 
CK >ULN 
Both ≤1.5 x ULN 
No Toxicity Flag 
No Toxicity Flag 
No Toxicity Flag 
No Toxicity Flag 
Either >1.5 x ULN 
Neither 
Muscle 
Liver 
Both 
 
8.7.3 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressures, and pulse rate) 
and changes from baseline values at each scheduled visit and at the end of study will be 
presented. 


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Statistical Analysis Plan  
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8.7.4 
Cardiac Safety – Echocardiograms  
LVEF (% and Z-score) over time from echocardiograms will be summarized descriptively.  
Shift table for LVEF will be provided comparing baseline and post-baseline changes.  
Echocardiogram results will be provided in subject listing. 
CTCAE severity grades for decreased ejection fraction are: 
• Grade 1: Not available 
• Grade 2: LVEF 50-40% or 10-19% drop from baseline 
• Grade 3: LVEF 39-20% or >20% drop from baseline 
• Grade 4: LVEF  < 20% 
8.7.5 
Physical Examination 
A complete physical examination is performed at the Baseline visit and at 6-month intervals 
(or Early Termination).  Clinically significant changes from baseline to scheduled timepoints 
in physical examination will be reported on the adverse event CRF and thus not presented 
separately. 
8.7.6 
Pregnancy Test 
Pregnancy test for females with child-bearing potential will be conducted at the scheduled 
study visit and the results will be provided in a listing. 


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Statistical Analysis Plan  
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9 LIST OF PLANNED TABLES, LISTINGS, AND FIGURES  
List of planned tables, listings, and figures will be provided in a separate document. 


Protocol Number: UX007-CL202-Amendment 6  
Statistical Analysis Plan  
21 Dec 2020, Version 2.0 
 
 
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10 REFERENCES 
Kuczmarski, R, Ogden, C, Grummer-Strawn, L, Flegal, K, Guo, S, Wei, R, Mei, Z, Curtin, L, 
Roche, A, and Johnson, C. 2000. "CDC growth charts: United States." Adv Data (314):1-27. 
 


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Protocol Number: UX007-CL202-Amendment 6  
Statistical Analysis Plan  
21 Dec 2020, Version 2.0 
 
 
Proprietary and Confidential 
Page 52 
Hepatobiliary 
Disorders 
System Organ Class 
Preferred Term 
 
Hepatobiliary Disorders 
Cholelithiasis 
 
Hepatobiliary Disorders 
Cholelithiasis obstructive 
 
Hepatobiliary Disorders 
Pseudocholelithiasis 
 
Hepatobiliary Disorders 
Gallbladder enlargement 
 
Hepatobiliary Disorders 
Gallbladder obstruction 
 
Hepatobiliary Disorders 
Hepatic failure 
 
Hepatobiliary Disorders 
Acute hepatic failure 
 
Hepatobiliary Disorders 
Subacute hepatic failure 
 
Hepatobiliary Disorders 
Acute on Chronic hepatic failure 
 
Hepatobiliary Disorders 
Chronic hepatic failure 
 
Hepatobiliary Disorders 
Drug-induced liver injury 
 
Hepatobiliary Disorders 
Mixed liver injury 
 
Hepatobiliary Disorders 
Cholestasis 
 
Hepatobiliary Disorders 
Hepatitis cholestatic 
 
Hepatobiliary Disorders 
Jaundice 
 
Hepatobiliary Disorders 
Jaundice cholestatic 
 
Hepatobiliary Disorders 
Icterus 
 
Hepatobiliary Disorders 
Ocular icterus 
 
Hepatobiliary Disorders 
Ascites 
 
Hepatobiliary Disorders 
Biliary ascites 
 
Hepatobiliary Disorders 
Hepatic congestion 
 
Hepatobiliary Disorders 
Hepatomegaly 
 
Hepatobiliary Disorders 
Hepatosplenomegaly 
 
Hepatobiliary Disorders 
Hepatic liver injury 
 
Hepatobiliary Disorders 
Hepatic steato-fibrosis 
 
Hepatobiliary Disorders 
Hepatic steatosis 
 
Hepatobiliary Disorders 
Hepatocellular injury 
 
Hepatobiliary Disorders 
Liver injury 
 
Hepatobiliary Disorders 
Non-alcoholic fatty liver 
 
Hepatobiliary Disorders 
Non-alcoholic steatohepatitis 
 
Hepatobiliary Disorders 
Steatohepatitis 
 
Investigations 
Alanine aminotransferase abnormal 
 
Investigations 
Alanine aminotransferase increased 
 
Investigations 
Aspartate aminotransferase abnormal 
 
Investigations 
Aspartate aminotransferase increased 
 
Investigations 
Blood bilirubin abnormal 
 
Investigations 
Blood bilirubin increased 
 
Investigations 
Bilirubin conjugated abnormal 
 
Investigations 
Bilirubin conjugated increased 
 
Investigations 
Gamma-glutamyltransferase abnormal 
 
Investigations 
Gamma-glutamyltransferase increased 
 
Investigations 
Hepatic enzyme abnormal 
 
Investigations 
Hepatic enzyme increased 
 
Investigations 
Transaminases abnormal 
 
Investigations 
Transaminases increased 
 
Investigations 
Amylase abnormal 


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Protocol Number: UX007-CL202  
Statistical Analysis Plan  
21 December 2020, Version 2.0 
 
Proprietary and Confidential 
Page 55 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dietary Assessment and 
Diet diary11 
 
 
 
X 
 
X 
 
X 
X 
X 
 
UX007 Treatment & 
Compliance12 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
X12 
 
Plasma UX007 and 
Metabolites14 
 
 
 
X14 
 
X14 
 
X14 
X14 
 
 
Standardized Meal14 
 
 
 
X14 
 
X14 
 
X14 
X14 
 
 
 
The Baseline visit may occur in conjunction with the last scheduled visit from study UX007-CL201.  Assessments conducted at the last UX007-CL201 visit will 
be used for Baseline data to avoid duplication. Minor subjects who turn 18, should provide consent at their next visit. 
Clinic Visits will occur at 6 month intervals (± 2 weeks). The window for phone visits is ± 1 week. 
Early Termination Visit should take place within 4 weeks of treatment discontinuation, if possible. The End of Study Visit will take place following commercial 
availability of UX007 in any region; if the End of Study Visit occurs within 2 weeks of a previous clinic visit, only the following assessments will occur: 
growth, vital signs, physical examination, urine pregnancy testing, AEs, concomitant medications, and UX007 compliance. 
Medical history including major medical illness, diagnoses and surgeries will be collected for all subjects not previously enrolled in UX007-CL201.  LCFAOD 
maintenance treatment history, including triheptanoin treatment history, and relevant concomitant medications will be recorded (start date, stop date, dose, 
dose regimen). Any available sibling history of LC-FAOD will be noted.   
Growth measurements include height and weight for all subjects, as well as head circumference for subjects aged ≤ 36 months.  
ECHO will be performed at Baseline and annually thereafter at indicated clinic visits (or if performed as routine care within 30 days prior to the Baseline or 
indicated clinic visits) or Early Termination if not performed within 6 months prior to termination.  Additional tests may be performed during Treatment 
Extension Period if any abnormalities are detected or if medically indicated.   
Major LC-FAOD events include skeletal myopathy (rhabdomyolysis), hepatic (hypoglycemia) and cardiac disease (cardiomyopathy) events, and are defined as 
any visit to the ER/acute care, hospitalization, emergency intervention (ie any unscheduled administration of therapeutics at home or in the clinic), or any 
similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD.  The event type, levels of relevant laboratory 
parameters (including CK, glucose, and BNP/troponin), the number of days hospitalized and days in ICU, and the type and number of days of treatment and 
intervention will be recorded. 
Biomarkers of clinical manifestations include skeletal myopathy (CK) and hepatic disease (fasting serum glucose and liver enzymes [ALT, AST, GGT]). 
Laboratory measures of LC-FAOD disease activity include total and free plasma carnitine, plasma acylcarnitines, and urine organic acids.   
Vital sign measurements consist of seated systolic/diastolic BP measured in millimeters of mercury (mm Hg), HR (beats per minute), respiration rate (breaths per 
minute), and temperature in degrees Celsius (°C).  Obtain at the beginning of each visit before any additional assessments are completed. 
Clinical Laboratory Tests include standard serum chemistry, hematology, and urinalysis. These panels may overlap with LC-FAOD-specific biomarkers 
(including glucose and liver enzymes) which are called out separately in the table.   
Subjects and/or caregivers are required to maintain record of daily diet in a diary for 3 days prior to each clinic visit after consenting to participate in the trial. 
The daily diet should be representative of typical consumption for the subject. The diet diary will be reviewed with the site staff upon each indicated visit.  


Protocol Number: UX007-CL202  
Statistical Analysis Plan  
21 December 2020, Version 2.0 
 
Proprietary and Confidential 
Page 56 
Treatment with UX007 will begin after any necessary washout period for prohibited medications. UX007 dosing will be targeted at 25-35% of total caloric 
intake.  If a subject has been receiving a lower dose, the individual may be titrated to a UX007 dose up to 25-35% of total caloric intake, while ensuring 
tolerability. However, a subject may remain at a lower dose if higher doses are not tolerated or at a higher dose at the discretion of the Investigator.  UX007 
will not be dispensed at the Month 84 (end-of-treatment visit), End of Study, Early Termination visits (as applicable). 
Safety Follow-up Phone Call to be conducted 30-35 days after last dose of investigational study drug.  Following commercial availability of UX007, a Safety 
Followup Phone Call will be conducted 30-35 days after last dose of investigational study drug for subjects not immediately continuing UX007 through 
another mechanism (ie, commercial product, IST, or compassionate use). The site personnel will initiate this safety follow-up telephone call to collect 
information on any ongoing or new AEs, serious adverse events (SAEs), and concomitant medications, as appropriate.  Appropriate follow-up should 
continue until all safety concerns, in the Investigator’s opinion, are resolved. 
PK measurements will occur at select sites in a subset of subjects at two consecutively scheduled clinic visits (eg Month 18 and Month 
 24), excluding the Baseline Visit. Participating subjects (minimum of 12 subjects) will be fed a standardized meal containing one of their divided daily doses of 
UX007.  Blood for plasma UX007 and metabolites will be collected pre-dose (within 15 minutes prior to start of meal) and at 30, 90, 120, and 240 minutes 
[± 5 minutes] after finishing the meal. For each sample collection, the meal start/stop times, calories consumed, UX007 dosing, and sampling times will be 
recorded.