A Phase 2b, Multicenter, Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta
Phase: PHASE2
Conditions: Osteogenesis Imperfecta
Sponsor: Ultragenyx Pharmaceutical Inc

Protocol 
UX143-CL203 
A Phase 2b, Multicenter, Long-term Extension Study of Setrusumab in Adults with Type I, 
III, or IV Osteogenesis Imperfecta 
Product name (INN): 
Indication: 
IND Number: 
Sponsor: 
Sponsor's Responsible 
Medical Monitor: 
Coordinating Investigator: 
Protocol Number: UX143-CL203 
Original Protocol: 01 December 2021 
Setmsumab 
Osteogenesis imperfecta 
113385 
Ultragenyx Phannaceutical Inc. 
60 Leveroni Comt 
Novato, CA 94949 
USA 
PPD 
-=_...,..,MD,MS
PPD 
Global Clinical Development 
Telephone: 1-'l-'L) 
To be deten,___m_n_e_..., ____ .... 
This study will be performed in compliance with the protocol, Good Clinical Practice 
(GCP), and all applicable regulatory requirements and guidelines. 
Confidentiality Statement: This document and the information it contains is confidential and proprietary and is the 
property ofUltragenyx Phannaceutical 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 
info1mation it contains will not be disclosed without prior written authorization from Ultragenyx, except to the 
extent required to satisfy Institutional Review Board/Independent Ethics Committee procedures, to obtain written 
info1med consent from potential subjects, or as required by law. 
Due to the early te1mination of the study, no SAP was finalized 
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2. 
SYNOPSIS  
Sponsor: Ultragenyx Pharmaceutical Inc. (Ultragenyx) 
Product Name (International Nonproprietary Name [INN]): Setrusumab 
Title: A Phase 2b, Multicenter, Long-term Extension Study of Setrusumab in Adults with Type 
I, III, or IV Osteogenesis Imperfecta  
Development Phase: Phase 2b  
Introduction  
Setrusumab is a fully human anti-sclerostin monoclonal antibody that is being developed for the 
treatment of osteogenesis imperfecta (OI).  
The purpose of this study is to investigate 1) safety and disease progression after discontinuation 
of setrusumab, 2) the safety and efficacy of 12 months of retreatment with setrusumab, and 3) the 
safety and efficacy of 
 dosing beyond 12 months of retreatment with setrusumab in 
adults with OI who previously participated in ASTEROID. 
Objectives and Endpoints 
Study objectives and endpoints are defined for each study period. The primary and secondary 
endpoints will be evaluated for the Retreatment Period and are shown in Table 1. All objectives 
and endpoints for the Observation, Retreatment, and Extension Periods are shown in Section 6.  
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Exclusion Criteria for Enrollment into UX143-CL203:  
1. Known hypersensitivity to setrusumab or its excipients that, in the judgment of the 
Investigator, places the subject at increased risk for adverse effects. 
2. Presence or history of any condition that, in the view of the Investigator, would interfere 
with participation, pose undue risk, or would confound interpretation of results.  
3. Pregnant or breastfeeding or planning to become pregnant (self or partner) at any time 
during the study  
4. Willing to discontinue bisphosphonate use at least 3 months prior to the Retreatment 
Screening Visit (if applicable).Once enrolled in UX143-CL203, individuals who meet 
any of the following exclusion criteria will not be eligible to participate in the 
Retreatment Period: 
5. Concurrent participation in any study that is examining the safety and efficacy of any 
investigational product or investigational medical device that alters bone health during 
the Retreatment and Extension Periods, per discretion of the Investigator in consultation 
with the Medical Monitor. Presence or history of any condition that, in the view of the 
Investigator, would interfere with participation, pose undue risk, or would confound 
interpretation of results.  
7. Calcium levels outside the normal range. If the subject’s calcium level is not within the 
normal range, decision to retest should be made in conjunction with the Medical Monitor. 
8. Glomerular filtration rate (GFR) ≤ 29 mL/min. If the subject’s GFR is ≤ 29 mL/min, 
decision to retest should be made in conjunction with the Medical Monitor. 
9. History of skeletal malignancies or bone metastases at any time 
10. History of neural foraminal stenosis (except if due to scoliosis) 
11. History of myocardial infarction, angina pectoris, ischemic stroke or transient ischemic 
attack 
a. Investigators should consider whether the potential benefits of treatment outweigh the 
potential risks in patients with other cardiovascular risk factors such as hypertension, 
hyperlipidemia, familial hyperlipidemia, family history of premature ischemic 
cardiovascular disease, smoking, diabetes mellitus, and metabolic 
syndrome. Suggested criteria and references for evaluation of risk factors will be 
provided in the Study Reference Manual. 
12. History of or concomitant uncontrolled diseases such as hypo-/hyperparathyroidism, 
hypo-/hyperthyroidism, Paget’s disease, abnormal thyroid function or thyroid disease or 
other endocrine disorders or conditions that could affect bone metabolism eg, Stage IV/V 
renal disease 
13. A history of rickets or osteomalacia or any skeletal condition (other than OI) leading to 
long-bone deformities and/or increased risk of fractures 
14. Documented alcohol and/or drug abuse within 12 months prior to dosing or evidence of 
such abuse as indicated by the laboratory results during the screening/baseline 
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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................2 
3. 
TABLE OF CONTENTS ...........................................................................................11 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................15 
5. 
INTRODUCTION ......................................................................................................18 
5.1. 
Overview of Osteogenesis Imperfecta ........................................................................18 
5.2. 
Overview of Setrusumab Development ......................................................................19 
5.3. 
Rationale for Setrusumab in Osteogenesis Imperfecta ...............................................20 
5.4. 
Potential Benefits and Risks .......................................................................................21 
5.4.1. 
Potential Benefits of Setrusumab ................................................................................21 
5.4.2. 
Potential Risks ............................................................................................................21 
5.4.3. 
Benefit Risk Conclusion .............................................................................................23 
5.5. 
Risk Minimization ......................................................................................................23 
6. 
OBJECTIVES AND ENDPOINTS ............................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................29 
7.1. 
Study Design ...............................................................................................................29 
7.1.1. 
Number of Sites ..........................................................................................................30 
7.1.2. 
Number of Subjects ....................................................................................................30 
7.1.3. 
Rationale for Study Design .........................................................................................30 
7.1.4 
Dose Rationale ............................................................................................................31 
7.2. 
Duration ......................................................................................................................31 
7.2.1. 
Duration of Subject Participation ...............................................................................31 
7.2.2. 
End of Study Definition ..............................................................................................31 
7.3. 
Changes to the Protocol due to Covid-19 ...................................................................32 
8. 
POPULATION ...........................................................................................................33 
8.1. 
Inclusion Criteria ........................................................................................................33 
8.2. 
Exclusion Criteria .......................................................................................................33 
8.3. 
Subject Discontinuation and Stopping Rule Criteria ..................................................34 
8.3.1. 
Discontinuation of Intervention ..................................................................................34 
8.3.2. 
Discontinuation from Study ........................................................................................34 
8.3.3. 
Study Stopping Criteria ..............................................................................................35 

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8.4. 
Informed Consent .......................................................................................................35 
8.5. 
Screening Requirements .............................................................................................35 
9. 
INTERVENTION(S) ..................................................................................................36 
9.1. 
Investigational Product: Setrusumab ..........................................................................36 
9.1.1. 
Preparation and Administration ..................................................................................36 
9.1.2. 
Clinical Observation and Supportive Care .................................................................36 
9.2. 
Prior and Concomitant Therapy ..................................................................................36 
9.3. 
Restricted or Prohibited Medications, Devices, and Procedures ................................37 
9.4. 
Treatment Compliance ................................................................................................37 
9.5. 
Treatment Assignment ................................................................................................37 
9.5.1. 
Treatment Assignment ................................................................................................37 
10. 
ASSESSMENTS.........................................................................................................38 
10.1. 
Skeletal Assessments ..................................................................................................38 
10.1.1. 
Dual-energy X-ray Absorptiometry ............................................................................38 
10.1.2. 
Radiography ................................................................................................................38 
10.1.3. 
39 
10.2. 
Patient-reported Assessments .....................................................................................39 
10.2.1. 
 .............................................................................................................39 
10.2.2. 
 ..............39 
10.2.3. 
......................................................................39 
10.2.4. 
Fracture Event Diary ...................................................................................................39 
10.3. 
 ..............................................................40 
10.4. 
 ........................................................40 
10.4.1. 
 ....................................................................40 
10.4.2. 
 ..............................................40 
10.5. 
 ....................................................................................40 
10.6. 
Safety Assessments .....................................................................................................40 
10.6.1. 
Adverse Events of Special Interest .............................................................................41 
10.6.2. 
General Medical History .............................................................................................41 
10.6.3. 
Vital Signs ..................................................................................................................41 
10.6.4. 
Electrocardiograms .....................................................................................................41 
10.6.5. 
Safety Laboratory Tests ..............................................................................................41 
10.6.6. 
Pregnancy Testing ......................................................................................................42 
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10.6.7. 
Concomitant Medications ...........................................................................................42 
10.6.8. 
 ....................................................................................42 
10.7. 
Physical and Neurologic Assessments ........................................................................43 
10.7.1. 
Physical Examinations ................................................................................................43 
10.7.2. 
Focused Neurological Examinations ..........................................................................43 
10.7.3. 
Audiometry .................................................................................................................43 
10.7.4. 
Dental Health Assessment ..........................................................................................43 
10.8. 
Appropriateness of Measurements .............................................................................43 
11. 
STATISTICAL CONSIDERATIONS .......................................................................44 
11.1. 
Sample Size Determination ........................................................................................44 
11.2. 
Planned Methods of Analysis .....................................................................................44 
11.2.1. 
General Principles .......................................................................................................44 
11.2.2. 
Efficacy Analyses .......................................................................................................44 
11.2.2.1. 
Primary and Secondary Efficacy Endpoints ...............................................................44 
11.2.2.2. 
Tertiary Efficacy Endpoints ........................................................................................45 
11.3. 
Safety Analyses ..........................................................................................................46 
11.4. 
Planned Analyses ........................................................................................................46 
11.5. 
Data Monitoring Committee .......................................................................................46 
12. 
REFERENCES ...........................................................................................................48 
13. 
GENERAL APPENDICES ........................................................................................50 
APPENDIX 1. SAFETY LABORATORY ASSESSMENTS ....................................................50 
APPENDIX 2. CONTRACEPTION GUIDANCE .....................................................................51 
APPENDIX 3. SAFETY DEFINITIONS AND ASSESSMENTS .............................................53 
APPENDIX 4. ADVERSE EVENT COLLECTION, ELICITING, RECORDING 
AND REPORTING ....................................................................................................57 
APPENDIX 5. ETHICS AND CONDUCT ................................................................................62 
STATEMENT OF COMPLIANCE ...............................................................................................67 
INVESTIGATOR SIGNATURE: .................................................................................................67 
SPONSOR SIGNATURE: .............................................................................................................67 
 
 
 
 
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LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints for the Retreatment Period .......................................3 
Table 2: 
Study Interventions .......................................................................................................7 
Table 3: 
Schedule of Events .......................................................................................................8 
Table 4: 
Detailed Sample Collection Schedule ........................................................................10 
Table 5: 
OI Subtypes ................................................................................................................18 
Table 6: 
Study Objectives and Endpoints for the Observation Period .....................................26 
Table 7: 
Study Objectives and Endpoints for the Retreatment Period .....................................27 
Table 8: 
Study Objectives and Endpoints for the Extension Period .........................................28 
Table 9: 
Study Interventions .....................................................................................................36 
Table 10: Specified Laboratory Assessments .............................................................................50 
Table 11: Collection Period and Reporting Timeframes for Adverse Event and Other 
Safety Information Reporting .....................................................................................57 
Table 12: Safety Contact Information .........................................................................................58 
 
LIST OF FIGURES 
Figure 1: 
UX143-CL203 Study Schema ......................................................................................5 
 
 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition or Explanation 
ADA 
antidrug antibodies 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMD 
bone mineral density 
 
 
BUN 
blood urea nitrogen 
COL1A1 
collagen type 1 alpha 1 
COL1A2 
collagen type 1 alpha 2 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation and Coordination Group 
 
 
DMC 
Data Monitoring Committee 
DSPV 
Drug Safety and Pharmacovigilance 
DXA 
dual-energy X-ray absorptiometry 
ECG 
electrocardiogram 
EMA 
European Medicines Agency 
EOI 
end of injection 
 
 
ET 
early termination  
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
 
  
IB 
Investigator’s Brochure  
ICF 
informed consent form 
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Abbreviation 
Definition or Explanation 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG2 
immunoglobulin G subclass 2 
IND 
Investigational New Drug 
INN 
international nonproprietary name 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous  
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
NOAEL 
no-observed-adverse-effect-level 
 
 
OI 
osteogenesis imperfecta 
 
 
 
 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
QM 
once a month 
 
 
 
 
 
 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
 
 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
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Definition of Terms  
Investigational Product (IP) is defined as, “A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical study, 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 Council on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH] Harmonised 
Tripartite Guideline E6: Guideline for Good Clinical Practice (GCP)). 
The term “study drug” may also be used in place of “investigational product (IP)” in the 
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5. 
INTRODUCTION 
Setrusumab is a fully human anti-sclerostin monoclonal antibody that is being developed for the 
treatment of osteogenesis imperfecta (OI).  
The purpose of this study is to investigate 1) safety and disease progression after discontinuation 
of setrusumab, 2) the safety and efficacy of 12 months of retreatment with setrusumab in adults 
with OI who previously participated in the Phase 2b study (ASTEROID; MBPS205), and 3) the 
safety and efficacy of 
 dosing beyond 12 months of retreatment with setrusumab in 
adults with OI who previously participated in ASTEROID. 
5.1. 
Overview of Osteogenesis Imperfecta  
OI comprises a heterogenous group of serious and debilitating genetic disorders characterized by 
low bone mass and bone fragility, resulting in multiple fractures and skeletal deformities. 
The estimated incidence of OI is 1 in 10,000 to 20,000 births (Marini et al., 2017; Lindahl et al., 
2015). The initial diagnosis of OI, usually in early childhood, is typically based on clinical 
features and radiographic findings, and can be confirmed by collagen or DNA testing. 
About 85% of OI cases are caused by autosomal dominant mutations in collagen type 1 alpha 1 
or 2 (COL1A1 or COL1A2), the genes that encode Type I collagen (Biggin and Munns, 2014). 
These mutations result in a reduced amount of normal collagen or structural modifications that 
impact trabecular and cortical bone architecture. A small proportion of OI cases are caused by 
other genes involved in collagen biosynthesis or osteoblast differentiation and bone 
mineralization (Marom et al., 2020). 
Bone fragility is the hallmark of OI, resulting in recurrent nontraumatic fractures, skeletal 
deformities, and growth retardation (Tournis and Dede, 2018). Fractures can occur from birth, 
and continue at a high rate throughout childhood, typically involving the long bones, vertebrae, 
and ribs. Although the incidence of fractures is highest in the first two decades of life, adults 
remain at elevated risk of fractures that can impact activities of daily living and quality of life 
(Wekre et al., 2011; Hald et al., 2017).  
Most experts classify OI caused by mutations in COL1A1 or COL1A2 as Types I to IV based on 
clinical presentation, radiographic features, and patterns of inheritance (Sillence et al., 1979) 
(Table 5). The clinical phenotype of OI can vary widely from mild to severe, depending on the 
specific mutations in COL1A1 or COL1A2 (Biggin and Munns, 2014). OI Type I is caused by a 
reduced amount of normal collagen in the bone, while Types III and IV are caused by structural 
defects in collagen (Marini et al., 2017). With the discovery of other genetic causes of OI, 
additional numerical designations have been adopted to classify newer OI types. The OI types 
described in this protocol include Types I, III and IV. 
Table 5: 
OI Subtypes 
OI Subtype 
Phenotypic Characteristics 
Type I 
Blue sclerae, near-normal stature, multiple fractures from childhood and late-onset hearing loss 
Type II 
Perinatally lethal OI 
Type III 
Progressively deforming OI 
Type IV 
White sclerae, deforming fractures from infancy, short stature, bone deformity and 
dentinogenesis imperfecta; more severe than Type I but less severe than Types II and III 
OI, osteogenesis imperfecta 
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No treatments for OI have been approved by the Food and Drug Administration (FDA) or 
European Medicines Agency (EMA). Current treatment approaches are primarily focused on 
symptomatic relief, address comorbidities, and can vary depending on patient age and disease 
severity. A multidisciplinary treatment approach is typically employed, including 
pharmacological treatment, physical therapy, occupational therapy, orthopedic interventions, and 
follow-up by other subspecialists (Marom et al., 2020). Patients may need to undergo 1 or more 
surgeries to correct skeletal deformities and to prevent and/or heal fractures (Hidalgo Perea and 
Green, 2021). Although not approved for the treatment of OI, children with OI who fracture 
frequently are often treated with intravenous (IV) bisphosphonates, typically starting at very 
young age upon diagnosis (Nijhuis et al., 2019). While bisphosphonates do not directly alter the 
defect in bone quality (Arshad and Bishop, 2021), their antiresorptive action is known to 
improve bone mass and microarchitecture in patients with OI (Rauch et al., 2002). 
Bisphosphonates are not typically used to treat adults with OI, as their impact on bone mineral 
density (BMD) is greatly reduced upon cessation of growth. Discontinuation of bisphosphonates 
is associated with only modest decreases in dual-energy X-ray absorptiometry (DXA) BMD 
(Rauch et al., 2006). Fracture risk reduction with bisphosphonates has not been definitively 
demonstrated in either adults or children with OI (Dwan et al., 2016).  
Osteoanabolic therapies may be beneficial in pediatric and adult patients by stimulating bone 
formation and increasing bone mass. The effects of the osteoanabolic agent teriparatide were 
examined in a placebo-controlled study in adult subjects with Types I, III, and IV OI (Orwoll et 
al., 2014). Although significant gains in DXA BMD were observed after 18 months of 
teriparatide at the spine and hip in subjects with Type I OI; these effects were not observed in the 
Type III/IV subjects.  
Given the elevated risk of fractures in adults with OI, and the associated disease burden and 
negative impact on daily living, there is a high unmet medical need for a safe and effective 
treatment that reduces the incidence of fractures and prevents the long-term consequences of OI. 
5.2. 
Overview of Setrusumab Development 
A brief overview of existing information on setrusumab is provided below; a comprehensive 
review of available data, including potential risks and expected benefits of setrusumab is 
contained in the Investigator’s Brochure. 
Setrusumab is a fully human anti-sclerostin monoclonal antibody that belongs to the 
immunoglobulin G subclass 2 (IgG2) lambda isotype subclass. It has an affinity of 
 pM for 
human sclerostin. 
Setrusumab has been administered in 5 clinical studies including a Phase 1 study and a Phase 2a 
study in healthy postmenopausal women (CBPS804A2101, CBPS804A2203), 2 Phase 2 studies 
(CBPS804A2201 in adults with moderate OI and CBPS804A2202 in adults with 
hypophosphatasia [HPP]), and a Phase 2b study (ASTEROID; MBPS205) in adults with OI 
Types I, III, or IV. 
In the first-in-human study with setrusumab, CBPS804A2101, healthy post-menopausal women 
with low BMD experienced increases in serological biomarkers of bone anabolism and lumbar 
spine BMD. This was further demonstrated in the Phase 2 study, CBPS804A2201, in adult 
patients with OI where setrusumab treatment led to significant increases in bone formation 
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biomarkers and lumbar spine BMD, indicating enhanced skeletal remodeling and bone 
formation. These findings were further corroborated by data from ASTEROID in adults with OI 
Types I, III, or IV. In ASTEROID, setrusumab treatment demonstrated notable improvements in 
DXA BMD and bone strength indices at the peripheral bone sites, and increased serum 
biomarkers of bone formation, with an acceptable safety profile. These effects were consistent 
across OI types.  
5.3. 
Rationale for Setrusumab in Osteogenesis Imperfecta 
Setrusumab is being investigated for the treatment of OI based on 1) the serious unmet need for a 
treatment for OI, 2) the mechanism of action for setrusumab that addresses the mechanism of 
disease for OI, and 3) previous clinical experience with setrusumab suggesting a positive 
benefit-risk profile in patients with OI, supporting further development.  
As described in Section 5.1, there are no FDA- or EMA-approved therapies for OI. 
Current treatment consists of a multidisciplinary approach focusing on symptomatic relief, 
including pharmacological intervention, physical therapy, occupational therapy, orthopedic 
interventions, and follow-up by other subspecialists. Despite these approaches, patients with OI 
have bone fragility and remain at elevated risk of fractures, substantially impacting their daily 
living and quality of life.  
Low bone mass and the resultant bone fragility in OI can be attributed to an imbalance in bone 
resorption versus bone formation. Although bisphosphonates are frequently used off-label in 
pediatric patients with OI, inhibition of bone resorption with bisphosphonate treatment may not 
be adequate to restore skeletal health in OI. Osteoanabolic therapies may be beneficial in 
pediatric and adult patients by stimulating bone formation and increasing bone mass. One of 
these potential approaches is through inhibition with Sclerostin.  
Sclerostin, a small protein produced by osteocytes, inhibits canonical Wnt signaling, and thereby 
suppresses osteoblast differentiation and bone formation (Poole et al., 2005). Sclerostin levels 
have been found to be absent or low in several rare, genetic skeletal disorders that present with 
high BMD and low fracture risk, such as sclerosteosis and van Buchem disease. This has led to 
the concept that inhibiting sclerostin and thereby increasing bone formation may be useful for the 
treatment of disorders such as OI that are characterized by bone fragility and increased risk of 
fractures (Olvera et al., 2018). Anti-sclerostin antibodies have been shown to stimulate osteoblast 
bone formation and improve trabecular and cortical bone mass in multiple mouse models of OI, 
with effects that were generally similar across growing and skeletally mature mice. In a murine 
model of Type III OI (oim/oim), anti‐sclerostin antibody therapy was also shown to reduce the 
number of fractures (Roschger et al., 2014). The anti-sclerostin antibody, romosozumab is 
approved for use in women with post-menopausal osteoporosis, in whom the increases in bone 
mass corresponded to significant reductions in fracture risk (Cosman et al., 2016). 
As described in Section 5.2, across 5 Phase 1 or 2 studies, setrusumab increased serological 
markers of bone anabolism and lumbar spine BMD in healthy post-menopausal women with low 
BMD; and increased markers of bone formation, bone strength indices at peripheral bone sites, 
and lumbar spine BMD in patients with OI. Setrusumab also demonstrated an acceptable safety 
profile in these studies. Available nonclinical data with setrusumab support further evaluation 
and development of setrusumab for treatment of adults with OI and is provided in the 
Investigator’s Brochure (IB). 

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7.3. 
Changes to the Protocol due to Covid-19 
Changes to the protocol or Investigational Plan to minimize or eliminate immediate hazards or to 
protect the life and well-being of research subjects and/or study staff may be implemented 
without Institutional Review Board/Independent Ethics Committee (IRB/IEC) approval or before 
filing an amendment to the competent authority but are required to be reported afterward. 
Investigators should contact Ultragenyx or Designee to determine an appropriate course of 
action, which may include but is not limited to remote visits, home health visits, and out of 
window visits or assessments. Any changes to the protocol or investigational plan must be 
documented. The Investigator will work with Ultragenyx or Designee and IRB/IEC to prioritize 
reporting of protocol deviations that impact safety of trial subjects. 

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8. 
POPULATION 
Prospective protocol deviations (ie, protocol waivers or exemptions) are not permitted. 
8.1. 
Inclusion Criteria 
Subjects who participated in ASTEROID were ages 19 to 74 years at the time of enrollment. 
Eligible individuals must meet all of the following criteria:  
1. Males or females who participated in the Phase 2b ASTEROID study 
2. Females of childbearing potential must consent to use highly effective contraception 
(Appendix 2) during the Observation, Retreatment, and Extension Periods through 2 
months after the last dose of setrusumab and agree not to become pregnant. Provide 
informed consent after the nature of the study has been explained, and prior to any 
research-related procedures 
8.2. 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to enroll in 
UX143-CL203: 
1. Known hypersensitivity to setrusumab or its excipients that, in the judgment of the 
Investigator, places the subject at increased risk for adverse effects. 
2. Presence or history of any condition that, in the view of the Investigator, would interfere 
with participation, pose undue risk, or would confound interpretation of results.  
3. Pregnant or breastfeeding or planning to become pregnant (self or partner) at any time 
during the study  
4. Willing to discontinue bisphosphonate use at least 3 months prior to the Retreatment 
Screening Visit (if applicable).Once enrolled in UX143-CL203, individuals who meet 
any of the following exclusion criteria will not be eligible to participate in the 
Retreatment Period: 
5. Concurrent participation in any study that is examining the safety and efficacy of any 
investigational product or investigational medical device that alters bone health during 
the Retreatment and Extension Periods, per discretion of the Investigator in consultation 
with the Medical Monitor. 
6. Presence or history of any condition that, in the view of the Investigator, would interfere 
with participation, pose undue risk, or would confound interpretation of results.  
7. Calcium levels outside the normal range. If the subject’s calcium level is not within the 
normal range, decision to retest should be made in conjunction with the Medical Monitor. 
8. GFR ≤ 29 mL/min. If the subject’s GFR is ≤ 29 mL/min, decision to retest should be 
made in conjunction with the Medical Monitor. 
9. History of skeletal malignancies or bone metastases at any time 
10. History of neural foraminal stenosis (except if due to scoliosis) 

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11. History of myocardial infarction, angina pectoris, ischemic stroke or transient ischemic 
attack 
a. Investigators should consider whether the potential benefits of treatment outweigh the 
potential risks in patients with other cardiovascular risk factors such as hypertension, 
hyperlipidemia, familial hyperlipidemia, family history of premature ischemic 
cardiovascular disease, smoking, diabetes mellitus, and metabolic 
syndrome. Suggested criteria and references for evaluation of risk factors will be 
provided in the Study Reference Manual. 
12. History of or concomitant uncontrolled diseases such as hypo-/hyperparathyroidism, 
hypo-/hyperthyroidism, Paget’s disease, abnormal thyroid function or thyroid disease or 
other endocrine disorders or conditions that could affect bone metabolism eg, Stage IV/V 
renal disease 
13. A history of rickets or osteomalacia or any skeletal condition (other than OI) leading to 
long-bone deformities and/or increased risk of fractures 
14. Documented alcohol and/or drug abuse within 12 months prior to dosing or evidence of 
such abuse as indicated by the laboratory results during the screening/baseline 
assessments 
15. Documented history of significant psychiatric or medical disorder that would prevent the 
participant complying with the requirements of the protocol or would make it unsafe for 
the participant to participate in the study as judged by the investigator 
16. Current/previously reported allergy to the study drug or any of its excipients or the class 
of drug under investigation 
17. History of external radiation 
8.3. 
Subject Discontinuation and Stopping Rule Criteria 
8.3.1. 
Discontinuation of Intervention 
If a subject is withdrawn from treatment due to safety reasons or if a subject has an ongoing SAE 
or AESI considered related to study drug at the end of participation, the subject should be 
followed until the event resolves, or the subject’s condition has stabilized. 
8.3.2. 
Discontinuation from Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or compliance 
reasons. Ultragenyx must be notified of all subject withdrawals as soon as possible. 
Ultragenyx also reserves the right to discontinue participation of an Investigator due to poor 
enrollment or noncompliance, as applicable. 
In the event a subject discontinues treatment, he or she will remain in the study for safety 
monitoring purposes, unless continued participation in the study poses a risk to the subject as 
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If a subject discontinues from the study prematurely, reasonable efforts should be made to 
perform the early termination (ET) Visit procedures within 2 weeks of discontinuation. A safety 
follow-up will be performed 2 months after the subject’s last treatment. In the event a subject has 
an ET, all efforts will be made to monitor the subject through the end of the study. 
8.3.3. 
Study Stopping Criteria  
If, at any time during the study, any of the criteria listed below are reported in subjects treated 
with setrusumab, DMC will be notified to review if any alteration of study procedures is 
warranted:  
x 7ZRRUPRUHVXEMHFWVZLWKDQ\VHULRXV7($(ZLWKDVHYHULW\ Grade 3 (according to the 
Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) that is assessed 
as related to study drug or study procedures by the Investigator or Ultragenyx 
x One or more subjects with a hypersensitivity reaction that is considered Grade 4 or higher 
and assessed as related to study drug by the Investigator or Ultragenyx  
8.4. 
Informed Consent  
Informed consent must be obtained from the patient at the Screening visit, prior to entry into the 
Observation period and prior to performing any study-related procedures. In the event that a 
subject is rescreened, a new informed consent form (ICF) must be signed unless it has been 
< 30 days since the previous ICF signature was obtained.  
8.5. 
Screening Requirements 
There are 2 screening visits: the Screening Visit to determine eligibility for entry into the 
Observation Period of the study and the Retreatment Screening Visit to confirm eligibility to 
enter the Retreatment Period of the study in order to receive retreatment with setrusumab. 
All screening evaluations specified in Table 3 must be completed and reviewed to confirm 
eligibility for study entry (initial Screening Visit into the Observational /period) and Retreatment 
Period entry (Retreatment Screening Visit). The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
At the Screening Visit, informed consent will be obtained, general medical information 
(ie, demographics, general medical history, and concomitant medications) will be collected.  
During the Retreatment Screening Visit subjects are rescreened and safety laboratory tests are 
run to ensure subject safety prior to retreatment with setrusumab (Section 8.2). Calcium levels 
assessed at the Retreatment Screening Visit must be in the normal range prior to the Retreatment 
Visit. While receiving treatment with setrusumab, subjects can receive a daily dose of 
 mg 
calcium as background treatment or maintain a higher dose if they are already receiving a higher 
dose. If the subject’s calcium level is not within the normal range, decision to retest should be 
made in conjunction with the Medical Monitor. 25-OH-vitamin D should be 
 nmol/L prior to 
setrusumab retreatment. If the subject’s 25-OH-vitamin D is < 
 nmol/L at the Retreatment 
Screening Visit, the subject should be treated as per the local guidelines and retested during the 
study to maintain levels above 
 nmol/L. 
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Study site personnel should indicate on relevant laboratory request documents if the subject is 
taking high dose biotin supplements (found in multivitamins, biotin supplements, and some 
supplements to support hair, skin and nail growth) due to potential risk of assay interference 
(eg, troponin) (FDA, 2019). 
9.3. 
Restricted or Prohibited Medications, Devices, and Procedures 
Certain medications and procedures are prohibited per the exclusion criteria in Section 8.2, 
including:  
x Concurrent participation in any study that is examining the safety and efficacy of any 
investigational product or investigational medical device that alters bone health during 
the Retreatment and Extension Periods, per discretion of the Investigator in consultation 
with the Medical Monitor  
x Willing to discontinue bisphosphonate use at least 3 months prior to the Retreatment 
Screening Visit (if applicable). 
9.4. 
Treatment Compliance 
Study drug will be administered at the study site via a single IV infusion by qualified personnel. 
The dose, start time, stop time, and volume of infusion will be recorded in the subject’s case 
report form (CRF). 
9.5. 
Treatment Assignment  
9.5.1. 
Treatment Assignment 
This is an open-label study. No study drug is provided during the Observation Period. During the 
Retreatment Period, all subjects will receive the same dose of setrusumab administered QM. 
During the Extension Period, subjects will be randomized 1:1 to either continue treatment with 
open-label setrusumab QM or transition to open-label setrusumab 
. For the Extension 
Period dosing groups, randomization will be stratified by OI type (I vs III/IV). Randomization 
will be completed using interactive response technology (IRT). 
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prior to entering the Retreatment Period to scheduled time points in vital signs, physical 
examination, focused neurological examination, audiometry, dental health evaluations, clinical 
laboratory evaluations, and ECGs. Safety will also be evaluated by the development of 
anti-setrusumab antibodies and pregnancy testing.  
Safety definitions and instructions for assessing severity and causality are presented in 
Appendix 3.  
Refer to Appendix 4 for instructions how to elicit, record, and report including collection period 
timeframes and timelines for AEs, SAEs, AESIs, pregnancies, other safety information and any 
urgent safety measures taken to protect the safety or welfare of subjects. 
10.6.1. 
Adverse Events of Special Interest 
AESIs for this study include the potential risks of ischemic cardiovascular events, infusion 
reactions and hypersensitivity, and neurologic sequelae associated with bone overgrowth. 
Medical Dictionary for Regulatory Activities (MedDRA) search strategies will be specified for 
AESIs in the Statistical Analysis Plan, and include standardized MedDRA queries, if available. 
AESI will be collected from the time the subject signs the ICF and through the safety follow-up 
period and should be reported within 24 hours of site Investigator, designee or site personnel’s 
knowledge of the event as outlined in Table 11. 
10.6.2. 
General Medical History 
General medical history will be collected during screening (Table 3). General medical 
information includes subject demographics and a history of major medical illnesses, diagnoses, 
and surgeries. Medical history also includes a chart review, including the collection of DXA and 
fracture events.  
10.6.3. 
Vital Signs 
Vital signs to be measured include seated systolic blood pressure and diastolic blood pressure, 
heart rate, respiration rate, and temperature. Vital signs will be measured after the subject has 
rested for at least 5 minutes, and prior to any other study assessments and drug administration. 
10.6.4. 
Electrocardiograms 
Single 12-lead ECG will be obtained using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT and (QTc) intervals. ECGs will be performed at timepoints 
indicated in the Schedule of Events (Table 3). 
While conduction intervals provided by the ECG machine may be used, final interpretation of 
ECGs, including any rhythm abnormalities, will be made by an independent central vendor to 
ensure reliability and reproducibility. Any abnormalities will be recorded.  
10.6.5. 
Safety Laboratory Tests 
Blood and urine samples will be collected prior to administration of study drug, as specified in 
Table 3 and Table 4, and analyzed by a central laboratory. Fasting is required for visits that 
coincide with blood sample collection for
 (Table 3 and 
Table 4).  
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11.3. 
Safety Analyses 
Safety variables including all SAEs, TEAEs, AESIs, safety laboratory assessments, 
anti-setrusumab antibodies, vital signs, ECGs, physical examination, focused neurological 
examination, audiometry, and dental health assessments will be summarized descriptively and 
listed by subject.  
All AEs will be coded according to the MedDRA Version 24.0 or above. The frequency and 
severity of all TEAEs, SAEs, AESIs and clinically relevant laboratory and ECG abnormalities 
reported as AEs will be reported by System Organ Class, Preferred Term, by severity, and by 
relationship to study drug, if applicable. All non-serious AEs reported with onset after the first 
dose of study drug (ie, TEAEs) will be included in the analysis. All SAEs will also be reported 
by relationship to study drug as reported by Investigator, seriousness criteria, timing, duration, 
and outcome. For all TEAEs; SAEs; AESIs; and treatment-related TEAEs, SAEs, and AESIs; the 
percentage of subjects who experienced at least 1 occurrence of the given event will be 
summarized. Data summaries and\or listings, and narratives will be provided for subjects who 
died, discontinued treatment or withdrew from study due to TEAE, or experienced SAEs, AESIs, 
and any study procedure-related AEs.  
Clinical laboratory data changes from ASTEROID Baseline and Retreatment Baseline will be 
summarized by the type of laboratory test. Reference ranges and abnormal results (specified in 
the SAP) will be used in the summary of laboratory and ECG data. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (ie, outside of 
reference ranges) and/or clinically significant abnormalities (as determined by the Investigator) 
will be presented for each clinical laboratory measurement, including for Hy’s Law analysis 
(alanine transaminase [ALT], aspartate aminotransferase [AST], total and direct bilirubin, 
alkaline phosphatase). Shift tables will be provided for changes from ASTEROID Baseline and 
Retreatment Baseline in selected chemistry and hematology laboratory parameters (if 
applicable). Listings of abnormal vital signs and physical findings will be provided (if 
applicable).  
The SAP will provide additional details on the planned safety analyses.  
11.4. 
Planned Analyses 
The primary analysis is planned at the end of the Retreatment Period, reflecting 12 months of 
retreatment with setrusumab. No interim analyses are planned. The final analysis will be 
conducted at the end of the study.  
11.5. 
Data Monitoring Committee  
An independent DMC will be established with subject matter experts to serve in an advisory 
capacity to Ultragenyx.  
The DMC will meet and review study data, including cardiovascular events and other AESIs, at 
the frequency defined and in accordance with the scope and objectives set forth in the DMC 
Charter. The DMC will provide advice to Ultragenyx regarding the safety of subjects, the ethics 
of the study and the continuing scientific validity of the study. The DMC may also make 
recommendations to Ultragenyx concerning continuation, termination or other modifications of 

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the study based on their review of data. Further details regarding the DMC can be found in the 
DMC charter. 
Ultragenyx Data Review Board will review the DMC recommendations and determine necessary 
actions that will be communicated accordingly to all stakeholders, eg, Regulatory Authorities, 
IRB/IECs, and Investigators.  

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12. 
REFERENCES 
Arshad F and Bishop N (2021) Osteogenesis imperfecta in children. Bone 148: 115914. 
Biggin A and Munns CF (2014) Osteogenesis imperfecta: diagnosis and treatment. Curr 
Osteoporos Rep 12(3): 279-288. 
Bovijn J, Krebs K, Chen CY, et al. (2020) Evaluating the cardiovascular safety of sclerostin 
inhibition using evidence from meta-analysis of clinical trials and human genetics. Sci Transl 
Med 12(549). 
Cosman F, Crittenden DB, Adachi JD, et al. (2016) Romosozumab Treatment in Postmenopausal 
Women with Osteoporosis. N Engl J Med 375(16): 1532-1543. 
CTFG (2020) Clinical Trials Facilitiation and Coordintion Group: Recommendations related to 
contraception and pregnancy in clinical trials. Version 1.1 (21 September 2020). Available at: 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Versio
n_1.1.pdf. 
Dwan K, Phillipi CA, Steiner RD, et al. (2016) Bisphosphonate therapy for osteogenesis 
imperfecta. Cochrane Database Syst Rev 10: CD005088. 
EMA EVENITY SmPC (2019). 
FDA (2019) The FDA Warns that Biotin May Interfere with Lab Tests: FDA Safety 
Communication. Available at: https://www.fda.gov/medical-devices/safety-communications/fda-
warns-biotin-may-interfere-lab-tests-fda-safety-communication (accessed 22Sep2020). 
FDA EVENITY PI (2019) EVENITY Prescribing Information. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761062s000lbl.pdf. 
Hald JD, Folkestad L, Harsløf T, et al. (2017) Health-Related Quality of Life in Adults with 
Osteogenesis Imperfecta. Calcif Tissue Int 101(5): 473-478. 
Health Canada EVENITY Product Monograph 2019. 
Hidalgo Perea S and Green DW (2021) Osteogenesis imperfecta: treatment and surgical 
management. Curr Opin Pediatr 33(1): 74-78. 
Lindahl K, Åström E, Rubin CJ, et al. (2015) Genetic epidemiology, prevalence, and genotype-
phenotype correlations in the Swedish population with osteogenesis imperfecta. Eur J Hum 
Genet 23(8): 1042-1050. 
Marini JC, Forlino A, Bachinger HP, et al. (2017) Osteogenesis imperfecta. Nat Rev Dis Primers 
3: 17052. 
Marom R, Rabenhorst BM and Morello R (2020) Osteogenesis imperfecta: an update on clinical 
features and therapies. Eur J Endocrinol 183(4): R95-r106. 

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Nijhuis WH, Eastwood DM, Allgrove J, et al. (2019) Current concepts in osteogenesis 
imperfecta: bone structure, biomechanics and medical management. J Child Orthop 13(1): 1-11. 
Olvera D, Stolzenfeld R, Marini JC, et al. (2018) Low Dose of Bisphosphonate Enhances 
Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta 
Mouse Model. Journal of Bone and Mineral Research 33(7): 1272-1282. 
Orwoll ES, Shapiro J, Veith S, et al. (2014) Evaluation of teriparatide treatment in adults with 
osteogenesis imperfecta. J Clin Invest 124(2): 491-498. 
Poole KE, van Bezooijen RL, Loveridge N, et al. (2005) Sclerostin is a delayed secreted product 
of osteocytes that inhibits bone formation. FASEB J 19(13): 1842-1844. 
Rauch F, Munns C, Land C, et al. (2006) Pamidronate in children and adolescents with 
osteogenesis imperfecta: effect of treatment discontinuation. J Clin Endocrinol Metab 91(4): 
1268-1274. 
Rauch F, Travers R, Plotkin H, et al. (2002) The effects of intravenous pamidronate on the bone 
tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest 110(9): 1293-1299. 
Roschger A, Roschger P, Keplingter P, et al. (2014) Effect of sclerostin antibody treatment in a 
mouse model of severe osteogenesis imperfecta. Bone 66: 182-188. 
Saag KG, Petersen J, Brandi ML, et al. (2017) Romosozumab or Alendronate for Fracture 
Prevention in Women with Osteoporosis. N Engl J Med 377(15): 1417-1427. 
Sillence DO, Senn A and Danks DM (1979) Genetic heterogeneity in osteogenesis imperfecta. J 
Med Genet 16(2): 101-116. 
Tournis S and Dede AD (2018) Osteogenesis imperfecta - A clinical update. Metabolism 80: 27-
37. 
van Lierop AH, Appelman-Dijkstra NM and Papapoulos SE (2017) Sclerostin deficiency in 
humans. Bone 96: 51-62. 
Wekre LL, Eriksen EF and Falch JA (2011) Bone mass, bone markers and prevalence of 
fractures in adults with osteogenesis imperfecta. Arch Osteoporos 6(1-2): 31-38. 
World Medical Association (2013) World Medical Association Declaration of Helsinki: ethical 
principles for medical research involving human subjects. JAMA 310(20): 2191-2194. 
  
 
 

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13. 
GENERAL APPENDICES 
APPENDIX 1. SAFETY LABORATORY ASSESSMENTS 
Table 10: 
Specified Laboratory Assessments 
Chemistry 
Hematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Hematocrit 
Appearance 
Alkaline phosphatase 
Hemoglobin 
Color 
Amylase 
Mean corpuscular hemoglobin (MCH) 
pH 
Aspartate aminotransferase (AST) 
MCH concentration (MCHC) 
Specific gravity 
Bicarbonate (Total CO2) 
 
 
Bilirubin (direct and total) 
Mean corpuscular volume (MCV) 
 
Blood urea nitrogen (BUN) 
Platelet count 
Bilirubin 
Calcium 
Red blood cell (RBC) count 
Creatinine 
Chloride 
Reticulocyte count 
Glucose 
Cholesterol (total) 
White blood cell (WBC) count 
Hemoglobin 
Creatine kinase 
WBC differential: 
Ketones 
Creatinine 
Basophil count (absolute and %) 
Nitrite 
Gamma-glutamyl transpeptidase 
(GGT) 
Eosinophil count (absolute and %) 
Protein 
Glucose 
Lymphocyte count (absolute and %) 
Urobilinogen 
Lactate dehydrogenase (LDH) 
Monocyte count (absolute and %) 
 
Lipase 
Neutrophil count (absolute and %) 
Pregnancy test (if applicable) 
Magnesium 
 
 
Phosphorus 
Complete blood count with differential 
(CBC/diff) 
 
Potassium 
 
 
Protein (albumin and total) 
 
*Special assessment 
Sodium 
 
Serum pregnancy test if a 
positive urine pregnancy test 
Triglycerides 
 
 
 

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APPENDIX 2. CONTRACEPTION GUIDANCE 
The guidance below applies for development products with potential or unknown reproductive 
toxicity (for products in clinical trials, where pre-clinical data are indicative of risk or have not 
yet been completed). 
Female subjects of childbearing potential who are heterosexually active must consent to use a 
highly effective method of contraception as listed below to prevent pregnancy over the time 
period required for product levels to decrease to a concentration that is no longer considered 
relevant for human teratogenicity/fetotoxicity. This time period is generally determined by the 
pharmacokinetic properties of the study product and non-clinical reproductive toxicity data and 
is defined in the protocol or product Investigator Brochure.  
Highly effective contraceptive methods are those with a failure rate of less than 1% per year 
when used consistently and correctly.  
Female subjects of childbearing potential are defined as having reached menarche prior to or 
during the study. Females not of childbearing potential include those who have not experienced 
menarche, are postmenopausal (defined as having no menses for at least 12 months without an 
alternative medical cause) or are permanently sterile due to having total hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy.  
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient and multiple measurements are needed.  
Male subjects who are heterosexually active with female partners of childbearing potential must 
consent to use one of the highly effective methods of contraception listed below to prevent 
pregnancy over the period defined in the protocol or product Investigator Brochure. The time 
period required is generally determined by the pharmacokinetic properties of the study product 
and non-clinical reproductive toxicity data, plus 90 days for a full sperm cycle. 
Highly effective methods of contraception (CTFG, 2020) include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (eg, oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(eg, oral, injectable, implantable) 
• Intrauterine device or intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Male sterilization, also called vasectomy  
• Sexual abstinence is defined as refraining from heterosexual intercourse during the entire 
study period associated with risk of the Investigational Product (IP), other study 
treatments or procedures 
The reliability of sexual abstinence should be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the subject.  

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Abstinence is only considered a highly effective method of contraception if practiced 
consistently for the entire period of exposure to IP or other study treatments. 
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea methods are not acceptable methods 
of contraception. 
Note: Barrier methods (such as a condom used with or without a spermicide or a diaphragm or 
cervical cap used with a spermicide) used alone are NOT highly effective contraception methods. 
Additional Requirement: If IP is an advanced therapy medicinal product (eg, gene therapy), a 
condom with spermicide is also required to be used by all sexually active males in the study in 
order to prevent potential transmission of the vector via seminal fluid. 
 

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APPENDIX 3. SAFETY DEFINITIONS AND ASSESSMENTS 
Adverse Event (AE)  
An 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. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. Worsening of a pre-
existing condition is considered an AE. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urine) or other safety 
assessments (eg, vital sign measurements), including those that worsen from Screening/baseline 
that are felt to be clinically significant in the medical and scientific judgment of the Investigator 
are to be recorded as AEs. 
Treatment-emergent AE (TEAE) 
A TEAE is defined as any AE not present prior to the initiation of the drug treatment or any AE 
already present that worsens in either intensity or frequency following exposure to the drug 
treatment. 
Serious Adverse Event (SAE) 
An SAE is an AE that meets any of the following criteria in the view of either the Investigator or 
Ultragenyx:  
• Death 
• Life-threatening 
A life-threatening AE is an event that places the patient or subject at immediate risk of death. It 
does not include events that if it had occurred in a more serious or severe form might have 
caused death. For example, drug induced hepatitis that resolved without evidence of hepatic failure 
would not be considered life threatening even though drug induced hepatitis can be fatal. 
• Inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is defined by Ultragenyx as a full admission to hospital for a period of 24 hours 
or longer for diagnosis and treatment. This includes prolongation of an existing inpatient 
hospitalization. Examples of visits to a hospital facility that do not meet the serious criteria for 
hospitalization include: 
• Emergency room visits (that do not result in a full hospital admission)  
• Preplanned or elective procedures prior to study enrollment (e.g., outpatient 
surgery)  
• Protocol procedures  
Hospitalization signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 

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not have been appropriate in the physician's office or outpatient setting. When in doubt as to 
whether 'hospitalization' occurred or was necessary, the AE should be considered serious.  
AEs requiring hospitalization should be considered SAEs. Hospitalization planned prior to study 
enrollment (eg, for elective surgery or routine clinical procedures) that are not the result of AE 
(e.g., elective surgery for a pre-existing condition that has not worsened) need not be considered 
AEs or SAEs. If anything untoward is reported during the procedure, that occurrence must be 
reported as an AE, either 'serious' or 'nonserious' according to seriousness criteria described 
above. 
• Disability/Incapacity 
An AE is disabling or incapacitating if it results in substantial and/or permanent disruption of 
the subject’s ability to carry out normal life functions. 
• Congenital anomaly/birth defect not present at screening 
• 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 criteria listed in the definition. Examples of 
such events are: 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
Blood dyscrasias that do not result in inpatient hospitalization 
Development of drug dependency or drug abuse  
Adverse Events of Special Interest (AESI) 
An AESI is one of scientific or medical interest specific to the product (or product class) or 
program requiring further investigation and ongoing monitoring to better characterize them. Such 
events can be serious or non-serious and could include events that might be potential precursors 
or prodromes for more serious medical conditions in susceptible individuals.  
Participation-emergent Adverse Events 
These events may be related to study participation or biological specimen collection and will be 
reported by the investigator and noted as such in the case report form (CRF) as related to study 
intervention. 
Overdose  
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. All cases of overdose (with or without associated AEs) will be 
documented in the CRF. Assessment of Severity  
The severity or intensity of an AE refers to the extent to which an AE affects the patient’s daily 
activities. The severity of all AEs will be graded using the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0, published on 27 November 2017.  
If an AE cannot be graded using the CTCAE criteria, it should be graded using the following 
definitions:  

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• Mild (Grade 1): Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Moderate (Grade 2): Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). Note: Instrumental ADL refer 
to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
• Severe (Grade 3): Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
ADL. Note: Self care ADL refer to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications and not bedridden. 
• Life-threatening (Grade 4): Urgent intervention indicated. 
• Death (Grade 5): Death related to AE. 
Note: 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 and is 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. 
Assessment of Causality 
The Investigator will make a causality assessment about the relationship of each AE to study 
drug. Treatment-related conditions must be distinguished from disease-related conditions. 
The Investigator should determine the causality (relation to the study drug) based on his/her 
clinical experience and on the information given in the Investigator’s Brochure. The causal 
relationship of all AEs to the study drug will be judged as either related (which includes 
possibly, probably or definitely related) or not related (which includes unlikely or doubtfully 
related). 
To ensure consistency of AE and SAE causality assessments, Investigators should apply the 
following general guideline:  
• A related causal relationship means that there is at least a reasonable possibility that the 
event is caused by the study drug or the research procedures. There may be a reasonable 
possibility of a causal relationship between study drug/Investigational Product (IP) and 
the AE when the event: 
Follows a reasonable temporal sequence post IP administration 
The event is known to be or could be a response to the IP, based upon pre-clinical or clinical data 
with the product or similar products 
The event could not be explained by the subject's primary disease including 
progression/expression of the disease state, other concurrent or underlying illness, and/or 
prior/concomitant therapies 
Positive dechallenge: the event resolves or improves after discontinuation of IP (when this 
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Positive rechallenge: the event reappears or worsens when dosing with IP is resumed after an 
interruption (when this information is available)  
• Not related means there is unlikely to be a reasonable possibility of a causal relationship 
between the event and study drug/IP or the research procedures, and/or that there is a 
clear causal relationship between other conditions and the AE. There is not likely to be a 
reasonable possibility of a causal relationship between study drug/IP and the AE when:  
The event does not follow a reasonable temporal sequence post IP administration 
There are no data with the IP or similar products, suggesting the event occurs or may occur with 
the IP 
There is a more likely alternative etiology, such as subject’s underlying primary disease 
including disease progression or expression, other concurrent or underlying illness, or 
prior/concomitant therapies 
Negative dechallenge: the event does not improve after discontinuation of IP (when this 
information is available) 
Negative rechallenge: the event does not worsen after interruption of IP when dosing is resumed 
after an interruption (when this information is available) 
Note: The Investigator’s assessment of causality for individual AEs is part of the study 
documentation process and will be recorded in the patient’s medical record, CRF, and SAE form, 
if applicable. AEs recorded without the Investigator’s assessment of the relationship to study 
drug will be followed up until causality is assigned. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) means an SAE that occurs in a 
clinical trial subject, which is assessed by the Investigator or Ultragenyx as being serious and 
unexpected based on Reference Study Information (e.g., Investigators Brochure), and as having a 
reasonable possibility of a causal relationship with the study drug/IP. 
Urgent Safety Measure means any measure taken to protect the subjects of a clinical trial 
against an immediate hazard to their health or safety. 
 

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APPENDIX 4. ADVERSE EVENT COLLECTION, ELICITING, 
RECORDING AND REPORTING 
Collection Period & Reporting Timeframe: Adverse Event & Other Safety Information 
Reporting 
Table 11: 
Collection Period and Reporting Timeframes for Adverse Event and Other 
Safety Information Reporting 
Event Type 
Collection Period  
Reporting Timeframe 
Report to:  
Serious 
Adverse Event 
(SAE) 
Start:  
From the time the subject 
signs the ICF 
End:  
Two months after the final 
administration of study drug  
Report all SAEs within 
24 hours of site 
Investigator, designee or 
site personnel’s 
knowledge of the event. 
Electronic Data Capture (primary) 
 
Ultragenyx  
(back-up if Electronic Data Capture 
is down or not available) 
email: 
ultragenyx@primevigilance.com 
Fax: 1 (415) 930-4033 
Adverse Event 
(AE)  
Start:  
From the time the subject 
signs the ICF 
End:  
Two months after the final 
administration of study drug 
Report all non-serious 
AEs within a target of 3 
business days of site 
Investigator, designee or 
site personnel’s 
knowledge of the event. 
Electronic Data Capture 
Treatment-
emergent 
adverse events 
(TEAEs)  
Start:  
From the time the subject 
signs the ICF 
End:  
Two months after the final 
administration of study drug 
Report all non-serious 
TEAEs within a target of 
3 business days of site 
Investigator, designee or 
site personnel’s 
knowledge of the event. 
Electronic Data Capture 
Pregnancy 
(includes 
Partner 
pregnancy) 
Start:  
From the time the subject 
signs the ICF 
End:  
Two months after the final 
administration of study drug 
Report all pregnancies 
within 24 hours of site 
Investigator, designee or 
site personnel’s 
knowledge of the event 
Electronic Data Capture (primary) 
 
Ultragenyx  
(back-up if Electronic Data Capture 
is down or not available) 
email: 
ultragenyx@primevigilance.com 
Fax: 1 (415) 930-4033 
Adverse 
Events of 
Special 
Interest 
(AESI)  
Start:  
From the time the subject 
signs the ICF 
End:  
Two months after the final 
administration of study drug 
Report all AESI within 
24 hours of site 
Investigator, designee or 
site personnel’s 
knowledge of the event. 
Electronic Data Capture (primary) 
 
Ultragenyx  
(back-up if Electronic Data Capture 
is down or not available) 
email: 
ultragenyx@primevigilance.com 
Fax: 1 (415) 930-4033 

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Table 12: 
Safety Contact Information 
Global Drug Safety & Pharmacovigilance  
Serious Adverse Events, Adverse Events of 
Special Interest, and Pregnancy Reporting 
Medical Monitor 
Email: ultragenyx@primevigilance.com 
Fax: +1 (415) 930-4033 
 
, MD, MS  
 
 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all patient evaluation 
time points should be adopted. Examples of non-directive questions include:  
x “Since the last visit, has the patient experienced any health problems?”  
x “Have there been any new or changed health problems since you were last here?” 
Recording AEs and SAEs 
All AEs (ie, any new condition or worsening in severity or frequency of a preexisting condition) 
experienced by the patient within the protocol defined timeframes must be promptly documented 
on the case report form (CRF) and SAE form if applicable. For clinically significant worsening 
of a preexisting condition from Baseline the changes will be documented as AEs on the CRF. 
Clinical significance is defined as any variation in signs, symptoms, or testing that has medical 
relevance and may result in an alteration in medical care. The Investigator will continue to 
monitor the patient until the assessment returns to Baseline or until the Investigator determines 
that follow-up is no longer medically necessary. 
For IP and for non-IP studies, any AEs or SAEs considered associated with study protocol-
required procedures will also be collected 
The Investigator is responsible for evaluating all AEs, obtaining supporting documents, and 
ensuring documentation of the events is adequate. Details of the AEs must include severity, 
seriousness, relationship to study drug/IP, duration (dates of onset and resolution), and outcome.  
In addition, the Investigator should report any AE or SAE they are made aware of that occurs 
after this time period and that is believed to have a reasonable possibility of being associated 
with study drug.  
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF and SAE form (if applicable) rather than 
individual signs and symptoms. Whenever medically appropriate, the Investigator should group 
signs or symptoms that constitute a single diagnosis into a unifying event term. For example, 
record “liver failure” rather than jaundice, asterixis, and elevated transaminases, or record “upper 
respiratory tract infection” rather than cough, rhinitis, and sneezing. However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE on the CRF and SAE 
form (if applicable). If a diagnosis is subsequently established, it should be reported as follow-up 
information by revising the CRF and SAE form (if applicable). Vague, nonspecific AE terms 
such as “erythema,” “rash,” or “lump on head” should be avoided and more specific information 
PPD
PPD
PPD

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should be provided, such as “erythematous macule on right leg,” “allergic dermatitis,” or “scalp 
cyst.” 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as the AE on the CRF and, if also 
serious, on the SAE form. However, medically significant AEs occurring secondary to an 
initiating event that are separated in time should be recorded as independent events on the CRF. 
For example, if a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
recorded separately on the CRF. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient evaluation 
time points. Such events should only be recorded once in the CRF unless their severity increases. 
If a persistent AE becomes more severe, it should be recorded again on the CRF.  
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded individually on the CRF. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities in the opinion of the Investigator are to be 
recorded as AEs on the CRF and SAE form (if applicable). For example, abnormalities that 
require study drug dose modification, discontinuation of study drug, more frequent follow-up 
assessments, or further diagnostic investigation may be considered clinically significant by the 
Investigator. 
If the clinical significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 × upper limit of normal associated with cholecystitis), only the 
diagnosis (eg, cholecystitis) needs to be recorded on the CRF and the SAE form (if applicable). 
If the laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.”  
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs on the CRF and SAE form (if applicable), unless their 
severity, seriousness, or etiology changes. 
Reporting Serious Adverse Events  
Any AE that meets SAE criteria must be reported to Ultragenyx or its designee within 24 hours 
of the site Investigator, designee or site personnel’s knowledge of the event. Regardless of 
causality, all SAEs must be reported during the time period specified. All SAEs must also be 
recorded in the patient’s source documentation and on the CRF. Copies of discharge summaries, 
consultant reports, and any other relevant documents should be provided with the SAE report 
when available.  
If follow-up is obtained or requested by Ultragenyx and/or the Medical Monitor, the additional 
information should be sent within 24 hours of knowledge.  

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Refer to Safety Contact Information for SAE reporting. 
Reporting of Pregnancy in Subject or Partner 
For protocols requiring pregnancy reporting, any reported pregnancy of a subject or a subject’s 
partner that occurs during participation in the study will be monitored for the full duration of the 
study 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. 
Pregnancy in a subject or subject’s partner, complications of the pregnancy and the outcomes of 
pregnancy should be reported to the Ultragenyx or designee within 24 hours of site Investigator, 
designee or site personnel’s knowledge of the event.  
Pregnancies will be reported by completing and submitting Pregnancy Notification Form to 
Ultragenyx or designee.  
Pregnancy outcomes will be reported by completing and submitting Pregnancy Outcome Form to 
Ultragenyx or designee.  
The following pregnancy outcomes should always be classified as serious and reported to 
Ultragenyx or designee within 24 hours by completing and submitting the SAE and Pregnancy 
Outcome Form: 
• Spontaneous abortion/Miscarriage  
• Therapeutic abortion  
• Ectopic pregnancy  
• Fetal death/Still birth  
• Molar pregnancy  
• Birth defect/Congenital anomaly 
Reporting Suspected Unexpected Serious Adverse Reactions 
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSARs) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), Institutional Review Boards /Independent Ethics Committees 
(IRBs/IECs), and Investigators as per local laws and regulations. Fatal and life-threatening 
SUSARs will be submitted no later than seven calendar days of first knowledge of the event and 
follow-up information submitted within an additional eight days. All other SUSARs will be 
submitted within 15 calendar days of first knowledge of the event.  
The Investigator will notify the IRBs/IECs of SUSAR, in accordance with IRB/IEC requirements 
and local laws and regulations.  
Non-SUSARs will be maintained in the Ultragenyx global safety database and provided in 
annual safety reports and/or other aggregate periodic summary reports to Regulatory Authorities 
and IRBs/IECs per local laws and regulations. 

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Reporting Urgent Safety Measures 
Investigators are required to report any urgent safety measures taken to protect the safety or 
welfare of subject to Ultragenyx or its designee within 24 hours. Ultragenyx or its designee will 
inform the Regulatory Authorities, IRBs/IECs, and other investigators of any events (eg, change 
to the safety profile of Investigational Product (IP), major safety findings) that may occur during 
the clinical study that do not fall within the definition of a SUSAR but may affect the safety of 
subjects participating in the clinical study, as required, in accordance with applicable laws and 
regulations.  
The Investigator will notify the IRBs/IECs of urgent safety measures, in accordance with 
IRB/IEC requirements and local laws and regulations.  

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APPENDIX 5. ETHICS AND CONDUCT 
This protocol is written in accordance with the principles established by the 18th World Medical 
Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human 
Subjects and subsequent amendments and clarifications adopted by the General Assemblies 
(World Medical Association, 2013). 
Ultragenyx and the Investigator will ensure the study described in this protocol is conducted in 
compliance with those principles and International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and 
applicable local law, eg, Food and Drug Administration (FDA) regulations, European Union 
(EU) regulations, and any other local ethical and regulatory requirements (“Applicable Study 
Conduct Obligations”). Should a conflict arise, Ultragenyx and the Investigator will follow 
whichever Applicable Study Conduct Obligations affords the greater protection to the subject(s). 
Institutional Review Board or Independent Ethics Committee and Competent Health 
Authority 
The Institutional Review Boards /Independent Ethics Committees (IRBs/IECs) must be a 
properly constituted board or committee operating in accordance with Applicable Study Conduct 
Obligations and should safeguard the rights, safety, and well-being of all study subjects. Before 
screening any subject, the IRB/IEC, and as applicable Competent Health Authority, must review 
and approve this protocol and if applicable, the associated assents and informed consent forms 
(ICFs), agreed to by the study site (ie, Institution) and by Ultragenyx. Further, IRB/IEC and 
Competent Health Authority approval of any protocol amendments must be received before any 
of the changes outlined in the amendments are put into effect, unless there is a need to protect 
subject safety. In that case and with prior IRB/IEC approval/favorable opinion, the Investigator 
may deviate from the protocol to eliminate an immediate hazard(s) to study subjects and will 
immediately notify the chair of the IRB/IEC and Ultragenyx of the amendment. 
If Investigational product (IP) is provided under the protocol, IP will not be shipped to the study 
site until Ultragenyx or its designee has received a copy of the letter or certificate of 
approval/favorable opinion from the IRB/IEC, all Ultragenyx-required documents, and, where 
required, the Competent Health Authority authorization/approval of the protocol. If IP is not 
provided under the protocol, this paragraph and the section on IP accountability do not apply. 
Before releasing advertisements or solicitations to the public for subject enrollment in the study, 
such advertisements or public solicitations must be submitted to Ultragenyx or its designee for 
review and approval. After receiving Ultragenyx approval for the advertisements or public 
solicitations, the Investigator must submit them to his/her IRB/IEC for review and approval 
before using them. 
Subject Information and Consent 
The contents of the ICF and any assents for minors, as well as the method of obtaining and 
documenting informed consent must comply with Applicable Study Conduct Obligations. 
Ultragenyx or its designee will provide the Investigator written informed consent(s), which 
includes assents for minors. Any revisions to the ICF must be reviewed and approved by 
Ultragenyx before submission to the IRB/IEC for its approval. The study site agrees not to begin 
enrolling subjects until the IRB/IEC approval is complete. 

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Adequate consent for access to, use of, and/or processing of coded personal health information 
and other personally identifiable information will be obtained in accordance with the applicable 
laws, such as U.S. Health Insurance Portability and Accountability Act regulations, state data 
privacy laws, the EU General Data Protection Regulation, or other applicable national or local 
data usage and protection laws. 
In accordance with applicable local laws and with the subject’s express and optional consent, any 
remaining biological samples taken for the purposes of the study, as well as any voluntary 
samples, may be used by Ultragenyx for additional research and development in accordance with 
the subject’s express consent. Any such consent will be optional and not a requirement to study 
participation. 
Before conducting any study procedures, the Investigator must obtain informed consent for or 
from each potential subject. Part of obtaining that informed consent requires the Investigator to 
fully explain to each potential subject the methods, objectives, requirements, and potential risks 
of the study and to answer any inquiries. Further, the Investigator must explain to each potential 
subject that the subject is completely free to refuse to enter the study or to withdraw from the 
study at any time without either decision impacting his/her care. The Investigator or a qualified 
designee must 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. 
Pediatric subjects or adult subjects with cognitive limitations will provide assent (if possible) and 
a legally authorized representative (parent or legal guardian) must provide informed consent for 
such subjects. If, over the course of the study, a pediatric subject becomes old enough for a 
subsequent assent or reaches the legal age of majority, he/she must sign the then-age-appropriate 
assent or consent as the case may be. 
Subjects will be given a copy of the signed ICF and/or assent and will be provided any new 
information during the course of the study that might affect their continued participation in the 
study. If the protocol is amended and the ICF is revised, each subject as applicable will be 
required to provide informed consent again using the revised ICF. The signed ICF or assent will 
remain in each subject's study file and must be available to the study monitor(s) at all times. 
Data Protection, Anonymization and Security 
Any study data transferred to Ultragenyx will be coded and will not contain names or any other 
information that would make the subject identifiable. 
Study information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Ultragenyx.  
The subject must be informed that the Ultragenyx auditors or other authorized personnel 
appointed by Ultragenyx may examine his/her medical records. The same applies for appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.  
Ultragenyx has a Standard Operating Procedure to address data breaches. Ultragenyx also 
requires all vendors supporting the study to comply with applicable data protection laws and to 
agree to data protection terms that include a data breach response plan and an obligation to 
collaborate with Ultragenyx. These measures exist so Ultragenyx can mitigate the breach and 
meet their obligations under applicable data protection laws. 

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Protocol Deviations 
A protocol deviation is any instance of protocol noncompliance, either at study entry or during 
the study conduct. A major protocol deviation is defined by Ultragenyx as a having a significant 
impact on a clinical study data and subject rights, safety, or welfare. All other protocol deviations 
are considered minor protocol deviations. 
Ultragenyx does not issue protocol deviation waivers. The Investigator must inform Ultragenyx 
of all protocol deviations in a timely manner; provided, however, that Ultragenyx be informed of 
all major Protocol deviations immediately of becoming aware of such deviations. 
Future Use of Stored Study Samples 
With the subject’s consent, Ultragenyx will use remaining protocol-driven samples and/or will 
collect optional, non-protocol-required biologic samples to be used for additional future research. 
These samples will be de-identified and may be stored for up to 20 years from the end of the 
study, or shorter as required by local law. 
Investigators and Study Administrative Structure 
Prior to the Investigator beginning performance of the study, Ultragenyx must be in receipt of all 
essential documents, including, among others, a signed Form Food and Drug Administration 
(FDA) 1572 or equivalent signed by the Investigator and an appropriate Financial Disclosure 
Form from each. 
A Coordinating Investigator will be identified for multicenter studies. The Coordinating 
Investigator will be selected on the basis of active participation in the study, thorough knowledge 
of the therapeutic area being studied, and the ability to interpret data. The Coordinating 
Investigator will read and sign the Clinical Study Report. 
Investigational Product Accountability  
The Investigator must be thoroughly familiar with the appropriate administration and potential 
risks of administration of the IP, as described in this protocol and the Investigator Brochure (IB), 
prior to initiation of the study. 
IP delivered to the study site and/or Investigator must be stored in a secure limited access 
location at controlled temperature as described in the Investigator’s Brochure and product 
packaging. Any such location must be available for inspection by the study monitor or auditors 
for inspection at any time during the study. If subjects take IP offsite, they will be given 
instructions on the proper storage of IP when initially dispensed and reminded of storage 
requirements at all subsequent visits. 
An IP accountability record must be maintained for all IP received, dispensed, returned, 
destroyed, and/or lost during the study. This record must be kept current and made available to 
the study monitor or auditors for inspection. At the completion of the study, all unused IP must 
be returned to Ultragenyx and/or its designee, unless other instructions have been provided for 
final disposition of the IP. 

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Data Handling and Record Keeping 
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. 
Data must be recorded on Case Report Forms (CRFs), electronic or otherwise, in accordance 
with the Clinical Trial Agreement executed between Ultragenyx and the study site and/or 
Investigator. Recorded data is subject to Ultragenyx verification. All information recorded on 
CRFs must be consistent with the subject's source documentation. For electronic CRFs, a 
validated Electronic Data Capture system will be used for entry of the data. 
Data entry and data corrections will be made only by Ultragenyx-authorized users, and will be 
captured in an electronic audit trail. 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 Ultragenyx or its 
designee direct access to all source documents. 
Data Quality Assurance 
Monitoring and auditing procedures will be implemented to ensure compliance with Applicable 
Study Conduct Obligations. The Ultragenyx designated representative (i.e., the site monitor) will 
contact the Investigator and conduct regular visits to the study site. The site monitor will also be 
responsible for confirming adherence to the study protocol, inspecting CRFs and source 
documents, and ensuring the integrity of the data. Instances of missing or uninterpretable data 
will be resolved in coordination with the Investigator. 
The site monitor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The site monitor will 
maintain contact through frequent direct communications with the study site by e-mail, 
telephone, facsimile, and/or mail. The Investigator and all other personnel supporting the study 
(ie, Project Personnel) must agree to cooperate fully with the site monitor and will work in good 
faith with the site monitor to resolve all questions raised and all identified issues. 
Record Retention 
For study monitoring, audit, or inspection, the IRB/IEC and Ultragenyx or its designees have the 
right to access all CRFs, source documents, and other study documentation. The Investigator or 
study site will retain such documents from the start of the study to at least 25 years after the close 
of the study, guarantee access to these documents and cooperate with and support such audits 
and inspections. 
Publication Policy 
The Investigator and/or study site must submit any publication or presentation about the study to 
Ultragenyx prior to making it public in accordance with the process in the Clinical Trial 
Agreement executed between Ultragenyx and the study site and/or Investigator. 
Registration of Study and Disclosure of Results 
Ultragenyx will register the study and post results regardless of outcome on a publicly accessible 
website in accordance with the applicable laws and regulations. 

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Budgeting and Insurance 
The budget and insurance for this clinical study will be addressed in the Clinical Trial 
Agreement between Ultragenyx and the study site and/or Investigator executed between 
Ultragenyx and the study site and/or Investigator.