Clinical trial NCT02915705
Conditions: X-Linked Hypophosphatemia
Sponsor: Kyowa Kirin, Inc.
Start date: 2016-09-08; Completion date: 2019-07-15
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the effect of KRN23 (burosumab) therapy in improving rickets in children with XLH compared with active control (oral phosphate/active vitamin D).

Detailed description:

Arms: arm 1: Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period. arm 2: Multiple daily doses of oral phosphate and one or more daily doses of active vitamin D therapy, titrated and individualized by the investigator based on published recommendations during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Interventions: intervention 1: burosumab intervention 2: Oral Phosphate Supplement intervention 3: active vitamin D
Intervention descriptions: intervention 1: solution for subcutaneous (SC) injection intervention 2: oral tablet; oral solution; oral powder intervention 3: tablet, oral solution

Protocol documents:
Prot_000.pdf: 
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Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
Confidential 
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX023-CL301 Amendment 1 (Global) 
03 November 2017 
 
The original version of Protocol UX023-CL301 (dated 04 April 2016) has been modified by 
Amendment 1 (Global) to extend the duration of the study, to clarify procedures, and to 
incorporate changes based on additional information acquired since the beginning of the 
study from the clinical investigators and from Health Authorities. The major changes to the 
protocol are summarized below; additional minor changes have also been made for 
consistency and clarity but are not included in this summary. 
1. Overall Study Design and Plan 
a. Treatment Periods and Treatment Duration: A Treatment Extension Period was 
added to the study for subjects in Europe, the US, Canada, and Australia 
(Section 7.1). All subjects who continue into the Treatment Extension Period 
will receive KRN23 (refer to Summary of Change Item #1b). The total 
treatment duration will vary by region. For subjects at study sites in Japan and 
Korea, the final visit for the study (ie, the end of the Treatment Period) will be 
Week 64 (final dose of KRN23 at Week 62); subjects in these countries will be 
enrolled into a separate clinical trial of KRN23 or will receive KRN23 through 
another mechanism. For subjects in Europe, the US, Canada, and Australia, the 
study consists of the Treatment Period (64 weeks) and the Treatment Extension 
Period (up to 76 weeks) for a total treatment duration of up to 140 weeks. 
For subjects in Europe and Australia, the Treatment Extension Period will end 
in September 2018; subjects will be enrolled into separate clinical trials of 
KRN23 or will receive KRN23 through another mechanism. For subjects in the US 
and Canada, the Treatment Extension Period will end in September 2018 and 
June 2019, respectively, when commercial KRN23 is expected to be available; 
subjects will receive commercial KRN23 or will receive KRN23 through another 
mechanism. The total duration of treatment in this study for subjects in Europe, 
the US, Canada, and Australia will vary based on the subjects’ initial date of 
enrollment but will not exceed 140 weeks. 
Rationale: It is important to prevent treatment interruption in children with XLH 
to maximize their bone health and growth potential. The 76-week Treatment 
Extension Period has been added to provide KRN23 treatment until KRN23 is 
expected to be commercially available in regions of the clinical sites 
participating in the study.  


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b. Treatment in Treatment Extension Period (subjects in Europe, the US, Canada, 
and Australia only). After completion of the 64-week Treatment Period, 
subjects who were randomized to KRN23 will continue treatment with KRN23, 
and subjects randomized to active control will cross over to receive open-label 
KRN23 at the starting dose and regimen administered to subjects in the KRN23 
arm. Subjects in the active control arm will discontinue treatment the day after 
the Week 64 visit to allow washout of oral phosphate and active vitamin D 
treatments before their first dose of KRN23 at Week 66 (Synopsis [Study 
Design and Methodology, Duration of Treatment], Section 7.6 and subsections) 
Rationale: This change implements the extension of treatment as noted in the 
original protocol, “Subjects from either treatment groups who complete the 
active controlled Treatment Period of the study (64 weeks) may be eligible for 
an extension study and receive KRN23 treatment for up to an additional 
96 weeks or until the study drug is commercially available.”  
c. Procedures: Evaluation of PD parameters, rickets, growth, and safety will 
continue in the Treatment Extension period. The description of the timing of the 
planned analyses has been clarified, and additional analyses time points have 
been added for the Treatment Extension Period at Weeks 88, Week 112, and 
end of study (Synopsis [Study Design and Methodology, Duration of 
Treatment], Section 7.6 and subsections). All AEs will be recorded from the 
time the informed consent is signed through 12 weeks following the last dose of 
study drug, unless the subject enrolls in another clinical study of KRN23, is 
treated with commercially available KRN23, or is treated with KRN23 through 
another mechanism, at which point the collection of AEs within this study is no 
longer applicable (however, AEs will continue to be reported either under 
another KRN23 protocol or per post-approval requirements for safety 
monitoring, as applicable).  
Rationale: Describes planned evaluations of the safety and efficacy parameters 
that will continue to be followed while subjects remain on study and receive 
treatment. 
d. End of Study: In Section 7.1 and related sections, the description of the study 
periods has been updated to describe the end of study procedures for different 
regions. For subjects in Japan and Korea, the End of Study (EOS) Visit is 
Week 64 (referred to as “Week 64/EOS I”). Subjects in Europe, the US, 
Canada, and Australia will have an EOS visit that includes efficacy assessments 
(EOS II). (refer to Summary of Change Item #1e). (Synopsis [Study Design and 
Methodology], Section 7.4.4, and Section 7.5.1). 
Rationale: These changes clarify the end of study procedures for different 
regions. 


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e. Safety follow-up: All subjects are expected to continue KRN23 treatment 
post-study in another clinical trial, through commercial use, or through another 
mechanism; post-study safety follow-up calls and safety visits will occur only 
for subjects who are not documented to be continuing on KRN23 at the EOS 
visits. A safety follow-up telephone call will occur at 5 weeks (+5 days) after 
the Week 64/EOS I or EOS II visit, as applicable, to determine if KRN23 
therapy has been started in another clinical trial, as commercial product, or 
through another mechanism; if KRN23 therapy has not been started, 
information on any ongoing or new AEs, SAEs, or concomitant medications 
will be collected. For subjects who do not continue KRN23 therapy, 
an additional safety visit will occur 12 weeks ±1 week after the last dose of 
study drug. Every reasonable effort should be made to have required subjects 
return to the clinic for the final safety visit; however, subjects who are unable to 
return to the clinic for the final safety visit will be given the option of providing 
blood and urine samples as part of a Home Health visit. The end of the study is 
defined as the date of the last protocol-specified procedures (including 
telephone contact) for the last subject in the study (Synopsis [Study Design and 
Methodology], Section 7.4.4, and Section 7.5.1). 
Rationale: These changes clarify the post-study procedures. 
f. Clarified that “at least” (rather than “approximately”) 20 subjects age 1 to 
< 5 years will be included (Synopsis [Study Design and Methodology], 
Section 7.1 and Section 7.3). 
Rationale: Clarifies the intent of the protocol to have at least 20 subjects 
enrolled who are age 1 to < 5 years. 
g. The maximum proportion of female subjects was increased from 60% to 70% 
(Synopsis [Study Design and Methodology], Section 7.1, and Section 7.3). 
Rationale: The proportion of female subjects allowed into the study was 
increased to better reflect the gender distribution of X-linked dominant disease 
and study experience. 
h. Specified that the terms “study drug” and “investigational product” refer to 
KRN23, and “active control” and “active control arm” refer to oral 
phosphate/active vitamin D therapy (Section 4, Definition of Terms). 
Rationale: Clarification of nomenclature. 


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i. Added a substudy to assess pre- and post-prandial serum phosphorus and 
calcium concentrations. Assessments for this substudy will occur at a single 
clinic visit anytime 10 to 14 days after a KRN23 dose; this clinic visit may take 
the place of a Home Health visit. Approximately 20 subjects, age ≥ 3 years, will 
fast overnight for a minimum of 8 hours, and fasting serum will be collected 
prior to a breakfast of a standardized meal. Dietary phosphate will be estimated 
based on the calculated phosphate content and the amount of food consumed. 
Serum samples will be drawn 1 and 2 hours after the completion of the meal. 
(Synopsis [Study Design and Methodology, Exploratory Assessments], 
Table 2.1 - Table 2.3 [footnote #12], Section 7.1, Section 7.5.3.8, new 
Section 7.5.4.3) 
Rationale: KRN23 blocks FGF23 action, leading to a sustained increase in 
serum phosphorus levels due to increased phosphate reabsorption at the distal 
renal tubule (measured as TmP/GFR) and increased intestinal absorption caused 
by increased 1,25(OH)2D. The effect of burosumab on postprandial 
physiological excursions of serum phosphorus has not been studied. The 
substudy was added to evaluate the post-prandial increases in serum phosphorus 
during KRN23 treatment. 
2. Selection of Study Population 
a. Inclusion Criterion #4 was revised to “Serum creatinine below age-adjusted 
upper normal limit” (Synopsis [Diagnosis and Criteria for Inclusion and 
Exclusion], Section 7.3.1). 
Rationale: The criterion was revised to align with the original intent that 
subjects with serum creatinine values higher than the age-adjusted upper limit of 
normal should not be included in the study. Low serum creatinine is not a 
concern and should not be a consideration for eligibility. 
b. Inclusion Criterion #6 was revised to indicate that conventional therapy should 
be discontinued “…7 days prior to the Randomization Visit” rather than 
“…prior to the Screening Visit” (Synopsis [Diagnosis and Criteria for Inclusion 
and Exclusion], Section 7.3.1). 
Rationale: The change in the window will give subjects more time to meet this 
requirement. It is clinically immaterial whether subjects meet the requirement 
prior to the Screening visit or prior to Randomization Visit. 
c. Inclusion Criterion #10 was updated to require sexually active male subjects 
with female partners of childbearing potential to use a condom with spermicide 
or a highly effective method of contraception (rather than 2 methods) for the 
duration of the study plus 12 weeks after stopping the study drug.  


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Rationale: Changes to contraception and pregnancy testing language were made 
to align with the Clinical Trial Facilitation Group (CTFG) recommendations 
related to contraception and pregnancy testing in clinical trials. 
d. Exclusion Criterion #1 was revised to specify that Tanner stage 4 or higher is 
assessed through physical examination in any of the following: genitals, breast, 
or pubic hair (Synopsis [Diagnosis and Criteria for Inclusion and Exclusion], 
Section 7.3.2). 
Rationale: Added to specify physical exam requirements. 
e. Exclusion Criterion #7 was corrected to “Planned orthopedic surgery, including 
osteotomy or implantation or removal of staples, 8-plates, or any other 
hardware, within the first 40 weeks of the study” (Synopsis [Diagnosis and 
Criteria for Inclusion and Exclusion], Section 7.3.2). 
Rationale: The language was corrected to match the language in the Synopsis. 
“Recommended” terminology was removed to provide greater specificity for the 
criteria. Also the timeframe of the surgery prior to Screening was clarified to 
match the Synopsis. 
3. Schedule of Events (Tables 2.1-2.3) 
a. Added Table 2.3, Schedule of Events – Treatment Extension Period 
Weeks 66-140 
Rationale: To define assessments for the 76-week Treatment Extension Period 
b. Additional assessments at clinic visits at Weeks 52, 76, 88, 100, 112, 124, and 
140 have been added to Urine Pregnancy Test for females administered KRN23 
who have reached menarche. 
Rationale: The additional assessments were added for female subjects of 
childbearing potential administered KRN23 (ie, those assigned to KRN23 
initially and those who cross over to KRN23 in the Treatment Extension 
Period). 
c. Clarified that all study visits will be scheduled relative to the Baseline visit, 
with an allowable variance of ±3 days for each visit (with the exception of the 
Screening and Safety Follow-up Visits) to accommodate scheduling; clarified 
that KRN23 dosing should occur no sooner than 8 days after the last dose 
administered, and that the Safety Follow-up Visit visit has an allowable 
variance of ±7 days (Table 2.1 - Table 2.3 [footnote #1], Section 7.4.1, and 
Section 7.5.1).  
Rationale: Provides clarity to facilitate subject scheduling. 


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d. Changed “within 7 days” to “after 7 days” to describe the time frame when 
subjects may return to the site after weaning from oral phosphate/ active 
vitamin D therapy (Section 7.5.1).  
Rationale: For consistency with Section 7.4.5.1 and the intent of the protocol 
4. Study Drug 
a. Specified that subjects may resume KRN23 at half of the last dose received 
(ie, half the dose of either 0.8 or 1.2 mg/kg) following withdrawal from KRN23 
due to increased serum phosphorus levels above the upper limit of normal 
(ULN), with a maximum dose of 40 mg (Synopsis [Study Design and 
Methodology; Investigational Product(s), Dose and Mode of Administration], 
Section 7.1 and Section 7.4.1). The maximum allowable dose of KRN23 was 
defined as 90 mg per administration. Additional language has been added to 
define the term “unscheduled serum phosphorus assessment.”  
Rationale: The language on KRN23 dose, including the maximum dose 
requirements and definition of an unscheduled serum phosphorus assessment, 
provides greater specificity and clarity consistent with the original intent of the 
protocol.  
b. Changed criterion 2 for dose escalation, from “serum phosphorus has increased 
by < 0.5 mg/dL from baseline” to “serum phosphorus has increased by 
≤ 0.5 mg/dL from baseline” (Synopsis [Study Design and Methodology; 
Investigational Product(s), Dose and Mode of Administration], Section 7.1 and 
Section 7.4.1). 
Rationale: Based on investigator input and clinical experience thus far in the 
study, some subjects with low serum phosphorus at Baseline who have met the 
other dose escalation criteria and who have responded to KRN23 (increase in 
serum phosphorus of 0.5 mg/dL) would likely benefit from a higher dose of 
KRN23.  
c. Buttocks are included as a potential injection site for the administration of 
KRN23, and guidance provided to clarify the rotation of injection sites 
(Synopsis [Investigational Product(s), Dose and Mode of Administration], 
Section 7.4.1).  
Rationale: Buttocks were added to the list of potential injection sites to allow 
for flexibility in administration. In addition, the text regarding injection site 
rotation was clarified to provide guidance the rotation of the site with each 
injection. While the Sponsor’s preference is to rotate the site of injection to 
minimize the risk for an injection site reaction, this is not always possible in 
practice in a pediatric population based on subject fat distribution and subject 
preference. The injection location should be rotated at each visit. 


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5. Prohibited Medications 
a. Clarified that active vitamin D, not vitamin D supplementation, is prohibited in 
the KRN23 treatment arm (Section 7.4.5.1). 
Rationale: The original protocol stated that subjects in the KRN23 treatment 
arm were prohibited from receiving oral phosphates and vitamin D for the 
duration of the study. This has been corrected to oral phosphates and active 
vitamin D because vitamin D supplementation is allowed during the study to 
correct for clinically meaningful low nutritional vitamin D laboratory values. 
6. Efficacy Assessments 
a. Provided additional information regarding the collection of historical radiograph 
images and recumbent length/standing height data prior to Screening 
(Section 7.5.1).  
Rationale: Provides greater specificity to the data collection process. 
The radiographs will be used to evaluate rickets severity and to determine how 
much rickets fluctuate over time in patients who were treated with oral 
phosphate/active vitamin D prior to study enrollment. The recumbent 
length/standing height data will be used to evaluate growth over time in patients 
who were treated with oral phosphate/active vitamin D prior to study 
enrollment. 
b. A new section, Change in Lower Extremity Abnormalities, has been added to 
describe how this endpoint will be evaluated (Section 7.5.2.2.2).  
Rationale: To provide details on how changes in lower extremity abnormalities 
will be measured over time.  
c. Provided greater clarity about how growth will be assessed (Section 7.5.2.2.3). 
At each time point, height will be assessed 3 times; an average of the 
3 measurements will be calculated. For subjects < 2 years old, recumbent length 
will be used as the growth measurement. For subjects ≥ 2 years old, standing 
and sitting heights will be collected for growth measurement. (Table 2.1 - 
Table 2.3 [footnote #5], Section 7.5.2.2.3). 
Rationale: To describe how height will be measured. 
d. The method used to calculate the ratio of the maximum renal tubular 
reabsorption rate of phosphate to the glomerular filtration rate (TmP/GFR) was 
updated to Payne, 1998 (Section 7.5.2.2.4).  
Rationale: The protocol was updated to include the appropriate reference. 


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e. Version 2.0 of the PROMIS instrument will be used (rather that Version 1.0) 
(Section 7.5.2.2.5). 
Rationale: To reflect the study use of the updated version of PROMIS 
(Version 2.0). 
f. Clarified the process for a subject ≥ 8 years old at Screening who has difficulty 
completing the PROMIS self-report (Section 7.5.2.2.5). 
Rationale: To allow completion of the PROMIS Parent Proxy while maintaining 
consistent practice in cases where a child 8 to ≤ 12 years old may not be able to 
perform the PROMIS self-report. 
7. PK and ADA Assessments 
a. Specified that subjects randomized to receive active control during the study 
will not have a blood sample drawn for these assessments (Section 7.5.2.2.6 and 
Section 7.5.3.8.2). 
Rationale: PK and ADA assessments are relevant to subjects in the KRN23 
treatment arm and are not necessary for subjects in the active control arm during 
the Treatment Period. 
8. Safety Assessments 
a. Clarified the acceptable method for measuring blood pressure and updated the 
literature reference (Tables 2.1-2.3 [footnote #14] and Section 7.5.3.2). 
Rationale: The National Heart, Lung, and Blood Institute (NHBLI) guidelines 
specifically recommend auscultation as the preferred method for measuring 
blood pressure and have reported that automated devices do not always closely 
match with those obtained by auscultation.  
b. Specified that the genitourinary exam should be non-invasive, age-appropriate, 
and consistent with the investigator’s standard of care, and that the purpose of 
the exam is establish and monitor Tanner staging (Section 7.5.3.5). 
Rationale: To clarify the scope and purpose of the genitourinary exam. 
c. Added the definition of a highly effective contraceptive method 
(Section 7.5.3.9). 
Rationale: Changes to contraception and pregnancy testing language were made 
to align with the CTFG recommendations related to contraception and 
pregnancy testing in clinical trials. 


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d. Clarified “dental events” as “dental caries, tooth extraction, root canal, dental 
abscesses, and gingivitis” (Synopsis [Exploratory Assessments], Table 2.1 - 
Table 2.3 [footnote #19], Section 7.5.4.2). 
Rationale: To specify the events to be evaluated for the assessment of dental 
health. 
e. Clarified serious adverse event (SAE) reporting for the active control arm 
(Section 8.5.5.1) and added Appendix 1, which serves as reference safety 
information (RSI) for the oral phosphate and active vitamin D products used in 
the active control arm of this study. 
Rationale: The study allows use of different oral phosphate and active 
vitamin D products that are approved in several European Union (EU) Member 
States with different Summaries of Product Characteristics (SmPCs). Per CT3 
section 7.2.3.2. (54) and CTFG, the sponsor is required to select the most 
appropriate SmPC, with reference to subject safety, as the RSI. The Sponsor has 
selected the SmPCs in Appendix 1 to serve as RSI for the active control arm of 
the study, based on factors including widespread use, consistency of safety 
information across multiple countries, and marketing authorization holder. 
f. Clarified the visits at which subject weight is determined (Table 2.1 - Table 2.3 
[footnote #15], Section 7.5.3.4). 
Rationale: The instruction is clarified to match the original intent of the protocol 
to use the most recent in clinic weight as the basis for dose calculation. 
g. Section 8.5.5.3, Pregnancy Reporting, was deleted 
Rationale: Text was redundant with text in Section 8.5.4.3, Pregnancy in 
Subject or Partner, and Requirements for Immediate Reporting. 
9. Investigators and Study Administrative Structure 
a. Included a requirement for a Coordinating Investigator (Section 8.2). 
The Coordinating Investigator is Erik Imel, MD (Indiana University School of 
Medicine). 
Rationale: Regulatory guidance in the EU requires designation of a 
Coordinating Investigator for a multicenter clinical trial. 


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2 SYNOPSIS 
TITLE OF STUDY:  
A Randomized, Open-Label, Phase 3 Study to Assess the Efficacy and Safety of KRN23 Versus Oral 
Phosphate and Active Vitamin D Treatment in Pediatric Patients with X-linked Hypophosphatemia 
(XLH) 
PROTOCOL NUMBER: 
UX023-CL301 
STUDY SITES: 
Approximately 30 sites globally 
PHASE OF DEVELOPMENT: 
Phase 3 
RATIONALE FOR THIS STUDY: 
X-linked hypophosphatemia (XLH) is a disorder of renal phosphate wasting, defective bone 
mineralization, and impaired growth plate or endochondral ossification caused by inactivating 
mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the 
X chromosome), and is the most common form of heritable rickets. In the absence of functional 
PHEX, release of fibroblast growth factor 23 (FGF23) by osteocytes is greatly increased, leading to 
impaired conservation of phosphate and consequent hypophosphatemia. FGF23 also suppresses 
1,25-dihydroxyvitamin D (1,25(OH)2D) production, resulting in decreased intestinal absorption of 
calcium and phosphate. Chronic low serum phosphorus levels result in defective bone mineralization 
and the 2 major pathologic consequences of the hypophosphatemia, rickets and osteomalacia. 
Rickets and osteomalacia are both disorders of bone mineralization; however, rickets is a disease of 
the growth plates specifically characterized by deficient mineralization as well as by delayed 
endochondral ossification, leading to reduced growth and skeletal deformities. The goal of therapy in 
children with XLH is to correct or minimize rickets, radiographic abnormalities, and skeletal 
deformities, and to promote maximal growth potential while preventing the lifelong bone- and 
joint-related complications of rickets. Published retrospective data suggest that earlier treatment leads 
to better outcomes for children with XLH (Makitie et al. 2003), (Quinlan et al. 2012). 
Although there are no approved treatments specific for XLH, the most common therapy for children 
with XLH consists of multiple daily doses of oral phosphate combined with doses of active vitamin D 
analogs, the most common being calcitriol and alfacalcidol. Dosing is individualized and depends on 
tolerability of the phosphate dose and the age, size, and growth of the child. The goal of therapy with 
phosphate and active vitamin D is to sufficiently supplement the body’s pool of phosphate to allow 
mineralization of bone and improve skeletal outcomes; however, because supplementation therapy 
does not address the mechanism of urinary phosphate wasting, increasing phosphate through 
supplementation also increases renal phosphate throughput and urinary phosphate concentrations, thus 
raising the risk of nephrocalcinosis. More therapeutic options that are efficacious, safe, and 
convenient, and that target the underlying pathophysiology of XLH (ie, renal phosphate wasting 
induced by high FGF23 levels), are needed.  


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KRN23 is a recombinant human IgG1 monoclonal antibody that binds to and inhibits the activity of 
FGF23. Phase 1 and Phase 2 studies in adults and children (aged 5-12 years) with XLH have shown 
that KRN23 increases serum phosphorus and 1,25(OH)2D levels and the ratio of renal tubular 
maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR). Initial 40-week 
Phase 2 data (UX023-CL201) in children with XLH (aged 5-12 years) suggest that KRN23 treatment 
also improves rickets severity with a favorable safety profile. The 40-week interim analysis 
demonstrated that KRN23 significantly improved rickets across the 2 dosing groups, with subjects in 
the every 2 weeks (Q2W) dosing group having better outcomes that may reflect the more steady levels 
of serum phosphorus, 1,25(OH)2D, and other PD parameters observed with Q2W dosing than with 
every 4 weeks (Q4W) dosing of KRN23. 
Data from the ongoing pediatric Phase 2 study helped establish the dose regimen and provided 
information for the design of this Phase 3 clinical trial in children with XLH. Interim data from the 
pediatric Phase 2 study suggested KRN23, administered Q2W at approximately 0.8 mg/kg for 
40 weeks, increased serum phosphorus by an average of 0.7 mg/dL; increases of > 0.5 mg/dL were 
seen in 83.3% of subjects. Serum 1,25(OH)2D concentrations and TmP/GFR levels also increased, 
demonstrating overall improved phosphorus homeostasis. The increases in serum phosphorus and 
1,25(OH)2D were sufficient to provide substantial healing of rickets. No subjects have experienced 
serum phosphorus levels above the upper limit of normal. The Q2W dosing regimen was chosen for 
this Phase 3 study because it appeared to produce a more stable and consistent increase in serum 
phosphorus levels with less fluctuation over time than the Q4W dosing regimen, and a safety profile 
that was not substantially different from the Q4W dosing regimen.  
The objectives of this study are to evaluate the effects of KRN23 on improving rickets, maximizing 
growth, and restoring phosphorus homeostasis compared with active control (oral phosphate/active 
vitamin D therapy), as well as to evaluate the safety of KRN23, in children with XLH (aged 1 to 
≤ 12 years) with confirmed evidence of rickets. In addition, this study will evaluate whether every 
2 week dosing of KRN23 improves functional outcomes and quality of life in children with XLH. 
OBJECTIVES:  
Primary Objectives: 
 
Evaluate the effect of KRN23 therapy in improving rickets in children with XLH compared with 
active control (oral phosphate/active vitamin D)  
Secondary Efficacy Objectives: 
Evaluate the effects of KRN23 as compared with active control on: 
 
Growth velocity and lower extremity deformity  
 
Pharmacodynamic markers that reflect the status of phosphorus homeostasis, including serum 
1,25(OH)2D, serum and urinary phosphorus, ratio of renal tubular maximum reabsorption rate of 
phosphate to glomerular filtration rate (TmP/GFR), and tubular reabsorption of phosphate (TRP) 
 
Biochemical markers of bone turnover that reflect rickets severity (alkaline phosphatase [ALP]) 
 
Walking ability and patient-/parent-reported pain, fatigue, and physical function/mobility  


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Pharmacokinetic Objective: 
Assess the PK of KRN23 throughout the dosing cycle 
Safety Objective: 
Evaluate the safety and tolerability profile of KRN23 in the treatment of children with XLH (aged 1 to 
≤ 12 years), including adverse events (AEs) (eg, nephrocalcinosis), as compared with active control, 
and immunogenicity profile 
Treatment Extension Period Objective: 
To evaluate the long-term safety and efficacy of KRN23 
STUDY DESIGN AND METHODOLOGY:  
UX023-CL301 is a multicenter, randomized, open-label, Phase 3 study comparing the efficacy and 
safety of KRN23 with active control (oral phosphate/active vitamin D therapy) in children with 
clinical evidence consistent with XLH (aged 1 to ≤ 12 years), including demonstrated 
hypophosphatemia, radiographic evidence of rickets (≥ 2.0 points RSS total score), and PHEX 
mutation or variants of uncertain significance. Patients will also be required to have open epiphyses 
and have received oral phosphate/active vitamin D therapy for ≥ 12 consecutive months (for children 
≥ 3 years of age) or ≥ 6 consecutive months (for children < 3 years of age) 7 days prior to the 
Randomization Visit. Approximately 60 subjects will be randomized 1:1 to receive open-label KRN23 
administered by subcutaneous injection or oral phosphate and active vitamin D therapy for a total of 
64 weeks in the Treatment Period. Randomization will be stratified by baseline rickets severity (RSS 
total score ≤ 2.5 vs > 2.5) and age (< 5 vs ≥ 5 years). At least 20 subjects aged 1 to < 5 years will be 
included (approximately 10 in each treatment arm), and no more than 10 subjects between the ages of 
1 to < 3 years will be enrolled. The age range of eligible subjects will be monitored for enrollment for 
age distribution. No more than 70% female subjects will be enrolled. All subjects will washout of oral 
phosphate and active vitamin D therapy for 7 days prior to randomization.  
Treatment Period (Weeks 0 – 64) – All Subjects 
Subjects randomized to KRN23 will remain off of oral phosphate/active vitamin D therapy throughout 
the duration of the study. Subjects assigned to the KRN23 treatment group will receive KRN23 at a 
starting dose of 0.8 mg/kg Q2W. The dose may be increased to 1.2 mg/kg at any time during the study 
if a subject meets the following dose-adjustment criteria: 1) 2 consecutive serum phosphorus 
measurements are below the normal range; 2) serum phosphorus has increased by ≤ 0.5 mg/dL from 
baseline; and 3) the subject has not missed a dose of KRN23 that would account for the decrease in 
serum phosphorus. The maximum allowable dose of KRN23 per administration is 90 mg. At any time 
during the study, if serum phosphorus increases above the upper limit of normal (ULN) for age, the 
subsequent dose(s) will be withheld and the site will contact the medical monitor before dosing 
resumes. Once other causes of increased serum phosphorus are excluded, KRN23 treatment will 
resume at half the total dose of the last dose received (ie, half of either 0.8 mg/kg or 1.2 mg/kg; 
maximum dose per administration: 40 mg). Serum phosphorus will be followed through unscheduled 
serum phosphorus assessments (approximately 2 weeks post-dose and assessed by the central 
laboratory; the assessments may be repeated as necessary). A subject will resume dosing at the 
previous full total dose level if they meet the same dose-adjustment criteria listed above. 


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Subjects assigned to active control will typically receive multiple daily doses of oral phosphate and 
active vitamin D. Because of the variability in the doses and dosing frequencies of oral phosphates and 
active vitamin D therapies in clinical practice, these treatments will be individualized for each subject 
at the investigator’s discretion; general guidance is provided based on expert recommendations in the 
US and Europe. Detailed information about the brand, starting dosages, and any changes in oral 
phosphate and active vitamin D therapy will be determined by the treating Investigator within the 
guidelines (provided in Section 7.1 and summarized below) and recorded at every site visit. US 
guidelines generally recommend a calcitriol dosage of 20 to 30 ng/kg/day in 2 to 3 divided doses 
and an elemental phosphorus dose of 20 to 40 mg/kg/day (in 3 to 5 divided doses), acknowledging 
that some children require more, whereas some do well with less (Carpenter et al. 2011). 
European guidelines recommend an alfacalcidol dosage of 1 to 2 µg/day (once daily) and a phosphate 
supplemental dose of 45 to 70 mg/kg/day (in 3 to 4 divided doses) (Linglart et al. 2014). Calcitriol and 
alfacalcidol dosages should be adjusted based on the clinical and laboratory values that guide best 
possible treatment. 
For subjects in Japan and Korea, the Week 64 visit at the end of the Treatment Period will be the End 
of Study (EOS) Visit (“Week 64/EOS I”); subjects in these countries will be enrolled into a separate 
clinical trial of KRN23 or will receive KRN23 through another mechanism. Post-study safety 
follow-up calls and safety visits will occur only for subjects who are not documented to be continuing 
on KRN23 at the Week 64/EOS I Visit. A safety follow-up telephone call will occur at 5 weeks 
(+5 days) after the Week 64/EOS I Visit to determine if KRN23 therapy has been started in another 
clinical trial or through another mechanism; if KRN23 therapy has not been started, information on 
any ongoing or new AEs, SAEs, or concomitant medications will be collected. For subjects who do 
not continue KRN23 therapy, an additional safety visit will occur 12 weeks ±1 week after the last dose 
of study drug. Every reasonable effort should be made to have required subjects return to the clinic for 
the final safety visit; however, subjects who are unable to return to the clinic for the final safety visit 
will be given the option of providing blood and urine samples as part of a Home Health visit. 
Treatment Extension Period (Weeks 66 – 140) – Subjects in Europe, the US, Canada, and 
Australia 
After completion of the 64-week Treatment Period, subjects in Europe, the US, Canada, and Australia 
who were randomized to KRN23 will continue treatment with KRN23 at their previous dose and 
regimen in the Treatment Extension Period. Subjects in Europe, the US, Canada, and Australia who 
were randomized to active control will cross over to receive KRN23 at the starting dose and regimen 
administered to subjects in the KRN23 arm (starting dose of 0.8 mg/kg Q2W; dose may be increased 
to 1.2 mg/kg Q2W).  
Before their first dose of KRN23 at Week 66, subjects who were in the active control arm in the 
Treatment Period will discontinue treatment the day after the Week 64/EOS I visit to allow washout of 
oral phosphate and active vitamin D treatments. These subjects must have serum phosphorus 
< 3.2 mg/dL (< 1.03 mmol/L) (ie, below the lower limit of normal) to continue on study and receive 
KRN23 in the Treatment Extension Period. If hypophosphatemia is not observed, the subject should be 
retested for serum phosphorus within a week to ensure that the test result was not due to a technical 
issue. If hypophosphatemia is still not observed after test and retest, the subject will be discontinued 


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from the study. The assessment of serum phosphorus to document hypophosphatemia before 
administration of the first dose of KRN23 in subjects originally assigned to active control will be done 
at the local laboratory so that KRN23 can be administered the same day. A sample will also be drawn 
for a serum phosphorus assessment at the central laboratory. For subjects crossing over to KRN23 
treatment, the Weeks 66 and 68 visits will be in-clinic visits. 
For subjects in Europe and Australia, the Treatment Extension Period will end in September 2018, and 
subjects will be enrolled into separate clinical trials of KRN23 or will receive KRN23 through another 
mechanism. For subjects in the US and Canada, the Treatment Extension Period will end in 
September 2018 and June 2019, respectively, when commercial KRN23 is expected to be available; 
subjects will receive commercial KRN23 or will receive KRN23 through another mechanism. Subjects 
leaving the study will have an EOS visit that includes efficacy assessments (EOS II). Post-study safety 
follow-up calls and safety visits will occur only for subjects who are not documented to be continuing 
on KRN23 at the EOS II Visit. A safety follow-up telephone call will occur at 5 weeks (+5 days) after 
the EOS II Visit to determine if KRN23 therapy has been started in another clinical trial, as 
commercial product, or through another mechanism; if KRN23 therapy has not been started, 
information on any ongoing or new AEs, SAEs, or concomitant medications will be collected. For 
subjects who do not continue KRN23 therapy, an additional safety visit will occur 12 weeks ±1 week 
after the last dose of study drug. Every reasonable effort should be made to have required subjects 
return to the clinic for the final safety visit; however, subjects who are unable to return to the clinic for 
the final safety visit will be given the option of providing blood and urine samples as part of a Home 
Health visit.  
The study will be conducted in a pediatric population. Where possible, measures to minimize pain and 
distress to the subject have been considered for this study protocol including the use of home health 
visits (KRN23 group only). At every home health visit for subjects in the KRN23 treatment arm, all 
subjects randomized to the active control arm will receive a phone call to assess adverse events and 
concomitant medications. Home Health visits are not applicable to subjects in Japan or Korea. 
Where possible, timing of assessments has been coordinated with standard safety laboratory tests to 
minimize risk and discomfort and avoid unnecessary duplication of testing. The primary analysis will 
be at Week 40; analyses at Week 64/EOS I and Week 140/EOS II will assess the durability of 
treatment effect, additional efficacy outcomes, and long term safety. The end of the study is defined as 
the date of the last protocol-specified procedures (including telephone contact) for the last subject in 
the study.  
Figure 2.1 provides a schematic of the overall study design.  


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4) Serum creatinine below the age-adjusted upper limit of normal *  
5) Serum 25(OH)D above the lower limit of normal (≥16 ng/mL) at the Screening Visit** 
6) Have received both oral phosphate and active vitamin D therapy for ≥ 12 consecutive 
months (for children ≥3 years of age) or ≥ 6 consecutive months (for children <3 years of 
age) 7 days prior to the Randomization Visit 
7) Willing to provide access to prior medical records for the collection of historical growth and 
radiographic data and disease history.  
8) Provide written or verbal assent (as appropriate for the subject and region) and written 
informed consent by a legally authorized representative after the nature of the study has 
been explained, and prior to any research-related procedures. 
9) Must, in the opinion of the investigator, be willing and able to complete all aspects of the 
study, adhere to the study visit schedule and comply with the assessments. 
10) Females who have reached menarche must have a negative pregnancy test at Screening and 
undergo additional pregnancy testing during the study. Female subjects of childbearing 
potential must be willing to use a highly effective method of contraception for the duration 
of the study plus 12 weeks after stopping the study drug. Sexually active male subjects with 
female partners of childbearing potential must consent to use a condom with spermicide or a 
highly effective method of contraception for the duration of the study plus 12 weeks after 
stopping the study drug. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1) Tanner stage 4 or higher in any of the following: genitals, breast, or pubic hair, based on 
physical examination 
2) Height percentile > 50th based on country-specific norms 
3) Use of aluminum hydroxide antacids (eg, Maalox® and Mylanta®), systemic corticosteroids, 
acetazolamide, and thiazides within 7 days prior to the Screening Visit 
4) Current or prior use of leuprorelin (eg, Lupron®, Viadur®, Eligard®), triptorelin 
(TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty 
5) Use of growth hormone therapy within 12 months before the Screening Visit 
6) Presence of nephrocalcinosis on renal ultrasound grade 4 based on the following scale: 
0 = Normal 
1 = Faint hyperechogenic rim around the medullary pyramids 
2 = More intense echogenic rim with echoes faintly filling the entire pyramid 
3 = Uniformly intense echoes throughout the pyramid 
4 = Stone formation: solitary focus of echoes at the tip of the pyramid 
7) Planned orthopedic surgery, including osteotomy or implantation or removal of staples, 
8-plates, or any other hardware, within the first 40 weeks of the study 
8) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted 
normal limits* 


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9) Evidence of hyperparathyroidism (parathyroid hormone [PTH] levels 2.5X upper limit of 
normal [ULN])  
10) Use of medication to suppress PTH (eg, cinacalcet, calcimimetics) within 2 months prior to 
the Screening Visit 
11) Presence or history of any condition that, in the view of the Investigator, places the subject 
at high risk of poor treatment compliance or of not completing the study. 
12) Presence of a concurrent disease or condition that would interfere with study participation or 
affect safety  
13) History of recurrent infection or predisposition to infection, or of known immunodeficiency 
14) Use of a therapeutic monoclonal antibody within 90 days prior to the Screening Visit or 
history of allergic or anaphylactic reactions to any monoclonal antibody 
15) Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the 
investigator, places the subject at increased risk for adverse effects 
16) Use of any investigational product or investigational medical device within 30 days prior to 
screening, or requirement for any investigational agent prior to completion of all scheduled 
study assessments 
OR, in Japan, use of any investigational product or investigational medical device within 
4 months prior to screening, or requirement for any investigational agent prior to completion 
of all scheduled study assessments. 
* Criteria to be determined based on overnight fasting (min. 4 hours) values collected at the 
Screening and/or Baseline Visit. 
** If 25(OH)D levels are below the normal range, 25(OH)D supplementation will be prescribed. 
Assuming a subject meets all other eligibility requirements, the subject may be rescreened 
after a minimum of 7 days of treatment. 
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION:  
KRN23 is a sterile, clear, colorless, and preservative-free solution in single-use 5-mL vials 
containing 1 mL of KRN23 at a concentration of 10 mg/mL or 30 mg/mL. The starting dose will be 
0.8 mg/kg Q2W. The dose may be increased to 1.2 mg/kg at any time during the study if a subject 
meets the following dose-adjustment criteria: 1) 2 consecutive serum phosphorus measurements are 
below the normal range; 2) serum phosphorus has increased by ≤ 0.5 mg/dL from baseline; and 3) the 
subject has not missed a dose of study drug that would account for the decrease in serum phosphorus. 
The maximum allowable dose of KRN23 per administration is 90 mg. At any time during the study, if 
serum phosphorus increases above the upper limit of normal (ULN) for age, the subsequent dose(s) 
will be withheld and the site will contact the medical monitor before dosing resumes. Once other 
causes of increased serum phosphorus are excluded, KRN23 treatment will resume at half the total 
dose of the last dose received (ie, half of either 0.8 mg/kg or 1.2 mg/kg; maximum dose per 
administration: 40 mg). Serum phosphorus will be followed through unscheduled serum phosphorus 
assessments (approximately 2 weeks post-dose and assessed by the central laboratory; the assessments 
may be repeated as necessary). A subject will resume dosing at the previous full total dose level if they 
meet the same dose-adjustment criteria listed above. KRN23 will be administered via subcutaneous 


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(SC) injection to the abdomen, upper arms, thighs, or buttocks; the injection site should be rotated with 
each injection. 
ACTIVE CONTROL, DOSE, AND MODE OF ADMINISTRATION:  
The first 64 weeks of the study is designed as an open-label comparison with active control (oral 
phosphate and active vitamin D therapy). Active control will be administered on an individualized 
basis at the discretion of the investigator. However, general guidance will be provided based on expert 
recommendations in the US and Europe (see Section 7.1 for more information). The brand, starting 
dosages, and any changes in oral phosphate and active vitamin D therapy will be determined and 
recorded at every site visit. US expert guidelines generally recommend a calcitriol dosage of 20 to 
30 ng/kg/day in 2 to 3 divided doses and an elemental phosphorus dose of 20 to 40 mg/kg/day (in 3 to 
5 divided doses), acknowledging that some children require more, whereas some do well with less 
(Carpenter et al. 2011). European expert guidelines recommend an alfacalcidol dosage of 1 to 2 µg/day 
(once daily) and a phosphate supplemental dose of 45 to 70 mg/kg/day (in 3 to 4 divided doses) 
(Linglart et al. 2014). Calcitriol and alfacalcidol dosages should be adjusted based on the clinical and 
laboratory values that guide best possible treatment. 
DURATION OF TREATMENT:  
Treatment duration will vary by region. The study consists of a Treatment Period (64 weeks) for all 
subjects and a Treatment Extension Period (up to 76 weeks) for subjects in Europe, the US, Canada, 
and Australia. For subjects in Japan and Korea, the planned duration of treatment in this study is 
64 weeks, and the Week 64 visit at the end of the Treatment Period will be the EOS I visit. For 
subjects in Europe, the US, Canada, and Australia, the planned duration of treatment is up to 
140 weeks (64 weeks in the Treatment Period and up to 76 weeks in the Treatment Extension period). 
In Europe, the US, and Australia, treatment in the Treatment Extension Period will end by September 
2018; in Canada, treatment in the Treatment Extension Period will end by June 2019. The duration of 
Treatment Extension Period will vary for individual subjects and will be determined by the time from 
Week 64/EOS I through the EOS II visit. The maximum duration of treatment is 140 weeks. 
CRITERIA FOR EVALUATION: 
Primary Efficacy Endpoint: 
The primary endpoint will be compared between the KRN23 and active control groups: 
 
Change in rickets at Week 40 as assessed by the RGI-C global score 
Secondary Efficacy Endpoints: 
The following secondary endpoints will be compared between the KRN23 and active control groups:  
 
Proportion of subjects with a mean RGI-C global score ≥ +2.0 (substantial healing) at Week 40 
and Week 64 
 
Change in rickets at Week 64 as assessed by the RGI-C global score 
 
Change from baseline in RSS total score at Weeks 40 and 64 


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 
Change in lower extremity skeletal abnormalities, including genu varum and genu valgus, as 
assessed by the RGI-C long leg score at Weeks 40 and 64 
 
Change in standing height (or recumbent length in children < 2 years) from baseline to Weeks 24, 
40, and 64 in cm 
 
Change in height-for-age z-scores from baseline to Weeks 24, 40, 64 
 
Change in growth velocity from pre-treatment and post-treatment at Weeks 40 and 64 in cm/yr 
 
Pharmacodynamic* assessments including  
o Change from baseline over time in serum phosphorus  
o Change from baseline over time in serum 1,25(OH)2D, urinary phosphorus, ratio of renal 
tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), 
and tubular reabsorption of phosphate (TRP) 
o Change and percent change from baseline over time in biochemical markers of bone 
turnover that reflects rickets severity (alkaline phosphatase [ALP])  
* Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior 
to drug administration (if applicable) per dosing regimen 
 
Pain, fatigue and physical function: Change from baseline in the PROMIS (Patient-Reported 
Outcomes Measurement Information System) Pediatric Pain Interference, Physical Function 
Mobility and Fatigue domain scores (for subjects ≥ 5 years of age at the Screening Visit) at 
Weeks 24, 40 and 64 
 
Pain intensity: Change from baseline in the Faces Pain Scale- Revised (FPS-R) (for subjects 
≥ 5 years of age at the Screening Visit) at Weeks 24, 40 and 64 
 
Walking ability: Change from baseline in the Six Minute Walk Test (6MWT) total distance and 
percent of predicted normal (for subjects ≥ 5 years of age at the Screening Visit) at Weeks 24, 40, 
and 64 
Pharmacokinetic: 
 
Serum KRN23 concentration 
Safety Assessments: 
Safety will be evaluated and compared with active control by the incidence, frequency, and severity of 
AEs and serious adverse events (SAEs), including clinically significant changes from baseline to 
scheduled time points for the following variables:  
 
Vital signs and weight 
 
Physical examinations 
 
eGFR (calculated using the Bedside Schwartz equation) 
 
Renal ultrasound to evaluate nephrocalcinosis  
 
Echocardiogram (ECHO) (for subjects ≥ 5 years of age) 


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 
Chemistry, hematology, and urinalysis, including additional KRN23/XLH biochemical parameters 
of interest (serum 25(OH)D; lipase; amylase; creatinine; serum calcium and iPTH, and urinary 
calcium and creatinine) 
 
Anti-KRN23 antibody testing and dose-limiting toxicities 
 
Concomitant medications 
 
ECG 
Exploratory Assessments: 
 
Health-related quality of life: Change from baseline in the SF-10 for Children Health Survey 
(SF-10; for subjects ≥ 5 years of age at the Screening Visit) at Weeks 24, 40, and 64 
 
Dental evaluation to assess the number of dental events such as dental caries, tooth extraction, root 
canal, dental abscesses, and gingivitis 
 
Pre- and post-prandial serum phosphorus and calcium concentrations at a single visit 
Long-term Assessments in Treatment Extension Period: 
 
At Weeks 88, 112, and 140, efficacy, safety, pharmacokinetic, and exploratory assessments will be 
conducted as noted in the Schedule of Events. 
Data Monitoring Committee  
An independent DMC that includes members with expertise in metabolic bone disease, cardiology, 
and nephrology, and the conduct of clinical trials in children will act in an advisory capacity to 
monitor subject safety on a routine basis throughout the trial. The DMC will meet at least twice a year 
during the active-controlled period. The roles and responsibilities of the DMC will be defined in the 
DMC Charter. 
STATISTICAL METHODS:  
A full description of the statistical evaluations will be provided in the Statistical Analysis Plan. 
Sample Size: 
This Phase 3 study is powered to test the effect of KRN23 on improvement of rickets using RGI-C 
global score at Week 40 against the active control group based on the assumption of a mean RGI-C 
global score of 1.80 in the KRN23 group, 1.40 in the active control group, and a common standard 
deviation of 0.50. Given these assumption, a total sample size of 60 (30 per group) will provide 
approximately 80% power to detect such a difference in the mean RGI-C global score at Week 40 
between treatment groups using a 2-sample t-test with a 2-sided alpha level of 0.05. A 10% drop-out 
rate is incorporated in the sample size calculation. 
Efficacy Analysis: 
The Full Analysis Set will include all randomized subjects who received at least 1 dose of assigned 
medication, and the Full Analysis Set will be used for both efficacy and safety analyses. For efficacy 
analyses, subjects will be analyzed by the randomized treatment group. The primary efficacy endpoint 
will be tested to compare the mean RGI-C global score between the KRN23 and active control groups. 


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At the Week 40 Analysis (the primary efficacy analysis time point), the primary hypothesis of the 
primary endpoint is to test whether there is a difference between the KRN23 and active control groups 
in the mean RGI-C global scores at Week 40. An Analysis of Covariance (ANCOVA) model with 
treatment group adjusting for baseline rickets severity and age will be used to test this hypothesis at a 
2-sided alpha level of 0.05. The proportion of RGI-C responders will be summarized for each 
treatment group. 
At the Week 64 Analysis (secondary analysis), RGI-C global score over time will be analyzed using 
the repeat measurement model that includes treatment group, visit, treatment group by visit interaction, 
and adjusted for baseline rickets severity and age.  
The change from baseline in RSS total score over time will be analyzed using the same method as that 
of the RGI-C global score. 
Analyses of other efficacy and PD measures will be performed at Week 40, Week 64, and Week 140. 
Endpoints will be summarized descriptively by each treatment group. Treatment comparison will be 
performed using the repeat measurement model including treatment group, visit, treatment group by 
visit interaction, adjusting for baseline age, rickets severity. Other baseline covariates may be 
considered for adjustment.  
Safety Analysis: 
Full Analysis Set will be used for the safety analysis. Subjects will be analyzed based on the actual 
treatment received. Safety variables including AEs, SAEs safety laboratory assessments, vital signs, 
renal ultrasound, ECG, ECHO, and anti-KRN23 antibody will be summarized descriptively by 
treatment group. 
 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 23 
Table 2.1: 
Schedule of Events – Treatment Period Weeks 1-30 
 
Screening/ 
Baseline1 
Treatment Period 
VISIT ID 
SV 
BL 
V1 
V2 
H
H 
V3 
V4 
HH 
V5 
V6 
HH 
V7 
HH 
V8 
HH 
V9 
V10 
HH 
V11 
HH 
V12 
HH 
V13 
V14 
HH 
V15 
HH  
V16 
HH 
V17 
TIME (WEEK/DAY) 
W-8 
to BL 
W0 
W1 
W2 
W4 
W6 
W8 
W1
0 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
W28 
W30 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parents’ Heights 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tanner Staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHEX mutation analysis2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KRN23 Administration3 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Active Control3,4 
 
Administered at the discretion of the treating Investigator 
EFFICACY MEASURES 
Growth (standing height [or 
length], sitting height)5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Growth velocity 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilateral AP knee x-rays 6, 7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilateral PA hand/wrist 
x-rays6,7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standing long leg x-ray7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6MWT8 (aged ≥ 5 years at 
Screening Visit) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 24 
 
Screening/ 
Baseline1 
Treatment Period 
VISIT ID 
SV 
BL 
V1 
V2 
H
H 
V3 
V4 
HH 
V5 
V6 
HH 
V7 
HH 
V8 
HH 
V9 
V10 
HH 
V11 
HH 
V12 
HH 
V13 
V14 
HH 
V15 
HH  
V16 
HH 
V17 
TIME (WEEK/DAY) 
W-8 
to BL 
W0 
W1 
W2 
W4 
W6 
W8 
W1
0 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
W28 
W30 
PROMIS Pediatric Pain 
Interference, Fatigue and 
Physical Function Mobility 
(aged ≥ 5 years at Screening 
Visit)9 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Faces Pain Scale – Revised 
(aged > 5 years at Screening 
Visit) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
SF-10 (aged ≥ 5 years at 
Screening Visit)10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
PD MEASURES 
Serum Phosphorus11, 12 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Serum 1,25(OH)2D11  
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
ALP 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
PHARMACOKINETICS 
Serum KRN23 concentration 
13 
 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
SAFETY MEASURES 
Vital Signs 14 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Weight 15 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Concomitant Medication 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 25 
 
Screening/ 
Baseline1 
Treatment Period 
VISIT ID 
SV 
BL 
V1 
V2 
H
H 
V3 
V4 
HH 
V5 
V6 
HH 
V7 
HH 
V8 
HH 
V9 
V10 
HH 
V11 
HH 
V12 
HH 
V13 
V14 
HH 
V15 
HH  
V16 
HH 
V17 
TIME (WEEK/DAY) 
W-8 
to BL 
W0 
W1 
W2 
W4 
W6 
W8 
W1
0 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
W28 
W30 
Adverse Events 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ECHO (aged ≥ 5 years) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry16, Hematology, 
Urinalysis11 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Serum 25(OH)D 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum Calcium11, 12 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Serum Creatinine11 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Serum iPTH 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Serum iFGF23 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
2-hr Urine11,18 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
24-hr Urine11,18 (aged 
≥ 5 years) 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Dental assessment 19 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Immunogenicity (ADA) 13 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Urine Pregnancy Test 20 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
See footnotes after Table 2.3 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 26 
Table 2.2: 
Schedule of Events – Treatment Period Weeks 32-64 and Safety Follow-up 
 
Treatment Period 
Safety 
Follow 
Up TC 
21 
Safety 
Follow 
Up Visit 
22 
VISIT ID 
V18 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH  
V24 
HH 
V25 
HH  
V26 
HH 
V27 
HH  
V28 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
HH  
V33 
HH  
V34 
V35 
 
 
TIME 
(WEEK/DAY) 
W32 W33 W34 W36 W38 W40 W42 W44 W46 W48 W50 W52 W54 W56 W58 W60 W62 
W64/ 
EOS I 23 
W69 
W74 
Tanner staging 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
KRN23 
Administration3 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 23 
 
 
Active Control3,4 
Administered at the discretion of the treating Investigator 
 
EFFICACY MEASURES 
 
Growth (standing 
height [or length], 
sitting height)5 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Growth velocity 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Bilateral AP knee 
x-rays 6,7 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Bilateral PA hand/ 
wrist x-rays 6,7 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Standing long leg 
x-ray7 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
6MWT8 (aged 
≥ 5 years at 
Screening Visit) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 27 
 
Treatment Period 
Safety 
Follow 
Up TC 
21 
Safety 
Follow 
Up Visit 
22 
VISIT ID 
V18 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH  
V24 
HH 
V25 
HH  
V26 
HH 
V27 
HH  
V28 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
HH  
V33 
HH  
V34 
V35 
 
 
TIME 
(WEEK/DAY) 
W32 W33 W34 W36 W38 W40 W42 W44 W46 W48 W50 W52 W54 W56 W58 W60 W62 
W64/ 
EOS I 23 
W69 
W74 
PROMIS Pediatric 
Pain Interference, 
Fatigue and 
Physical Function 
Mobility (aged 
≥ 5 years at 
Screening Visit)9 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Faces Pain Scale – 
Revised (FPS-R) 
(aged ≥ 5 years at 
Screening Visit) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
SF-10 (aged 
≥ 5 years at 
Screening Visit)10 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
PD MEASURES 
 
Serum 
Phosphorus11, 12 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Serum 
1,25(OH)2D11  
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
ALP 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
PHARMACOKINETICS 
 
Serum KRN23 
concentration 13 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 28 
 
Treatment Period 
Safety 
Follow 
Up TC 
21 
Safety 
Follow 
Up Visit 
22 
VISIT ID 
V18 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH  
V24 
HH 
V25 
HH  
V26 
HH 
V27 
HH  
V28 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
HH  
V33 
HH  
V34 
V35 
 
 
TIME 
(WEEK/DAY) 
W32 W33 W34 W36 W38 W40 W42 W44 W46 W48 W50 W52 W54 W56 W58 W60 W62 
W64/ 
EOS I 23 
W69 
W74 
SAFETY MEASURES 
 
Vital Signs 14 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Weight 15 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Physical 
Examination 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Concomitant 
Medication 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Ultrasound 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECG 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECHO (aged 
≥ 5 years) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Chemistry 17, 
Hematology, 
Urinalysis11 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Serum 25(OH)D 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Serum Calcium11, 
12 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Serum Creatinine11 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Serum iPTH 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Serum iFGF23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
2-hr Urine11,18 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 29 
 
Treatment Period 
Safety 
Follow 
Up TC 
21 
Safety 
Follow 
Up Visit 
22 
VISIT ID 
V18 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH  
V24 
HH 
V25 
HH  
V26 
HH 
V27 
HH  
V28 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
HH  
V33 
HH  
V34 
V35 
 
 
TIME 
(WEEK/DAY) 
W32 W33 W34 W36 W38 W40 W42 W44 W46 W48 W50 W52 W54 W56 W58 W60 W62 
W64/ 
EOS I 23 
W69 
W74 
24-hr Urine11,18 
(aged ≥ 5 years) 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Dental assessment 
19 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Immunogenicity 
(ADA) 13 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine Pregnancy 
Test 20 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
See footnotes after Table 2.3 
 
 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 30 
Table 2.3: 
Schedule of Events – Treatment Extension Period Weeks 66-140 and Safety Follow-up 
 
Treatment Extension Period 
 
 
VISIT ID 
V36 
V37 
HH 24 
V41 
V47 
V53 
V59 
V65 
V73 
 
Safety 
Follow 
Up TC 28 
Safety 
Follow Up 
Visit 29 
TIME (WEEK/DAY) 
W66 25 
W68 25 
Q2W 
W76 
W88 
W100 W112 W124 
W140/ 
EOS II 26 
ET Visit 
27 
Tanner staging 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
KRN23 Administration 
X 30 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
EFFICACY MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
Growth (standing height [or length], sitting 
height)5 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Growth velocity 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Bilateral AP knee x-rays6,7 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
Bilateral PA hand/wrist x-rays6,7 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
Standing long leg x-ray7 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
6MWT8 (aged ≥ 5 years at Screening Visit) 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
PROMIS Pediatric Pain Interference, Fatigue 
and Physical Function Mobility (aged ≥ 5 years 
at Screening Visit)9 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
Faces Pain Scale – Revised (FPS-R) (aged 
≥ 5 years at Screening Visit) 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
SF-10 (aged ≥ 5 years at Screening Visit)10 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
PD MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Phosphorus11, 12 
X 30 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum 1,25(OH)2D11  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
ALP 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
Serum KRN23 concentration 13 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
SAFETY MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 14 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 31 
 
Treatment Extension Period 
 
 
VISIT ID 
V36 
V37 
HH 24 
V41 
V47 
V53 
V59 
V65 
V73 
 
Safety 
Follow 
Up TC 28 
Safety 
Follow Up 
Visit 29 
TIME (WEEK/DAY) 
W66 25 
W68 25 
Q2W 
W76 
W88 
W100 W112 W124 
W140/ 
EOS II 26 
ET Visit 
27 
Weight 15 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Examination 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medication 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Ultrasound 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
ECG 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
ECHO (aged ≥ 5 years) 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
Chemistry 17, Hematology, Urinalysis11 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum 25(OH)D 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Calcium11, 12 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum Creatinine11 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum iPTH 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Serum iFGF23 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
2-hr Urine11,18 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
24-hr Urine11,18 (aged ≥ 5 years) 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Immunogenicity (ADA) 11 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
Urine Pregnancy Test 20 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; 6MWT = Six Minute Walk Test; ADA = anti-drug antibodies; ALP = alkaline phosphatase; 
AP = anteroposterior; BP = blood pressure; ECG = electrocardiogram; ECHO = echocardiogram; EOS I = End of Study I (for subjects in Japan and Korea); EOS II = End 
of Study II (for subjects in Europe, the US, Canada, and Australia); ET = End of Treatment; FPS-R = Faces Pain Scale – Revised; HH = Home Health; iFGF23 = intact 
fibroblast growth factor 23; iPTH = intact parathyroid hormone; PA = posteroanterior; PD = pharmacodynamic; PROMIS = Patient-Reported Outcomes Measurement 
Information System; SF-10 = Short Form 10; TC = teleconference; V = visit; W = week 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 32 
1. All study visits will be scheduled relative to the Baseline visit, with an allowable variance of ±3 days for each visit (with the exception of the Screening and the 
Safety Follow-up Visits) to accommodate scheduling. All Screening/Baseline assessments and inclusion/exclusion criteria must be satisfied prior to randomization 
and dosing. The Screening Visit window may be up to 8 weeks for PHEX mutation analysis and washout of oral phosphate and active vitamin D therapy. KRN23 
dosing should occur no sooner than 8 days since the last dose administered. 
2. PHEX mutation analysis will be performed in all subjects. Potential subjects with prior confirmation of a PHEX mutation or variant of uncertain significance in either 
self or a family member with appropriate X-linked inheritance who meet other eligibility requirements may enroll before screening PHEX mutation results are 
returned. 
3. Patients will be randomized 1:1 to either the KRN23 treatment arm or the active control arm (oral phosphate/active vitamin D therapy). 
4. Active control will be administered at the discretion of the treating Investigator. Subjects randomized to the active control arm will visit the clinic at Weeks 1, 4, 8, 
16, 24, 32, 40, 52, and 64. Active control will be discontinued after the Week 64 visit to allow washout of oral phosphate and active vitamin D treatments before the 
first dose of KRN23 at Week 66 for subjects originally randomized to active control. 
5. In subjects < 2 years old, recumbent length will be measured instead of standing and sitting height. At each time point, height will be assessed 3 times and each 
assessment will be recorded onto the subject chart and eCRF. An average of the 3 measurements will be calculated. Pre-study recumbent length/standing height data 
will be collected as discussed in Section 7.5.1. 
6. Screening results will be treated as Baseline data. 
7. AP knee and PA hand/wrist x-rays will be acquired for all subjects and standing long leg x-rays will be acquired for all qualifying subjects. Pre-study radiographs will 
be collected as discussed in Section 7.5.1. 
8. 6MWT will be conducted only for subjects ≥ 5 years of age at the Screening Visit. If a subject is < 5 years of age at the Screening Visit, the 6MWT will not be 
assessed when the subject is over 5 years of age during the post-baseline visits. 
9. For the PROMIS Pediatric Pain Interference, Fatigue, and Physical Function Mobility scales, the parent or legal guardian will complete a Parent/Legal Guardian form 
for subjects ages 5 to < 8 years of age at the Screening Visit. Subjects ≥ 8 years of age at the Screening Visit will complete a pediatric self-report form. Parent/Legal 
Guardian forms will be used for the duration of the study for subjects < 8 years of age at the Screening Visit who had a baseline assessment, even when a subject 
turns 8 during the study. If a subject ≥ 8 years of age at screening has difficulty completing the PROMIS self-report, the investigator may allow the PROMIS 
interview to be administered by trained clinic staff or allow the parent to complete the PROMIS Parent Proxy version. The reason should be carefully documented 
and consistent practice of administration should be maintained for every visit from Baseline. 
10. If a subject is < 5 years of age at the Screening Visit and therefore has no baseline data, SF-10 will not be administered even when the subject turns 5 during the 
study. 
11. Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug administration (if applicable). Record fasting duration on CRF. 
Serum phosphorus may be collected as an unscheduled laboratory assessment if necessary. Details for blood and urine collection can be found in the central 
laboratory manual. 
12. Pre- and post-prandial serum phosphorus and calcium concentrations will be assessed at a single clinic visit anytime 10 to 14 days after a KRN23 dose; this clinic 
visit may take the place of a Home Health visit. Approximately 20 subjects, age ≥ 3 years, will fast overnight for a minimum of 8 hours, and fasting serum will be 
collected prior to a breakfast containing predefined ranges of phosphate, calories, and carbohydrate representative of a typical Western diet for children. Serum 
samples will be drawn 1 and 2 hours after the completion of the meal (refer to Table 7.5.4.3.1). 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 33 
13. Serum KRN23 concentrations and ADA assessment will be performed only for subjects randomized to KRN23 during the Treatment Period and for all subjects 
during the Treatment Extension Period. If development of anti-KRN23 antibodies is suspected in a given subject, samples may be obtained at additional time points 
on a case-by-case basis. 
14. Vital sign measurements consist of seated systolic/diastolic blood pressure (BP) measured in millimeters of mercury (mm Hg), heart rate (beats per minute), 
respiration rate (breaths per minute), and temperature in degrees Celsius (°C). Vital signs will be obtained at the beginning of each visit before any additional 
assessments are completed and after the subject has rested for 5 minutes. BP measurements will only be obtained at clinic visits and only for subjects ≥3 years of age. 
At the Screening Visit and at Baseline, 2 sets of 3 BP measurements will be obtained – the first set will be done at the beginning of the visit and the second set at end 
of the visit after all site procedures are completed. BP measurements should be obtained by auscultation (ie, manually and without using an automated device) dafter 
the subject has rested for 5 minutes and a second and third BP measurement should be obtained, each performed 30 seconds apart.  
15. The subject’s weight collected at in-clinic visits will be the basis of the KRN23 dose calculation until the next in-clinic weight collection. 
16. Adverse events and concomitant medications information will be collected at HH visits for subjects in the KRN23 arm during the Treatment Period and for all 
subjects during the Treatment Extension Period (HH visits are not applicable to subjects in Japan or Korea). For subjects in the active control arm during the 
Treatment Period, adverse events and concomitant medications information will be collected by telephone call.  
17. Serum chemistry panels may include PD parameters (ie, serum phosphorus and ALP), and safety parameters of interest (ie, calcium) to avoid duplication of testing. 
18. Both 2-hr and 24-hr urine will be used for measurements of urinary phosphorus, creatinine, and calcium; 2-hr urine will be used for the derivation of TmP/GFR and 
TRP. For subjects < 5 years of age, spot urine may be collected in place of the 2-hr urine samples for measurements of urinary calcium, phosphorus, and creatinine. 
19. Separate dental assessments are not required and will be captured under AEs as dental issues arise. At each clinic visit, an oral examination will be conducted and 
subjects will be proactively asked if they had any dental events such as dental caries, tooth extraction, root canal, dental abscesses, and gingivitis. 
20. Pregnancy testing will be performed on any female subject of childbearing potential who has experienced menarche. 
21. To be completed for those subjects who complete Week 64 and do not continue on KRN23 treatment immediately on a clinical trial or through another mechanism. 
For subjects in Japan and Korea, site personnel will initiate a safety follow-up telephone call 5 weeks (+5 days) after the Week 64/EOS I Visit to determine if KRN23 
therapy has been started in another clinical trial or through another mechanism. If KRN23 therapy has not been started, information on any ongoing or new AEs, 
SAEs, or concomitant medications will be collected.  
22. For subjects in Japan and Korea who complete the Week 64/EOS I Visit and do not continue on KRN23 on a separate clinical trial or through another mechanism, a 
safety visit will take place 12 weeks ±1 week after the last dose of study drug. Every reasonable effort should be made to have required subjects return to the clinic 
for the final safety visit; however, subjects who are unable to return to the clinic for the final safety visit will be given the option of providing blood and urine samples 
as part of a Home Health visit. This safety visit will not occur for subjects who are documented to be continuing on KRN23 on a separate clinical trial or another 
mechanism. 
23. The Week 64/EOS I Visit is the end of the study for subjects in Japan and Korea. KRN23 will be administered at the Week 64 visit for subjects in Europe, the US, 
Canada, and Australia in the KRN23 arm; these subjects will continue into the Treatment Extension Period. For subjects Japan and Korea in the KRN23 arm, KRN23 
will not be administered at the Week 64/EOS I visit. 
24.  HH visits will be conducted every 2 weeks (Q2W). At the HH visit, study drug will be administered (Q2W); information regarding concomitant medications and 
adverse events will be collected. The visit window is ±5 days. For subjects originally randomized to KRN23 and who continue on KRN23 in the Treatment Extension 
Period, the first HH visit will be at Week 66. For subjects originally randomized to active control and who cross over to KRN23 in the Treatment Extension Period, 
the Weeks 66 and 68 visits are clinic visits; the Week 70 HH visit will be the first HH visit for these subjects.  


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25. The Weeks 66 and 68 clinic visits are for subjects originally randomized to active control and who cross over to KRN23 in the Treatment Extension Period. For 
subjects originally randomized to KRN23 and who continue to receive KRN23 in the Treatment Extension period, the Weeks 66 and 68 visits are Q2W HH visits. 
26. The EOS II visit will be the End of Study efficacy visit for subjects in Europe, the US, Canada, and Australia. EOS II should occur before 30 September 2018 for 
subjects in Europe, the US, and Australia and before 30 June 2019 for subjects in Canada. 6MWT and ECHO will not be performed at the EOS II Visit if the 
assessment was conducted within 3 months of termination. Radiography (x-rays) of wrists and knees will not be performed at the EOS II Visit if the assessment was 
conducted within 6 months of termination. Radiography (x-rays) of standing long legs will not be performed at the EOS II visit if a postbaseline assessment was 
conducted within 12 months of termination. 
27. For subjects who discontinue prior to completing the study (in either the Treatment Period or the Treatment Extension Period), every reasonable effort should be 
made to perform the ET Visit procedures within 4 weeks of early discontinuation. 6MWT and ECHO will not be performed at the ET Visit if the assessment was 
conducted within 3 months of termination. Radiography (x-rays) of wrists and knees will not be performed at the ET Visit if the assessment was conducted within 6 
months of termination. Radiography (x-rays) of standing long legs will not be performed at the ET visit if a postbaseline assessment was conducted within 12 months 
of termination. 
28. To be completed for those subjects who complete EOS II and do not continue on KRN23 treatment immediately on a clinical trial or through another mechanism. For 
subjects in Europe, the US, Canada, and Australia, site personnel will initiate a safety follow-up telephone call 5 weeks (+5 days) after the EOS II Visit to determine 
if KRN23 therapy has been started in another clinical trial, through commercial use, or through another mechanism. If KRN23 therapy has not been started, 
information on any ongoing or new AEs, SAEs, or concomitant medications will be collected. 
29. For subjects in Europe, the US, Canada, and Australia who complete the ET or EOS II Visit and do not continue on KRN23 on another clinical trial, through 
commercial use, or through another mechanism, a safety visit will take place 12 weeks ±1 week after the last dose of study drug. Every reasonable effort should be 
made to have required subjects return to the clinic for the final safety visit; however, subjects who are unable to return to the clinic for the final safety visit will be 
given the option of providing blood and urine samples as part of a Home Health visit. This safety visit will not occur for subjects who are documented to be 
continuing on KRN23 on a separate clinical trial or another mechanism. 
30. Subjects originally randomized to active control will have serum phosphorus assessed at the local laboratory to document hypophosphatemia before administration of 
the first dose of KRN23. A sample will also be drawn for a serum phosphorus assessment at the central laboratory. 


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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS .........................................................................................................................11 
3 TABLE OF CONTENTS ...................................................................................................35 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................39 
5 INTRODUCTION .............................................................................................................43 
5.1 Overview of XLH .....................................................................................................44 
5.2 Brief Overview of KRN23 Development .................................................................46 
5.2.1 
Brief Description of KRN23 .......................................................................46 
5.2.2 
Nonclinical Studies ......................................................................................46 
5.2.3 
Clinical Studies ............................................................................................48 
5.3 Summary of Overall Risks and Potential Benefits ....................................................49 
5.4 Study Rationale .........................................................................................................50 
6 STUDY OBJECTIVES ......................................................................................................53 
7 INVESTIGATIONAL PLAN ............................................................................................54 
7.1 Overall Study Design and Plan .................................................................................54 
7.2 Discussion of Study Design, Including Choice of Control Group ............................59 
7.3 Selection of Study Population ...................................................................................61 
7.3.1 
Inclusion Criteria .........................................................................................62 
7.3.2 
Exclusion Criteria ........................................................................................63 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................64 
7.4 Treatments .................................................................................................................66 
7.4.1 
Investigational Product (KRN23) ................................................................66 
7.4.2 
Active Control (Reference) Therapy ...........................................................67 
7.4.3 
Method of Assigning Subjects to Treatment Groups ..................................67 
7.4.4 
Selection of Doses and Study Duration .......................................................67 
7.4.5 
Prior and Concomitant Therapy ..................................................................68 
7.4.6 
Treatment Compliance ................................................................................69 


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7.5 Study Procedures and Assessments ..........................................................................70 
7.5.1 
Schedule of Events ......................................................................................70 
7.5.2 
Efficacy Measurements ...............................................................................72 
7.5.3 
Safety Measurements ..................................................................................75 
7.5.4 
Exploratory Assessments ............................................................................83 
7.5.5 
Appropriateness of Measurements ..............................................................85 
7.6 Statistical Methods and Determination of Sample Size ............................................86 
7.6.1 
Determination of Sample Size .....................................................................86 
7.6.2 
Primary and Secondary Efficacy Endpoints ................................................86 
7.6.3 
General Principles .......................................................................................88 
7.6.4 
Efficacy Endpoints and Analyses ................................................................88 
7.6.5 
Safety Analyses ...........................................................................................89 
7.6.6 
Data Monitoring Committee .......................................................................89 
8 STUDY CONDUCT ..........................................................................................................90 
8.1 Ethics .........................................................................................................................90 
8.1.1 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) ............................................................................................................90 
8.1.2 
Ethical Conduct of Study ............................................................................90 
8.1.3 
Subject Information and Consent ................................................................90 
8.2 Investigators and Study Administrative Structure ....................................................91 
8.3 Investigational Product Accountability .....................................................................92 
8.4 Data Handling and Record Keeping .........................................................................92 
8.4.1 
Case Report Forms and Source Documents ................................................92 
8.4.2 
Data Quality Assurance ...............................................................................92 
8.4.3 
Record Retention .........................................................................................93 
8.5 Reporting and Follow-up of Adverse Events ............................................................93 
8.5.1 
Definition of Adverse Events ......................................................................93 
8.5.2 
Severity of Adverse Events .........................................................................94 


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8.5.3 
Relationship of Adverse Events to Study Drug ...........................................95 
8.5.4 
Adverse Event Reporting ............................................................................95 
8.5.5 
Communication Plan ...................................................................................97 
8.5.6 
Review of Safety Data .................................................................................98 
8.5.7 
Safety Contact Information .........................................................................98 
8.6 Financing and Insurance ...........................................................................................98 
8.7 Publication Policy .....................................................................................................98 
9 REFERENCES ..................................................................................................................99 
10 SIGNATURE PAGE .......................................................................................................103 
11 APPENDIX 1: REFERENCE SAFETY INFORMATION FOR THE ACTIVE 
CONTROL ARM.............................................................................................................104 
 


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LIST OF TABLES 
Table 2.1: 
Schedule of Events – Treatment Period Weeks 1-30...........................23 
Table 2.2: 
Schedule of Events – Treatment Period Weeks 32-64 and 
Safety Follow-up ..................................................................................26 
Table 2.3: 
Schedule of Events – Treatment Extension Period Weeks 66-
140 and Safety Follow-up ....................................................................30 
Table 7.1.1: 
Oral Phosphate and Active Vitamin D Agents in Common Use 
for XLH Treatment ..............................................................................55 
Table 7.1.2: 
Recommended Ranges of Doses for Phosphate and Active 
Vitamin D for Treatment of XLH ........................................................56 
Table 7.1.3: 
Enrollment in Treatment Extension Period, Study Duration, 
and Post-study KRN23 Treatment by Country or Region ...................58 
Table 7.5.3.8.1: 
Clinical Laboratory Assessments for Safety ........................................80 
Table 7.5.4.3.1: 
Schedule of Events for the Pre- and Post-prandial Serum 
Phosphorus Concentrations Substudy ..................................................85 
 
LIST OF FIGURES 
Figure 2.1: 
UX023-CL301 Study Schema .............................................................16 
Figure 7.1.1: 
UX023-CL301 Study Schema .............................................................59 
 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
1,25(OH)2D 
1,25-dihydroxyvitamin D 
25(OH)D 
25-hydroxyvitamin D 
6MWT 
Six Minute Walk Test 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALP 
alkaline phosphatase 
AP 
anteroposterior 
BALP 
bone-specific alkaline phosphatase 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CTx 
carboxy-terminal cross-linked telopeptide of type I collagen 
dL 
deciliter 
DLT 
dose limiting toxicity 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECLA 
electrochemiluminescent assay 
EDC 
electronic data capture 
EOS 
End of Study 
ET 
End of Treatment 
EU 
European Union 
eGFR 
estimated glomerular filtration rate 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 


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FGF23 
fibroblast growth factor 23 
FPS-R 
Faces Pain Scale – Revised 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
Hyp 
hypophosphatemic 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
iFGF23 
intact fibroblast growth factor 23 
IND 
Investigational New Drug (application) 
iPTH 
intact parathyroid hormone 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
IWRS 
Interactive Web Randomization System 
Kg 
kilogram 
KHK 
Kyowa Hakko Kirin Co., Ltd 
L 
liter 
LVH 
left ventricular hypertrophy 
M 
meter 
mAb 
monoclonal antibody 
Mg 
milligram 
mm Hg 
millimeters of mercury 
mmol 
millimole 
NaPi-IIa 
sodium/phosphate cotransporter IIa 


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NaPi-IIc 
sodium/phosphate cotransporter IIc 
NCI 
National Cancer Institute 
NOAEL 
no adverse effect level 
P1NP 
procollagen type 1 N-propeptide 
PA 
posteroanterior 
PD 
pharmacodynamic (s) 
PHEX 
phosphate-regulating gene with homologies to endopeptidases on the X 
chromosome 
PK 
pharmacokinetic(s) 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PTH 
parathyroid hormone 
Q2W 
once every 2 weeks 
Q4W 
once every 4 weeks 
RBC 
red blood cell 
RGI-C 
Radiographic Global Impression of Change 
RSI 
Reference Safety Information 
RSS 
Rickets Severity Score 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SF-10 
Short Form 10 
SmPC 
Summary of Product Characteristics 
SV 
Screening Visit 
TmP/GFR 
ratio of renal tubular maximum reabsorption rate of phosphate to 
glomerular filtration rate 
TRP 
tubular reabsorption of phosphate 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
XLH 
X-linked hypophosphatemia 
 


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Definition of Terms 
Investigational Product is defined as, “A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use” (from International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use [ICH] Harmonised Tripartite Guideline E6: Guideline for Good Clinical Practice). 
The terms “Investigational Product” and “study drug” are used interchangeably in the 
protocol and refer to KRN23. 
The terms “Active Control” or “Active Control Arm” refer to oral phosphate/active 
vitamin D therapy. 


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5 INTRODUCTION 
X-linked hypophosphatemia (XLH) is a disorder of hypophosphatemia, renal phosphate 
wasting, defective bone mineralization, and impaired growth plate or endochondral 
ossification caused by inactivating mutations in the PHEX gene (phosphate-regulating gene 
with homologies to endopeptidases on the X chromosome), and is the most common form of 
heritable rickets. In the absence of functional PHEX, release of fibroblast growth factor 23 
(FGF23) by osteocytes is greatly increased, leading to impaired conservation of phosphate by 
the kidney and consequent hypophosphatemia. FGF23 also suppresses 1,25-
dihydroxyvitamin D (1,25(OH)2D) production resulting in decreased intestinal absorption of 
calcium and phosphate. 
Chronic hypophosphatemia leads to rickets in children and osteomalacia in adults, the 
2 major pathologic features of XLH. Rickets and osteomalacia are both disorders of bone 
mineralization; however, rickets is a disease of the growth plates specifically characterized 
by deficient mineralization as well as by delayed endochondral ossification, leading to 
reduced growth and skeletal deformities (Shore et al. 2013). Osteomalacia occurs in both 
children and adults wherein low levels of phosphorus prevent normal mineralization of 
osteoid, resulting in low bone turnover and poor quality bone (Shore et al. 2013). 
Published data suggest that earlier treatment leads to better outcomes. In retrospective 
studies, children beginning treatment before age 1 had consistently higher z scores and lower 
alkaline phosphatase levels than children starting treatment later in life (Makitie et al. 2003),  
(Quinlan et al. 2012). 
There is no available medicine that specifically treats the underlying pathophysiology of 
elevated FGF23-induced hypophosphatemia in XLH. The most common therapy for pediatric 
XLH patients consists of multiple daily doses of oral phosphate often combined with doses of 
active vitamin D analogs, the most common being calcitriol and alfacalcidol. Dosing is 
individualized and depends on tolerability of the phosphate dose and the age, size, and 
growth of the child. Doses may be further adjusted based on the efficacy response to 
treatment or evidence of secondary complications (Carpenter et al. 2011). Treatment is 
typically discontinued in adolescence once longitudinal bone growth is complete. The goal of 
therapy with oral phosphate/active vitamin D is to sufficiently supplement the body’s pool of 
phosphate to allow mineralization of bone and improve skeletal outcomes; however, because 
supplementation therapy does not address the mechanism of urinary phosphate wasting, 
increasing phosphate through supplementation also increases renal phosphate throughput and 
urinary phosphate concentrations, thus raising the risk of nephrocalcinosis. Therefore, an 
opportunity exists for more targeted treatment of XLH by blocking the action of aberrantly 
elevated FGF23 to normalize serum phosphorus and prevent long term consequences of 
chronic hypophosphatemia.  
Proof-of-concept studies in a relevant murine model support the use of an anti-FGF23 
monoclonal antibody (mAb) as a treatment for XLH. Experiments in both juvenile and adult 
hypophosphatemic mice provided evidence that treatment with an anti-FGF23 mAb 
normalized or ameliorated many of the characteristic abnormalities associated with XLH 


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(Aono et al. 2009), (Aono et al. 2011). KRN23 is a fully human IgG1 mAb that binds to and 
inhibits FGF23. The Sponsor and development partner, Kyowa Hakko Kirin Co., Ltd. (KHK) 
are investigating KRN23 as a potential therapeutic candidate for the treatment of XLH, a 
disease distinguished by high levels of serum FGF23. 
KHK has conducted a series of nonclinical pharmacology, pharmacokinetic (PK), and 
toxicology studies supporting the investigation of KRN23 in adults and children. 
Four clinical studies of KRN23 have been completed in adult patients with XLH: 
2 single-dose Phase 1 safety and tolerability studies, a repeat dose Phase 1/2 dose escalation 
study, and an associated treatment extension study. An additional open-label, long-term 
extension study is ongoing. A Phase 2 study (UX023-CL201) in pediatric XLH subjects aged 
5 to 12 years receiving KRN23 at multiple doses up to 2.0 mg/kg every 2 weeks (Q2W) or 
every 4 weeks (Q4W) is ongoing and no new safety concerns have been identified. Studies in 
both adults and children (aged 5-12 years) with XLH have shown that KRN23 increases 
serum phosphorus and 1,25(OH)2D levels and ratio of renal tubular maximum reabsorption 
rate of phosphate to glomerular filtration rate (TmP/GFR). Initial 40-week data from the 
pediatric Phase 2 study also suggest that KRN23 treatment improves rickets severity with a 
favorable safety profile. The 40-week interim analysis demonstrated that KRN23 
significantly improved rickets across the 2 dosing groups, with subjects in the Q2W dosing 
group having better outcomes that may reflect the more steady levels of serum phosphorus, 
1,25(OH)2D, and other PD parameters observed with Q2W dosing than with Q4W dosing of 
KRN23. 
Data from the pediatric Phase 2 study were used to establish the dosing regimen and 
provided information for the design of the current Phase 3 study. This Phase 3 study will be 
conducted in children with XLH (aged 1 to ≤ 12 years) with confirmed evidence of rickets to 
evaluate the efficacy (ie, improvement in rickets) and safety profile of KRN23 treatment, and 
to compare KRN23 treatment with active control (oral phosphate/active vitamin D therapy). 
In addition, this study will evaluate whether every 2 week dosing of KRN23 improves 
growth velocity, restores phosphorus homeostasis, and improves functional outcomes and 
quality of life in children with XLH. A Treatment Extension Period, which provides for 
continued treatment until KRN23 is expected to be commercially available, will also allow 
evaluation of subject who cross over from active control to KRN23. 
5.1 
Overview of XLH 
XLH is a rare, genetic disorder that is serious, chronically debilitating, and represents an 
unmet medical need. This genetic deficiency is estimated to occur in about 1:20,000 live 
births (Burnett et al. 1964), (Imel et al. 2005), (Beck-Nielsen et al. 2009). XLH is the most 
common inherited form of rickets and the most common inherited defect in renal tubular 
phosphate transport. XLH is transmitted as an X-linked dominant disorder  
(Dixon et al. 1998). Mutations resulting in the loss of function of PHEX form the genetic 
basis for XLH (Carpenter et al. 2011). More than 300 different PHEX gene mutations have 
been identified in patients with XLH (PHEXdb); however, few definitive correlations have 
been observed between specific mutations and phenotypic severity. 


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Patients with XLH have hypophosphatemia due to excessive FGF23 levels  
(Jonsson et al. 2003), (Yamazaki et al. 2002); however, the precise mechanism by which 
PHEX disruption results in elevated FGF23 is complex and not fully understood  
(Carpenter et al. 2011), (Rowe 2012). FGF23 plays an important role as a specific regulator 
of serum phosphorus; its major function is to reduce serum phosphorus levels by inhibiting 
renal proximal tubular phosphate reabsorption (Fukumoto 2008), (Razzaque et al. 2007). 
FGF23 also decreases serum 1,25(OH)2D levels by inhibiting 1-alpha-hydroxylase activity in 
the kidney, thereby decreasing intestinal absorption of phosphate and calcium. Both actions 
by FGF23 on the tubular reabsorption and intestinal absorption via vitamin D metabolism 
lead to a decrease in serum phosphorus levels. 
Patients with XLH often present during childhood with rickets due to hypophosphatemia and 
frequently develop skeletal abnormalities (eg, bowed legs), impaired growth, and short adult 
stature (Tenenhouse et al. 2001). As young patients age and progress into adulthood, the 
symptom pattern evolves due to decreased phosphate requirements for bone growth. 
Adult XLH patients suffer from bone pain and osteomalacia, increased risk of bone fractures, 
joint abnormalities and joint pain, enthesopathy, and osteoarthritis (Carpenter et al. 2011). 
There is a great deal of variability in the manifestations of XLH. In more severe disease, 
hypophosphatemia leads to decreased mineralization of newly formed bone and rickets. 
Surgical correction of limb deformities is often required (Santos et al. 2013),  
(Zivicnjak et al. 2011). 
Although there is no approved therapy for XLH that specifically treats the underlying 
pathophysiology of elevated FGF23-induced hypophosphatemia., the most common 
treatment for pediatric XLH patients consists of multiple daily doses of oral phosphate often 
combined with doses of active vitamin D metabolites (eg, calcitriol and alfacalcidol). General 
guidelines for treatment of children with XLH with oral phosphates and active vitamin D 
therapy are published in both the US and Europe, as described in Table 7.1.1 and Table 7.1.2. 
No consensus exists regarding treatment of adult patients with XLH (Linglart et al. 2014). 
The use of oral phosphate and vitamin D may be initiated for the treatment of osteomalacia, 
bone/joint pain, and pseudofractures in symptomatic patients, although evidence of efficacy 
in adults is limited (Sullivan et al. 1992). Treatment with oral phosphate and active vitamin D 
requires frequent and continued monitoring of patients. Serum and urine mineral metabolites 
levels and imaging studies are required to assess toxicity and secondary complications, 
including nephrocalcinosis, hypercalciuria, and hyperparathyroidism (Carpenter et al. 2011). 


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5.2 
Brief Overview of KRN23 Development 
A brief overview of existing information on KRN23 is provided below; a comprehensive 
review of the data is contained in the Investigator’s Brochure (IB) provided by Ultragenyx 
Pharmaceutical Inc. (Ultragenyx), which should be reviewed prior to initiating the study. 
5.2.1 
Brief Description of KRN23 
KRN23 is a recombinant human IgG1 monoclonal antibody (mAb) that binds to and inhibits 
the activity of FGF23. KRN23 is expressed in Chinese hamster ovary dihydrofolate 
reductase-deficient cells. The secreted KRN23 antibody is recovered from the culture 
medium and purified using a series of chromatographic and filtration steps. Based on the 
amino acid sequence, the predicted molecular mass of KRN23 is approximately 
140 kilodaltons (kDa). Nonclinical studies demonstrated KRN23 possesses high binding 
affinity to the N-terminal domain of FGF23. KRN23 binds to FGF23 from humans, 
cynomolgus monkeys and rabbits, but not to other species tested. 
5.2.1.1 
Mechanism of Action in XLH 
Patients with XLH have hypophosphatemia due to excessive serum FGF23 levels. FGF23 
reduces serum phosphorus levels by 2 distinct mechanisms of action (Fukumoto 2008), 
(Razzaque et al. 2007), (Yamazaki et al. 2008). The primary mechanism is to inhibit 
phosphate reabsorption in the proximal tubule of the kidney. The secondary mechanism is to 
decrease phosphate absorption by the small intestine through the inhibition of 1,25(OH)2D 
production in the kidney. 
KRN23 has the potential to block or reduce FGF23 action and improve phosphorus 
homeostasis in XLH patients. KRN23 binds the amino-terminal domain of FGF23 that 
interacts with the FGF-binding portion of the combination FGFR1/Klotho receptor, 
preventing FGF23 from binding to and signaling from its receptor. Both intact and 
fragmented FGF23 polypeptides are immunoprecipitated with KRN23 (Yamazaki et al. 
2008). By inhibiting FGF23, KRN23 restores tubular reabsorption of phosphate (as measured 
by the ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration 
rate [TmP/GFR]) from the kidney and increases the production of 1,25(OH)2D that also 
enhances intestinal absorption of phosphate. It is expected that by directly inhibiting excess 
FGF23, the underlying cause of XLH, and thereby improving phosphorus homeostasis and 
healing rickets, KRN23 has the potential to significantly alter the natural history of the 
disease. 
5.2.2 
Nonclinical Studies 
The hypophosphatemic (Hyp) mouse is a murine homologue of XLH with a deletion in the 
3ꞌ region of the PHEX gene (Liu et al. 2007), (Perwad et al. 2005). In addition to 
hypophosphatemia, rickets, and associated developmental abnormalities, these animals 
display elevated serum FGF23 levels and increased expression of FGF23 in the bone. 
Since KRN23 does not bind murine FGF23, the pharmacological effects of murine 


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anti-FGF23 mAbs were examined in juvenile and adult Hyp mice (Aono et al. 2009),  
(Aono et al. 2011). In juvenile Hyp mice, anti-FGF23 treatment corrected hypophosphatemia 
and ameliorated the rachitic bone phenotypes (Aono et al. 2009). In adult Hyp mice, 
anti-FGF23 treatment increased serum phosphate and 1,25(OH)2D levels, and increased grip 
strength and spontaneous movement (Aono et al. 2011). These studies provide proof-of-
concept that treatment with antibodies targeting FGF23 may reverse or ameliorate 
characteristic abnormalities associated with XLH. 
KRN23 binds to human, rabbit, and monkey FGF23 with comparable affinities. In a study 
conducted under Good Laboratory Practice (GLP) conditions, KRN23 cross-reactivity was 
evaluated against a full panel of human, rabbit (32 tissues), and cynomolgus monkey 
(33 tissues) tissues by immunohistochemistry. No specific KRN23 staining was observed 
suggesting untoward direct-effects of KRN23 are not expected in any tissues of normal 
humans, rabbits, or cynomolgus monkeys.  
A series of nonclinical pharmacology, PK, and toxicity studies have been conducted in 
rabbits and cynomolgus monkeys to support the use of KRN23 in adults and children. 
Findings of potential clinical significance and relevance to this protocol are summarized 
below; additional information is provided in the IB. 
 The no adverse effect level (NOAEL) in a 40-week toxicity study in adult cynomolgus 
monkeys was 0.03 mg/kg KRN23 for males and 0.3 mg/kg KRN23 for females. 
The NOAEL in a 40-week toxicity study in juvenile cynomolgus monkeys and a 
single-dose study in rabbits was 0.3 mg/kg KRN23. 
 Soft tissue and organ mineralization was a consistent finding associated with prolonged 
and excessive serum phosphate levels including the kidney where nephrocalcinosis was 
observed at the highest dose tested and reversibility of mineralization could not be 
established. 
 The most prominent pharmacologic actions of KRN23 were dose-dependent changes in 
serum inorganic phosphorus and 1,25(OH)2D in rabbits and juvenile, adult, and pregnant 
cynomolgus monkeys. 
 No gross or histopathological abnormalities were observed at the intravenous (IV) 
infusion sites or subcutaneous (SC) injection sites in the 40-week repeat dose toxicity 
studies in adult and juvenile cynomolgus monkeys.  
 KRN23 demonstrated consistent and predictable PK behavior in both rabbits and 
cynomolgus monkeys based on the results of single and repeat dose studies where 
exposure was by either the IV or SC route. 
The NOAEL was the same in juvenile and adult monkeys suggesting no difference in 
sensitivity to the adverse effects of KRN23. The results from single- and repeat-dose 
toxicology studies in rabbits and juvenile, adult and pregnant cynomolgus monkeys suggest 
the primary toxicological effects of KRN23 are associated with prolonged and excessive 


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antagonism of the normal regulatory actions of FGF23 on renal tubular phosphate 
reabsorption and vitamin D metabolism. 
5.2.3 
Clinical Studies 
Multiple clinical studies of FGF23 in adults or children with XLH are completed or ongoing. 
Four clinical studies have been conducted in adult patients with XLH: a single dose Phase 1 
safety and tolerability study of KRN23 (KRN23-US-02), a single dose Phase 1 safety and 
tolerability study of KRN23 in Japan and Korea (KRN23-001), a repeat dose Phase 1/2 dose 
escalation study (KRN23-INT-001), and an associated treatment extension study 
(KRN23-INT-002). An additional open-label long-term extension study (UX023-CL203), a 
double-blind, placebo-controlled, Phase 3 study (UX023-CL303), and an open-label, paired 
bone biopsy Phase 3 study (UX023-CL304) to evaluate changes in osteomalacia at the tissue 
level with KRN23 treatment are ongoing. Details of study parameters and PK, PD, clinical 
efficacy and safety results are provided in the IB. A Phase 2 dose-finding, pharmacodynamic 
(PD) and safety study in pediatric XLH patients aged 5 to 12 years (UX023-CL201) and an 
open-label, Phase 2 safety, PD, and efficacy study in 1-to-4-year-old children with XLH 
(UX023-CL205) are also ongoing.  
Data from clinical studies to date are consistent with the proposed mechanism of action: that 
KRN23 blocks FGF23 action, leading to a sustained increase in serum phosphorus levels due 
to increased TmP/GFR and increased intestinal absorption caused by increased 1,25(OH)2D. 
Single and repeat-dose clinical studies indicate SC administration of KRN23 consistently 
increased and sustained serum phosphorus levels and TmP/GFR, without a major impact on 
urine calcium levels or vitamin D metabolism (Carpenter et al. 2014), (Imel et al. 2015). 
Data from the long-term extension study in adults suggest KRN23 could provide sustained 
increases in serum phosphorus levels such that improvements in bone physiology, structure, 
and function would be expected (Imel et al. 2015).  
Repeated doses of KRN23 up to 1.0 mg/kg were well tolerated by adult XLH subjects 
throughout the Phase 1/2 dose escalation study and associated treatment extension study 
(Imel et al. 2015). In the extension study, serious adverse events (SAEs) reported for 
3 subjects were unlikely to be or were not study drug related: breast cancer, hypertensive 
crisis, and cervical spinal stenosis. Throughout the long-term extension study, 
treatment-related AEs were reported for 14 subjects (63.6%) treated with KRN23 and 
included injection site reaction (5 subjects, 22.7%), arthralgia (3 subjects, 13.6%), restless 
legs syndrome (2 subjects, 9.1%), and injection site pain (2 subjects, 9.1%). No discernible 
clinically significant trends of lab abnormalities suggestive of a treatment-related adverse 
effect were noted. Overall, no immunogenicity or patterns of dose-limiting toxicity have been 
associated with KRN23 treatment. 
Similar to the adult studies, interim analyses from the Phase 2 pediatric study 
(UX023-CL201) showed KRN23 treatment up to 2 mg/kg Q2W or Q4W increased serum 
phosphorus, TmP/GFR, and 1,25(OH)2D levels. A 40-week interim analysis of the first 
36 subjects enrolled demonstrated that KRN23 significantly improved rickets from baseline 


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to Week 40 by 30% (p=0.0076) as assessed by the Thacher Rickets Severity Score (RSS), 
with greater improvements seen with Q2W dosing (44% reduction; p=0.0126) than with 
Q4W dosing (14% reduction). The greatest improvement was observed in a subset of patients 
(n=18) with clear evidence of rickets at baseline (baseline RSS ≥1.5) (59% reduction with 
Q2W dosing and 47% reduction with Q4W dosing; p<0.0001 for both dose groups). 
Consistency in the rickets results was observed using the Radiographic Global Impression 
of Change (RGI-C; -3=worsening; +3=complete healing), with rickets improving by 
+1.56 points (p<0.0001) in the Q2W dosing group and by +1.20 points (p<0.0001) in the 
Q4W dosing group at Week 40. In the subgroup with a baseline RSS ≥1.5, RGI-C improved 
by +2.0 points (p<0.0001) in patients who received Q2W dosing, indicating substantial 
healing of rickets, and by +1.70 (p<0.0001) in patients who received Q4W dosing. 
The 40-week analysis also revealed that the Q4W dosing group showed a peak in serum 
phosphorus at 2 weeks after dosing followed by a decrease in serum phosphorus levels before 
the next dose (though remaining above baseline), whereas the Q2W regimen showed stable 
serum phosphorus levels slowly increasing over time. Overall, the dose-response and PD 
results observed in the pediatric study were consistent with the adult XLH data generated to 
date. None of the subjects had serum phosphorus levels above the normal range in either 
dosing group. Most treatment-related adverse events (AE) were mild, most commonly a 
transient injection site reaction (39%). One child experienced a serious AE and was 
hospitalized for fever/muscle pain that improved and continues in the trial. No clinically 
meaningful changes occurred in serum or urine calcium, serum iPTH, or renal ultrasound.  
5.3 
Summary of Overall Risks and Potential Benefits 
KRN23, a fully human mAb that binds and inhibits FGF23, is being developed as a potential 
therapeutic candidate for XLH, a rare genetic disease characterized by chronic 
hypophosphatemia and elevated levels of FGF23. By blocking the activity of FGF23, KRN23 
can restore phosphate, vitamin D, and bone metabolism homeostasis, and has the potential to 
improve the lives of children with this disorder by correcting or minimizing rickets, 
radiographic abnormalities, and skeletal deformities, and by promoting maximal growth 
potential while preventing the lifelong bone- and joint-related complications of rickets. 
This therapeutic approach directly targets the inherent dysregulation in XLH (ie, excess 
FGF23). In contrast, supplementation therapy with phosphate and/or active vitamin D is only 
partially effective and carries a significant burden and risk of ectopic mineralization, 
particularly nephrocalcinosis. 
Clinical studies to date have demonstrated that KRN23 treatment blocks FGF23 action and 
leads to a sustained increase in serum phosphorus levels due to increased TmP/GFR. 
Increased 1,25(OH)2D was also observed, as expected, based on the inhibition of the excess 
of FGF23. Bone formation and resorption markers also increased. Interim data in children 
with XLH suggest that KRN23 treatment also improves rickets. KRN23 was well tolerated in 
the population studied. No major safety concerns were observed; there was no evidence of 
immunogenicity, and no evidence of left ventricular hypertrophy (LVH) based on 
electrocardiogram (ECG) even though FGF23 levels were increased following KRN23 
treatment. Although ectopic mineralization is a known risk related to XLH disease and is 


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exacerbated by oral phosphate and/or active vitamin D supplementation, KRN23 does not 
appear to be associated with progression of cardiac or renal ectopic mineralization beyond 
the natural course of pre-existing disease. 
KRN23 administered SC Q2W or Q4W as doses up to 2 mg/kg achieved the desired PD 
effect in children and evidence of a clinical effect in healing rickets, positioning KRN23 as a 
drug that could be administered twice per month by SC injection, which is a convenient and 
acceptable therapeutic regimen for a chronic condition. 
In conclusion, KRN23 inhibits the effects of FGF23, restoring phosphate, vitamin D and 
bone metabolism homeostasis. In children with XLH, interim data suggest that KRN23 
treatment improves rickets. By targeting FGF23 and increasing serum phosphorus levels, it is 
expected that rickets severity in children with XLH will be healed or reduced, leading to 
improved clinical outcomes and the quality of life of children with XLH. To date, KRN23 
has a favorable safety profile without evidence of increased ectopic mineralization or other 
concerns associated with the excess of FGF23. KRN23 has the potential to be an effective 
and safe treatment option for patients with XLH. 
5.4 
Study Rationale 
XLH is a disorder of hypophosphatemia, renal phosphate wasting, defective bone 
mineralization, and impaired growth plate or endochondral ossification caused by 
inactivating mutations in the PHEX gene (phosphate-regulating gene with homologies to 
endopeptidases on the X chromosome), and is the most common form of heritable rickets. 
In the absence of functional PHEX, release of FGF23 by osteocytes is greatly increased. 
Excess circulating FGF23 impairs conservation of phosphate by down-regulating NaPi-IIa 
and NaPi-IIc in the renal tubule cells and suppressing 1,25(OH)2D production, resulting in 
decreased intestinal absorption of calcium and phosphate. Chronic low serum phosphorus 
levels lead to rickets in children and osteomalacia in both children and adults, the 2 major 
pathologic outcomes of the hypophosphatemia. Rickets is a disorder of open growth plates 
characterized by both defective bone mineralization and defective endochondral ossification, 
leading to reduced growth and skeletal deformities. Osteomalacia is characterized by a lack 
of proper mineralization, a prolonged mineralization process, and an accumulation of osteoid 
tissue with a consequent deterioration of bone remodeling (Shore et al. 2013). 
Although there is no approved therapy for XLH that specifically treats the underlying 
pathophysiology of elevated FGF23-induced hypophosphatemia, the most common therapy 
for children with XLH consists of multiple daily doses of oral phosphate often combined 
with doses of active vitamin D analogs, the most common being calcitriol and alfacalcidol. 
Dosing is individualized and depends on tolerability of the phosphate dose and the age, size, 
and growth of the child. The goal of therapy with phosphate and active vitamin D is to 
sufficiently supplement the body’s pool of phosphate to allow mineralization of bone and 
improve skeletal outcomes; however, because supplementation therapy does not address the 
mechanism of urinary phosphate wasting, increasing phosphate through supplementation also 
increases renal phosphate throughput and urinary phosphate concentrations, thus raising the 


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risk of nephrocalcinosis. More therapeutic options that are efficacious, safe, and convenient, 
and that target the underlying pathophysiology of XLH (ie, renal phosphate wasting induced 
by high FGF23 levels), are needed. 
KRN23 is a recombinant human IgG1 mAb that binds to and inhibits the activity of FGF23. 
By inhibiting FGF23, KRN23 restores tubular reabsorption of phosphate from the kidney and 
increases the production of 1,25(OH)2D that enhances intestinal absorption of calcium and 
phosphate (Carpenter et al. 2014). It is expected that by directly inhibiting excess FGF23-the 
underlying cause of XLH-improving phosphorus homeostasis, and healing rickets, KRN23 
has the potential to significantly alter the natural history of the disease. A Phase 1 study 
established the PK profile of KRN23. A Phase 1/2 study and associated extension study 
evaluated the PD of KRN23 on phosphate metabolism and related measures of the 
phosphate-calcium mineral control system. The safety data from these studies have shown 
that KRN23 in single and repeated every 4 week doses up to 1.0 mg/kg was well tolerated by 
adult XLH subjects. KRN23 sufficiently increased serum phosphorus levels, such that 
improvements in bone physiology, structure and function would be expected. These data 
support the initiation of further studies to evaluate the therapeutic benefit of KRN23 in 
children who experience the most severe physical and health manifestations associated with 
XLH. Currently, there are no approved treatments and a high unmet medical need in pediatric 
XLH patients. 
Adults and children with XLH have the same underlying defect, but are at a different stage of 
the disease. In childhood, normal phosphorus levels are higher to promote bone formation, 
whereas in adults, the normal range is lower, coincident with reduced demand for bone 
formation. Therefore, smaller, more frequent dosing may be preferred for pediatric 
hypophosphatemic patients to maximize treatment effect without a plateau, to drive serum 
phosphorus levels closer to the normal range, and to minimize the troughs.  
A Phase 2 study (UX023-CL201) in pediatric XLH subjects aged 5 to 12 years receiving 
KRN23 at multiple doses up to 2.0 mg/kg every 2 weeks (Q2W) or every 4 weeks (Q4W) is 
ongoing and no new safety concerns have been identified. Interim data from the Phase 2 
pediatric study showed that KRN23 treatment for 40 weeks leads to significant improvement 
in rickets severity, with the greatest improvement observed with Q2W dosing in those 
subjects with higher rickets severity at baseline. KRN23 treatment also improved serum 
phosphorus, TmP/GFR, and serum 1,25(OH)2D levels, consistent with results observed in 
studies of adults with XLH. The 40-week analysis also revealed that the Q4W dosing group 
showed a peak in serum phosphorus at 2 weeks after dosing followed by a decrease in serum 
phosphorus levels before the next dose (though remaining above baseline), whereas the Q2W 
regimen showed stable serum phosphorus levels slowly increasing over time. Overall, the 
dose-response, serum phosphorus, and other pharmacodynamic results observed in the 
pediatric study were consistent with the adult XLH data generated to date. There have been 
no discontinuations from the study for any reason. Most treatment-related adverse events 
(AE) were mild, most commonly a transient injection site reaction (39%). One child 
experienced a serious AE and was hospitalized for fever/muscle pain that improved and 
continues in the trial. There have been no deaths or discontinuations from the study for any 


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reason. No clinically meaningful changes occurred in serum or urine calcium, serum iPTH, 
or renal ultrasound. The current Phase 3 study will be conducted in children with XLH 
(aged 1 to ≤12 years) who have radiographic evidence of rickets (≥ 2.0 points RSS total 
score), open epiphyses, and have received oral phosphate/active vitamin D therapy for 
≥ 12 consecutive months (for children ≥ 3 years of age) or ≥ 6 consecutive months (for 
children < 3 years of age), 7 days prior to the Randomization Visit. The design is intended to 
evaluate the efficacy (change in rickets severity) and safety of KRN23 treatment compared 
with active control (oral phosphate/active vitamin D therapy). In addition, this study will 
evaluate whether every 2 week dosing of KRN23 improves growth velocity, restores 
phosphorus homeostasis, and improves functional outcomes and quality of life in children 
with XLH.  
RGI-C global score at Week 40 was selected as the primary efficacy measure as this endpoint 
directly assesses improvements in rickets, which is the basis for, and correlates with the 
major morbidities patients with XLH suffer from during their lifespan.  


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6 STUDY OBJECTIVES 
Primary Objective: 
 Evaluate the effect of KRN23 therapy in improving rickets in children with XLH 
compared with the active control (oral phosphate/active vitamin D) 
Secondary Efficacy Objectives: 
Evaluate the effects of KRN23 as compared with the active control on: 
 Growth velocity and lower extremity deformity 
 Pharmacodynamic markers that reflect the status of phosphorus homeostasis, including 
serum 1,25(OH)2D, serum and urinary phosphorus, ratio of renal tubular maximum 
reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), and tubular 
reabsorption of phosphate (TRP) 
 Biochemical markers of bone turnover that reflect rickets severity (alkaline phosphatase 
[ALP]) 
 Walking ability and patient-/parent-reported pain, fatigue, and physical function/mobility 
Pharmacokinetic Objective: 
Assess the PK of KRN23 throughout the dosing cycle  
Safety Objective: 
Evaluate the safety and tolerability profile of KRN23 in the treatment of children with XLH 
(aged 1 to ≤ 12 years), including adverse events (AEs) (eg, nephrocalcinosis), as compared 
with active control, and immunogenicity profile 
Treatment Extension Period Objective: 
To evaluate the long-term safety and efficacy of KRN23 


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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
UX023-CL301 is a multicenter, randomized, open-label, Phase 3 study comparing the 
efficacy and safety of KRN23 with the active control (oral phosphate/active vitamin D 
therapy) in pediatric patients with XLH. The study will be conducted in children with clinical 
evidence consistent with XLH (aged 1 to ≤ 12 years), including demonstrated 
hypophosphatemia, radiographic evidence of rickets (≥ 2.0 points RSS total score), and 
PHEX mutation or variants of uncertain significance. Patients will also be required to have 
open epiphyses and have received oral phosphate/active vitamin D therapy for ≥ 12 
consecutive months (for children ≥ 3 years of age) or ≥ 6 consecutive months (for children 
< 3 years of age), 7 days prior to the Randomization Visit. Approximately 60 subjects will be 
randomized 1:1 to receive open-label KRN23 administered by subcutaneous injection or 
active control for a total of 64 weeks in the Treatment Period. Randomization will be 
stratified by baseline rickets severity (RSS total score ≤ 2.5 vs > 2.5) and age (< 5 vs 
≥ 5 years). At least 20 subjects aged 1 to < 5 years will be included (approximately 10 in 
each treatment arm), and no more than 10 subjects between the ages of 1 to < 3 years will be 
enrolled. The age range of eligible subjects will be monitored for enrollment for age 
distribution. No more than 70% female subjects will be enrolled. All subjects will washout of 
oral phosphate and active vitamin D therapy for 7 days prior to randomization. Subjects 
randomized to KRN23 will remain off of oral phosphate/active vitamin D therapy throughout 
the duration of the study.  
Treatment Extension Period (Weeks 66 – 140) – All Subjects 
Subjects assigned to the KRN23 treatment group will receive KRN23 at a starting dose of 
0.8 mg/kg Q2W. The dose may be increased to 1.2 mg/kg at any time during the study if a 
subject meets the following dose-adjustment criteria: 1) 2 consecutive serum phosphorus 
measurements are below the normal range; 2) serum phosphorus has increased by 
≤ 0.5 mg/dL from baseline; and 3) the subject has not missed a dose of KRN23 that would 
account for the decrease in serum phosphorus. The maximum allowable dose of KRN23 per 
administration is 90 mg. At any time during the study, if serum phosphorus increases above 
the upper limit of normal (ULN) for age, the subsequent dose(s) will be withheld and the site 
will contact the medical monitor before dosing resumes. Once other causes of increased 
serum phosphorus are excluded, KRN23 treatment will resume at half the total dose of the 
last dose received (ie, half of either 0.8 mg/kg or 1.2 mg/kg; maximum dose per 
administration: 40 mg). Serum phosphorus will be followed through unscheduled serum 
phosphorus assessments (approximately 2 weeks post-dose and assessed by the central 
laboratory; the assessments may be repeated as necessary). A subject will resume dosing at 
the previous full total dose level if they meet the same dose-adjustment criteria listed above.  
Subjects assigned to active control will typically receive multiple daily doses of oral 
phosphate and active vitamin D. Because of the variability in the doses and dosing 
frequencies of oral phosphates and active vitamin D therapies in clinical practice, these 
treatments will be individualized for each subject at the investigator’s discretion, but the 


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following general guidance is provided based on expert recommendations in the US and 
Europe (in Table 7.1.1 and Table 7.1.2). Detailed information about the brand, starting 
dosages, and any changes in oral phosphate and active vitamin D therapy will be determined 
by the treating Investigator within the guidelines and recorded at every site visit. US expert 
guidelines generally recommend a calcitriol dosage of 20 to 30 ng/kg/day in 2 to 3 divided 
doses and an elemental phosphorus dose of 20 to 40 mg/kg/day (in 3 to 5 divided doses), 
acknowledging that some children require more, whereas some do well with less  
(Carpenter et al. 2011). European expert guidelines recommend an alfacalcidol dosage of 1 to 
2 µg/day (once daily) and a phosphate supplemental dose of 45 to 70 mg/kg/day (in 3 to 4 
divided doses) (Linglart et al. 2014). Calcitriol and alfacalcidol dosages should be adjusted 
based on the clinical and laboratory values that guide best possible treatment. 
Table 7.1.1: Oral Phosphate and Active Vitamin D Agents in Common Use for XLH 
Treatment 
 
(Carpenter et al. 2011) 


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Table 7.1.2: Recommended Ranges of Doses for Phosphate and Active Vitamin D for 
Treatment of XLH 
 
(Linglart et al. 2014) 
For subjects in Japan and Korea, the Week 64 visit at the end of the Treatment Period will be 
the End of Study (EOS) Visit (“Week 64/EOS I”); subjects in these countries will be enrolled 
into a separate clinical trial of KRN23 or will receive KRN23 through another mechanism. 
Post-study safety follow up calls and safety visits will occur only for subjects who are not 
documented to be continuing on KRN23 at the Week 64/EOS I Visit. A safety follow-up 
telephone call will occur at 5 weeks (+5 days) after the Week 64/EOS I Visit to determine if 
KRN23 therapy has been started in another clinical trial, as commercial product, or through 
another mechanism; if KRN23 therapy has not been started, information on any ongoing or 
new AEs, SAEs, or concomitant medications will be collected. For subjects who do not 
continue KRN23 therapy, an additional safety visit will occur 12 weeks ±1 week after the last 
dose of study drug. Every reasonable effort should be made to have required subjects return 
to the clinic for the final safety visit; however, subjects who are unable to return to the clinic 
for the final safety visit will be given the option of providing the blood and urine samples as 
part of a Home Health visit. 
Treatment Extension Period (Weeks 66 – 140) – Subjects in Europe, the US, Canada, 
and Australia 
The purpose of Treatment Extension Period is to continue to provide KRN23 treatment after 
the Treatment Period to subjects in Europe, the US, Canada, and Australia while also 
continuing to collect long-term safety and efficacy data. Safety and efficacy parameters will 
continue to be followed while subjects remain on study and receive treatment. After 
completion of the 64-week Treatment Period, subjects in Europe, the US, Canada, and 
Australia who were randomized to KRN23 will continue treatment with KRN23 at their 
previous dose and regimen in the Treatment Extension Period. Subjects who were 
randomized to active control will cross over to receive KRN23 at the starting dose and 
regimen administered to subjects in the KRN23 arm (starting dose of 0.8 mg/kg Q2W; dose 
may be increased to 1.2 mg/kg Q2W).  


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Before their first dose of KRN23 at Week 66, subjects who were in the active control arm in 
the Treatment Period will discontinue treatment with active control the day after the Week 64 
visit to allow washout of oral phosphate and active vitamin D treatments. These subjects 
must have serum phosphorus < 3.2 mg/dL (< 1.03 mmol/L) (ie, below the lower limit of 
normal) to continue on study and receive KRN23 in the Treatment Extension Period. 
If hypophosphatemia is not observed, the subject should be retested for serum phosphorus 
within a week to ensure that the test result was not due to a technical issue. 
If hypophosphatemia is still not observed after test and retest, the subject will be 
discontinued from the study. The assessment of serum phosphorus to document 
hypophosphatemia before administration of the first dose of KRN23 in subjects originally 
assigned to active control will be done at the local laboratory so that KRN23 can be 
administered the same day. A sample will also be drawn for a serum phosphorus assessment 
at the central laboratory. For subjects crossing over to KRN23 treatment, the Weeks 66 and 
68 visits will be in-clinic visits. 
For subjects in Europe and Australia, the Treatment Extension Period will end in 
September 2018, and subjects will be enrolled into separate clinical trials of KRN23 or will 
receive KRN23 through another mechanism (Table 7.1.3). For subjects in the US and 
Canada, the Treatment Extension Period will end in September 2018 and June 2019, 
respectively, when commercial KRN23 is expected to be available; subjects will receive 
commercial KRN23 or will receive KRN23 through another mechanism. Subjects leaving the 
study will have an EOS visit that includes efficacy assessments (EOS II). Post-study safety 
follow-up calls and safety visits will occur only for subjects who are not documented to be 
continuing on KRN23 at the EOS II Visit. A safety follow-up telephone call will occur at 
5 weeks (+5 days) after the EOS II Visit to determine if KRN23 therapy has been started in 
another clinical trial, as commercial product, or through another mechanism; if KRN23 
therapy has not been started, information on any ongoing or new AEs, SAEs, or concomitant 
medications will be collected. For subjects who do not continue KRN23 therapy, 
an additional safety visit will occur 12 weeks ±1 week after the last dose of study drug. 
Every reasonable effort should be made to have required subjects return to the clinic for the 
final safety visit; however, subjects who are unable to return to the clinic for the final safety 
visit will be given the option of providing blood and urine samples as part of a Home Health 
visit. 


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Table 7.1.3: Enrollment in Treatment Extension Period, Study Duration, and Post-
study KRN23 Treatment by Country or Region 
Country/ 
Region 
Enrollment in 
Treatment 
Extension Period 
Expected End of 
Study 
Study Duration 
Post-study KRN23 
Treatment  
Japan, Korea 
No 
Week 64/EOS I 
64 weeks 
Separate clinical trial or 
other mechanism 
Europe, 
Australia 
Yes 
September 2018 
Varies for individual 
subjectsa 
Separate clinical trial or 
other mechanism 
US 
Yes 
September 2018 
Varies for individual 
subjectsa 
Commercial KRN23 or 
other mechanism 
Canada 
Yes 
June 2019 
Varies for individual 
subjectsa 
Commercial KRN23 or 
other mechanism 
a 
Maximum: 140 weeks 
 
The study will be conducted in a pediatric population; as such, additional measures including 
an external, independent DMC have been incorporated into the study design. Where possible, 
measures to minimize pain and distress to the subject have been considered for this study 
protocol including the use of home health visits (KRN23 treatment arm only). At every home 
health visit for subjects in the KRN23 treatment arm, all subjects randomized to the active 
control arm will receive a phone call to assess adverse events and concomitant medications. 
Home Health visits are not applicable to subjects in Japan or Korea. Where possible, timing 
of assessments will be coordinated with standard safety laboratory tests to minimize risk and 
discomfort and avoid unnecessary duplication of testing. The primary analysis will be at 
Week 40; analyses at Week 64/EOS I and Week 140/EOS II will assess the durability of 
treatment effect, additional efficacy outcomes, and long-term safety. The end of the study is 
defined as the date of the last protocol-specified procedures (including telephone contact) for 
the last subject in the study.  
Figure 7.1.1 provides a schematic of the overall study design.  


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An open-label study design was chosen since blinding such a study would be problematic 
due to the different methods of administration and the individualized nature and frequent 
dose adjustments needed with oral phosphate/active vitamin D therapy.  
Data from the ongoing pediatric Phase 2 study (UX023-CL201) helped establish the dose 
regimen and provided information for the design of this Phase 3 clinical trial in children with 
XLH. Interim data from the pediatric Phase 2 study suggested KRN23, administered Q2W 
at approximately 0.8 mg/kg for 40 weeks, increased serum phosphorus by an average of 
0.7 mg/dL; increases of > 0.5 mg/dL were seen in 83.3% of subjects. Serum 1,25(OH)2D 
concentrations and TmP/GFR levels also increased, demonstrating overall improved 
phosphorus homeostasis. The increases in serum phosphorus and 1,25(OH)2D were sufficient 
to provide substantial healing of rickets. No subjects have experienced serum phosphorus 
levels above the upper limit of normal. The Q2W dosing regimen was chosen for this Phase 3 
study because it appeared to produce a more stable and consistent increase in serum 
phosphorus levels with less fluctuation over time than the Q4W dosing regimen, and a safety 
profile that was not substantially different from the Q4W dosing regimen. 
Although there are no approved therapies for children with XLH, the most common 
treatment consists of multiple daily doses of oral phosphate combined with appropriate doses 
of active vitamin D analogs, most frequently calcitriol or alfacalcidol. Because of the 
variability in the doses and dosing frequencies of oral phosphates and active vitamin D 
therapies in clinical practice, these treatments will be individualized for each subject at the 
investigator’s discretion, but general guidance is provided based on expert recommendations 
in the US and Europe as described in Table 7.1.1 and Table 7.1.2.  
The duration of treatment is intended to define whether KRN23 is safe for long-term use and 
provide sufficient insight on sustained clinical effects and improvements in rickets and active 
bone disease in pediatric XLH patients. The primary analysis will be at Week 40; analyses at 
Week 64/EOS I and Week 140/EOS II will assess the durability of treatment effect, 
additional efficacy outcomes, and long-term safety. 
Change in rickets as measured by the RGI-C is deemed to be an appropriate primary efficacy 
endpoint in this study since it is the basis for, and correlates with the major morbidities 
patients with XLH suffer during their lifespan. A disease-specific RGI-C scale can be used to 
evaluate treatment-related changes in the severity of rickets and bowing in an individual 
subject. The RGI-C system of evaluating pre- and post- images in a side-by-side comparison 
is also ideal for the evaluation of healing of rickets as it most closely resembles the approach 
used by radiologists in the clinical setting to evaluate changes in the appearance of bone. 
Three pediatric radiologists not affiliated with the conduct of the study and who are blinded 
to subject number and treatment assignment will be contracted by a central imaging facility 
to perform RGI-C ratings. The ratings will be performed independently using an EDC system 
with the raters having no opportunity to discuss images or compare ratings. The mean of the 
scores assigned by the 3 independent raters is used to calculate an RGI-C wrist score, an 
RGI-C knee score, and a global RGI-C score. 


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The primary hypothesis of the primary endpoint is to test whether there is a difference 
between the KRN23 and active control (oral phosphate/active vitamin D) groups in the mean 
RGI-C global scores at Week 40. The RSS will serve as a complementary analysis to the 
RGI-C scale and is the method currently being used in the ongoing pediatric Phase 2 Study. 
Additional secondary endpoints are designed to evaluate the beneficial impact of KRN23 in 
maximizing growth, restoring phosphorus homeostasis, ameliorating defective bone 
mineralization, reducing the clinical burden of disease, as well as to evaluate the safety of 
KRN23 in pediatric XLH.  
The purpose of Treatment Extension Period is to continue to provide KRN23 treatment after 
the Treatment Period to subjects in Europe, the US, Canada, and Australia while also 
continuing to collect long-term safety and efficacy data. 
7.3 
Selection of Study Population 
The proposed patient population for this Phase 3 study is pediatric patients with a diagnosis 
of XLH and rickets (as documented by bilateral PA hand/wrist radiographs). The proposed 
key inclusion/exclusion criteria are summarized in Sections 7.3.1 and 7.3.2.  
To ensure that appropriate patients are selected, eligibility requirements include 
demonstrated hypophosphatemia, radiographic evidence of rickets, and genetic evidence 
consistent with a diagnosis of XLH. PHEX sequence variants will be classified consistent 
with the joint consensus recommendations of the American College of Medical Genetics and 
Genomics and the Association for Molecular Pathology (Richards et al. 2015). Patients with 
PHEX mutations classified as pathogenic, likely pathogenic, and possibly pathogenic will be 
included. Patients with PHEX variants of uncertain significance will also be included, as was 
recommended by experts in pediatric XLH. There are hundreds of variants of the PHEX gene 
and many of these have not yet been fully characterized. The study also requires patients to 
receive oral phosphate/active vitamin D therapy for ≥ 12 consecutive months prior to 
screening (for children ≥ 3 years of age) or ≥ 6 consecutive months (for children < 3 years of 
age), 7 days prior to the Randomization Visit.. 
To ensure that the patients enrolled will have open epiphyses for the duration of the study, 
only patients ≤ 12 years of age will be included and patients with a Tanner stage 4 or higher 
will be excluded. Limiting the maximum age to 12 years will help to ensure patients’ 
epiphyses will remain open during the course of the study so that changes in rickets and 
growth can be evaluated. Week 40 results (N=36) from Phase 2 Study (UX023-CL201) 
indicated that to best demonstrate a treatment effect and maximize the ability to detect 
change, baseline rickets should be clearly evident radiographically; the minimal threshold of 
baseline rickets severity to consistently detect change with treatment based on the current 
UX023-CL201 data is an RSS score of ≥1.5. To ensure that all patients will have significant 
rickets at baseline, the study will include patients with a baseline total RSS of 2.0 or higher. 
Patients will be required to have been on oral phosphate/active vitamin D treatment for at 
least 12 consecutive months (for children ≥3 years of age) or ≥ 6 consecutive months (for 


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children <3 years of age) and have residual disease despite this in order to show the effect of 
KRN23 in a relevant population in which the unmet medical need is very clear. A majority of 
patients with XLH receive treatment within the first 2 years of life. Therefore, the study will 
not enroll any treatment-naïve patients. To ensure the protection and safety of the study 
population, the study excludes patients with evidence of hyperparathyroidism, hypocalcemia, 
and hypercalcemia. 
Females are affected more frequently than males, consistent with X-linked dominant 
inheritance (Ichikawa et al. 2013). However, it is unclear whether the severity of disease is 
affected by sex or gene dosage. Therefore, no more than 70% female subjects will be 
enrolled. 
Children with XLH undergo a normal pubertal growth spurt. Post-pubertal height is predicted 
by pre-pubertal height, indicating that loss of height potential generally occurs prior to 
puberty. Published retrospective data suggest that earlier treatment leads to better outcomes 
for children with XLH (Makitie et al. 2003), (Quinlan et al. 2012). Thus, initiation of therapy 
at early ages is recommended to achieve improved height outcomes (Carpenter et al. 2011). 
Consequently, children younger than 5 years of age were included to determine if earlier 
treatment with KRN23 would confer greater benefits in improving rickets and growth 
potential, as well as in restoring normal phosphorus homeostasis. At least 20 subjects aged 1 
to < 5 years will be included (approximately 10 in each treatment arm). 
The Sponsor has taken reasonable measures to ensure the protection and safety of this 
population. Patients with evidence of tertiary hyperparathyroidism or nephrocalcinosis will 
be excluded. Appropriate pediatric expertise will be available at all trial sites, and site 
personnel will be focused on minimizing risk, fear, pain and distress during conduct of the 
study. 
7.3.1 
Inclusion Criteria 
Note: All laboratory evaluations required for study eligibility will be determined centrally 
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Male or female, aged 1 to ≤12 years with radiographic evidence of rickets with a 
minimum rickets severity score (RSS) total score of 2.0 as determined by central 
read  
2) PHEX mutation or variant of uncertain significance in either the patient or in a 
directly related family member with appropriate X-linked inheritance  
3) Biochemical findings associated with XLH: Serum phosphorus < 3.0 mg/dL 
(< 0.97 mmol/L)*  
4) Serum creatinine below the age-adjusted upper limit of normal * 
5) Serum 25(OH)D above the lower limit of normal (≥16 ng/mL) at the Screening 
Visit** 


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6) Have received both oral phosphate and active vitamin D therapy for 
≥ 12 consecutive months (for children ≥ 3 years of age) or ≥ 6 consecutive months 
(for children <3 years of age) 7 days prior to the Randomization Visit 
7) Willing to provide access to prior medical records for the collection of historical 
growth and radiographic data and disease history.  
8) Provide written or verbal assent (as appropriate for the subject and region) and 
written informed consent by a legally authorized representative after the nature of 
the study has been explained, and prior to any research-related procedures. 
9) Must, in the opinion of the investigator, be willing and able to complete all aspects 
of the study, adhere to the study visit schedule and comply with the assessments. 
10) Females who have reached menarche must have a negative pregnancy test at 
Screening and undergo additional pregnancy testing during the study. Female 
subjects of childbearing potential must be willing to use a highly effective method 
of contraception for the duration of the study plus 12 weeks after stopping the study 
drug. Sexually active male subjects with female partners of childbearing potential 
must consent to use a condom with spermicide or a highly effective method of 
contraception for the duration of the study plus 12 weeks after stopping the study 
drug. 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1) Tanner stage 4 or higher in any of the following: genitals, breast, or pubic hair, 
based on physical examination 
2) Height percentile > 50th based on country-specific norms 
3) Use of aluminum hydroxide antacids (eg, Maalox® and Mylanta®), systemic 
corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit 
4) Current or prior use of leuprorelin (eg, Lupron®, Viadur®, Eligard®), triptorelin 
(TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty  
5) Use of growth hormone therapy within 12 months before the Screening Visit 
6) Presence of nephrocalcinosis on renal ultrasound grade 4 based on the following scale:  
0 = Normal 
1 = Faint hyperechogenic rim around the medullary pyramids 
2 = More intense echogenic rim with echoes faintly filling the entire pyramid 
3 = Uniformly intense echoes throughout the pyramid 
4 = Stone formation: solitary focus of echoes at the tip of the pyramid 


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7) Planned orthopedic surgery, including osteotomy or implantation or removal of 
staples, 8-plates, or any other hardware, within the first 40 weeks of the study 
8) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the 
age-adjusted normal limits* 
9) Evidence of hyperparathyroidism (PTH levels 2.5X upper limit of normal [ULN])  
10) Use of medication to suppress PTH (eg, cinacalcet, calcimimetics) within 2 months 
prior to the Screening Visit 
11) Presence or history of any condition that, in the view of the investigator, places the 
subject at high risk of poor treatment compliance or of not completing the study. 
12) Presence of a concurrent disease or condition that would interfere with study 
participation or affect safety  
13) History of recurrent infection or predisposition to infection, or of known 
immunodeficiency 
14) Use of a therapeutic monoclonal antibody within 90 days prior to the Screening 
Visit or history of allergic or anaphylactic reactions to any monoclonal antibody 
15) Presence or history of any hypersensitivity to KRN23 excipients that, in the 
judgment of the investigator, places the subject at increased risk for adverse effects. 
16) Use of any investigational product or investigational medical device within 30 days 
prior to screening, or requirement for any investigational agent prior to completion 
of all scheduled study assessments. 
OR, in Japan, use of any investigational product or investigational medical device 
within 4 months prior to screening, or requirement for any investigational agent 
prior to completion of all scheduled study assessments. 
* Criteria to be determined based on overnight fasting (min. 4 hours) values collected at 
the Screening and/or Baseline Visit  
** If 25(OH)D levels are below the normal range, 25(OH)D supplementation will be 
prescribed. Assuming a subject meets all other eligibility requirements, the subject may 
be rescreened after a minimum of 7 days of treatment 
7.3.3 
Removal of Subjects from Therapy or Assessment 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason. The investigator and Ultragenyx also have the right to 
remove subjects from the study. Ultragenyx must be notified of all subject withdrawals as 
soon as possible. Ultragenyx also reserves the right to discontinue the study at any time for 
either clinical or administrative reasons and to discontinue participation of an individual 
subject or investigator due to poor enrollment or noncompliance, as applicable. 


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Subjects may be removed from the study for the following reasons: 
 Occurrence of an unacceptable AE 
 An illness that, in the judgment of the investigator or Ultragenyx, might place the subject 
at risk or invalidate the study  
 Pregnancy in subject 
 At the request of the subject, investigator, or Ultragenyx, for administrative or other 
reasons 
 Protocol deviation or noncompliance 
If the reason for removal of a subject from the study is an AE, the AE and any related test or 
procedure results will be recorded in the source documents and transcribed onto the Case 
Report Form (CRF). Each clinically significant abnormal laboratory value or other clinically 
meaningful abnormality should be followed until the abnormality resolves or until a decision 
is made that it is not likely to resolve. If such abnormalities do not return to normal within 
12 weeks after the last dose given, their etiology should be identified and Ultragenyx should 
be notified. All unscheduled tests must be reported to Ultragenyx immediately. 
If a subject discontinues from the study prematurely, every reasonable effort should be made 
to perform the Early Termination Visit procedures within 4 weeks of discontinuation. 
Subjects who discontinue KRN23 due to an SAE will be monitored for safety for a period of 
12 weeks after the date of last study drug administration. 
7.3.3.1 
Stopping Rules 
A Data Monitoring Committee (DMC) will be constituted for Study UX023-CL301 and will 
act in an advisory capacity to monitor the safety of KRN23 on a routine basis throughout the 
trial (Section 7.6.6). The DMC may provide advice to Ultragenyx to aid in the determination 
of whether study enrollment should be paused or if the study should be stopped. If the 
Sponsor deems it appropriate to restart the trial following an internal safety review, this will 
be done only following approval by Regulatory Authorities. 
Individual subjects who experience any unexpected and possibly, probably, or definitely 
drug-related SAEs (Section 8.5.3) that represent a change in the nature or an increase in 
frequency of the serious event from their prior medical history will be assessed as to whether 
the subject will continue on the study.  
Individual subjects will be monitored for renal ultrasound (Section 7.5.3). If new or clinically 
significant worsening in mineralization is considered clinically meaningful by the 
investigator and/or sponsor and related to study drug, the subject will be discontinued from 
the study. 
Regulatory Authorities, as well as the Institutional Review Board (IRB)/Ethics Committee 
(EC) will be informed should unexpected and possibly, probably, or definitely drug-related 


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SAEs occur. A full clinical evaluation of the event will be performed in order to make a 
decision regarding what actions to take, including whether to recommend stopping the study. 
Regulatory Authorities, as well as IRBs/ECs, will be informed if the study is paused or 
stopped. 
7.4 
Treatments 
The study drug and reference products are manufactured, packaged, and labeled according to 
Good Manufacturing Practice (GMP) regulations. The Investigational Product should be 
securely stored under conditions indicated in the IB. 
The amount of investigational product administered will be calculated based on a subject’s 
weight (Section 7.4.1). Treatment with oral phosphates and active vitamin D will be 
individualized to reflect real-world clinical practice, but general guidance will be provided 
(Section 7.4.2).  
Selection of doses, dose titration, and dose adjustments for the investigational product are 
described in Section 7.4.4. 
7.4.1 
Investigational Product (KRN23) 
KRN23 is a sterile, clear, colorless, and preservative-free solution in single-use 5-mL vials 
containing 1 mL of KRN23 at a concentration of 10 mg/mL or 30 mg/mL. The starting dose 
will be 0.8 mg/kg Q2W. The dose may be increased to 1.2 mg/kg at any time during the 
study if a subject meets the following dose-adjustment criteria: 1) 2 consecutive serum 
phosphorus measurements are below the normal range; 2) serum phosphorus has increased 
by ≤ 0.5 mg/dL from baseline; and 3) the subject has not missed a dose of KRN23 that would 
account for the decrease in serum phosphorus. The maximum allowable dose of KRN23 per 
administration is 90 mg. 
At any time during the study, if serum phosphorus increases above the upper limit of normal 
(ULN) for age, the subsequent dose(s) will be withheld and the site will contact the medical 
monitor before dosing resumes. Once other causes of increased serum phosphorus are 
excluded, KRN23 treatment will resume at half the total dose of the last dose received (ie, 
half of either 0.8 mg/kg or 1.2 mg/kg; maximum dose per administration: 40 mg). Serum 
phosphorus will be followed through unscheduled serum phosphorus assessments 
(approximately 2 weeks post-dose and assessed by the central laboratory; the assessments 
may be repeated as necessary). A subject will resume dosing at the previous full total dose 
level if they meet the same dose-adjustment criteria listed above.  
Subjects will receive study drug via SC injection to the abdomen, upper arms, thighs, or 
buttocks; the injection site should be rotated with each injection. If the dose level exceeds 1.5 
mL in volume, the dose should be administered at 2 injection sites.  
KRN23 dosing should occur no sooner than 8 days after the last dose administered. 


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7.4.2 
Active Control (Reference) Therapy 
The study is designed as an open-label comparison with oral phosphate and active vitamin D 
therapy, which will be individualized by subject at the investigator’s discretion based on 
published US and European expert guidelines (Carpenter et al. 2011), (Linglart et al. 2014) 
(in Table 7.1.1 and Table 7.1.2). It should be noted that while commonly used, oral 
phosphate and active vitamin D therapy are not approved for the treatment of XLH.  
Detailed information about the brand, starting dosages, and any changes in oral phosphate 
and active vitamin D therapy will be determined by the treating Investigator within the expert 
guidelines and recorded at every site visit. US expert guidelines generally recommend a 
calcitriol dosage of 20 to 30 ng/kg/day in 2 to 3 divided doses and an elemental phosphorus 
dose of 20 to 40 mg/kg/day (in 3 to 5 divided doses), acknowledging that some children 
require more, whereas some do well with less (Carpenter et al. 2011). European expert 
guidelines recommend an alfacalcidol dosage of 1 to 2 µg/day (once daily) and a phosphate 
supplemental dose of 45 to 70 mg/kg/day (in 3 to 4 divided doses) (Linglart et al. 2014). 
Calcitriol and alfacalcidol dosages should be adjusted based on the clinical and laboratory 
values that guide best possible treatment. 
7.4.3 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be enrolled in the study and sequentially assigned an identification 
number. Subjects will be randomized 1:1 to receive open-label KRN23 by subcutaneous 
injection or active control via an Interactive Web Response System (IWRS) based on a 
randomization schedule developed by an independent third-party vendor. Randomization will 
be stratified by baseline rickets severity (RSS total score ≤ 2.5 vs > 2.5) and age (< 5 vs 
≥ 5 years).  
After completion of the 64-week Treatment Period, subjects in Europe, the US, Canada, and 
Australia who were randomized to KRN23 will continue treatment with KRN23 at their 
previous dose and regimen in the Treatment Extension Period. Subjects in Europe, the US, 
Canada, and Australia who were randomized to active control will cross over to receive 
KRN23 at the starting dose and regimen administered to subjects in the KRN23 arm (starting 
dose of 0.8 mg/kg Q2W; dose may be increased to 1.2 mg/kg Q2W). 
7.4.4 
Selection of Doses and Study Duration 
The amount of KRN23 administered will be calculated based on the subject’s weight. 
As discussed earlier, data from the pediatric Phase 2 study suggested KRN23, administered 
Q2W at approximately 0.8 mg/kg for 40 weeks, increased serum phosphorus by an average 
of 0.7 mg/dL; increases of > 0.5 mg/dL were seen in 83.3% of subjects. The Q2W dosing 
regimen was chosen for this Phase 3 study because it appeared to produce a more stable and 
consistent increase in serum phosphorus levels with less fluctuation over time than the every 
4 week (Q4W) dosing regimen, and a safety profile that was not substantially different from 
the Q4W dosing regimen. 


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The duration of treatment is intended to define whether KRN23 is safe for long-term use and 
provide sufficient insight on sustained clinical effects and improvements in rickets and active 
bone disease in pediatric XLH patients. A study duration of 40 weeks, similar to the Phase 2 
study (UX023-CL201), is considered sufficient to observe treatment effect on rickets; 
therefore, the primary analysis was established at Week 40. A longer period of 64 weeks will 
assess the durability of treatment effect, additional efficacy outcomes, and long-term safety. 
The Treatment Extension Period will provide long-term safety and efficacy data up to 
140 weeks.  
Treatment duration will vary by region. The study consists of a Treatment Period (64 weeks) 
for all subjects and a Treatment Extension Period (up to 76 weeks) for subjects in Europe, the 
US, Canada, and Australia. For subjects in Japan and Korea, the planned duration of 
treatment in this study is 64 weeks, and the Week 64 visit at the end of the Treatment Period 
will be the EOS I visit. For subjects in Europe, the US, Canada, and Australia, the planned 
duration of treatment is up to 140 weeks (64 weeks in the Treatment Period and up to 
76 weeks in the Treatment Extension period). In Europe and Australia, treatment in the 
Treatment Extension Period will end by September 2018, and subjects will be enrolled in 
separate clinical trials of KRN23 or will receive KRN23 through another mechanism. In the 
US and Canada, treatment in the Treatment Extension Period will end by September 2018 or 
June 2019, respectively (expected availability of commercial KRN23); subjects will receive 
commercial KRN23 or will receive KRN23 through another mechanism. The duration of 
Treatment Extension Period will vary for individual subjects and will be determined by the 
time from Week 64 through the EOS II visit. 
The end of the study for reporting purposes is defined as the date of the last protocol-
specified procedures (including telephone contact) for the last subject in the study. 
7.4.5 
Prior and Concomitant Therapy 
Throughout the study, there should be no significant changes to a subject’s diet or medication 
schedule unless medically indicated. Investigators may prescribe any concomitant 
medications or treatments deemed necessary to provide adequate supportive care, except 
those listed in Section 7.4.5.1. All concomitant medications taken during the study will be 
recorded in the CRF with indication, dose information, and dates of administration. 
Any changes to concomitant medication will also be documented. 
7.4.5.1 
Prohibited Medications 
To be eligible for the study, all subjects will undergo a washout period where they will 
discontinue treatment with oral phosphates and pharmacologic vitamin D metabolites or 
analogs (eg, calcitriol, doxercalciferol, alfacalcidol, and paricalcitol) for 7 days prior to 
randomization. Eligible subjects will then be randomly assigned to receive either KRN23 
treatment or oral phosphates/active vitamin D treatment (control). Subjects randomly 
assigned to KRN23 are prohibited from receiving oral phosphates and active vitamin D for 


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the duration of the study. Subjects randomly assigned to the active control arm will be 
permitted to receive oral phosphates/active vitamin D treatment after randomization.  
At Week 64 for subjects continuing into the Treatment Extension Period, subjects 
randomized to active control in the Treatment Period will cross over to receive KRN23 at the 
dose and regimen administered to subjects in the KRN23 arm. Active control will be 
discontinued after the Week 64 visit to allow washout of oral phosphate and active vitamin D 
treatments before the first dose of KRN23 at Week 66. 
In addition, subjects must agree to discontinue use of certain medications for the indicated 
timeframe to qualify for study entry (Section 7.3).  
 Growth hormone therapy within 12 months before the Screening Visit 
 Aluminum hydroxide antacids (eg, Maalox® and Mylanta®), systemic corticosteroids, 
acetazolamide, and thiazides within 7 days prior to the Screening Visit 
 Current and prior use of leuprorelin (eg, Lupron®, Viadur®, Eligard®), triptorelin 
(TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty 
 PTH suppressors (eg, Sensipar®, cinacalcet, calcimimetics) within 2 months prior to the 
Screening Visit 
 Any therapeutic mAb therapy within 90 days prior to the Screening Visit 
NOTE: Oral phosphate treatment must be down-titrated slowly to avoid hypercalciuria. 
Vitamin D metabolites or analogs may be discontinued without titration.  
7.4.5.2 
Permitted Medications 
Other than the medications specifically prohibited in this protocol, subjects may receive 
concomitant medications as required. Subjects randomly assigned to the active control arm 
may receive oral phosphate/active vitamin D treatment after a 7-day washout and 
randomization. If serum 25-hydroxyvitamin D (25(OH)D) levels fall below 16 ng/mL, 
oral supplementation may be provided. Medications (investigational, prescription, over-the-
counter, and herbal) and nutritional supplements taken during the 30 days prior to Screening 
Visit will be reviewed and recorded. 
7.4.6 
Treatment Compliance 
Trained personnel will administer KRN23 by SC injection or dispense oral phosphates and 
active vitamin D treatment at the investigational site or during home health visits (KRN23 
treatment arm only) as indicated in the Schedule of Events (Table 2.1 Table 2.2, and 
Table 2.3). Each administration of study drug or oral phosphate/active vitamin D (including 
type, dose, and frequency) will be recorded on the CRF. If a subject does not receive a dose 
within 10 days of a scheduled dose for the Q2W regimen of study drug, that dose should be 
skipped and the next dose will be administered at the next scheduled Q2W dosing visit.  


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7.5 
Study Procedures and Assessments 
7.5.1 
Schedule of Events 
The schedule of visits and assessments are provided in Table 2.1 and Table 2.2, and 
Table 2.3. Home Health visits (KRN23 treatment arm only) may be conducted at the 
investigational site depending on the preference of the subject and proximity of the subject to 
the clinic. Refer to the Study Reference Manual for additional details and a recommended 
schedule of specific assessments.  
Potential subjects will come in to the site for an initial Screening Visit and provide informed 
consent. All subjects will have x-rays (knees and hand/wrist) at the Screening Visit and 
confirmed by central read prior the Baseline visit to determine if the subject meets the 
eligibility criteria. If radiographic evidence of rickets is not present (ie, RSS total score ≥2.0), 
the subject will be considered a screen failure. Patients with confirmed rickets who also have 
a PHEX mutation or variant of uncertain significance in either self or an appropriate directly 
related family member can start the process of weaning from oral phosphate/active vitamin D 
therapy (Section 7.4.5.1) and return to the site after 7 days for the Baseline visit if all other 
inclusion criteria are met. PHEX mutation analysis will be performed in all subjects. 
Potential subjects without a previously confirmed PHEX mutation will be notified of PHEX 
mutation results, and if presence of a mutation is confirmed, will have the baseline visit 
scheduled. 
Subjects who successfully pass the requirements at the Screening Visit will discontinue oral 
phosphate for a minimum of 7 days and active vitamin D therapy for a minimum of 7 days 
prior to the Baseline visit. The Screening Visit window may be up to 8 weeks for PHEX 
mutation analysis and washout of oral phosphate and active vitamin D therapy. Subjects who 
have serum 25(OH)D below the lower limit of normal (16 ng/mL) will need to have the 
levels corrected and, assuming they meet all other eligibility requirements, the subject may 
be rescreened after a minimum of 7 days. Walking ability (6MWT; for subjects ≥ 5 years of 
age at the Screening Visit) will be completed at the Screening Visit (for practice) and at the 
Baseline (Week 0) visit; the Baseline 6MWT must be assessed on the same day that the 
questionnaires are administered. Pain, fatigue, and physical function (PROMIS [Patient-
Reported Outcomes Measurement Information System] Pain Interference, Physical Function 
Mobility and Fatigue domain scores; for subjects ≥ 5 years of age at the Screening Visit); 
pain intensity (Faces Pain Scale – Revised [FPS-R] for subjects ≥ 5 years of age at the 
Screening Visit, and the SF-10 for Children Health Survey (SF-10; for subjects ≥ 5 years of 
age at the Screening Visit) may be completed at the Baseline visit.  
Historical radiographs of the anteroposterior (AP) knee, posteroanterior (PA) hand/wrist, and 
long leg are of importance and interest to evaluate the presentation and severity of the 
subject’s XLH disease and rickets severity over time. Available AP knee, PA hand/wrist, and 
standing long leg radiographs taken in the 5 years prior to the Screening Visit will be 
collected; radiographs of other skeletal locations will not be collected. Approximately 1 set 
of radiographs per year will be collected; if there are multiple sets within a year, the set 


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closest to the subject’s birthday should be obtained. The wrist and knee radiographs will be 
used to evaluate rickets severity and to determine how much rickets fluctuate over time in 
patients who were treated with oral phosphate/active vitamin D prior to study enrollment. 
The standing long leg radiographs will be used to assess changes in genu varum and/or 
valgum following prolonged treatment with oral phosphate/active vitamin D prior to study 
enrollment. The images will be de-identified and rated using the RSS and RGI-C. 
Similarly, historical growth data are of importance and interest. All available recumbent 
length and standing height data assessed prior to the Screening visit will be collected.  
All study visits will be scheduled relative to the Baseline visit, with an allowable variance of 
± 3 days for each visit (with the exception of the Screening and Safety Follow-up Visits) to 
accommodate scheduling. All Screening/Baseline assessments and inclusion/exclusion 
criteria based on central laboratory results must be satisfied prior to randomization and 
dosing. KRN23 dosing should occur no sooner than 8 days since the last dose administered. 
Subjects may be monitored between site visits through a series of Home Health visits 
(KRN23 treatment arm only) depending on the preference of the subject and the proximity of 
the subject to the site. Home Health visits are not applicable to subjects in Japan or Korea. 
The visit window for Home Health visits is ±3 days during the Treatment Period. HH visits 
are not required for subjects randomized to the active control arm because they do not require 
their medicine to be administered by a healthcare professional. To more closely mimic 
clinical practice, subjects randomized to the active control arm will only be seen at the site 
visits. For subjects who discontinue prior to completing the study, every reasonable effort 
should be made to perform the Early Termination visit procedures within 4 weeks of 
discontinuation. X-rays will not be performed at the Early Termination visit if post-treatment 
test(s) have been performed within 6 months of Early Termination. Similarly, the 6MWT 
will not be performed at the Early Termination visit if post-treatment test(s) have been 
performed within 3 months of Early Termination or if Early Termination occurs after 
Week 64. 
Post-study safety follow-up calls and safety visits will occur only for subjects who are not 
documented to be continuing on KRN23 at the Week 64/EOS I Visit or EOS II Visit, as 
appropriate. A safety follow-up telephone call will occur for these subjects at 5 weeks 
(+5 days) after the Week 64/EOS I visit (in Japan and Korea) or after the EOS II visit (in 
Europe, the US, Canada, and Australia) to determine if the subject is receiving KRN23 
therapy in another clinical trial, as commercial product, or through another mechanism. If 
KRN23 therapy has not been started, information on any ongoing or new AEs, SAEs, or 
concomitant medications will be collected. For subjects who do not continue KRN23 
therapy, an additional safety visit will occur 12 weeks ±1 week after the last dose of study 
drug. Every reasonable effort should be made to have required subjects return to the clinic for 
the final safety visit; however, subjects who are unable to return to the clinic for the final 
safety visit will be given the option of providing blood and urine samples as part of a Home 
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The end of the study is defined as the date of the last protocol-specified procedures 
(including telephone contact) for the last subject in the study. 
7.5.2 
Efficacy Measurements 
Clinical efficacy measures will evaluate the effect of KRN23 on bone health and functional 
outcome in children with XLH. Measures of healing of rickets, growth, and correction of 
skeletal deformity in the legs (including tibial/femoral bowing) will provide an overall 
assessment of KRN23 treatment on bone health. Assessments of walking ability and 
patient/parent-reported pain, fatigue, and physical function/mobility will provide insight into 
the effect of KRN23 on clinical outcomes.  
Refer to the Study Reference Manual for additional details on clinical efficacy measures. 
7.5.2.1 
Primary Efficacy Measurement 
XLH causes rickets in the wrists and/or knees and other bone abnormalities and the primary 
goals of treatment in children with XLH are to prevent and heal rickets and radiographic 
abnormalities. The primary efficacy endpoint in this study is change in rickets at Week 40 as 
assessed by the RGI-C global score.  
Bilateral AP knee radiographs and bilateral PA hand/wrist radiographs will be taken at the 
Screening Visit to confirm eligibility and at the Weeks 40, 64, 88, 112, and 140/EOS II (or 
Early Termination) study visits. Screening radiographs will be read centrally. Standing long-
leg radiographs will be taken at Baseline, Weeks 40, 64, 88, 112, and 140/EOS II (or Early 
Termination). Knee, hand/wrist, and standing long leg radiographs will be taken at Early 
Termination if post-baseline radiographs have not been obtained within 6 months of 
termination. Radiographs will be read centrally and will be interpreted. AP knee and PA 
hand/wrist x-rays will be acquired for all subjects and standing long leg x-rays will be 
acquired for all qualifying subjects. 
The RGI-C utilizes a 7-point ordinal scale to evaluate the extent of healing in pre- vs. 
post-treatment x-rays with scores ranging from -3 (very much worse or severe worsening of 
rickets or bowing) to +3 (very much better, indicating complete or near complete healing of 
rickets or significant improvement in bowing). Three pediatric radiologists not affiliated with 
the conduct of the study will be contracted by a central imaging facility to perform RGI-C 
ratings for the wrist, knee, and long leg images. The 3 raters will be blinded to subject 
number and treatment assignment. To keep the radiologists blinded to group (ie, KRN23 
treatment or active control group), x-ray pairs will be presented for review in random order 
and the radiologists will not be provided access to the protocol, subject identifiers, or 
information related to KRN23 or oral phosphate/active vitamin D treatment. The ratings will 
be performed independently using an EDC system with the raters having no opportunity to 
discuss images or compare ratings. For each rating exercise, radiographs are presented 
side-by-side with the earlier image (baseline) on the left and the later image on the right. 


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Radiographs will be taken at the Screening Visit and Weeks 40, 64/EOS I, 88, 112, and 
140/EOS II (or Early Termination). 
7.5.2.2 
Secondary Efficacy Measurements 
7.5.2.2.1 
Rickets Severity Score (RSS) 
As a complementary measure to the RGI-C, the RSS system is a 10-point radiographic 
scoring method that was developed to assess the severity of nutritional rickets in the wrists 
and knees based on the degree of metaphyseal fraying and cupping and the proportion of the 
growth plate affected (Thacher et al. 2000). With the RSS method, radiographs of the wrist 
and knee are scored individually by a central rater who is blinded to subject number, 
characteristics, and treatment assignment. Radiographs of the wrists and knees will be taken 
at the Screening Visit and Weeks 40, 64/EOS I, 88, 112, and 140/EOS II (or Early 
Termination). 
7.5.2.2.2 
Lower Extremity Deformities 
Clinical manifestations of XLH vary in severity, but patients most commonly present in 
childhood with genu varum or genu valgus deformities of the legs from prolonged weight 
bearing. Progressive bowing, knock knees, and antero-medial rotational torsion of tibiae are 
the predominant skeletal features of XLH in growing children (Carpenter et al. 2011). 
To assess lower extremity deformity, as well as other disease-specific lower extremity 
abnormalities, standing long leg x-rays will be taken at the Baseline Screening Visit and 
Weeks 40, 64/EOS I, 88, 112, and 140/EOS II (or Early Termination if post-baseline x-rays 
have not been obtained within 12 months of termination). Central readings of the standing 
long leg X-rays will be performed and ratings assigned using a disease-specific qualitative 
RGI-C scoring system. 
7.5.2.2.3 
Growth 
Short stature is one of the predominant features in growing children with XLH. Growth of 
the legs and trunk has been shown to be uncoupled in XLH and related to serum phosphate 
levels (Zivicnjak et al. 2011). Growth will be measured prior to and following treatment by 
changes in standing height and sitting height (and percentiles) for subjects ≥ 2 years old or in 
recumbent length (and percentiles) for subjects < 2 years old. Recumbent length will be 
measured in subjects < 2 years old or those unable or unwilling to stand for the measurement. 
Standing height/recumbent length measurements prior to treatment will be abstracted from 
medical records. Parents will also be asked to report their final adult height and this 
information will be recorded in the CRF. To assess growth during KRN23 treatment, 
standing height/recumbent length and sitting height will be measured by a clinical evaluator 
at Baseline and Weeks 24, 40, 64, 76, 88, 100, 112, 124, and 140 (or Early Termination). 
At each time point, heights or recumbent length will be assessed 3 times and each assessment 
will be recorded onto the subject chart and eCRF. An average of the 3 measurements will be 
calculated. All pre-treatment growth historical records will be collected. Change in growth 


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velocity will be evaluated pre-treatment and post-treatment at Weeks 40, 64/EOS I, 76, 88, 
100, 112, 124, and 140/EOS II (or Early Termination). 
7.5.2.2.4 
Pharmacodynamic Assessments 
KRN23 binds to and inhibits FGF23, which is an important regulator of serum phosphorus 
levels. Serum phosphorus will be measured as a key PD assessment in this study. To assess 
the spectrum of KRN23 biological activity on phosphorus homeostasis and markers of bone 
health, and optimize dose level and regimen, a panel of PD markers will be assessed as 
indicated in the Schedule of Events, including serum PD markers (phosphorus and 
1,25(OH)2D), markers of phosphate reabsorption (TmP/GFR and TRP), and a bone 
biomarker (ALP). 
PD parameters will be assessed by central laboratory to determine study eligibility. 
Where possible, PD parameters (serum phosphorus and ALP) will be assessed as part of the 
standard clinical laboratory tests for safety (Section 7.5.3.8).  
Two-hour fasting urine collection is required to assess phosphate reabsorption (TmP/GFR 
and TRP) based on simultaneous urine and blood creatinine and phosphorus concentrations, 
and is applicable in both fasting and non-fasting children (Payne 1998). For subjects 
< 5 years of age, spot urine may be collected in place of the 2-hr urine samples for 
measurements of urinary calcium, phosphorus, and creatinine. The duration of fasting time 
for all PD parameters will be recorded on the CRF. 
Refer to the study reference manual for additional details on PD parameters. 
7.5.2.2.5 
Walking Ability and Patient-reported Outcomes 
Gross motor impairment, including diminished walking ability, pain and muscle weakness 
are potential complications associated with XLH-related skeletal deformities.  
The Six Minute Walk Test (6MWT) will be administered in subjects ≥ 5 years of age at the 
Screening Visit at the following study visits: at the Screening Visit (for practice), Baseline 
(Week 0), and Weeks 24, 40, 64, 88, 112, and 140 (or Early Termination if post-baseline 
6MWT has not been obtained within 3 months of termination and Early Termination occurs 
at or before Week 140). If a subject is < 5 years of age at the Screening Visit, the 6MWT will 
not be assessed when the subject is over 5 years of age during the post-baseline visits. The 
6MWT will be administered by a trained clinician. Subjects will be instructed to walk the 
length of a pre-measured course for 6 consecutive minutes. The total distance walked at the 
end of 6 minutes will be recorded in meters (Geiger et al. 2007). 
The Patient-Reported Outcomes Measurement Information System (PROMIS) was 
developed by the National Institutes of Health and uses domain-specific measures to assess 
patient well-being (Broderick et al. 2013), (NIH 2015). The domain-specific approach is 
based on the idea that health attributes, such as pain and physical function are not unique to a 
specific disease. The PROMIS contains a bank of questions from which relevant items can be 


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extracted and used to create a custom form. The PROMIS Pain Interference, Physical 
Function Mobility, and Fatigue domain scores will be administered to subjects ≥ 5 years of 
age at the Screening Visit. To assess these health domains, items from the Pediatric Pain 
Interference, Physical Function Mobility, and Fatigue item banks (Version 2.0) were 
extracted to develop a self-report form that will be completed by children 8 years of age and 
older at the Screening Visit. For children ages 5 to < 8 years at the Screening Visit, the same 
items were extracted from the Parent Proxy item banks (Version 2.0) that will be completed 
by the parent or legal guardian. The Parent/Legal Guardian form will be used for the duration 
of the study for subjects < 8 years of age at the Screening Visit, even when a subject turns 
8 years old during the study. If a subject who is > 8 years of age at Screening has difficulty 
completing the PROMIS self-report, the investigator may allow the PROMIS interview to be 
administered by a trained clinic staff or allow the parent to complete the PROMIS Parent 
Proxy version. The reason should be carefully documented and consistent practice of 
administration should be maintained for every visit from Baseline. The PROMIS Pain 
Interference, Physical Function Mobility, and Fatigue measurements will be administered at 
Baseline (Week 0) and Weeks 24, 40, 64/EOS I, 88, 112, and 140/EOS II (or Early 
Termination).  
Pain intensity will be self-reported by subjects using the Faces Pain Scale – Revised (FPS-R) 
for subjects ≥ 5 years of age at the Screening Visit. The FPS-R is a self-reported measure of 
pain intensity developed for children (Hicks et al. 2001). It was adapted from the Faces Pain 
Scale (Bieri et al. 1990) to make it possible to score the sensation of pain on the widely 
accepted 0-to-10 metric. The FPS-R has been validated for use in children 5 to 16 years of 
age. The FPS-R graphically depicts pain intensity using faces with scores chosen from 0, 2, 
4, 6, 8, and 10 (0=no hurt; 10=hurts worst). The FPS-R will be administered at Baseline 
(Week 0) and Weeks 24, 40, 64, 88, 112, and 140 (or Early Termination).  
7.5.2.2.6 
Pharmacokinetic Assessment 
To assess KRN23 concentration and possible accumulation, serum pre-dose levels will be 
evaluated as a PK parameter in this study. A pre-dose blood sample will be obtained at 
Weeks 1, 2, 4, 8, 16, 24, 33, 40, 64/EOS I during the Treatment Period. For each sample 
collection, the time elapsed since last study drug administration will be recorded on the CRF. 
Subjects randomized to active control will not have blood samples drawn for this assessment 
during the Treatment Period; during the Treatment Extension Period, blood samples for 
KRN23 concentrations will be drawn on the same schedule as subjects originally randomized 
to KRN23, ie, Weeks 88, 112, and 140/EOS II (or Early Termination). In addition, for 
subjects crossing over to KRN23 during the Treatment Extension Period, a sample for 
KRN23 serum concentration will be drawn at Week 68. 
7.5.3 
Safety Measurements 
General assessments include Tanner staging for breast and testicular development, PHEX 
mutation analysis, medical history, and demographics. Safety will be evaluated by the 
incidence, frequency, and severity of adverse events (AEs) and serious adverse events 


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(SAEs), including clinically significant changes from baseline to scheduled time points in 
vital signs, weight, interval history and physical examination, eGFR, clinical laboratory 
evaluations (including additional KRN23/XLH biochemical parameters of interest), and 
concomitant medications. Ectopic mineralization safety assessments include renal ultrasound, 
echocardiogram (ECHO) and ECG, serum calcium and iPTH, and urinary calcium and 
creatinine. The development of anti-KRN23 antibodies and dose limiting toxicities (DLTs) 
will also be assessed. Refer to the Study Reference Manual for additional details on safety 
assessments. 
7.5.3.1 
Medical History 
General medical information includes subject demographics (date of birth, ethnicity, and sex) 
and a history of major medical illnesses, diagnoses, and surgeries. The review will also 
include an assessment of symptoms and conditions associated with XLH and previous 
treatments (eg, oral phosphate/active vitamin D).  
Subjects must be willing to provide access to prior medical records for the collection of 
radiographic data, as well as disease history. The specific diagnosis of XLH will be recorded, 
along with date of onset, clinical presentation, and date and method of diagnosis. Any 
available family history of XLH will be noted, including any available previous PHEX 
mutation analysis results for the subject or relevant family members with appropriate 
X-linked inheritance pattern. The height of both parents will also be recorded. 
XLH treatment history and relevant concomitant medications will be recorded (start date, 
stop date, dose, dose regimen). Previous treatments may include calcitriol and oral 
phosphate, calcimimetics, and or other adjunctive therapy. Medications include 
investigational, prescription, over-the-counter, herbal and nutritional supplements. 
Any relevant concomitant therapy, including physical/occupational therapy will be recorded.  
7.5.3.2 
Vital Signs Including Standardized Blood Pressure Measurement Procedure 
Vital signs will include seated systolic blood pressure and diastolic blood pressure measured 
in millimeters of mercury (mm Hg), heart rate in beats per minute, respiration rate in breaths 
per minute, and temperature in degrees Celsius (°C). Blood pressure (BP) measurements will 
only be obtained at clinic visits and only in children ≥3 years of age at the Screening Visit. 
Children who turn 3 years of age during the study will start BP assessments at the next 
scheduled clinic visit and continue with subsequent scheduled BP assessments for the 
duration of the study. The guidance provided by The Fourth Report on the Diagnosis, 
Evaluation, and Treatment of High Blood Pressure in Children and Adolescents (NIH 2005) 
will be used as a reference.  
Vital signs measurements will be obtained at each indicated visit (Table 2.1, Table 2.2, and 
Table 2.3). On the Screening and Baseline Visit, 2 sets of 3 BP measurements will be 
obtained - the first set will be done at the beginning of the visit and the second set at end of 
the visit after all site procedures are completed. BP measurements should be done after the 


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subject has rested for 5 minutes and a second and third BP measurement should be obtained, 
each performed 30 seconds apart. Thus there will be a total of 6 BP measurements on these 
2 visits. As part of the site initiation visit, standardized BP measurement training will be 
provided to all study personnel responsible for BP measurement and appropriate 
documentation in monitoring report. In addition, evidence of annual calibration of BP 
measurement device will be documented. 
Participants are instructed to refrain from exercise at least 30 minutes before and until 
completion of BP measurement. They are also instructed to refrain from playing video 
games, or other activities that may affect BP until all measurements are obtained. Clinic BP 
measurements are obtained in the right arm of the study participant. At each study visit, 
before BP determination, arm circumference is measured (in centimeters) with a plastic 
measuring tape at the midpoint of the upper arm between the acromium (tip of shoulder) and 
olecranon (tip of elbow) and a cuff is then selected so that the length of the cuff bladder is 
equal to 80% to 100% of the arm circumference. Effort should be made to use the same BP 
measuring device for BP measurements during subsequent visits. 
After 5 minutes of rest, pulse and BP measurements begin. The cuff is inflated approximately 
30 mm Hg above the pressure when the radial pulse is no longer felt. The BP measurements 
are obtained by auscultation (ie, manually and without using an automated device) of the 
brachial artery using the first Korotkoff sound for systolic BP (SBP) and the fifth Korotkoff 
sound for diastolic BP (DBP). Three BP measurements are obtained at a sitting and recorded 
in the participant’s BP records for the study visit. For the subsequent site visits post-baseline, 
3 BP measurements is recorded during the site visit. 
7.5.3.3 
Echocardiogram 
ECHO will be performed at Baseline and Weeks 40, 64/EOS I, 88, 112, and 140/EOS II (or 
Early Termination if not performed within 3 months of termination) in subjects ≥ 5 years of 
age at the Screening Visit. Children who turn 5 years of age during the study will start ECHO 
assessments at the next scheduled clinic visit and continue with subsequent scheduled ECHO 
assessments for the duration of the study. The goal is to assess for evidence of ectopic 
mineralization in the heart and aorta. Additional tests may be performed if any abnormalities 
are detected or if medically indicated. ECHO administration procedures will be standardized 
and results will be read centrally by trained site personnel.  
7.5.3.4 
Weight  
Weight will be obtained using a scale and recorded in kilograms at the Screening Visit, 
Baseline, and at study visits at Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64/EOS I, 76, 88, 100, 112, 
124, and 140/EOS II (or Early Termination) (Table 2.1, Table 2.2, and Table 2.3). 
In addition, for subjects crossing over to KRN23 during the Treatment Extension Period, 
weight will be obtained at Week 68. The subject’s weight collected at in-clinic visits will be 
the basis of the KRN23 dose calculation until the next in-clinic weight collection. 


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7.5.3.5 
Physical Examination 
Complete physical examinations will be performed at the Screening Visit, Baseline, and at 
the study visits at Weeks 8, 16, 24, 32, 40, 52, 64, 76, 88, 100, 112, 124, and 140 (or Early 
Termination) and at the Safety Visit (if applicable). In addition, for subjects crossing over to 
KRN23 during the Treatment Extension Period, a complete physical exam will be performed 
at Week 68. Physical examinations will include assessments of general appearance; head, 
eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, respiratory, 
gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. The genitourinary 
exam should be non-invasive, age-appropriate and consistent with the standard of care 
principles of the Investigator. The primary purpose of the genitourinary exam is to establish 
and monitor Tanner staging over the course of the study. 
7.5.3.6 
Renal Ultrasound and Glomerular Filtration Rate 
Renal ultrasounds will be conducted at the Screening Visit, and Weeks 24, 40, 64/EOS I, 88, 
112, and 140/EOS II visits (or Early Termination). The ultrasound will be interpreted by 
qualified personnel at the central laboratory for purposes of inclusion criteria.  
Baseline and all post-treatment renal ultrasounds will be evaluated by a trained central reader 
blinded to treatment assignment and subject data to evaluate changes in calcifications and all 
other renal abnormalities from baseline (.e, screening assessment). Ultrasonographic findings 
of nephrocalcinosis will be graded on a 5-point scale (Verge et al. 1991). 
The eGFR will be calculated using the Bedside Schwartz equation (Schwartz et al. 1976) for 
determining creatinine clearance.  
7.5.3.7 
Electrocardiogram 
A standardized 12-lead ECG will measure PR, QRS, QT, and QTc at Baseline and Weeks 24, 
40, 64/EOS I, 88, 112, and 140/EOS II (or Early Termination). The goal is to evaluate both 
for left ventricular hypertrophy (LVH) changes, as well as for changes in conductivity and 
intervals. ECG administration procedures will be standardized and results will be read 
centrally by qualified personnel blinded to treatment assignment and subject data. The ECG 
results will be assessed for any clinically significant abnormality or relevant changes from 
baseline. 
7.5.3.8 
Clinical Laboratory Tests for Safety 
A comprehensive serum metabolic panel (Chem-20), complete blood count, and urinalysis 
will be used as routine screens to assess safety. Certain analytes (eg, serum phosphorus) in 
the routine Chem-20 panel are also designated as PD/efficacy parameters in this study. 
Additional KRN23/XLH biochemical parameters of interest include serum 1,25(OH)2D, 
calcium, creatinine, and iPTH; and urinary phosphorus, calcium, and creatinine.  


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Blood and urine samples will be collected at Screening, Baseline, and regular intervals 
throughout the study as indicated in the Schedule of Events (Table 2.1, Table 2.2, and 
Table 2.3).  
Fasting for a minimum of 4 hours (overnight) is required prior to each blood draw; the 
duration of fasting will be recorded on the CRF. Twenty-four-hour urine collection for 
subjects ≥ 5 years of age is required to assess urinary phosphorus:creatinine and 
calcium:creatinine ratios; urinary phosphorus, a PD parameter will also be obtained from 
24-hour urine samples. Details for blood and urine collection can be found in the central 
laboratory manual. 
Pre- and post-prandial serum phosphorus and calcium concentrations will be assessed at a 
single visit in approximately 20 subjects (Section 7.5.4.3). 
Clinical laboratory parameters to be assessed for safety are provided in Table 7.5.3.8.1. 
See the Study Reference Manual for details on sample collection and processing.  


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Table 7.5.3.8.1: Clinical Laboratory Assessments for Safety 
Chemistry 
Hematology 
Urinalysis 
1,25(OH)2D 
Hematocrit 
Appearance 
Alanine aminotransferase (ALT) 
Hemoglobin 
Color 
Alkaline phosphatase (ALP)  
Platelet count 
pH 
Amylase 
Red blood cell (RBC) count 
Specific gravity 
Aspartate aminotransferase (AST) 
White blood cell (WBC) count 
Ketones 
Bilirubin (direct and total) 
Mean corpuscular volume (MCV) 
Protein  
Blood urea nitrogen (BUN) 
Mean corpuscular hemoglobin 
(MCH) 
Glucose  
Calcium (total) 
MCH concentration 
 
Chloride 
 
 
Cholesterol (total) 
 
24-hour Urine 
Creatinine 
 
Calcium 
Gamma-glutamyl transpeptidase 
(GGT) 
 
Calcium/creatinine 
ratio 
Glucose 
 
Creatinine 
Intact parathyroid hormone 
(iPTH) 
 
Phosphorus 
Lactate dehydrogenase (LDH) 
 
Phosphorus/creatinine 
ratio 
Lipase 
 
 
Phosphorus 
 
2-hour Urine 
Potassium 
 
Calcium 
Protein (albumin and total) 
 
Creatinine 
Sodium 
 
Phosphorus 
Uric acid 
 
Pregnancy test (if 
applicable) 
 
Subjects who experience a SAE possibly or probably related to study drug or other AE of 
concern may, at the discretion of the Investigator (and/or medical monitor), have additional 
blood samples taken for safety laboratory tests. 
7.5.3.8.1 
Intact Fibroblast Growth Factor 23 
Intact FGF23 (iFGF23) concentrations will be measured at Baseline and Weeks 24, 
64/EOS I, 88, 112, and 140/EOS II (or Early Termination) using a validated 
electrochemiluminescent assay (ECLA) developed by the Sponsor’s development partner 
KHK, and transferred to and run by a central laboratory.  


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7.5.3.8.2 
Anti-KRN23 Antibody Testing 
To determine the immunogenicity profile of KRN23 in children with XLH, blood samples 
will be obtained for anti-KRN23 antibody (anti-drug antibodies [ADA]) testing at Baseline, 
and at Weeks 4, 8, 16, 24, 40, 64/EOS I, 88, 112, and 140/EOS II (or Early Termination). 
The formation of anti-KRN23 antibodies in human serum will be determined using a 
validated ECLA and a 2-tiered strategy: screening assay and specificity confirmation assay. 
If the development of anti-KRN23 antibodies is suspected in a given subject, samples may be 
obtained at additional time points on a case-by-case basis, if warranted. Subjects randomized 
to active control will not have blood samples drawn for this assessment during the Treatment 
Period; during the Treatment Extension Period, blood samples for ADA will be drawn on the 
same schedule as subjects originally randomized to KRN23, ie, Weeks 88, 112, and 
140/EOS II. 
7.5.3.9 
Pregnancy Testing 
Female subjects of childbearing potential will have urine pregnancy tests throughout the 
study as indicated in Table 2.1, Table 2.2, and Table 2.3. Females not of childbearing 
potential are not required to undergo pregnancy testing, including those who have not 
experienced menarche or are permanently sterile. 
Female subjects of childbearing potential with a positive pregnancy test at Screening will not 
be enrolled in the study. 
Additional pregnancy tests will be performed at any visit in which pregnancy status is in 
question. A serum pregnancy test will be performed in the event of a positive or equivocal 
urine pregnancy test result, or can be performed if pregnancy test by urine is not feasible.  
Experience with KRN23 in pregnant women is limited. The study drug may involve risks to a 
pregnant female or unborn baby which are currently unknown. Female participants of child‐
bearing potential must consent to use a highly effective method of contraception listed below 
from the period following the signing of the informed consent through 12 weeks after 
stopping the study drug. Sexually active male subjects with female partners of childbearing 
potential must consent to use a condom with spermicide or one of the highly effective 
methods of contraception listed below from the period following the signing of informed 
consent through 12 weeks after stopping the study drug. 
Highly effective methods of contraception (CTFG 2014) 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 (IUD) or intrauterine hormone-releasing system (IUS) 


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 Bilateral tubal occlusion 
 Male sterilization, also called vasectomy  
 Sexual abstinence (ie, refraining from heterosexual intercourse during the entire period of 
risk associated with the study treatments, when this is in line with the preferred and usual 
lifestyle of the subject) 
Refer to Section 8.5.4.3 for Pregnancy Reporting requirements. 
7.5.3.10 Pregnancy of Subject or Partner 
Pregnancies in subjects or partners must be reported within 24 hours of knowledge of the 
event to Ultragenyx or its designee. Female subjects who, at any time during the study, have 
a positive serum pregnancy test will be discontinued from the study. The investigator must 
make every effort to follow the pregnancy of either subject or partner through resolution of 
the pregnancy (delivery or termination) and report the resolution to Ultragenyx or its 
designee. 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. 
Refer to the Study Reference Manual for details on the reporting procedures to follow in the 
event of pregnancy. 
7.5.3.11 Concomitant Medications/Therapies 
Concomitant medications and therapies will be reviewed and recorded in the subject’s CRF 
at each study visit to the investigational site and during Home Health visits (KNR23 
treatment arm only during the Treatment Period). Medications (investigational, prescription, 
over-the-counter, and herbal) and nutritional supplements taken during the 30 days prior to 
Screening will be reviewed and recorded. Therapies (physical therapy, occupational therapy 
as well as mobility and walking devices, including ankle-foot orthosis, braces, cane, crutches, 
walker, wheelchair etc.) utilized during the 30 days prior to Screening will also be reviewed 
and recorded. At each subsequent visit, change in medications and therapies since the 
previous visit will be recorded. A discussion of concomitant medications and therapies is 
provided in Section 7.4.5. 
7.5.3.12 Dose-limiting Toxicity 
A DLT is defined as the occurrence of any of the following:  
 Unexpected SAEs occurring during treatment considered to be either definitely, probably, 
or possibly related to the investigational product or the active control 
 A confirmed serum phosphorus level of ≥ 6.5 mg/dL (defined as hyperphosphatemia) at 
any time after dosing  
If a subject experiences a DLT, the planned dosing for that subject will be evaluated by the 
Investigator and Medical Monitor. The outcome of this investigation will determine the 
subjects’ continuation or withdrawal from the study. 


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7.5.3.13 Adverse Events 
All AEs will be recorded from the time the informed consent is signed through 12 weeks 
following the last dose of study drug, unless the subject enrolls in another clinical study of 
KRN23, is treated with commercially available KRN23, or is treated with KRN23 through 
another mechanism, at which point the collection of AEs within this study is no longer 
applicable. However, AEs will continue to be reported either under another KRN23 protocol 
or per post-approval requirements for safety monitoring, as applicable. 
For subjects not continuing KRN23 treatment under commercial use or another mechanism 
upon completion of study drug treatment or early withdrawal from this study, a Safety Visit 
will be conducted 12 weeks ±1 week after the last dose of KRN23 in this protocol. 
The determination, evaluation, reporting, and follow-up of AEs will be performed as outlined 
in Section 8.5. At-each visit, subjects will be asked about any new or ongoing AEs since the 
previous visit. Assessments of AEs will occur at each visit to the investigational site and at 
Home Health Visits (KNR23 treatment arm only).  
Clinically significant changes from baseline in physical examination findings, vital signs, 
clinical laboratory parameters, renal ultrasounds, eGFR, and ECGs will be recorded as AEs 
or SAEs, if deemed appropriate by the investigator. 
7.5.4 
Exploratory Assessments 
7.5.4.1 
Health-related Quality of Life 
Individuals with XLH are affected by skeletal abnormalities which may impact their 
physical and mental health status. The SF-10 for Children Health Survey (SF-10) is a 
caregiver-completed questionnaire designed to assess physical and psychosocial 
health-related quality of life in healthy and ill children (Saris-Baglama et al. 2006). 
The 10 items were adapted from the Child Health Questionnaire and utilize a 4-week recall 
period. Responses are used to generate 2 component summary scores: physical summary 
score (PHS-10) and psychosocial summary score (PSS-10). Higher global scores are 
associated with better quality of life. The SF-10 will be administered in subjects ≥ 5 years of 
age at the Screening Visit during the Baseline visit (Week 0), and Weeks 24, 40, 64/EOS II, 
88, 112, and 140/EOS II (or Early Termination). If a subject is < 5 years of age at the 
Screening Visit and therefore has no baseline data, SF-10 will not be administered even when 
the subject turns 5 during the study. Every attempt should be made to ensure that the 
responder completing the first administration completes subsequent administrations to 
minimize variability. 
7.5.4.2 
Dental Evaluation 
Some children with XLH may present with severe dental defects, which typically manifest as 
spontaneous infections leading in dental abscesses (Carpenter et al. 2011). These infections 


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are a result of defective dentin and enamel hypoplasia that diminishes the layer surrounding 
the pulp chamber, enabling oral bacteria to enter the pulp chamber and form abscesses.  
Dental evaluations will be conducted to assess the number of dental events from dental 
caries, delay in eruption of the dentition, enamel hypoplasia, dental abscesses, and gingivitis. 
At each clinic visit, an oral examination will be conducted by the investigator and subjects 
will be proactively asked if they had any dental events such as dental caries, tooth extraction, 
root canal, dental abscesses, and gingivitis. 
7.5.4.3 
Pre- and Post-prandial Serum Phosphorus and Calcium Concentrations 
Substudy 
Pre- and post-prandial serum phosphorus and calcium concentrations will be assessed at a 
single clinic visit anytime 10 to 14 days after a KRN23 dose. The substudy will be conducted 
at sites in the US, Canada, and Australia that are able to provide and observe a nutritionally 
defined meal in their clinic. The substudy will be conducted in approximately 20 subjects, 
age ≥ 3 years. 
The Investigators or Study Coordinators at the sites chosen will contact the subject/caregiver 
asking for participation in the substudy. If agreed, a clinic visit will be scheduled and the 
subject will be consented at that time and prior to any substudy assessments being conducted. 
The clinic visit may take the place of a Home Health visit or be at a regularly scheduled 
clinic visit. Before the visit at which the substudy assessments are conducted, subjects must 
have received at least 4 doses of KRN23 (≥ 8 weeks of treatment) with at least 80% 
compliance and did not miss the previous dose of KRN23. 
Subjects will fast overnight for a minimum of 8 hours, and fasting serum will be collected 
prior to breakfast (Table 7.5.4.3.1). Meals will contain predefined ranges of phosphate, 
calories, and carbohydrate and will be representative of a typical Western diet for children. 
Subjects will have the option of 2 to 3 nutritionally defined meals (depending on the clinical 
site). Subjects will be given a 1-hour window to consume the meal. Dietary phosphate will be 
estimated based on the amount of food consumed. Serum samples will be drawn 1 and 
2 hours after the completion of the meal. 


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Table 7.5.4.3.1: Schedule of Events for the Pre- and Post-prandial Serum Phosphorus 
Concentrations Substudy 
 
Prior to 
Substudy 
Assessments 
Hour 0 
Hour 1 
Hour 2 
Hour 3 
Informed consent 
X 
 
 
 
 
Serum phosphorus and calcium1 
 
X 
 
 
 
Begin meal2 
 
X 
 
 
 
End meal3 
 
 
X 
 
 
Serum phosphorus and calcium4 
 
 
 
X 
X 
1. Serum collected after at least 8 hours of fasting and before meal. 
2. Nutritionally defined meal typical of a Western diet for children with a known phosphate content 
(approximately 200 to 500 mg).  
3. Meal should be completed within 1 hour. If the meal cannot be completely consumed, record the quantity 
consumed. 
4. Serum collected 1 and 2 hours after completion of the meal. 
 
7.5.5 
Appropriateness of Measurements 
The assessments and timing of assessments used in this study, and the variables analyzed, are 
typical of those used to evaluate healing and severity of rickets, as well hypophosphatemia, 
renal reabsorption, and vitamin D metabolism in subjects with XLH. The primary goals of 
treatment in pediatric XLH patients are to correct or minimize rickets/osteomalacia, 
radiographic abnormalities, and skeletal deformities and improve growth outcomes 
(Carpenter et al. 2011). KRN23 binds to and inhibits FGF23. FGF23-mediated 
hypophosphatemia plays leads to rickets in children with XLH. Therefore, change in rickets 
in the KRN23 group will be the primary endpoint in this study. 
Radiographs are routinely recommended during the initial evaluation of XLH, and to 
evaluate healing of rickets and skeletal deformities. Performance measures such as the 
6MWT (≥ 5 years old at the Screening Visit) in subjects have been successfully used in other 
clinical development programs. Additionally, age-appropriate, patient-reported outcome were 
included to assess functional disability, pain, and health-related quality of life (ie, PROMIS 
Pediatric Pain Interference, Fatigue and Physical Function Mobility; FPS-R; and SF-10 in 
subjects ≥ 5 years old at the Screening Visit).  
Additional assessments are included both as PD measures and safety indicators of potential 
secondary complications associated with treatment, including serum phosphorus, serum 
calcium, 1,25(OH)2D, and urinary calcium and creatinine, as hypercalciuria may occur in the 
absence of hypercalcemia.  
Intact PTH (iPTH) levels and TmP/GFR are routinely measured as a part of oral 
phosphate/active vitamin D therapy in XLH, as secondary hyperparathyroidism is common. 
Biochemical markers of bone turnover that reflect rickets severity (eg, alkaline phosphatase 


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[ALP]) may provide an indication of treatment effect. The relatively extensive panel of 
biomarkers has been included in this Phase 3 study to provide the most information on 
relevant clinical laboratory parameters for endpoint confirmation and analysis. 
Where possible, timing of assessments has been coordinated with standard safety laboratory 
tests to minimize risk and discomfort and avoid unnecessary duplication of testing. 
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs, serum 
chemistry, concomitant medications, and other routine clinical and laboratory procedures. 
Routine, non-invasive procedures will provide relevant indicators of possible renal and 
cardiac risk; renal ultrasounds will be used to detect any calcinosis in susceptible organs. 
Since elevated free FGF23 has been associated with left ventricular hypertrophy (LVH) in 
patients with chronic kidney disease, ECGs will examine the potential risk in XLH subjects. 
The study will be conducted in a pediatric population, as such additional safety measures 
including Home Health care visits (KRN23 treatment arm only) and a DMC have been 
incorporated into the study design. Where possible, measures to minimize pain and distress 
to the subject have been considered for this study protocol.  
7.6 
Statistical Methods and Determination of Sample Size 
A full description of the analysis details will be provided in the Statistical Analysis Plan 
(SAP).  
7.6.1 
Determination of Sample Size 
This Phase 3 study is adequately powered to test the effect of KRN23 on improvement of 
rickets using RGI-C global score at Week 40 against the active control (oral phosphate and 
active vitamin D) based on the assumption of a mean RGI-C global score of 1.80 in the 
KRN23 group, 1.40 in the active control group, and a common standard deviation of 0.50. 
Given these assumption, a total sample size of 60 (30 per group) will provide approximately 
80% power to detect such a difference in the mean RGI-C global score at Week 40 between 
treatment groups using a 2-sample t-test with a 2-sided alpha level of 0.05. A 10% drop-out 
rate is incorporated in the sample size calculation. 
7.6.2 
Primary and Secondary Efficacy Endpoints 
7.6.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in rickets at Week 40 as assessed by the RGI-C 
global score. The primary endpoint will be compared between the KRN23 and active control 
(oral phosphate/active vitamin D) groups.  


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7.6.2.2 
Secondary Efficacy Endpoint(s) 
The following secondary endpoints will be compared between the KRN23 and active control 
groups: 
 Proportion of subjects with a mean RGI-C global score ≥+2.0 (substantial healing) at 
Week 40 and Week 64 
 Change in rickets at Week 64 as assessed by the RGI-C global score 
 Change from baseline in RSS total score at Weeks 40 and 64 
 Change in lower extremity skeletal abnormalities, including genu varum and genu valgus, 
as assessed by the RGI-C long leg score at Weeks 40 and 64 
 Change in standing height (or recumbent length in children <2 years) from baseline to 
Weeks 24, 40, and 64 in cm 
 Change in height-for-age z-scores from baseline to Weeks 24, 40, 64 
 Change in growth velocity from pre-treatment and post-treatment at Weeks 40 and 64 in 
cm/yr 
 Pharmacodynamic* assessments including  
o Change from baseline over time in serum phosphorus  
o Change from baseline over time in serum 1,25(OH)2D, urinary phosphorus, ratio 
of renal tubular maximum reabsorption rate of phosphate to glomerular filtration 
rate (TmP/GFR), and tubular reabsorption of phosphate (TRP) 
o Change and percent change from baseline over time in biochemical markers of 
bone turnover that reflect rickets severity (alkaline phosphatase [ALP]) 
* Blood and urine to be collected after a minimum overnight fasting time of 4 hours 
and prior to drug administration (if applicable) per dosing regimen 
 Pain, fatigue and physical function: Change from baseline in the PROMIS (Patient-
Reported Outcomes Measurement Information System) Pain Interference, Physical 
Function Mobility and Fatigue domain scores (for subjects ≥ 5 years of age at the 
Screening Visit) at Weeks 24, 40 and 64 
 Pain intensity: Change from baseline in the Faces Pain Scale – Revised (FPS-R) (for 
subjects ≥ 5 years of age at the Screening Visit) at Weeks 24, 40 and 64 
 Walking ability: Change from baseline in the Six Minute Walk Test (6MWT) total 
distance and percent of predicted normal (for subjects ≥ 5 years of age at the Screening 
Visit) at Weeks 24, 40, and 64 


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7.6.3 
General Principles 
A general description of the statistical methods to be used to analyze the efficacy and safety 
of KRN23 is outlined below. The analyses planned in this protocol will be expanded in the 
SAP to include detailed description of the analyses. The SAP will be finalized and approved 
prior to the database lock. Any deviations from the analyses described in the protocol and 
SAP will be noted in the final clinical study report. 
The completeness of the data affects the integrity and accuracy of the final study analysis. 
Therefore, every effort will be made to ensure complete, accurate and timely data collection, 
and to avoid missing data. The procedures for handling missing, unused, or spurious data, 
along with the detailed method for analyses will be presented in the SAP. 
The statistical analyses will be reported using summary tables, figures, and data listings. 
Descriptive statistics will be used to summarize the data. For continuous variables, the mean, 
standard deviation, median, quartile, minimum, and maximum will be provided. For discrete 
data, the frequency and percent distributions will be provided.  
Full analysis set will include all randomized subjects who received at least 1 dose of assigned 
medication, and full analysis set will be used for both efficacy and safety analyses. 
7.6.3.1 
Subject Accountability 
The number of subjects randomized, who complete the study, and discontinue the study will 
be summarized. The reason for study treatment discontinuation and study discontinuation 
will also be summarized. 
7.6.3.2 
Demographic and Baseline Characteristics 
Demographics (age, gender, race, and ethnicity) and other baseline disease characteristics 
will be summarized using descriptive statistics. 
7.6.4 
Efficacy Endpoints and Analyses 
The full analysis set will be used for efficacy analyses, and subjects will be analyzed by the 
randomized treatment group.  
The primary efficacy endpoint will be tested to compare the mean RGI-C global score 
between the KRN23 and active control groups. 
At the Week 40 Analysis (the primary efficacy analysis time point), the primary hypothesis 
of the primary endpoint is to test whether there is a difference between the KRN23 and active 
control groups in the mean RGI-C global scores at Week 40. An Analysis of Covariance 
(ANCOVA) model with treatment group adjusting for baseline rickets severity and age will 
be used to test this hypothesis at a 2-sided alpha level of 0.05. The proportion of RGI-C 
responder will be summarized for each treatment group. 


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At the Week 64 Analysis (secondary analysis), RGI-C global score over time will be 
analyzed using the repeat measurement model that includes treatment group, visit, treatment 
group by visit interaction, and adjusted for baseline rickets severity and age.  
The change from baseline in RSS total score over time will be analyzed using the same 
method as that of the RGI-C score. 
Analyses of other efficacy and PD measures will be performed at Week 40,Week 64/EOS I, 
and Week 140/EOS II. Endpoints will be summarized descriptively by each treatment group. 
Treatment comparison will be performed using the repeat measurement model including 
treatment group, visit, treatment group by visit interaction, adjusting for baseline age, rickets 
severity. Other baseline covariate may be considered for adjustment.  
The SAP will provide additional details on the planned efficacy analyses. 
7.6.5 
Safety Analyses 
Full Analysis Set will be used for the safety analysis. Subjects will be analyzed based on the 
actual treatment received. Safety variables including AEs, SAEs, safety laboratory 
assessments, vital signs, renal ultrasound, ECG, ECHO, and anti-KRN23 antibody will be 
summarized descriptively by treatment group. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class, Preferred 
Term, relationship to study drug, and severity. All reported AEs with onset during the 
treatment (ie, treatment-emergent AEs) will be included in the analysis. For each AE, the 
percentage of subjects who experienced at least 1 occurrence of the given event will be 
summarized by treatment group. Special attention will be given to those subjects who died, 
discontinued treatment due to an AE, or experienced a SAE. 
Clinical laboratory data will be summarized by the type of laboratory test. Reference ranges 
and markedly abnormal results (specified in the SAP) will be used in the summary of 
laboratory 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. The SAP will provide additional details on the planned safety analyses. 
7.6.6 
Data Monitoring Committee 
An independent DMC that includes members with expertise in metabolic bone disease, 
cardiology, and nephrology, and the conduct of clinical trials in children will act in an 
advisory capacity to monitor subject safety on a routine basis throughout the trial. The DMC 
will meet at least twice a year during the active-controlled period. The roles and 
responsibilities of the DMC will be defined in the DMC Charter. 


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8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC)  
The IRB/EC must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, "Institutional Review Boards." This protocol, any protocol amendments, the 
associated informed consent forms (ICFs), and the informed consent procedures must be 
submitted to the IRB/EC for review and must be approved before the enrollment of any 
subject into the study. Investigational Product may not be shipped to the investigator until 
Ultragenyx or its designee has received a copy of the letter or certificate of approval from the 
IRB/EC for the protocol and any protocol amendments, as applicable. 
All subject recruitment and/or advertising information must be submitted to the IRB/EC and 
Ultragenyx or its designee for review and approval prior to implementation. IRB/EC 
approval of any protocol amendments must be received before any of the changes outlined in 
the amendments are put into effect, except when the amendment has been enacted to protect 
subject safety. In such cases, the chair of the IRB/EC should be notified immediately and the 
amendment forwarded to the IRB/EC for review and approval. 
8.1.2 
Ethical Conduct of Study 
This protocol is written in accordance with the principles established by the 18th World 
Medical Assembly General Assembly (Helsinki, 1964) and subsequent amendments and 
clarifications adopted by the General Assemblies. The sponsor and investigator will make 
every effort that the study described in this protocol is conducted in full conformance with 
those principles, current FDA regulations, ICH Good Clinical Practices (GCP) guidelines, 
and local ethical and regulatory requirements. Should a conflict arise, the sponsor and 
investigator will follow whichever law or guideline affords the greater protection to the 
individual subject. The investigator will also make sure he or she is thoroughly familiar with 
the appropriate administration and potential risks of administration of the Investigational 
Product, as described in this protocol and the Investigator's Brochure for KRN23 or the 
appropriate product labels for oral phosphate and active vitamin D (Appendix 1), prior to the 
initiation of the study. 
8.1.3 
Subject Information and Consent 
Appropriate forms for documenting written informed consent will be provided by the 
investigator and reviewed and approved by Ultragenyx or its designee before submission to 
the IRB/EC. Ultragenyx or its designee must receive a copy or acknowledgement of the 
IRB/EC's approval of the ICF before the shipment of Investigational Product to the study 
site. 
It is the investigator's responsibility to obtain signed written informed consent from each 
potential study subject prior to the conduct of any study procedures. This written informed 


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consent will be obtained after the methods, objectives, requirements, and potential risks of 
the study have been fully explained to each potential subject. The investigator must explain 
to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time. Subjects who are not of legal age (depending on the region) will provide 
written assent (if possible), and his/her legally authorized representative (parent or legal 
guardian) will provide written informed consent for such subjects. 
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements. Subjects will be given a copy of 
the signed ICF and will be provided any new information during the course of the study that 
might affect their continued participation in the study. The investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject's questions must be answered to the subject's satisfaction. If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
Receipt of written informed consent will be documented in each potential subject’s CRF. 
The signed ICF will remain in each subject's study file and must be available to the study 
monitor(s) at all times. 
8.2 
Investigators and Study Administrative Structure 
Each investigator must provide Ultragenyx and/or its designee a completed and signed Form 
FDA 1572 and a Financial Disclosure Form. All sub-investigators must be listed on Form 
FDA 1572 and Financial Disclosure Forms must be completed for all sub-investigators listed 
on Form FDA 1572 or equivalent. 
Ultragenyx and/or its designee will be responsible for managing and monitoring the clinical 
trial to ensure compliance with FDA and ICH GCP guidelines. Ultragenyx's trained 
designated representative (the monitor) will conduct regular visits to the clinical site, to 
perform Source Document Verification (SDV). The monitor will verify the investigator's 
ongoing qualifications, to inspect clinical site facilities, and to inspect study records, 
including proof of EC/IRB review, with the stipulation that patient confidentiality will be 
maintained in accordance with local and federal regulations, including HIPAA requirements. 
A Coordinating Investigator will be identified for multicenter trials. The Coordinating 
Investigator will be selected on the basis of active participation in the trial, 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. 


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8.3 
Investigational Product Accountability 
While at the clinical site, KRN23 must be stored in a secure limited access location at 
controlled temperature as described in the Investigator’s Brochure and according to product 
packaging. The storage facility must be available for inspection by the study monitor at any 
time during the study.  
A drug accountability record must be maintained for all KRN23 received, dispensed, 
returned, and/or lost during the study. This record must be kept current and made available to 
the study monitor for inspection. Following the close-out of the study, all unused KRN23 
must be returned to Ultragenyx and/or its designee unless other instructions have been 
provided for final disposition of the drug.  
8.4 
Data Handling and Record Keeping 
8.4.1 
Case Report Forms and Source Documents 
The investigator is required to initiate and maintain, for each subject, an adequate and 
accurate case history that records all observations and other data related to the study for that 
subject. A validated Electronic Data Capture (EDC) system will be used for entry of the data 
into electronic CRFs. Data must be recorded on CRFs approved by Ultragenyx or its 
designee. All information recorded on CRFs for this study must be consistent with the 
subject's source documentation. 
Initial data entry and any changes to the data will be made only by Ultragenyx-authorized 
users, and data entries and changes will be captured in an electronic audit trail. 
An explanation of any data change should be recorded in the CRF. All data entered in to the 
CRF must be verifiable; therefore, CRFs will be routinely checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records by Ultragenyx or its designee. 
The Investigator must allow direct access to all source documents. 
8.4.2 
Data Quality Assurance 
Monitoring and auditing procedures developed by Ultragenyx and/or its designee will be 
implemented to ensure compliance with FDA and ICH GCP guidelines. Ultragenyx's 
designated representative (the monitor) will contact the investigator and conduct regular 
visits to the study site. The monitor will be expected and allowed to verify the investigator's 
qualifications, to inspect clinical site facilities, and to inspect study records, including proof 
of IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. The monitor 
will also be responsible for confirming adherence to the study protocol, inspecting CRFs and 
source documents, and ensuring the integrity of the data. CRFs will be checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records. Instances of missing or 
uninterruptable data will be resolved in coordination with the investigator. 


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The monitor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications with the study site by 
e-mail, telephone, facsimile, and/or mail. The investigator and all other site personnel agree 
to cooperate fully with the monitor and will work in good faith with the monitor to resolve 
any and all questions raised and any and all issues identified by the monitor. 
The investigator understands that regulatory authorities, the IRB/EC, and/or Ultragenyx or its 
designees have the right to access all CRFs, source documents, and other study 
documentation for on-site audit or inspection and will retain this right from the start of the 
study to at least 2 years after the last approval of a marketing application or for at least 
2 years after clinical development of the study drug for the indication being studied has been 
discontinued. The investigator is required to guaranty access to these documents and to 
cooperate with and support such audits and inspections. 
8.4.3 
Record Retention 
All study records must be retained for at least 25 years after the end of the clinical trial or in 
accordance with national law. Subject files and other source data must be kept for the 
maximum period of time permitted by the hospital, institution or private practice, but not less 
than 25 years. Ultragenyx must be notified and will assist with retention should the 
Investigator/institution be unable to continue maintenance of subject files for the full 
25 years. All study records must be stored in a secure and safe facility. 
8.5 
Reporting and Follow-up of Adverse Events 
8.5.1 
Definition of Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related. An adverse event 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. 
Suspected Adverse Reaction is any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of expedited safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug. 
Life-threatening adverse event or life-threatening suspected adverse reaction is an adverse 
event or suspected adverse reaction that, in the view of either the investigator or sponsor, 
places the patient or subject at immediate risk of death. It does not include an adverse event 
or suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death. 


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Serious adverse event (SAE) or serious suspected adverse reaction is an adverse event or 
suspected adverse reaction that at any dose, in the view of either the investigator or sponsor, 
results in any of the following outcomes:  
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions 
 A congenital anomaly/birth defect 
Note that hospitalizations planned prior to study enrollment (eg, for elective surgeries) are 
not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs.  
Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
8.5.2 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (NCI 2010). 
The majority of AEs can be graded using this system.  
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions. 
 Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and are of a minor 
irritant type, causing no loss of time from normal activities. Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
 Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
 Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
 Life-threatening (Grade 4): Events that place the participant at immediate risk of death 
or are disabling. 
 Death (Grade 5): Events that result in death. 


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To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 
provided. The term "severe" is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache). This is not the same as 
"serious" which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning. Seriousness (not severity) serves as 
a guide for defining regulatory reporting obligations. 
8.5.3 
Relationship of Adverse Events to Study Drug 
The investigator will assess the potential relationship of the AE to study drug using the 
following descriptions. During the Treatment Period, the relationship of the AE to KRN23 
will be assessed for subjects in the KRN23 arm, and the relationship of the AE to oral 
phosphate and to active vitamin D will be assessed for subjects in the active control arm. 
During the Treatment Extension Period, the relationship of the AE to KRN23 will be 
assessed. 
Categories of attributions for “Unrelated” events: 
 Unrelated: This category applies to an AE that is clearly not related to the 
investigational agent/procedure. 
 Unlikely Related: This category applied to an AE that is doubtfully related to the 
investigational agent/procedure.  
Categories of attributions for “Related” events: 
 Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. 
 Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure.  
 Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Unrelated or Unlikely Related 
will be considered Unrelated. 
8.5.4 
Adverse Event Reporting 
8.5.4.1 
General 
All AEs (ie, any new or worsening in severity or frequency of a preexisting condition) with 
onset after the subject signs consent for study participation must be promptly documented on 
the CRF. The Investigator is responsible for evaluating all AEs, obtaining supporting 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 96 
documents, and ensuring documentation of the event is adequate. Details of the AE must 
include severity, relationship to study drug, duration, and outcome.  
For subjects not continuing KRN23 treatment under commercial use or another mechanism 
upon completion of study drug treatment or early withdrawal from this study, a Safety Visit 
will be conducted 12 weeks ±1 week after the last dose of study drug in this protocol. 
All AEs will be recorded from the time the informed consent is signed through 12 weeks 
following the last dose of study drug, unless the subject enrolls in another clinical study of 
KRN23, is treated with commercially available KRN23, or is treated with KRN23 through 
another mechanism, at which point the collection of AEs within this study is no longer 
applicable. In addition, the Investigator should report any AE that occurs after this time 
period that is believed to have a reasonable possibility of being associated with study drug. 
AEs will continue to be reported either under another KRN23 protocol or per post-approval 
requirements for safety monitoring, as applicable. 
AEs ongoing at 12 weeks following the last dose of study drug should have a comment in the 
source document by the Investigator that the event has recovered, recovered with sequelae, or 
stabilized.  
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and 
Requirements for Immediate Reporting 
Ultragenyx or its designee must be notified of the occurrence of any SAE that occurs during 
the reporting period within 24 hours of the Investigator, designee, or site personnel’s 
knowledge of the event. SAEs will be reported by completing and submitting SAE report 
forms to Ultragenyx or designee. 
Follow-up SAE information must be submitted in a timely manner as additional information 
becomes available. All SAEs regardless of relationship to study drug must be followed to 
resolution or stabilization if improvement is not expected.  
All deaths, regardless of causality, occurring from signing of the informed consent until 
12 weeks following the last dose of study drug are to be reported as SAEs to Ultragenyx or 
its designee within 24 hours of knowledge. 
8.5.4.3 
Pregnancy in Subject or Partner, and Requirements for Immediate 
Reporting 
Ultragenyx or its designee must be notified of the occurrence of any pregnancy in a subject 
or subject’s partner that occurs during the reporting period within 24 hours of the 
Investigator, designee, or site personnel’s knowledge of the event. Pregnancies will be 
reported by completing and submitting Pregnancy Notification forms to Ultragenyx or 
designee. Reported pregnancy of a subject or a subject’s partner, while participating in the 
study, will be monitored for the full duration and/or followed until the outcome of the 
pregnancy is known. In the event of a pregnancy in the partner of a subject, the Investigator 


Protocol Number: UX023-CL301 
Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 97 
should make every effort to obtain the female partner’s consent for release of protected 
health information. 
Ultragenyx or its designee must be notified of the outcome of the pregnancy within 24 hours 
of the Investigator, designee, or site personnel’s knowledge of the outcome. Pregnancy 
outcomes will be reported by completing and submitting Pregnancy Outcome forms to 
Ultragenyx or designee.  
Any pregnancy-associated SAEs must be reported as per the SAE reporting process indicated 
in Section 8.5.4.2. 
8.5.5 
Communication Plan 
8.5.5.1 
Serious Adverse Drug Reaction Reporting 
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSAR) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), ECs, and Investigators as per local laws and regulations. 
Fatal and life-threatening SUSARs will be submitted no later than 7-calendar days of first 
knowledge of the event and follow-up information submitted within an additional 8 days. 
All other SUSARs will be submitted within 15-calendar days of first knowledge of the event. 
Ultragenyx will use the current KRN23 Investigator’s Brochure to evaluate expectedness for 
SAEs occurring in the KRN23 treatment group. Ultragenyx will use applicable product labels 
(Appendix 1) to evaluate expectedness for SAEs occurring in the active control treatment 
group (oral phosphate and active vitamin D). 
The Investigator will notify the IRBs/Research Ethics Boards (REB)/ECs of SAEs, in 
accordance with IRB/REB/EC requirements and local laws and regulations. A copy of this 
notification must be provided to Ultragenyx or its designee. 
8.5.5.2 
Urgent Safety Matters and Non-SUSAR Reporting 
Principal Investigators are required to report any urgent safety matters to Ultragenyx or its 
designee within 24 hours. Ultragenyx or its designee will inform the Regulatory Authorities, 
ECs, and Investigators of any events (eg, change to the safety profile of KRN23, major safety 
findings) that may occur during the clinical trial that do not fall within the definition of a 
SUSAR but may affect the safety of subjects participating in the clinical trials, as required, in 
accordance with applicable laws and regulations. The reporting period for urgent safety 
issues is the period from the signing of the ICF through 12 weeks following the last dose of 
study drug. 
The Investigator will notify the IRBs/ REB/ECs of urgent safety matters, in accordance with 
IRB/REB/EC requirements and local laws and regulations. A copy of this notification must 
be provided to Ultragenyx or its designee. 


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Amendment 1 (Global): 03 November 2017 
 
 
 
Confidential 
Page 99 
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Aono, Y, Yamazaki, Y, Yasutake, J, Kawata, T, Hasegawa, H, Urakawa, I, Fujita, T, Wada, 
M, Yamashita, T, Fukumoto, S, and Shimada, T. 2009. "Therapeutic effects of anti-FGF23 
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Bieri, D, Reeve, RA, Champion, GD, Addicoat, L, and Ziegler, JB. 1990. "The Faces Pain 
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50. 
Broderick, JE, DeWitt, EM, Rothrock, N, Crane, PK, and Forrest, CB. 2013. "Advances in 
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Burnett, CH, Dent, CE, Harper, C, and Warland, BJ. 1964. "Vitamin D-Resistant Rickets. 
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Carpenter, TO, Imel, EA, Holm, IA, Jan de Beur, SM, and Insogna, KL. 2011. "A clinician's 
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Kawakami, T, Ito, T, Zhang, X, Humphrey, J, Insogna, KL, and Peacock, M. 2014. 
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CTFG. 2014. Clinical Trial Facilitation Group. Recommendations related to contraception 
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Dixon, PH, Christie, PT, Wooding, C, Trump, D, Grieff, M, Holm, I, Gertner, JM, 
Schmidtke, J, Shah, B, Shaw, N, Smith, C, Tau, C, Schlessinger, D, Whyte, MP, and 
Thakker, RV. 1998. "Mutational analysis of PHEX gene in X-linked hypophosphatemia." J 
Clin Endocrinol Metab 83 (10):3615-23. 


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Fukumoto, S. 2008. "Physiological regulation and disorders of phosphate metabolism--
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Pediatr 150 (4):395-9. 
Hicks, CL, von Baeyer, CL, Spafford, PA, van Korlaar, I, and Goodenough, B. 2001. "The 
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Ichikawa, S, Gray, AK, Bikorimana, E, and Econs, MJ. 2013. "Dosage effect of a Phex 
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Imel, EA, and Econs, MJ. 2005. "Fibroblast growth factor 23: roles in health and disease." J 
Am Soc Nephrol 16 (9):2565-75. 
Imel, EA, Zhang, X, Ruppe, MD, Weber, TJ, Klausner, MA, Ito, T, Vergeire, M, Humphrey, 
JS, Glorieux, FH, Portale, AA, Insogna, K, Peacock, M, and Carpenter, TO. 2015. 
"Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia 
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Hampson, G, Koshiyama, H, Ljunggren, O, Oba, K, Yang, IM, Miyauchi, A, Econs, MJ, 
Lavigne, J, and Juppner, H. 2003. "Fibroblast growth factor 23 in oncogenic osteomalacia 
and X-linked hypophosphatemia." N Engl J Med 348 (17):1656-63. 
Linglart, A, Biosse-Duplan, M, Briot, K, Chaussain, C, Esterle, L, Guillaume-Czitrom, S, 
Kamenicky, P, Nevoux, J, Prie, D, Rothenbuhler, A, Wicart, P, and Harvengt, P. 2014. 
"Therapeutic management of hypophosphatemic rickets from infancy to adulthood." Endocr 
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Liu, S, Tang, W, Zhou, J, Vierthaler, L, and Quarles, LD. 2007. "Distinct roles for intrinsic 
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Makitie, O, Doria, A, Kooh, SW, Cole, WG, Daneman, A, and Sochett, E. 2003. "Early 
treatment improves growth and biochemical and radiographic outcome in X-linked 
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NCI. National Cancer Institute Division of Cancer Treatment and Diagnosis (DCTD), 
National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health 
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(CTCAE). Published: June14, 2010. Available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.  
2010. 


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NIH. US National Heart, Lung, and Blood Institute. The Fourth Report on the Diagnosis, 
Evaluation, and Treatment of High Blood Pressure in Children and Adolescents  2005. 
Available from https://www.nhlbi.nih.gov/files/docs/resources/heart/hbp_ped.pdf. 
NIH. 2015. PROMIS  2015 [cited January 2015]. Available from 
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Payne, RB. 1998. "Renal tubular reabsorption of phosphate (TmP/GFR): indications and 
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Perwad, F, Azam, N, Zhang, MY, Yamashita, T, Tenenhouse, HS, and Portale, AA. 2005. 
"Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-
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PHEXdb. PHEX Locus Database, Search Engine Site  [cited November 2014. Available 
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Sullivan, W, Carpenter, T, Glorieux, F, Travers, R, and Insogna, K. 1992. "A prospective 
trial of phosphate and 1,25-dihydroxyvitamin D3 therapy in symptomatic adults with X-
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Zivicnjak, M, Schnabel, D, Billing, H, Staude, H, Filler, G, Querfeld, U, Schumacher, M, 
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(2):223-31. 
 


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Page 104 
11 APPENDIX 1: REFERENCE SAFETY INFORMATION FOR THE ACTIVE 
CONTROL ARM 
The attached SmPCs serve as RSI for the oral phosphate and active vitamin D products used 
in the active control arm of this study at clinical sites in Europe. For regulatory reporting 
purposes, the information located in Section 4.8 of the following SmPCs will be used to 
determine if a serious adverse event is unexpected for the applicable compound. 
Alfacalcidol – One-Alpha®  
Calcitriol – Rocaltrol®  
Oral Phosphate – Phosphate Sandoz® 


 
Confidential 
 
 
SUMMARY OF PRODUCT CHARACTERISTICS 
 
1 
NAME OF THE MEDICINAL PRODUCT 
 
One-Alpha Capsules 0.5 microgram. 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Alfacalcidol 0.5 μg 
 
 
 
3. 
PHARMACEUTICAL FORM 
 
Red soft gelatin capsules. 
 
 
 
 
 
4 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
 
One-Alpha® is indicated in all conditions where there is a disturbance of 
calcium metabolism due to impaired 1-ct hydroxylation such as when there is 
reduced renal function. The main indications are: 
 
a) 
Renal osteodystrophy 
b) 
Hyperparathyroidism (with bone disease) 
c) 
Hypoparathyroidism 
d) 
Neonatal hypocalcaemia 
e) 
Nutritional and malabsorptive rickets and osteomalacia 
f) 
Pseudo-deficiency (D-dependent) rickets and osteomalacia 
g) 
Hypophosphataemic vitamin D resistant rickets and osteomalacia 
 
4.2 
Posology and method of administration 
 
Route of administration: oral 
 
Initial dose for all indications: 
 
Adults: 
1 microgram/day 
Page 105


 
Confidential 
 
 
Dosage in the elderly: 
0.5 microgram/day 
Neonates and premature infants: 
0.05 - 0.1 microgram/kg/day 
Children under 20 kg bodyweight: 
0.05 microgram/kg/day 
Children over 20 kg bodyweight: 
1 microgram/day 
 
The dose of One-Alpha® should be adjusted thereafter to avoid 
hypercalcaemia according to the biochemical response. Indices of response 
include plasma levels of calcium (ideally corrected for protein binding), 
alkaline phosphatase, parathyroid hormone, as well as radiographic and 
histological investigations. 
 
Plasma levels should initially be measured at weekly intervals. The daily dose 
of One-Alpha® may be increased by increments of 0.25 - 0.5 microgram. 
When the dose is stabilised, measurements may be taken every 2 - 4 weeks. 
 
Most adult patients respond to doses between 1 and 3 micrograms per day. 
When there is biochemical or radiographic evidence of bone healing, (and in 
hypoparathyroid patients when normal plasma calcium levels have been 
attained), the dose generally decreases. Maintenance doses are generally in the 
range of 0.25 to 1 microgram per day. If hypercalcaemia occurs, One-Alpha® 
should be stopped until plasma calcium returns to normal (approximately 1 
week) then restarted at half the previous dose. 
 
(a)  Renal bone disease: 
 
Patients with relatively high initial plasma calcium levels may have 
autonomous hyperparathyroidism, often unresponsive to One-Alpha®. Other 
therapeutic measures may be indicated. 
 
Before and during treatment with One-Alpha®, phosphate binding agents 
should be considered to prevent hyperphosphataemia. It is particularly 
important to make frequent plasma calcium measurements in patients with 
chronic renal failure because prolonged hypercalcaemia may aggravate the 
decline of renal function. 
 
(b)  Hyperparathyroidism: 
 
In patients with primary or tertiary hyperparathyroidism about to undergo 
parathyroidectomy, preoperative treatment with One-Alpha® for 2-3 weeks 
alleviates bone pain and myopathy without aggravating pre-operative 
hypercalcaemia. In order to decrease post-operative hypocalcaemia, One-
Alpha® should be continued until plasma alkaline phosphatase levels fall to 
normal or hypercalcaemia occurs. 
 
(c)  Hypoparathyroidism: 
 
In contrast to the response to parent vitamin D, low plasma calcium levels are 
restored to normal relatively quickly with One-Alpha®. Severe hypocalcaemia 
is corrected more rapidly with higher doses of One-Alpha® (eg 3-5 
micrograms) together with calcium supplements. 
Page 106


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Page 109


 
Confidential 
 
 
hours. 1α-OHD3 also produced increases in plasma inorganic phosphorus due 
to increased intestinal absorption and renal tubular re-absorption. This latter 
effect is a result of PTH suppression by 1α-OHD3. The effect of the drug on 
calcium was about double its effect on phosphorus absorption. 
 
Patients with chronic renal failure have shown increased serum calcium levels 
within 5 days of receiving 1α-OHD3 in a dose of 0.5 - 1.0 μg/day. As serum 
calcium rose, PTH levels and alkaline phosphatase decreased toward normal. 
 
 
 
5.3 
Preclinical safety data 
 
There are no pre-clinical data of relevance to the prescriber which are 
additional to that already included in other sections of the SPC. 
 
 
 
 
 
6 
PHARMACEUTICAL PARTICULARS 
6.1 
List of excipients 
 
Sesame oil, all-rac-α-tocopherol, gelatin, glycerol, potassium sorbate, red iron oxide, 
titanium dioxide. 
 
6.2 
Incompatibilities 
 
Not applicable. 
 
 
 
6.3 
Shelf life 
2 years 
 
6.4 
Special precautions for storage 
 
Do not store above 25°C. 
 
 
 
6.5 
Nature and contents of container 
 
PVC/AL blister of 30 (OP), with polyamide-coated aluminium cover. 
 
 
Page 110


 
Confidential 
 
 
 
6.6 
Instructions for use/handling 
 
None. 
 
 
 
 
 
7 
MARKETING AUTHORISATION HOLDER 
LEO Laboratories Limited 
Horizon 
Honey Lane 
Hurley 
Maidenhead 
Berkshire 
SL6 6RJ 
UK 
8. 
MARKETING AUTHORISATION NUMBER 
 
PL   0043/0206 
 
 
 
9 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE 
AUTHORISATION 
 
26 January 1978 / 13 January 1994 
 
 
 
10 
DATE OF REVISION OF THE TEXT 
 
02/12/2013 
 
Page 111


 
Confidential 
 
 
SUMMARY OF PRODUCT CHARACTERISTICS 
 
1 
NAME OF THE MEDICINAL PRODUCT 
Rocaltrol 0.25 microgram Capsules. 
 
 
2 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
Each capsule contains 0.25 microgram of calcitriol. 
For excipients, see 6.1. 
 
3 
PHARMACEUTICAL FORM 
Soft capsules. 
One length brown-orange to red-orange opaque and the other white to grey-
yellow or grey-orange opaque. 
 
4 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
Rocaltrol is indicated for the correction of the abnormalities of calcium and 
phosphate metabolism in patients with renal osteodystrophy. 
Rocaltrol is also indicated for the treatment of established post-menopausal 
osteoporosis. 
 
4.2 
Posology and method of administration 
 
The dose of Rocaltrol should be carefully adjusted for each patient according to the 
biological response so as to avoid hypercalcaemia. 
 
The effectiveness of treatment depends in part on an adequate daily intake of calcium, 
which should be augmented by dietary changes or supplements if necessary.  The 
capsules should be swallowed with a little water. 
 
Adults 
Renal Osteodystrophy 
The initial daily dose is 0.25 mcg of Rocaltrol.  In patients with normal or only 
slightly reduced calcium levels, doses of 0.25 mcg every other day are sufficient.  If 
no satisfactory response in the biochemical parameters and clinical manifestations of 
the disease is observed within 2 - 4 weeks, the daily dosage may be increased by 0.25 
mcg at 2 - 4 week intervals.  During this period, serum calcium levels should be 
Page 112


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Page 113


 
Confidential 
 
 
All other vitamin D compounds and their derivatives, including proprietary 
compounds or foodstuffs which may be “fortified” with vitamin D, should be 
withheld during treatment with Rocaltrol. 
 
An abrupt increase in calcium intake as a result of changes in diet (e.g. increased 
consumption of dairy products) or uncontrolled intake of calcium preparations may 
trigger hypercalcaemia.  Patients and their families should be advised that strict 
adherence to the prescribed diet is mandatory and they should be instructed on how to 
recognise the symptoms of hypercalcaemia. 
 
As soon as the serum calcium levels rise to 1 mg/100 ml (250 µmol/l) above normal 
(9-11 mg/100 ml or 2250-2750 µmol/l), or serum creatinine rises to >120 µmol/l, 
treatment with Rocaltrol should be stopped immediately until normocalcaemia ensues 
(see section 4.2). 
 
Immobilised patients, e.g. those who have undergone surgery, are particularly 
exposed to the risk of hypercalcaemia. 
 
Calcitriol increases inorganic phosphate levels in serum. While this is desirable in 
patients with hypophosphataemia, caution is called for in patients with renal failure 
because of the danger of ectopic calcification.  In such cases, the plasma phosphate 
level should be maintained at the normal level (2-5 mg/100 ml or 0.65-1.62 mmol/l) 
by the oral administration of appropriate phosphate-binding agents and low phosphate 
diet.  
 
The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 
70 mg2/dl2. 
 
Patients with vitamin D-resistant rickets (familial hypophosphataemia) who are being 
treated with Rocaltrol must continue their oral phosphate therapy. However, possible 
stimulation of intestinal absorption of phosphate by Rocaltrol should be taken into 
account since this effect may modify the need for phosphate supplementation. 
 
Since calcitriol is the most effective vitamin D metabolite available, no other vitamin 
D preparation should be prescribed during treatment with Rocaltrol, thereby ensuring 
that the development of hypervitaminosis D is avoided. 
 
If the patient is switched from a long acting vitamin D preparation (e.g. ergocalciferol 
(vitamin D2) or colecalciferol) to calcitriol, it may take several months for the 
ergocalciferol level in the blood to return to the baseline value, thereby increasing the 
risk of hypercalcaemia (see section 4.9). 
 
Patients with normal renal function who are taking Rocaltrol should avoid 
dehydration.  Adequate fluid intake should be maintained. 
 
In patients with normal renal function, chronic hypercalcaemia may be associated 
with an increase in serum creatinine. 
 
Rocaltrol capsules contain sorbitol. Patients with rare hereditary problems of fructose 
intolerance should not take Rocaltrol capsules. 
Page 114


 
Confidential 
 
 
 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Dietary instructions, especially concerning calcium supplements, should be strictly 
observed, and uncontrolled intake of additional calcium-containing preparations 
avoided. 
 
Concomitant treatment with a thiazide diuretic increases the risk of hypercalcaemia.  
Calcitriol dosage must be determined with care in patients undergoing treatment with 
digitalis, as hypercalcaemia in such patients may precipitate cardiac arrhythmias (see 
section 4.4).  
 
A relationship of functional antagonism exists between vitamin D analogues, which 
promote calcium absorption, and corticosteroids, which inhibit it. 
 
Magnesium-containing drugs (e.g. antacids) may cause hypermagnesaemia and 
should therefore not be taken during therapy with Rocaltrol by patients on chronic 
renal dialysis.  
Since Rocaltrol also has an effect on phosphate transport in the intestine, kidneys and 
bones, the dosage of phosphate-binding agents must be adjusted in accordance with 
the serum phosphate concentration (normal values: 2-5 mg/100 ml, or 0.65-1.62 
mmol/l). 
 
Patients with vitamin D-resistant rickets (familial hypophosphataemia) should 
continue their oral phosphate therapy. However, possible stimulation of intestinal 
phosphate absorption by calcitriol should be taken into account since this effect may 
modify the requirement for phosphate supplements. 
 
Bile acid sequestrants including cholestyramine and sevelamer can reduce intestinal 
absorption of fat-soluble vitamins and therefore may impair intestinal absorption of 
calcitriol. 
 
4.6 
Fertility, pregnancy and lactation 
 
The safety of Rocaltrol during pregnancy has not been established. 
 
Supravalvular aortic stenosis has been produced in foetuses by near-fatal oral doses of 
vitamin D in pregnant rabbits. There is no evidence to suggest that vitamin D is 
teratogenic in humans even at very high doses. Rocaltrol should be used during 
pregnancy only if the benefits outweigh the potential risk to the foetus. 
 
It should be assumed that exogenous calcitriol passes into breast milk.  In view of the 
potential for hypercalcaemia in the mother and for adverse reactions from Rocaltrol in 
nursing infants, mothers may breastfeed while taking Rocaltrol, provided that the 
serum calcium levels of the mother and infant are monitored. 
 
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4.7 
Effects on ability to drive and use machines 
 
On the basis of the pharmacodynamic profile of reported adverse events, this product 
is presumed to be safe or unlikely to adversely affect such activities.  
  
 
4.8 
Undesirable effects 
 
The adverse reactions listed below reflect the experience from investigational studies 
of Rocaltrol, and the post-marketing experience.  
The most commonly reported adverse reaction was hypercalcaemia. 
 
The ADRs listed in Table 1 are presented by system organ class and frequency 
categories, defined using the following convention: Very common (≥1/10); common 
(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); 
very rare (<1/10,000); not known (cannot be estimated from the available data). 
Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
Table 1 Summary of ADRs Occurring in Patients Receiving Rocaltrol® 
(calcitriol)  
System Organ 
Class 
Very common 
Common 
Uncommon 
Not known 
Immune System 
Disorders 
 
 
 
Hypersensitivity, 
Urticaria 
Metabolism and 
Nutrition 
Disorders 
 
Hypercalcaemia  
Decreased 
appetite 
Polydipsia, 
Dehydration, 
Weight 
decreased 
 
Psychiatric 
Disorders 
 
 
 
Apathy, 
Psychiatric 
disturbances 
Nervous 
System 
Disorders 
 
 
Headache 
 
Muscular 
weakness, 
Sensory 
disturbance, 
Somnolence 
Cardiac 
Disorders 
 
 
 
Cardiac 
arrhythmias 
Gastrointestinal 
Disorders 
 
 
Abdominal 
pain, 
Nausea 
Vomiting  
Constipation, 
Abdominal pain 
upper, Paralytic 
ileus 
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Skin and 
subcutaneous 
tissue disorders 
 
Rash 
 
Erythema, 
Pruritus 
Musculoskeletal 
and Connective 
Tissue 
Disorders 
 
 
 
Growth 
retardation 
Renal and 
Urinary 
Disorders 
 
Urinary tract 
infection 
 
Polyuria, 
Nocturia 
General 
disorders and 
administration 
site conditions 
 
 
 
Calcinosis,  
Pyrexia, Thirst 
Investigations 
 
 
 
Blood 
creatinine 
increased 
 
 
Since calcitriol exerts vitamin D activity, adverse effects may occur which are similar 
to those found when an excessive dose of vitamin D is taken, i.e. hypercalcaemia 
syndrome or calcium intoxication (depending on the severity and duration of 
hypercalcaemia) (see sections 4.2 and 4.4). Occasional acute symptoms include 
decreased appetite, headache, nausea, vomiting, abdominal pain or abdominal pain 
upper and constipation. 
Because of the short biological half-life of calcitriol, pharmacokinetic investigations 
have shown normalisation of elevated serum calcium within a few days of treatment 
withdrawal, i.e. much faster than in treatment with vitamin D3 preparations. 
Chronic effects may include muscular weakness, weight decreased, sensory 
disturbances, pyrexia, thirst, polydipsia, polyuria, dehydration, apathy, growth 
retardation and urinary tract infections. 
In concurrent hypercalcaemia and hyperphosphataemia of > 6 mg/100 ml or > 1.9 
mmol/l, calcinosis may occur; this can be seen radiographically.  
Hypersensitivity reactions including rash, erythema, pruritus and urticaria may occur 
in susceptible individuals. 
Laboratory Abnormalities 
In patients with normal renal function, chronic hypercalcaemia may be associated 
with a blood creatinine increase. 
 
Post Marketing 
The number of adverse effects reported from clinical use of Rocaltrol over a period of 
15 years in all indications is very low with each individual effect, including 
hypercalcaemia, occurring at a rate of 0.001 % or less. 
 
Reporting of suspected adverse reactions 
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Reporting suspected adverse reactions after authorisation of the medicinal product is 
important. It allows continued monitoring of the benefit/risk balance of the medicinal 
product. Healthcare professionals are asked to report any suspected adverse reactions 
via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard. 
 
 
4.9 
Overdose 
 
Treatment of asymptomatic hypercalcaemia (see section 4.2). 
 
Since calcitriol is a derivative of vitamin D, the symptoms of overdose are the same as 
for an overdose of vitamin D. Intake of high doses of calcium and phosphate together 
with Rocaltrol may give rise to similar symptoms. The serum calcium times 
phosphate (Ca x P) product should not be allowed to exceed 70 mg2 / dl2. A high 
calcium level in the dialysate may contribute to the development of hypercalcaemia. 
 
Acute symptoms of vitamin D intoxication: anorexia, headache, vomiting, 
constipation. 
Chronic symptoms: dystrophy (weakness, loss of weight), sensory disturbances, 
possibly fever with thirst, polyuria, dehydration, apathy, arrested growth and urinary 
tract infections. Hypercalcaemia ensues, with metastatic calcification of the renal 
cortex, myocardium, lungs and pancreas. 
 
The following measures should be considered in treatment of accidental overdosage: 
immediate gastric lavage or induction of vomiting to prevent further absorption. 
Administration of liquid paraffin to promote faecal excretion. Repeated serum 
calcium determinations are advisable. If elevated calcium levels persist in the serum, 
phosphates and corticosteroids may be administered and measures instituted to bring 
about adequate diuresis. 
 
Hypercalcaemia at higher levels (>3.2 mmol/L) may lead to renal insufficiency 
particularly if blood phosphate levels are normal or elevated due to impaired renal 
function. 
 
Should hypercalcaemia occur following prolonged treatment, Rocaltrol should be 
discontinued until plasma calcium levels have returned to normal.  A low-calcium diet 
will speed this reversal.  Rocaltrol can then be restarted at a lower dose or given in the 
same dose but at less frequent intervals than previously. 
 
In patients treated by intermittent haemodialysis, a low concentration of calcium in 
the dialysate may also be used.   However, a high concentration of calcium in the 
dialysate may contribute to the development of hypercalcaemia. 
 
 
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5. PHARMACOLOGICAL PROPERTIES 
5.1 Pharmacodynamic properties 
Calcitriol is the most active known form of vitamin D3 in stimulating intestinal 
calcium transport. It is normally formed in the kidneys from its immediate precursor, 
25-hydroxycholecalciferol. In physiological amounts it augments the intestinal 
absorption of calcium and phosphate and plays a significant part in the regulation of 
bone mineralisation.  The defective production of calcitriol in chronic renal failure 
contributes to the abnormalities of mineral metabolism found in that disorder. 
 
The biological effects of calcitriol are mediated by the vitamin D receptor, a nuclear 
hormone receptor expressed in most cell types and functioning as a ligand-activated 
transcription factor that binds to DNA sites to modify the expression of target genes. 
 
Rocaltrol is a synthetic preparation of calcitriol.  Oral administration of Rocaltrol to 
patients with chronic renal failure compensates for impaired endogenous production 
of calcitriol which is decreased when the glomerular filtration rate falls below 30 
ml/min.  Consequently, intestinal malabsorption of calcium and phosphate and the 
resulting hypocalcaemia are improved, thereby reversing the signs and symptoms of 
bone disease. 
 
In patients with established post-menopausal osteoporosis, Rocaltrol increases 
calcium absorption, elevates circulating levels of calcitriol and reduces vertebral 
fracture frequency. 
 
The onset and reversal of the effects of Rocaltrol are more rapid than those of other 
compounds with vitamin D activity and adjustment of the dose can be achieved 
sooner and more precisely.  The effects of inadvertent overdosage can also be 
reversed more readily. 
 
 
 
5.2 Pharmacokinetic properties 
 
Absorption 
Calcitriol is rapidly absorbed from the intestine. Peak serum concentrations following 
a single oral dose of 0.25-1µg Rocaltrol in healthy subjects were found within 2-6 
hours. 
 
After a single oral dose of 0.5 mcg Rocaltrol in healthy subjects, the average serum 
concentrations of calcitriol rose from a baseline value of 40.0 ± 4.4 pg/ml to 60.0 ± 
4.4 pg/ml after two hours, and then fell to 53.0 ± 6.9 after four hours, to 50.0 ± 7.0 
after eight hours, to 44 ± 4.6 after twelve hours and to 41.5 ± 5.1 pg/ml after 24 hours. 
  
Distribution 
During transport in the blood at physiological concentrations, calcitriol is mostly 
bound to a specific vitamin D binding protein (DBP), but also, to a lesser degree, to 
Page 119


 
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lipoproteins and albumin.   At higher blood calcitriol concentrations, DBP appears to 
become saturated, and increased binding to lipoproteins and albumin occurs. 
 
Metabolism 
Calcitriol is hydroxylated and oxidised in the kidney and in the liver by a specific 
cytochrome P450 enzyme: CYP24A1. 
 
Several metabolites with different degrees of vitamin D activity have been identified. 
 
Elimination 
The elimination half-life of calcitriol in plasma ranges between 5 to 8 hours.  
However, the pharmacological effect of a single dose of calcitriol lasts at least 4 days. 
The elimination and absorption kinetics of calcitriol remain linear in a very broad 
dose range and up to 165 µg single oral dose. Calcitriol is excreted in the bile and may 
undergo an enterohepatic circulation 
5.3 
Preclinical safety data 
 
Subchronic toxicity studies in rats and dogs indicated that calcitriol at an oral 
dose of 20 ng/kg/day (twice the usual human dosage) for up to 6 months 
produced no or minimal adverse effects.  A dose of 80 ng/kg/day (8 times the 
usual human dosage) for up to 6 months produced moderate adverse effects; 
changes seen appeared to be primarily the result of prolonged hypercalcaemia. 
 
Reproductive toxicity studies in rats indicated that oral doses up to 300 
ng/kg/day (30 times the usual human dose) did not adversely affect 
reproduction.  In rabbits, multiple foetal abnormalities were observed in two 
litters at an oral maternally toxic dose of 300 ng/kg/day and one litter at 
80 ng/kg/day, but not at 20 ng/kg/day (twice the usual human dose).  Although 
there were no statistically significant differences between treated groups and 
controls in the numbers of litters or foetuses showing abnormalities, the 
possibility that these findings were due to calcitriol administration could not be 
discounted. 
 
6 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
Content 
Butylhydroxyanisole 
Butylhydroxytoluene 
Medium–chain triglycerides 
Shell 
Gelatin 
Glycerol 
Karion 83 (Sorbitol, Mannitol, Hydrogenated hydrolysed starch) 
Page 120


 
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Titanium dioxide E171  
Iron oxide red E172 
Iron oxide yellow E172 
 
6.2 
Incompatibilities 
None. 
 
6.3 
Shelf life 
3 years. 
 
6.4 
Special precautions for storage 
 
Do not store above 25°C.   Store in the original package and keep the blisters 
in the outer carton in order to protect from light and moisture. 
 
6.5 
Nature and contents of container 
PVC opaque blisters containing 100 capsules (5 strips of 20 capsules). 
 
6.6 
Special precautions for disposal 
Not applicable. 
 
7 
MARKETING AUTHORISATION HOLDER 
 
Roche Products Limited 
6 Falcon Way 
Shire Park 
Welwyn Garden City 
AL7 1TW 
United Kingdom 
8 
MARKETING AUTHORISATION NUMBER(S) 
 
PL 00031/0122 
9 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE 
AUTHORISATION 
13 January 2003 
 
Page 121


 
Confidential 
 
 
 
 
10 
DATE OF REVISION OF THE TEXT 
 
24/06/2014 
 
Page 122


 
Confidential 
 
 
SUMMARY OF PRODUCT CHARACTERISTICS 
 
1 
NAME OF THE MEDICINAL PRODUCT 
 
PHOSPHATE SANDOZ® Effervescent Tablet 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
PHOSPHATE SANDOZ Effervescent Tablets containing 1.936g of sodium 
acid phosphate anhydrous. 
 
 
 
3. 
PHARMACEUTICAL FORM 
 
Effervescent Tablets 
 
 
 
 
 
4. 
CLINICAL PARTICULARS 
 
4.1. 
Therapeutic Indications 
 
Hypercalcaemia associated with such conditions as hyperparathyroidism, 
multiple myelomatosis and malignancy. 
 
Hypophosphataemia associated with vitamin D resistant rickets and vitamin D 
resistant hypophosphataemic osteomalacia. 
 
 
 
4.2. 
Posology and Method of Administration 
 
PHOSPHATE SANDOZ Effervescent should be dissolved in 1/3 to 1/2 a 
tumblerful of water and taken orally. 
 
Dosage should be adjusted to suit the requirements of individual patients.  
Excessive dosage has been reported to produce hypocalcaemia in isolated 
cases.  Particular care should therefore be taken to ensure appropriate dosage 
in the elderly. 
 
Adults 
 
Hypercalcaemia: up to 6 tablets daily (adjustment being made according to 
requirements). 
 
Page 123


 
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Vitamin D resistant hypophosphateaemic osteomalacia: 4-6 tablets daily. 
 
Children under 5 years 
 
Hypercalcaemia: up to 3 tablets daily (adjustment being made according to 
requirements). 
 
Vitamin D resistant rickets: 2-3 tablets daily. 
 
 
 
4.3. 
Contra-Indications 
 
None. 
 
 
 
4.4. 
Special Warnings and Special Precautions for Use 
 
In cases of impaired renal function associated with hypercalcaemia and in 
cases where restricted sodium intake is required, eg. congestive cardiac failure, 
hypertension or pre-eclamptic toxaemia, the sodium (20.4mmol per tablet) and 
potassium (3.1mmol per tablet) content of PHOSPHATE SANDOZ should be 
taken into consideration.  In cases of hypercalcaemia associated with impaired 
renal function and hyperphosphataemia, the main effect of oral phosphate is to 
bind calcium in the gut and thus reduce calcium absorption. 
 
The effect of oral phosphate on serum phosphate is likely to be minimal, but 
close monitoring of serum levels is recommended. 
 
Soft tissue calcification and nephrocalcinosis have been reported in isolated 
cases following intravenous therapy with phosphate. 
 
This is thought to be a function of dosage and rapidity of phosphate 
administration.  While such effects appear less likely to occur with oral 
phosphates, careful surveillance of patients is recommended, especially if on 
long term therapy. 
 
 
 
4.5. 
Interactions with other Medicinal Products and other Forms of 
Interaction 
 
Concurrent administrations of antacids, containing agents such as aluminium 
hydroxide, may result in displacement of calcium from binding to oral 
phosphate, thus reducing efficacy. 
 
 
 
4.6. 
Pregnancy and Lactation 
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The safety of PHOSPHATE SANDOZ in human pregnancy has not been 
formally studied, but the drug has been widely used for many years without 
ill-consequence. 
 
 
 
4.7. 
Effects on Ability to Drive and Use Machines 
 
None. 
 
 
 
4.8 
Undesirable effects 
 
Apart from gastro-intestinal upsets, nausea and diarrhoea, very few side effects have 
been reported. 
 
 Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicinal product is 
important.  It allows continued monitoring of the benefit/risk balance of the medicinal 
product. Healthcare professionals are asked to report any suspected adverse reactions 
via the national reporting system in the United Kingdom: Yellow Card Scheme 
Website:   www.mhra.gov.uk/yellowcard 
 
 
 
4.9. 
Overdose 
 
Excessive dosage has been reported to produce hypocalcaemia in isolated 
cases.  This has proved reversible when dosage has been adjusted. 
 
 
 
 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1. 
Pharmacodynamic Properties 
 
Oral administration of inorganic phosphates produces a fall in serum calcium 
in patients with hypercalcaemia.  PHOSPHATE SANDOZ Effervescent 
Tablets also contain sodium ions which aid the correction of the dehydration 
and sodium depletion seen in hypercalcaemia. 
 
 
 
5.2. 
Pharmacokinetic Properties 
Page 125


 
Confidential 
 
 
 
Approximately two thirds of ingested phosphate is absorbed from the gastro-
intestinal tract; most of the absorbed phosphate is then filtered by the 
glomeruli and subsequently undergoes reabsorption.  Parathyroid hormone and 
vitamin D stimulate absorption of phosphate from the small intestine and its 
reabsorption from the proximal tubule.  Virtually all absorbed phosphate is 
eventually excreted in the urine, the remainder being excreted in the faeces. 
 
 
 
5.3. 
Pre-clinical Safety Data 
 
PHOSPHATE SANDOZ Effervescent Tablets contain sodium acid phosphate, 
anhydrous, sodium bicarbonate and potassium bicarbonate (all of which are 
subject to pharmacopoeial monographs).  The physiological, pharmacological 
and clinical toxicity of potassium salts  
are well documented and limited animal data are therefore available. 
 
 
 
 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1. 
List of Excipients 
 
Potassium bicarbonate, sodium bicarbonate, sodium saccharin, orange flavour 
52.570 TP, polyethylene glycol 4000, sugar icing CP, citric acid anhydrous, 
water. 
 
 
 
6.2. 
Incompatibilities 
 
None. 
 
 
 
6.3. 
Shelf-Life 
 
36 months. 
 
 
 
6.4. 
Special Precautions for Storage 
 
Do not store above 25°C. Store in the original container. Keep the container 
tightly closed. 
 
 
Page 126


 
Confidential 
 
 
 
6.5. 
Nature and Content of Container 
 
Polypropylene tubes of 20 effervescent tablets in boxes of 5 tubes (100 
tablets). 
 
 
 
6.6. 
Instruction for Use and Handling 
 
None. 
 
 
 
 
7 
MARKETING AUTHORISATION HOLDER 
 
HK Pharma Ltd 
PO BOX 845 
BEDFORD, 
MK45 9EB 
 
8. 
MARKETING AUTHORISATION NUMBER(S) 
 
PL 16784/0001 
 
 
 
9. 
DATE OF FIRST AUTHORISATION / RENEWAL OF 
AUTHORISATION 
 
28th April 1998 
 
 
 
 
 
10 
DATE OF REVISION OF THE TEXT 
 
27/07/2015 
 
Page 127

SAP_001.pdf: 
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Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
Proprietary and Confidential 
Page 2 
TABLE OF CONTENTS 
1 INTRODUCTION ...............................................................................................................9 
2 OBJECTIVES ....................................................................................................................10 
2.1 Primary Objective: ....................................................................................................10 
2.2 Secondary Efficacy Objectives: ................................................................................10 
2.3 Pharmacokinetic Objective: ......................................................................................10 
2.4 Safety Objective: .......................................................................................................10 
3 STUDY DESIGN...............................................................................................................11 
3.1 Study Population .......................................................................................................11 
3.2 Dosage and Administration .......................................................................................11 
3.3 Blinding and Randomization Methods .....................................................................13 
3.4 Stratification Factors .................................................................................................13 
3.5 Sample Size Considerations ......................................................................................13 
3.6 Primary Analysis .......................................................................................................13 
3.7 Additional Analysis...................................................................................................13 
3.8 Data Monitoring Committee .....................................................................................14 
4 STUDY ENDPOINTS AND COVARIATES ...................................................................15 
4.1 Primary Efficacy Endpoint........................................................................................15 
4.2 Secondary Efficacy Endpoint(s) ...............................................................................15 
4.2.1 
Key Secondary Endpoint(s) .........................................................................15 
4.2.2 
Other Secondary Endpoint(s) ......................................................................15 
4.3 Safety Endpoints .......................................................................................................16 
4.4 Pharmacokinetic Endpoint ........................................................................................16 
4.5 Exploratory Endpoints ..............................................................................................17 
4.6 Potential Covariate(s) ................................................................................................17 
4.7 Subgroups..................................................................................................................17 
5 DEFINITIONS ...................................................................................................................18 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
Proprietary and Confidential 
Page 3 
5.1 Baseline .....................................................................................................................18 
5.2 Duration of exposure .................................................................................................18 
5.3 Study Day ..................................................................................................................18 
5.4 Age ............................................................................................................................18 
5.5 RGI-C ........................................................................................................................18 
5.6 RSS............................................................................................................................20 
5.7 Growth ......................................................................................................................20 
5.7.1 
Standing height/recumbent length Z-score and Percentile ..........................20 
5.7.2 
Weight Z-score and Percentile ....................................................................21 
5.7.3 
Growth Velocity ..........................................................................................21 
5.8 Percent of Predicted Six-Minute Walk Test .............................................................22 
5.9 Health-related Quality of Life (SF-10 for Children Health Survey) .........................22 
5.10 Patient-Reported Outcomes Measurement Information System (PROMIS) ............22 
5.11 Faces Pain Scale – Revised (FPS-R).........................................................................23 
5.12 Blood Pressure and Blood Pressure Percentile .........................................................23 
5.13 Heart Rate Percentile ................................................................................................23 
5.14 ECG Normal Ranges .................................................................................................24 
5.15 Adverse Events to Monitor .......................................................................................24 
5.16 Dose-limiting Toxicity (DLT) ..................................................................................24 
5.17 Duration of Conventional therapy before Baseline ...................................................25 
6 ANALYSIS POPULATIONS ...........................................................................................26 
6.1 Screened Population ..................................................................................................26 
6.2 Full Analysis Set (FAS) ............................................................................................26 
6.2.1 
Full Analysis Subset – Baseline Age ≥ 5 Years ..........................................26 
6.3 Safety Analysis Set ...................................................................................................26 
6.4 Pharmakinetic (PK) Analysis Set ..............................................................................26 
6.5 Pharmacodynamic (PD) Analysis Set .......................................................................26 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
Proprietary and Confidential 
Page 4 
7 DATA SCREENING AND ACCEPTANCE ....................................................................27 
7.1 General Principles .....................................................................................................27 
7.2 Handling of Missing and Incomplete Data ...............................................................27 
7.2.1 
Missing Date Imputation for Adverse Events and Concomitant 
Medications .................................................................................................27 
7.2.2 
Missing Causal Relationship to Investigational Product for Adverse 
Events ..........................................................................................................28 
7.2.3 
Visit Time Windows ...................................................................................28 
7.3 Testing/Validation Plan.............................................................................................29 
7.4 Software ....................................................................................................................29 
8 STATISTICAL METHODS AND ANALYSES ..............................................................30 
8.1 General Principles .....................................................................................................30 
8.2 Subject Accountability ..............................................................................................30 
8.3 Protocol Deviations ...................................................................................................30 
8.4 Investigational Product Administration ....................................................................31 
8.4.1 
Extent of Exposure ......................................................................................31 
8.4.2 
Measurement of Treatment Compliance .....................................................31 
8.4.3 
Demographic and Baseline Characteristics .................................................31 
8.4.4 
Prior and Concomitant Medication .............................................................31 
8.5 Efficacy Analysis ......................................................................................................32 
8.5.1 
Generalized Estimating Equations Model (GEE) .......................................32 
8.5.2 
Sensitivity Analysis for Missing Data .........................................................32 
8.5.3 
Analysis of Primary Efficacy Endpoint .......................................................33 
8.5.4 
Analysis of Secondary Efficacy Endpoint(s) ..............................................33 
8.5.4.1 
RGI-C responder ..........................................................................33 
8.5.4.2 
RSS scores ...................................................................................34 
8.5.4.3 
Growth .........................................................................................34 
8.5.4.4 
Walking Ability (6MWT) ............................................................35 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
Proprietary and Confidential 
Page 5 
8.5.4.5 
Patient Reported Outcomes Measurement Information 
System (PROMIS) .......................................................................35 
8.5.4.6 
Faces Pain Scale – Revised (FPS-R) ...........................................36 
8.5.4.7 
PD Analysis .................................................................................36 
8.6 Analysis of Other Efficacy Endpoint(s) ....................................................................37 
8.6.1 
Health-related Quality of Life (SF-10 for Children Health Survey) ...........37 
8.6.2 
Dental Assessment ......................................................................................37 
8.7 Pharmacokinetics ......................................................................................................37 
8.8 Safety Analysis .........................................................................................................37 
8.8.1 
Adverse Events ............................................................................................37 
8.8.2 
Clinical Laboratory Parameters ...................................................................38 
8.8.3 
Vital Signs ...................................................................................................39 
8.8.4 
Concomitant Medications ............................................................................39 
8.8.5 
Physical Examination ..................................................................................39 
8.8.6 
Pregnancy Test ............................................................................................39 
8.8.7 
Renal Ultrasound .........................................................................................39 
8.8.8 
ECG .............................................................................................................40 
8.8.9 
ECHO ..........................................................................................................40 
8.8.10 Anti-KRN23 Antibody Testing ...................................................................40 
9 REFERENCES ..................................................................................................................41 
10 APPENDICES ...................................................................................................................43 
APPENDIX 1 
SUMMARY OF STATISTICAL ANALYSIS APPROACHES ON 
EFFICACY ENDPOINTS .................................................................................................43 
APPENDIX 2 
CLINICAL LABORATORY ASSESSMENTS FOR SAFETY ................45 
APPENDIX 3 
SCHEDULE OF EVENTS .........................................................................46 
APPENDIX 4 
RSS DATA COLLECTION FORM ...........................................................54 
APPENDIX 5 
RGI-C DATA COLLECTION FORM .......................................................55 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
Proprietary and Confidential 
Page 6 
APPENDIX 6 
GRWOTH VELOCITY MEAN AND SD VALUES BY AGE 
AND GENDER ..................................................................................................................59 
APPENDIX 7 
BLOOD PRESSURE PERCENTILES BY GENDER, AGE AND 
HEIGHT (NHLBI 2005) ....................................................................................................60 
APPENDIX 8 
HEART RATE PERCENTILES BY GENDER AND AGE ......................62 
APPENDIX 9 
ECG NORMAL RANGES .........................................................................63 
APPENDIX 10 EVENTS TO MONITOR ...........................................................................65 
 
List of Tables 
Table 10.1:  Schedule of Events – Treatment Period Weeks 1-30 ..........................................46 
Table 10.2:  Schedule of Events – Treatment Period Weeks 32-64 ........................................49 
 
List of Figures 
Figure 3.2.1:  UX023-CL301 Study Schema ...........................................................................12 
 
 
 
 
 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
Proprietary and Confidential 
Page 7 
LIST OF ABBREVIATIONS 
25(OH)D 
1,25(OH)2D 
6MWT 
25-hydroxyvitamin D 
1,25-dihydroxyvitamin D 
Six Minute Walk Test 
AE 
adverse event 
ALP 
ANCOVA 
BUN 
CDF 
alkaline phosphatase 
Analysis of Covariance 
blood urea nitrogen 
cumulative density function 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECHO 
eGFR 
Echocardiogram 
estimated glomerular filtration rate 
FGF23 
FPS-R 
fibroblast growth factor 23 
Faces Pain Scale – Revised 
GEE 
GFR 
Generalized Estimating Equations 
glomerular filtration rate 
HAHA 
human anti-human antibody 
iPTH 
intact parathyroid hormone 
kg 
LVH 
mAb 
Kilogram 
left ventricular hypertrophy 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
NCI CTCAE 
milligram 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
PD 
pharmacodynamic (s) 
PHEX 
Phosphate regulating gene with homology to endopeptidases located on 
the X chromosome 
PHS-10 
Physical Summary Score 
PSS-10 
Psychosocial Summary Score 
PK 
PROMIS 
pharmacokinetic(s) 
Patient-Reported Outcomes Measurement Information System  
PT 
Preferred Term 
PTH 
Q2W 
QIC 
parathyroid hormone 
biweekly, once every two weeks 
Quasi-Likelihood Information Criterion  


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RBC 
red blood cell 
RGI-C 
RSS 
Radiographic Global Impression of Change 
Rickets Severity Score 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF-10 
SF-10 for Children Health Survey 
TEAE 
TmP/GFR 
 
TRP 
treatment emergent adverse event 
ratio of renal tubular maximum reabsorption rate of phosphate to 
glomerular filtration rate 
tubular reabsorption of phosphate 
WBC 
XLH 
white blood cell 
X-linked hypophosphatemia 
 
 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the UX023-CL301 Protocol original version dated 
04APR2016. 
 
 


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2 OBJECTIVES 
2.1 
Primary Objective: 
• Evaluate the effect of KRN23 therapy in improving rickets in children with XLH 
compared with the active control (oral phosphate/active vitamin D) 
2.2 
Secondary Efficacy Objectives: 
Evaluate the effects of KRN23 as compared with the active control on: 
• Growth velocity and lower extremity deformity   
• Pharmacodynamic markers that reflect the status of phosphorus homeostasis, including 
serum 1,25(OH)2D, serum and urinary phosphorus, ratio of renal tubular maximum 
reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), and tubular 
reabsorption of phosphate (TRP) 
• Biochemical markers of bone turnover that reflect rickets severity (alkaline phosphatase 
[ALP]) 
• Walking ability and patient-/parent-reported pain, fatigue, and physical function/mobility 
2.3 
Pharmacokinetic Objective: 
Assess the PK of KRN23 throughout the dosing cycle.  
2.4 
Safety Objective: 
Evaluate the safety and tolerability profile of KRN23 in the treatment of children with XLH 
(aged 1 to ≤ 12 years), including adverse events (AEs) (e.g., nephrocalcinosis), as compared 
with active control, and immunogenicity profile.  
 


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3 STUDY DESIGN 
As background for the statistical methods presented below, this section provides an overview 
of the study design. This overview is a summary only. The protocol is the definitive 
reference for all matters discussed in what follows in this section. 
3.1 
Study Population 
UX023-CL301 is a multicenter, randomized, open-label, Phase 3 study comparing the 
efficacy and safety of KRN23 with the active control (oral phosphate/active vitamin D 
therapy) in pediatric patients with XLH. The study will be conducted in children with clinical 
evidence consistent with XLH (aged 1 to ≤ 12 years), including demonstrated 
hypophosphatemia, radiographic evidence of rickets (≥ 2.0 points RSS total score), and 
PHEX mutation or variants of uncertain significance. Patients will also be required to have 
received oral phosphate/active vitamin D therapy for ≥ 12 consecutive months (for children 
≥3 years of age) or ≥ 6 consecutive months (for children <3 years of age).), 7 days prior to 
the Randomization Visit.  
3.2 
Dosage and Administration 
Subjects assigned to the KRN23 treatment group will receive KRN23 at a starting dose of 
0.8 mg/kg Q2W. The dose may be increased to 1.2 mg/kg at any time during the study if a 
subject meets the following dose-adjustment criteria: 1) two consecutive serum phosphorus 
measurements are below the normal range; 2) serum phosphorus has increased by 
< 0.5 mg/dL from baseline; and 3) the subject has not missed a dose of KRN23 that would 
account for the decrease in serum phosphorus. At any time during the study, if serum 
phosphorus increases above the upper limit of normal (ULN) for age, the subsequent dose(s) 
will be withheld and the site will contact the medical monitor before dosing resumes. 
Once other causes of increased serum phosphorus are excluded, KRN23 treatment will 
resume at half the total dose of the last dose received (i.e., half the dose of either 0.8 mg/kg 
or 1.2 mg/kg). Serum phosphorus will be followed through unscheduled serum phosphorus 
assessments approximately 2 weeks post-dose and assessed by central laboratory; the 
assessments may be repeated as necessary. A subject will resume dosing at the previous full 
total dose level if they meet the same dose-adjustment criteria listed above (i.e., two 
consecutive serum phosphorus measurements are below the normal range; serum phosphorus 
has increased by < 0.7 mg/dL from baseline; and the subject has not missed a dose of KRN23 
that would account for the decrease in serum phosphorus). KRN23 will be administered up to 
a maximum dose of 90 mg in this study with no minimum dose requirement. 
Subjects assigned to active control will typically receive multiple daily doses of oral 
phosphate and active vitamin D. Because of the variability in the doses and dosing 
frequencies of oral phosphates and active vitamin D therapies in clinical practice, these 
treatments will be individualized for each subject at the investigator’s discretion, but the 
following general guidance is provided based on expert recommendations in the US and 
Europe (in Table 7.1.1 and 7.1.2 of the protocol). Detailed information about the brand, 


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starting dosages, and any changes in oral phosphate and active vitamin D therapy will be 
determined by the treating Investigator within the guidelines and recorded at every site visit. 
US expert guidelines generally recommend a calcitriol dosage of 20 to 30 ng/kg/day in 2 to 
3 divided doses and an elemental phosphorus dose of 20 to 40 mg/kg/day (in 3 to 5 divided 
doses), acknowledging that some children require more, whereas some do well with less 
(Carpenter et al. 2011). European expert guidelines recommend an alfacalcidol dosage of 1 to 
2 µg/day (once daily) and a phosphate supplemental dose of 45 to 70 mg/kg/day (in 3 to 
4 divided doses) (Linglart et al. 2014). Calcitriol and alfacalcidol dosages should be adjusted 
based on the clinical and laboratory values that guide best possible treatment. 
The study will be conducted in a pediatric population; as such, additional measures including 
an external, independent DMC have been incorporated into the study design. Where possible, 
measures to minimize pain and distress to the subject have been considered for this study 
protocol including the use of home health visits (KRN23 treatment arm only). At every home 
health visit for subjects in the KRN23 treatment arm, all subjects randomized to the active 
control arm will receive a phone call to assess adverse events and concomitant medications. 
Home Health visits are not applicable to subjects in Japan, Korea or Italy. Where possible, 
timing of assessments will be coordinated with standard safety laboratory tests to minimize 
risk and discomfort and avoid unnecessary duplication of testing. The primary analysis will 
be at Week 40; analyses at Week 64 will assess the durability of treatment effect, additional 
efficacy outcomes, and long-term safety. After completing the initial active-controlled 
Treatment Period of the study (64 weeks), subjects from either treatment groups may be 
eligible for an extension study and receive KRN23 treatment for up to an additional 96 weeks 
or until KRN23 is commercially available. Figure 3.2.1 provides a schematic of the overall 
study design. 
Figure 3.2.1:  UX023-CL301 Study Schema 
 
The schedule of assessments is shown in Appendix 3. 
KRN23
Q2W 
N=30
Oral Phosphate + Active Vitamin D Therapy 
N=30
Weeks
0
Primary 
Efficacy and 
Safety Analysis
Additional 
Efficacy and 
Safety Analysis
Randomization (1:1)
Screening and 
Standard of Care 
Washout
40
Extension Study
64


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3.3 
Blinding and Randomization Methods 
An open-label study design was chosen since blinding such a study would be problematic 
due to the different methods of administration and the individualized nature and frequent 
dose adjustments needed with oral phosphate/active vitamin D therapy. Eligible subjects will 
be enrolled in the study and sequentially assigned an identification number. Subjects will be 
randomized 1:1 to receive open-label KRN23 by subcutaneous injection or active control via 
an Interactive Web Response System (IWRS) based on a randomization schedule developed 
by an independent third-party vendor. Randomization will be stratified by baseline rickets 
severity, age, and region.   
3.4 
Stratification Factors 
Stratification factors include baseline rickets severity (RSS total score ≤ 2.5 vs > 2.5) and age 
(< 5 vs ≥ 5). The randomization was also stratified by region (Japan vs. rest of World) for 
operational and logistic considerations to ensure balance between the two treatment groups in 
Japan, as small number of subjects are expected to be enrolled.   
3.5 
Sample Size Considerations 
This Phase 3 study is powered to test the effect of KRN23 on improvement of rickets using 
RGI-C global score at Week 40 against the active control (oral phosphate and active vitamin 
D) based on the assumption of a mean RGI-C global score of 1.80 in the KRN23 group, 1.40 
in the active control group, and a common standard deviation of 0.50. Given these 
assumption, a total sample size of 60 (30 per group) will provide approximately 80% power 
to detect such a difference in the mean RGI-C global score at Week 40 between treatment 
groups using a two-sample t-test with a two-sided alpha level of 0.05. A 10% drop-out rate is 
incorporated in the sample size calculation. 
The age of eligible subjects will be monitored for enrollment for age distribution. 
Approximately 20 subjects aged 1 to <5 years will be included (approximately 10 in each 
treatment group), and no more than 10 subjects between the ages of 1 to < 3 years will be 
enrolled. No more than 60% female subjects will be enrolled. 
3.6 
Primary Analysis 
The primary analysis is planned at Week 40. 
3.7 
Additional Analysis 
Additional analysis will be performed at Week 64 to assess the durability of treatment effect, 
additional efficacy outcomes, and long-term safety. In addition, administrative analyses can 
be performed to support regulatory activities. 


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3.8 
Data Monitoring Committee  
An independent DMC that includes members with expertise in metabolic bone disease, 
cardiology, and nephrology, and the conduct of clinical trials in children will act in an 
advisory capacity to monitor subject safety on a routine basis throughout the trial. The DMC 
will meet at least twice a year during the active-controlled period. The roles and 
responsibilities of the DMC will be defined in the DMC Charter. 


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4 STUDY ENDPOINTS AND COVARIATES  
All data are collected according to the schedule of assessments (Appendix 3). 
4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in rickets at Week 40 as assessed by the RGI-C 
global score. The primary endpoint will be compared between the KRN23 and active control 
(oral phosphate/active vitamin D) groups.  
4.2 
Secondary Efficacy Endpoint(s) 
The secondary endpoints listed in Section 4.2.1 and 4.2.2 will be compared between the 
KRN23 and active control groups: 
4.2.1 
Key Secondary Endpoint(s) 
The key secondary endpoints include: 
• Change in lower extremity skeletal abnormalities as assessed by the RGI-C long leg score 
• Change from baseline in standing height/recumbent length Z score 
• Change from baseline in RSS total score 
• Change in serum phosphorus from baseline to mean post-baseline values 
• Change from baseline in ALP 
For the growth-related endpoints RGI-C long leg score and change from baseline in standing 
height/recumbent length Z score, the primary assessment time will be Week 64. For other 
key secondary endpoints, the primary assessment time will be Week 40. Because of the small 
sample size, no multiplicity will be adjusted for the key secondary endpoints. 
4.2.2 
Other Secondary Endpoint(s) 
• Rickets Endpoint(s) 
o Proportion of subjects with a mean RGI-C global score ≥ +2.0 (substantial healing) 
o Change in rickets as assessed by RGI-C wrist and knee scores 
o Change from baseline in RSS wrist and knee scores 
• Growth Endpoint 
o Change in growth velocity Z score from pre-treatment to post-treatment 
• PD Endpoint(s) 
o Change from baseline over time in serum phosphorus  


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o Number of subjects reach the normal range of serum phosphorus (3.2 - 6.1 mg/dL) 
over time 
o Change from baseline over time in serum 1,25(OH)2D, urinary phosphorus, 
TmP/GFR and TRP 
• Pain, Fatigue and Physical Function Endpoint(s) 
o Change from baseline in the PROMIS (Patient-Reported Outcomes Measurement 
Information System) scores in Pediatric Pain Interference, Physical Function Mobility 
and Fatigue domains 
o Change from baseline in the Faces Pain Scale – Revised (FPS-R) 
o Change from baseline in the Six Minute Walk Test (6MWT) total distance and 
percent of predicted normal 
4.3 
Safety Endpoints 
Safety endpoints will be summarized at Baseline and at each observed time that they are 
collected. The following endpoints will be examined:  
• Frequency (and %), and severity of adverse events (AEs) and serious adverse events 
(SAEs) 
• Prior and concomitant medications 
• Change from baseline to post-baseline visits in vital signs and weight 
• Physical examinations 
• Change from baseline to post-baseline visits in eGFR (calculated using the Bedside 
Schwartz equation) 
• Shift from baseline to post-baseline visits in renal ultrasound in nephrocalcinosis score 
• Change from baseline to post-baseline visits in Echocardiogram (ECHO)  
• Change from baseline to post-baseline visits in chemistry, hematology, and urinalysis, 
including additional KRN23/XLH biochemical parameters of interest (serum 25(OH)D; 
lipase; amylase; creatinine; serum calcium and iPTH, and urinary calcium and creatinine) 
• Shift from baseline to post-baseline visits in presence of anti-KRN23 antibody  
• Change from baseline to post-baseline visits in Electrocardiogram (ECG)  
4.4 
Pharmacokinetic Endpoint 
• 
Serum KRN23  


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4.5 
Exploratory Endpoints 
• Health-related quality of life: Change from baseline to post-baseline visits in the SF-10 
for Children Health Survey (SF-10; for subjects ≥ 5 years of age at the Screening Visit) 
physical summary score (PHS-10) and psychosocial summary score (PSS-10). 
• Dental evaluation: number of dental events in dental caries, tooth extraction, root canal, 
dental abscesses, and gingivitis assessed at baseline and post-baseline visits. 
4.6 
Potential Covariate(s) 
Unless specified otherwise, the randomization stratification factor (RSS total score ≤ 2.5 vs 
> 2.5) and age (< 5 vs ≥ 5) will be included as independent variables in the model for 
efficacy analysis. Region (Japan vs. rest of World) is used for randomization for operational 
and logistic considerations and will not be used as covariates in any analyses. For the GEE 
and ANCOVA analyses, baseline result of the response variable will be included as the 
covariate.  
Other potential covariates such as gender might be used in growth analyses. If the baseline 
RSS total score or age is to be used in the statistical model as a continuous covariate, the 
corresponding randomization stratification factor will not be included in the same model. 
Refer to Section 8 for the details of statistical models and covariates for each efficacy 
endpoint.303, 304 
4.7 
Subgroups 
Subgroup analysis by baseline rickets severity (RSS total score ≤2.5 vs >2.5), age (<5 vs ≥5) 
and region (Japan vs the rest of World) will be conducted for the following endpoints: 
• Demographics and baseline characteristics 
• Efficacy endpoints including rickets, growth, PD endpoints and ALP 
The confidence intervals for difference between treatment groups and treatment effect within 
individual treatment groups will be provided on efficacy endpoints. Subgroup analysis by 
region will be presented descriptively only.  
In addition, subgroup analysis by region will be performed for PK (serum KRN23) and 
selected AE summaries. Subgroup analysis by gender will be conducted for rickets and 
growth endpoints. Additional subgroup analysis by PHEX mutation (positive vs 
non-positive) may be considered if deemed as appropriate. For PROMIS, FPS-R and 6MWT, 
subgroup analysis by baseline rickets severity (RSS total score ≤2.5 vs >2.5) may be also 
considered. 


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5 DEFINITIONS 
5.1 
Baseline 
Baseline is defined as the last assessments prior to or on the date of initiation of the first dose 
of investigational product. 
5.2 
Duration of exposure  
Duration of exposure in days is defined as: Last date of investigational product – first date of 
investigational product + 14 days for KRN23 group and Last date of investigational product 
– first date of investigational product + 1 day for the active control group.  
5.3 
Study Day 
Study day is calculated as: 
• (visit date – date of the first dose of investigational product + 1) if the visit date is on or 
after the first dose of investigational product;  
• (visit date – date of the first dose of investigational product) if the visit data is prior the 
first dose of investigational product. 
5.4 
Age 
Unless specified, the age at baseline in demographics summary will be derived based on the 
informed consent date:  
Age = (Informed Consent Date – Birth Date +1)/365.25.  
Age at study visits for a particular measurement will be derived based on the measurement 
visit date: 
Age = (Visit Date – Birth Date +1)/365.25.  
The age will be rounded down to the nearest x.x years and keep one decimal place. 
5.5 
RGI-C 
Changes in the severity of rickets and bowing will be assessed centrally by three independent 
pediatric radiologists contracted by a central imaging facility using a disease specific 
qualitative Radiographic Global Impression of Change (RGI-C) scoring system.   
The RGI-C is a seven point ordinal scale with possible values:  
+3 = very much better (complete or near complete healing of rickets), 
+2 = much better (substantial healing of rickets),  
+1 = minimally better (i.e., minimal healing of rickets), 
  0 = unchanged,  


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-1 = minimally worse (minimal worsening of rickets),  
-2 = much worse (moderate worsening of rickets), 
-3 = very much worse (severe worsening of rickets), 
Raters will be presented with side-by-side images taken from subjects during the 
UX023-CL301 study with the Baseline image on the left (Image A) and Post-Treatment 
image (Week 40 and Week 64) on the right (Image B).  Raters will be asked to evaluate 
change in Image B for the abnormalities they consider to be present in the Baseline Image A. 
This exercise will be performed for the distal radius and ulna from the bilateral wrist X-rays, 
and the distal femur and proximal tibia and fibula from the bilateral knee X-rays at Week 40 
and Week 64. At Week 64, Image A (presented on the left) will remain the Baseline image 
and Image B (presented on the right) will be the post-treatment image from Week 
64.  In addition to bilateral wrists and knees, the Week 40 and Week 64 RGI-C analysis will 
include a rating of the full femur, tibia and fibula from the bilateral standing long leg film 
with the Baseline standing long leg image on the left (Image A) and the Week 40 
(or Week 64) standing long leg image on the right (Image B). See data collection form in 
Appendix 5. 
Prior to rating, the three raters will be trained to gain consensus on the terminology used to 
describe XLH-related radiographic abnormalities and to establish inter-rater reliability.  
Following the training, each rater will independently complete a quiz involving the rating of 
practice images to ensure the success of the training and the reliability of scores among the 
raters. For the Week 40 and Week 64 analysis, each of the three raters will perform the rating 
exercise at a work station at the central imaging facility. Only one rater can be present at the 
facility at any given time to prevent group rating or sharing of scores. Each rater will be 
presented with side-by-side images of the wrist and knee with Baseline on the left (Image A) 
and Post-Treatment on the right (Image B). Raters will be asked to evaluate the presence of 
various abnormalities in the wrist and knee in Image A and change in those abnormalities in 
Image B. At the Week 40 analysis, each rater will evaluate changes in rickets severity from 
Baseline to Week 40 in the wrists and knees by assigning a regional score for the wrist, a 
regional score for the knee, as well as an overall impression score. Raters will be blinded to 
the treatment group and subject’s baseline and demographics information. At Week 64, the 
same process will be followed as Week 40 except that the raters will also evaluate images 
from long leg radiographs. RGI-C scores will be entered into an EDC system at the time of 
the scoring and cannot be retrieved or changed by the rater after submission. RGI-C scores 
will be transferred electronically from the imaging facility to Ultragenyx after the image 
rating exercise is complete. 
The RGI-C scores for the three raters will be averaged and the mean scores for the wrist, 
knee, overall impression and RGI-C long leg score will be reported.  RGI-C response is 
defined as an averaged RGI-C global score of at least +2.0 (i.e. substantial healing of 
rickets). 


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5.6 
RSS 
The severity of rickets will be measured using a scale developed by Thomas Thacher, MD for 
the assessment of nutritional rickets (Thacher et al. 2000).  This scale will be referred to as 
the RSS. The RSS system is a 10-point radiographic scoring method that was developed to 
assess the severity of nutritional rickets in the wrists and knees based on the degree of 
metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are 
assigned for the unilateral wrist and knee X-rays deemed by Dr. Thacher to be the more 
severe of the bilateral images. The maximum total score on the RSS is 10 points, with a total 
possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate 
greater rickets severity. Each radiograph is scored individually by Dr. Thacher who will serve 
as the single central independent rater for all UX023-CL301 X-rays taken at Baseline, Week 
40 and Week 64. For the X-rays taken during the UX023-CL301 study, Dr. Thacher will be 
blinded to the treatment group and subject’s baseline and demographics information. Each 
rating performed by Dr. Thacher is entered into an EDC system at the time of the rating and 
transferred electronically to a central imaging facility. The scores cannot be retrieved from 
the system by Dr. Thacher after submission. See RSS data collection form in 
Appendix 4. 
5.7 
Growth 
5.7.1 
Standing height/recumbent length Z-score and Percentile 
Recumbent length will be measured in subjects < 2 years old or those unable or unwilling to 
stand for the measurement. Standing height/recumbent length measurements prior to 
treatment will be abstracted from medical records where available. 
Growth as measured by standing height or recumbent length will be evaluated on a percentile 
basis using the Centers for Disease Control/National Center for Health Statistics 
(CDC/NCHS) Clinical Growth Charts (Kuczmarski et al. 2000). Data used to produce the 
United States Growth Charts smoothed percentile curves will be downloaded from the 
official CDC/NCHS web site: http://www.cdc.gov/growthcharts/percentile_data_files.htm 
The data files from the CDC/NCHS that are used for this analysis are summarized below. 
These files represent the different growth curves for children. LMS refers to the parameters 
in the CDC Growth Charts Percentile Data Files used to construct the growth curves; these 
are: the power in the Box-Cox transformation (L); the median (M); and the generalized 
coefficient of variation (S). 
The data files used are: 
•
Length-for-age charts, birth to 36 months, LMS parameters and selected smoothed
recumbent length percentiles in centimeters, by sex and age (LENAGEINF).
•
Stature-for-age charts, 2 to 20 years, LMS parameters and selected smoothed stature
percentiles in centimeters, by gender and age (STATAGE).


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Calculation of Z-scores for length/stature values above and below the median will be 
performed. Using the CDC/NCHS Clinical Growth Charts, the height-for-age Z score will be 
calculated using the following equation: 
Z = {(X/M)L – 1} / (L x S), 
where X is the physical measurement (stature in cm) and the LMS parameters are obtained 
from the appropriate CDC/NCHS Clinical Growth Chart corresponding to the age in months 
of the child. The percentile corresponding to the Z score is then the corresponding percentile 
from the standard normal distribution. 
 
5.7.2 
Weight Z-score and Percentile 
Weight will be evaluated by z score and percentile using the same method as Section 5.7.1 
based on Centers for Disease Control/National Center for Health Statistics (CDC/NCHS) 
Clinical Growth Charts (Kuczmarski et al. 2000). The data files used for weight Z-score and 
percentile are: 
• Weight-for-age charts, birth to 36 months, LMS parameters and selected smoothed 
weight percentiles in kilograms, by sex and age (WTAGEINF). 
• Weight-for-age charts, 2 to 20 years, LMS parameters and selected smoothed weight 
percentiles in kilograms, by sex and age (WTAGE). 
5.7.3 
Growth Velocity 
Growth velocity of recumbent length/standing height in cm/year will be assessed by a 
model-based approach. A linear regression model for each subject will be built based on all 
recumbent length/standing height measurements by assuming a linear change in growth:  
Yt = β0 + β1Xt + εi 
Where 𝑌𝑌𝑡𝑡 is the recumbent length/standing height (cm) measured at Time t; 𝑋𝑋𝑡𝑡 is the time 
when recumbent length/standing height is measured;  𝛽𝛽0 is the intercept, 𝛽𝛽1is the slope of the 
regression model; 𝜀𝜀𝑖𝑖 is random error term. 
The growth velocity Z score will be calculated based on Tanner’s standard (Tanner et al. 
1985) in Appendix 6. Let [T1, T2] denotes the age interval (years) where the growth velocity 
is estimated from, for example, for post-treatment growth velocity at Week 40, T1 = age 
(years) at baseline and T2 = age (years) at Week 40. The mid-point of the age interval 
(T1 + T2)/2 will be used to locate the closest reference age in the reference table. 
The corresponding 50th percentile (Mean) and SD values will be used to calculate the growth 
velocity Z score in the following equation: 
 
Growth velocity Z score = Growth velocity −mean
SD
 


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If (T1 + T2)/2 is less than 2.25 years, the growth velocity Z score will not be calculated. 
5.8 
Percent of Predicted Six-Minute Walk Test 
The percent of predicted values will be calculated using published normative data based on 
age, gender, and height (Geiger et al. 2007). The percent of predicted walking distance 
6MWTD is given as: 
For males: 
𝑃𝑃ercent of predicted six minute walk test 
=
Observed 6MWD
196.72 + (39.81 ∗Age) −(1.36 ∗Age2) + (132.28 ∗Height) ∗100 
For females: 
Percent of predicted six minute walk test
=
Observed 6MWD
188.61 + (51.50 ∗Age) −(1.86 ∗Age2) + (86.10 ∗Height) ∗100 
where Age is the subject’s age at the time of the assessment (expressed as one digit decimal ) 
calculated using the following: (date of test – date of birth)/365.25, and height is the subject’s 
standing height at the time of the assessment (in m). If there is no height measured at the time 
of the 6MWT assessment, the closest prior height will be used. 
5.9 
Health-related Quality of Life (SF-10 for Children Health Survey) 
The SF-10 for Children Health Survey (SF-10) is a caregiver-completed questionnaire 
designed to assess physical and psychosocial health-related quality of life in healthy and ill 
children (Saris-Baglama et al. 2006). The 10 items were adapted from the Child Health 
Questionnaire and utilize a 4-week recall period. Responses are used to generate 
2 component summary scores: physical summary score (PHS-10) and psychosocial summary 
score (PSS-10).  The scale scores have been centered so that a score of 50 corresponds to the 
average score in a comprehensive 2006 sample (a combination of general population and 
supplemental disability and chronic condition samples). Scale scores are standardized to a 
mean of 50 and a standard deviation of 10 in the combined U.S. general population. 
The scoring of the SF-10 will be performed according to the method described in (Saris-
Baglama et al. 2007).  Higher global scores are associated with better quality of life. 
5.10 Patient-Reported Outcomes Measurement Information System (PROMIS) 
The PROMIS was developed by the National Institutes of Health and uses domain-specific 
measures to assess patient well-being (Broderick et al. 2013), (NIH 2015). It uses a T-score 
metric in which 50 is the mean of a relevant reference population and 10 is the standard 
deviation (SD) of that population. High scores mean more of the concept being measured. 
The domain-specific approach is based on the idea that health attributes, such as pain and 


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physical function are not unique to a specific disease. The PROMIS contains a bank of 
questions from which relevant items can be extracted and used to create a custom form. 
The PROMIS Pain Interference, Physical Function Mobility, and Fatigue domain scores will 
be administered to subjects ≥ 5 years of age at the Screening Visit. To assess these health 
domains, items from the Pediatric Pain Interference, Physical Function Mobility, and Fatigue 
item banks (Version 2.0) were extracted to develop a self-report form that will be completed 
by children 8 years of age and older at the Screening Visit. For children ages 5 to < 8 years at 
the Screening Visit, the same items were extracted from the Parent Proxy item banks 
(Version 2.0) that will be completed by the parent or legal guardian. The Parent/Legal 
Guardian form will be used for the duration of the study for subjects < 8 years of age at the 
Screening Visit, even when a subject turns 8 during the study. The answers collected from 
PROMIS questionnaire will be uploaded to the PROMIS online scoring system 
http://www.healthmeasures.net/explore-measurement-systems/promis to obtain the final 
scores for Pain Interference, Physical Function Mobility, and Fatigue domain.  
5.11 Faces Pain Scale – Revised (FPS-R) 
Pain intensity will be self-reported by subjects using the Faces Pain Scale – Revised (FPS-R) 
for subjects ≥ 5 years of age at the Screening Visit. The FPS-R is a self-reported measure of 
pain intensity developed for children (Hicks et al. 2001). It was adapted from the Faces Pain 
Scale (Bieri et al. 1990) to make it possible to score the sensation of pain on the widely 
accepted 0-to-10 metric. The FPS-R has been validated for use in children 5 to 16 years of 
age. The FPS-R graphically depicts pain intensity using faces with scores chosen from 0, 2, 
4, 6, 8, and 10 (0=no hurt; 10=hurts worst). 
5.12 Blood Pressure and Blood Pressure Percentile 
BP will only be collected for subjects who are ≥ 3 years old. At Screening and Baseline the 
blood pressure will be measured three time at both pre and post study visit assessment. After 
Baseline the blood pressures will be measured three times at pre-assessment only. At each 
visit, the average blood pressure will be calculated and used for analysis. 
The blood pressure percentile will be derived based on the forth report on the diagnosis, 
evaluation and treatment of high blood pressure in children and adolescents (NHLBI 2005). 
See Appendix 7 for details in deriving blood pressure percentile adjusting for age, gender and 
height. 
5.13 Heart Rate Percentile 
The heart rate percentile category will be derived based on the National Health Statistical 
Reports on resting pulse rate reference data for children, adolescents, and adults: United 
States, 1999-2008 (Ostchega et al. 2011). See Appendix 8 for details in deriving blood 
pressure percentile category adjusting for age and gender. 


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5.14 ECG Normal Ranges 
The ECG normal ranges are provided in BMS UX023-CL301 CAMI 7 12-Lead ECG 
analysis plan (Version 1.0, 15APR2016). See Appendix 9 for details in the normal ranges by 
age group and gender. 
5.15 Adverse Events to Monitor 
The definition for each type of adverse events to monitor is as the following: 
• Injection Site Reaction is defined by preferred terms under the Medical Dictionary for 
Regulatory Activities (MedDRA) high-level term (HLT) “Injection site reaction”  
• Hypersensitivity AE: Defined using relevant PTs in the narrow SMQs for 
“Hypersensitivity”.  
• Hyperphosphataemia AE: Defined by using PTs: “Hyperphosphataemia”, “Blood 
phosphorus increased”, “Blood phosphorus abnormal”.  
• Ectopic calcification related AE: There is no available SMQ. Ectopic calcification related 
AE is defined using a MedDRA search of ‘calcification’.  
• Restless leg syndrome AE: Defined by PTs “Restless legs syndrome”, “Restlessness”, 
“Akathisia”, “Sensory disturbance”, “Psychomotor hyperactivity”, “Limb discomfort”, 
“Neuromuscular pain”, “Formication”. 
See Appendix 10 for the search criteria. 
5.16 Dose-limiting Toxicity (DLT) 
A DLT is defined as the occurrence of any of the following:  
• Unexpected SAEs occurring during treatment considered to be either definitely, probably, 
or possibly related to the investigational product  
• A confirmed serum phosphorus level of ≥ 6.5 mg/dL (defined as hyperphosphatemia) at 
any time after dosing  
If a subject experiences a DLT, the planned dosing for that subject will be evaluated by the 
Investigator and Medical Monitor. The outcome of this investigation will determine the 
subjects’ continuation or withdrawal from the study. 
If a subject continues to experience increases in serum phosphorus above the ULN (however 
do not meet the criteria for a DLT) despite dose reduction measures, the planned dosing for 
that subject will be evaluated by the Investigator and Medical Monitor. The outcome of this 
investigation will determine the subjects’ continuation or withdrawal from the study. 


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5.17 Duration of Conventional therapy before Baseline 
The conventional therapy that subjects received before baseline will be identified by 
reviewing prior medication data. 
The definition for duration of conventional therapy a subject received before baseline is as 
follows: 
Duration of conventional therapy = End date of the latest conventional therapy taken - start 
date of earliest conventional therapy taken prior to randomization 
If the date is partially or completely missing, apply the following imputation rule: 
Start Dates 
• If the FIRST start date of conventional therapy is completely missing, then use the next 
earliest non-missing date. 
• If the year is known and month is missing, then assign ‘January 1st’; 
• If the year and month are both known and day is missing, then assign the first day of the 
month. 
Stop Dates 
• If LAST stop date is completely missing, then impute ‘one day’ prior to the 
randomization date 
• If year is known the month is missing, then assign “December 31th”. If this imputed date 
is after randomization date, use one day prior to randomization date instead. 
If year and month are both known and the day is missing, then assign the last day of the 
month. If this imputed date is after randomization date, use one day prior to randomization 
date instead. 
 


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6 ANALYSIS POPULATIONS 
6.1 
Screened Population 
The Screened Population will consist of all unique subjects who underwent a Screening Visit 
and received a subject identification number. 
6.2 
Full Analysis Set (FAS) 
The Full Analysis Set will consist of all randomized subjects who received at least one dose 
of assigned medication and had at least one post-baseline assessment. Subjects will be 
analyzed according to the assigned treatment at randomization. 
6.2.1 
Full Analysis Subset – Baseline Age ≥ 5 Years 
This is a subset of FAS that consists of all subjects with age ≥ 5 years at baseline. PROMIS, 
6MWT and FPS-R will be analyzed using this analysis set. 
6.3 
Safety Analysis Set 
The Safety Analysis Set will consist of all randomized subjects who received at least one 
dose of assigned medication. Subjects will be analyzed according to the actual treatment 
received in the study. 
6.4 
Pharmakinetic (PK) Analysis Set  
The PK analysis set consists of all subjects who received at least one dose of KRN23 and had 
evaluable PK data. 
6.5 
Pharmacodynamic (PD) Analysis Set  
The PD analysis set consists of all subjects who received at least one dose of study therapy 
and had evaluable serum data. 


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7 DATA SCREENING AND ACCEPTANCE  
7.1 
General Principles 
Data will be reviewed periodically. And any questionable data will be reported to the clinical 
data manager promptly for query and resolution. 
7.2 
Handling of Missing and Incomplete Data 
Missing clinical outcome data can occur for multiple reasons, including missed subject visits 
and scales or measures with missing item scores. Missing and incomplete data will be 
identified through the data quality review plan for this study.  Missing and incomplete data 
will be identified for investigation, and possible resolution, by Data Management prior to the 
study database lock or snapshot. 
Unless specified otherwise, only the observed data (not imputed data) will be presented in 
listings. 
7.2.1 
Missing Date Imputation for Adverse Events and Concomitant Medications 
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications.  Note that the imputed values outlined here may not 
always provide the most conservative date.   
Missing Start Dates 
• If the day is unknown, then: 
o If the month and year match the first dose of investigational product start date 
month and year in this study, then impute the day of the first dose date. 
o Otherwise, assign the first day of the month. 
• If the month is unknown, then: 
o If the year matches the year of the first dose of investigational product date in 
this study, then impute the month and day of the first dose date in this study. 
o Otherwise, assign ‘January’  
• If the year is unknown, then the date will not be imputed and will be assigned a missing 
value.  
If the imputed date is earlier than birth date, then birth date will be used. If the imputed start 
date is later than the end date, then the start date will be set as the same date as the end date. 
Missing Stop Dates and not ongoing 
• If the day is unknown, then assign the last day of the month. 
• If the month is unknown, then assign ‘December.’ 


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•
If the year is unknown, then the date will not be imputed and will be assigned a missing
value, and the event will be considered ongoing. If the AE has been recorded as
resolved/recovered, all efforts should be made to obtain the date from the Investigator.
If the resulting end date is after the date of study completion/discontinuation/data cutoff, set 
the imputed end date as close to the date of study completion/discontinuation/data cutoff as 
possible without overwritten existing information. 
If the year is missing for the start date, and stop date (observed or imputed) is on or after the 
first dose or event is ongoing. The start date will be imputed as the first dose date. 
7.2.2 
Missing Causal Relationship to Investigational Product for Adverse Events 
For the KRN23 group, if the causal relationship to the investigational product is missing for 
an AE that started on or after the date of the first dose of investigational product, a causality 
of “definitely related” will be assigned.  
For the active control group, if the causal relationship is missing for both oral phosphate and 
active vitamin D for an AE that started on or after the date of the first dose of investigational 
product, a causality of “definitely related” will be assigned to both oral phosphate and active 
vitamin D. If the causal relationship is missing for one of the oral phosphate or active vitamin 
D medication and not missing for the other one, the missing causality will not be imputed. 
The imputed values for causal relationship to investigational product will be used for the 
incidence summary; the values will be shown as missing in the data listings. 
7.2.3 
Visit Time Windows 
Unscheduled visit occurred prior to or on the date of initiation of the first dose will be 
mapped to the baseline visit if it is the last assessment prior to or on the date of initiation of 
the first dose; otherwise no mapping will be performed. 
Unscheduled visits that occurred after the date of initiation of the first dose will be mapped to 
the post-baseline scheduled visit with the closet target study day (refer to Section 5.3 for 
study day definition and Appendix 3 for the schedule of events). If the unscheduled visit is in 
the middle of two scheduled visits, map to the later scheduled visit. For PD, PK and safety 
assessments (refer to Section 4.2, 4.3 and 4.4), if the time difference between the unscheduled 
visit and closest scheduled visit is ≥ 14 days, the unscheduled visit will not be mapped.  
For descriptive summary tables, when more than one measurement is mapped to the same 
scheduled visit, the measurement taken on the scheduled visit will be used if it is not missing, 
otherwise the one closest to the target day will be used. If two or more visits have equal 
distances to the target day, then the later one will be used. If more than one measurement is 
collected on the same day, use the time or the sequence number to select the latest record. 
For listings and shift tables in safety analysis, all data points will be included. 


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Early termination visit will generally follow the same rule as unscheduled visit except for a 
special case in X-rays. X-rays will not be performed at the early termination visit if the 
assessment was conducted within 3 months of termination. Hence if a subject has X-rays at 
both Week 40 and early termination visits, the X-rays on early termination visit will be 
mapped to Week 64. 
7.3 
Testing/Validation Plan 
Data will be reviewed by cross functional teams periodically and issues will be addressed by 
clinical data management.  
7.4 
Software 
SAS® software version 9.4 or higher will be used to perform statistical analyses unless 
otherwise specified. 


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8 STATISTICAL METHODS AND ANALYSES  
8.1 
General Principles 
The efficacy analyses will be based on the full analysis set. The PD analyses will be based on 
the PD analysis set. The safety analyses will be based on the safety analysis set. Statistical 
tests will be two-sided hypothesis tests performed at the 5% level of significance for main 
effects. Confidence intervals will be 2-sided 95% confidence intervals, which will be 
provided for both within group estimate and between group difference. P-values will be 
rounded to and displayed in three decimals. If a p-value less than 0.0001 occurs, it will be 
shown in tables as <.0001. There will be no multiplicity adjustments, or adjustments for 
multiple comparisons. Continuous variables will be summarized by number of subjects and 
mean, standard deviation/standard error (SD/SE), median, Q1, Q3, minimum, and maximum 
values. Categorical variables will be summarized by number and percentage of subjects. 
If an outlier is identified and/or a pronounced non-normal probability distribution is found 
for the difference between the two treatment groups, then a non-parametric analysis 
corresponding to that of the parametric counterpart, e.g. the Wilcoxon rank test for median, 
will be performed and be considered as the primary analysis to assess the treatment 
difference between KRN23 and active control groups. Such a model violation may be 
identified by graphical methods, measures of non-normality (e.g., skewness, kurtosis) or 
other appropriate methods.  
8.2 
Subject Accountability  
The number and percentage of subjects in each of the analysis populations (Screened, Full, 
PK and PD) will be summarized by treatment group.  Subjects and their data excluded from 
any analysis set will be listed. 
Screen-failure subjects (ie, subjects screened but not randomized) and the associated reasons 
for failure to randomize will be tabulated overall for the Screened Population. The number 
and percentage of subjects who complete the treatment period and of subjects who 
prematurely discontinue will be presented for each treatment group and pooled across 
treatment groups for the Full Analysis set. The reasons for premature discontinuation from 
treatment period as recorded on eCRFs will be summarized.  
8.3 
Protocol Deviations 
Protocol deviations will be summarized by type in each treatment group for the Full Analysis 
set. All protocol deviations will be listed. 


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8.4 
Investigational Product Administration 
8.4.1 
Extent of Exposure 
Exposure duration to the investigational product for the full analysis set will be summarized 
for KRN23 therapy and the active control (oral phosphate/active vitamin D) separately. 
The total dose and prescribed weight-based dose of KRN23 will be summarized for the 
KRN23 group. The dosing information for oral phosphate and active vitamin D medications 
will be provided for the active control group.  
8.4.2 
Measurement of Treatment Compliance 
For KRN23 group, the number of dosing and cumulative dose per subject administered will 
be summarized. The number of missed dosing will also be summarized.  
For active control group, the number of full days with missed oral phosphate or active 
vitamin D medication will be summarized. The main reason for missed medication will also 
be summarized.   
Descriptive statistics for investigational product compliance will be presented by treatment 
group for the Full Analysis Set by study visit and overall 40 and 64-week treatment period. 
8.4.3 
Demographic and Baseline Characteristics 
Demographic parameters (age, age subgroup of < 5 years vs ≥ 5 years, sex, race, ethnicity, 
region, weight, recumbent length/standing height, body mass index [BMI]) and other 
baseline characteristics (general and disease-specific medical history, conventional therapy  
duration, age when conventional therapy  initiated, XLH treatment history, PHEX mutation, 
RSS scores, RSS total score subgroup of ≤ 2.5 vs > 2.5, XLH biochemical parameters, renal 
ultrasound scores) will be summarized descriptively by treatment group on the Full Analysis 
Set. 
8.4.4 
Prior and Concomitant Medication 
Prior medication is defined as any medication started before the date of the first dose of 
investigational product (medication start date prior to the first dose date).  
Concomitant medication is defined as any medication taken on or after the date of the first 
dose of investigational product [medication end date on or after first dose date (or ongoing), 
and medication start date prior or on the last dose date]. Any concomitant medications started 
after the date of the last dose of investigational product will not be presented in the summary 
tables but will be included in the subject data listings. 


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Baseline medication is defined as any medication taken on the first dose date [medication end 
date on or after first dose date (or ongoing), and medication start date prior or on the first 
dose date]. 
Both prior and concomitant medications will be coded by drug name and therapeutic class 
using WHO Drug Dictionary. If a subject took a specific medication multiple times or took 
multiple medications within a specific therapeutic class, that subject will be counted only 
once for the coded drug name or therapeutic class. 
8.5 
Efficacy Analysis 
The efficacy analyses will be based on the Full Analysis Set.   
8.5.1 
Generalized Estimating Equations Model (GEE) 
For repeated measures such as clinical outcomes, the GEE approach will be used for 
assessing the change over time. The GEE model will include treatment group, study visit and 
interaction between treatment group and study visit as categorical variables, stratification 
factors of baseline RSS total score and age will also be included, unless specified otherwise. 
To model the covariance structure, the exchangeable covariance matrix will be selected 
initially. If the exchangeable covariance structure leads to non-convergence, independence 
covariance structure will be applied. Model based estimates of the changes from baseline, SE 
and corresponding 95% confidence intervals (CIs) will also be provided along with P- values 
for assessing statistical significance. Other independent variables will be specified in the 
analysis section for each individual endpoints. 
 
8.5.2 
Sensitivity Analysis for Missing Data 
Sensitivity analyses to assess the robustness of the primary analysis result to missing data 
will be conducted on RSS and RGI-C endpoints. Theses may include, but are not limited to: 
• Last Observation Carried Forward (LOCF): the last non-missing post-baseline 
observation will be carried forward to the corresponding endpoint for evaluation. If no 
post-baseline observation is available, the baseline observation will be used for 
evaluation; if no baseline is available, the LOCF approach will not be performed. 
• Multiple imputation (MI): the PROC MI procedure in SAS will be utilized to impute 
missing values using a Markov Chain Monte Carlo (MCMC) approach by 100 times. 
The imputed dataset will be analyzed by the ANCOVA model at Week 40 analysis or 
GEE model at Week 64 analysis, the results will be combined using the PROC 
MIANALYZE procedure in SAS. Baseline RSS total score, treatment group and baseline 
age stratification factor will be used as predictor variables in the imputation. Other 
variables such as change from baseline in ALP may also be considered as a predictor 
variable. 


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8.5.3 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint will be tested to compare the mean RGI-C global score 
between the KRN23 and active control groups. 
At Week 40 analysis, an Analysis of Covariance (ANCOVA) model will be applied on the 
RGI-C global score with treatment group and baseline age stratification factor as independent 
variables, baseline RSS total score as a continuous covariate. The stratification factor of 
baseline RSS total score will not be included in the model. 
For RGI-C knee, wrist and lower limb deformity scores, a similar ANCOVA model with be 
applied with baseline RSS wrist score used in RGI-C wrist score modeling and baseline RSS 
knee score used in RGI-C knee score and lower limb deformity score modeling. 
At Week 64 analysis, RGI-C (global, knee, wrist and long leg) scores over time including 
Week 40 will be analyzed using GEE model that includes treatment group, visit, treatment 
group by visit interaction, baseline age stratification factor as independent variables, baseline 
RSS total score as a continuous covariate. The stratification factor of baseline RSS total score 
will not be included in the model. 
The estimated difference of RGI-C between KRN23 treatment and active control group will 
be provided along with 95% CI and p-value. The estimated RGI-C score and its 95% CI 
within individual treatment groups will also be provided. Descriptive statistics for all RGI-C 
scores will be provided in both continuous and categorical summary. Summary of 
abnormality at baseline and change in abnormality at Week 40 and Week 64 will also be 
provided. A listing of RGI-C scores will be provided for each subject. Graphic displays of 
RGI-C scores will also be provided over time by treatment group. 
If subjects receive orthopedic surgeries before week 40 X-ray visit, a sensitivity analysis will 
be performed by excluding these subjects from week 40 and week 64 RGI-C analyses. 
If subjects receive orthopedic surgery after week 40 but before week 64 X-ray visit, a 
sensitivity analysis will be performed at week 64 RGI-C analysis, where the week 40 RGI-C 
data will be used to impute Week 64 data for these subjects. 
8.5.4 
Analysis of Secondary Efficacy Endpoint(s) 
8.5.4.1 
RGI-C responder 
The proportion of RGI-C responder (subjects with a mean RGI-C global score ≥ +2.0) will be 
summarized for each treatment group at Week 40 and Week 64. At Week 40 analysis, a 
logistic regression model will be applied with treatment group and baseline age stratification 
factor as independent variables, baseline RSS total score as a continuous covariate. 
The stratification factor of baseline RSS total score will not be included in the model. 
At Week 64 analysis, a similar repeated measures logistic regression model will be applied 
including both Week 40 and Week 64 data as dependent variable, treatment group, study 
visit, interaction between treatment group and study visit, and baseline age stratification 


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factor as independent variables, baseline RSS total score as a continuous covariate. 
The stratification factor of baseline RSS total score will not be included in the model. 
The odds ratio comparing KRN23 treatment to conventional therapy will be provided along 
with 95% CI and p-value. The estimated responder rate and its 95% CI within individual 
treatment groups will also be provided. 
8.5.4.2 
RSS scores 
The change from baseline in RSS (total, knee and wrist) scores over time will be analyzed 
using the same method as that of the RGI-C score. At Week 40 analysis, an ANCOVA model 
will be applied with treatment group and baseline age stratification factor as independent 
variables, baseline RSS total score as a continuous covariate. The stratification factor of 
baseline RSS total score will not be included in the model. At Week 64 analysis, a GEE 
model will be used with all RSS change from baseline data as dependent variable, treatment 
group, study visit, interaction between treatment group and study visit, and baseline age 
stratification factor as independent variables, baseline RSS total score as a continuous 
covariate. The stratification factor of baseline RSS total score will not be included in the 
model.  The estimated different between KRN23 treatment and active control group will be 
provided along with 95% CI and p-value. The estimated change from baseline in RSS score 
and its 95% CI within individual treatment groups will also be provided. 
Descriptive statistics for all RSS scores and change from baseline in RSS score will be 
provided in both continuous and categorical summary. A listing of RSS scores for each 
subject will be provided. Graphic displays of RSS scores over time will also be provided by 
treatment group.  
8.5.4.3 
Growth  
Growth in standing height/recumbent length and weight will be summarized over time in 
observed value, Z-score and percentile. Individual subject growth curves will be plotted with 
CDC growth charts as reference. 
 
For standing height/recumbent length Z-score, the GEE model will be used to assess the 
difference between treatment groups. Treatment group and baseline RSS stratification factor 
will be included as independent variables, baseline age and height/length Z score will be 
included as continuous covariates. The mid-parental height Z score will be calculated by 
averaging the height Z scores of parents and may also be considered as a covariate in the 
model. The stratification factor of baseline age will not be included in the model. The 
estimated different between KRN23 treatment and active control group will be provided 
along with 95% CI and p-value. The estimated change from baseline and its 95% CI within 
individual treatment groups will also be provided. 
The growth velocity defined in Section 5.7.3 will be estimated for selected pre-treatment 
period (e.g. within 1.5 years prior to baseline) and post-treatment period from baseline to 
Week 40 and from baseline to Week 64 respectively for each subject. If a subject has both 


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recumbent length and standing height measurements from 1.5 years prior to baseline to 
post-baseline period, the recumbent length will be subtracted by 0.8 cm before pooling with 
standing height data (https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm). 
 
An ANCOVA model will be applied on the change in growth velocity Z score from baseline 
to Week 40 or Week 64 to assess the difference between treatment groups. Treatment group 
and baseline RSS total score stratification factor will be included as independent variables, 
baseline Z score and age will be included as continuous covariates. The stratification factor 
of baseline age will not be included in the model. The estimated different between KRN23 
treatment and active control group will be provided along with 95% CI and p-value. 
The estimated change from baseline and its 95% CI within individual treatment groups will 
also be provided. 
 
In addition, descriptive statistics of sitting height during the post-treatment period and its 
respective change from baseline will be provided by study visits. A listing of standing 
height/recumbent length and the respective Z score, percentile, growth velocity and sitting 
height will be provided.    
 
8.5.4.4 
Walking Ability (6MWT) 
For subjects ≥ 5 years of age at the screening visit, summary statistics of total distance 
walked and percent of predicted 6MWT will be tabulated for each study visit for the 
observed measures and their respective change from baseline based on the Full Analysis 
Subset (Baseline age ≥ 5 years). Change from baseline of total distance walked and percent 
of predicted 6MWT will be assessed using the GEE approach as outlined in Section 8.5.1 
with baseline measures and baseline RSS total score stratification factor included as 
independent variables. 
A listing containing the 6MWT details will be provided. Graphs showing change in total 
distance walked during 6MWT and percent of predicted 6MWT will be provided by treatment 
group. 
8.5.4.5 
Patient Reported Outcomes Measurement Information System (PROMIS) 
For subjects aged ≥ 5 years at screening visit, summaries statistics of Pediatric Pain 
Interference, Physical Function Mobility and Fatigue domain scores will be reported by study 
visit for both observed measures and their respective change from baseline based on the Full 
Analysis Subset (Baseline age ≥ 5 years). Change from baseline values over time will be 
assessed to compare KRN23 therapy with the active control (oral phosphate/active vitamin 
D) using the GEE approach as outlined in Section 8.5.1 with baseline measures and baseline 
RSS total score stratification factor included as independent variables. 
A listing of Pediatric Pain Interference, Physical Function Mobility and Fatigue domain 
scores will be provided. 


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Graphs showing change in Pediatric Pain Interference, Physical Function Mobility and 
Fatigue domain scores will be provided by treatment group. Cumulative Distribution 
Function (CDF) of change from baseline in each domain score will also be plotted by 
treatment group. 
8.5.4.6 
Faces Pain Scale – Revised (FPS-R) 
For subjects aged ≥ 5 years at screening visit, summaries statistics of FPS-R will be reported 
by study visit for both observed measures and their respective change from baseline based on 
the Full Analysis Subset (Baseline age ≥ 5 years). Change from baseline of FPS-R over time 
will be assessed to compare KRN23 therapy with the active control (oral phosphate/active 
vitamin D) using the GEE approach as outlined in Section 8.5.1 with baseline measures and 
baseline RSS total score stratification factor included as independent variables. 
Descriptive statistics for FPS-R scores as well as it change from baseline will be provided in 
both continuous and categorical summary. A listing of FPS-R will be provided. Graphs 
showing change in FPS-R will be provided by treatment group.  
8.5.4.7 
PD Analysis 
The PD parameters will include serum phosphorus, TmP/GFR, serum 1,25(OH)2D, TRP, and 
ALP. All PD analyses will be performed on the PD Analysis Set, unless stated otherwise.   
Descriptive statistics of PD parameters and their respective change from baseline and 
percentage change from baseline will be tabulated by treatment group at each study visit.  
The change in serum phosphorus from baseline to mean post-baseline values (average of 
Week 1, 4, 8, 16, 24, 32 and 40 serum phosphorus for Week 40 analysis and Week 1, 4, 8, 
16, 24, 32, 40, 52 and 64 serum phosphorus for Week 64 analysis) will be analyzed using an 
ANCOVA model. Treatment group, baseline age and RSS total score stratification factors 
will be included as independent variables, baseline serum phosphorus will be included as a 
continuous covariate. The estimated difference between KRN23 treatment and active control 
group will be provided along with 95% CI and p-value. The estimated change from baseline 
within individual treatment groups will also be provided. 
PD endpoints at all scheduled visits will be assessed using the GEE approach as outlined in 
Section 8.5.1 with change from baseline value as dependent variable, baseline measures and 
baseline age and RSS total score stratification factors included as independent variables. 
The proportion of subjects achieving the normal range (3.2-6.1 mg/dL) will be reported by 
treatment group at each study visit. Similarly, proportion of subjects achieving TmP/GFR 
within the normal range (2.6 – 4.4 mg/dL) will be reported by treatment group at each study 
visit.   
A listing containing PD parameters such as serum phosphate level, serum 1,25(OH)2D, 
TmP/GFR, TRP, and ALP will be provided for each subject. 


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Graphs showing the change over time in PD parameters for both observed measure and the 
respective change from baseline will be provided by treatment group.   
8.6 
Analysis of Other Efficacy Endpoint(s) 
8.6.1 
Health-related Quality of Life (SF-10 for Children Health Survey) 
Descriptive summary statistics of the PHS-10 and PSS-10 scores will be reported by study 
visit for both observed measures and their respective change from baseline based on the Full 
Analysis Subset (Baseline Age ≥5 years). A listing of PHS-10 and PSS-10 scores will be 
provided. 
8.6.2 
Dental Assessment 
The number of dental events (dental abscess, dental cavities, tooth extraction, root canal and 
gingivitis) will be summarized by treatment group at each study visit. A listing of dental 
events will be provided for each subject. 
8.7 
Pharmacokinetics 
The descriptive statistics for serum KRN23 will be tabulated and the listing of serum KRN23 
will be provided based on the PK analysis set. 
8.8 
Safety Analysis  
Safety Analysis Set will be used for the safety analysis. Subjects will be analyzed based on 
the actual treatment received. Safety variables including AEs, SAEs, events to monitor, 
safety laboratory assessments, vital signs, renal ultrasound, ECG, ECHO, and anti-KRN23 
antibody will be summarized descriptively by treatment group. 
8.8.1 
Adverse Events 
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities. 
An AE (classified by preferred term) will be considered a treatment emergent adverse event 
(TEAE) if it occurred on or after the first dose of investigational product and was not present 
prior to the first dose, or it was present before the first dose but increased in severity during 
the study.  
Subject incidence of TEAEs will be tabulated as the following: 
• Summary of TEAEs by treatment group  
• TEAEs by SOC and PT (preferred term) by treatment group (sorted by descending 
frequency by SOC and PT) 


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• Related TEAEs by SOC and PT by treatment group (sorted by descending frequency by 
SOC and PT) or TEAE by greatest relationship, SOC and PT by treatment group 
• Serious TEAEs by SOC and PT by treatment group (sorted by descending frequency by 
SOC and PT).  
• Serious and Related TEAEs by SOC and PT by treatment group (sorted by descending 
frequency by SOC and PT). 
• Grade 3 or 4 TEAEs by SOC and PT by treatment group (sorted by descending frequency 
by SOC and PT). or TEAE by greatest severity, treatment group, SOC and PT 
• Deaths by SOC and PT by treatment group (sorted by descending frequency by SOC and 
PT). 
• TEAEs leading to discontinuation of study by SOC and PT by treatment group (sorted by 
descending frequency by SOC and PT). 
• TEAEs leading to discontinuation of treatment by SOC and PT by treatment group 
(sorted by descending frequency by SOC and PT). 
• TEAEs by PT by treatment group (sorted by descending frequency of PT) 
• Serious TEAEs by PT by treatment group (sorted by descending frequency of PT) 
• Related TEAEs by PT by treatment group (sorted by descending frequency of PT) 
Subject incidence for each type of events to monitor will be tabulated as the following: 
• By PT by treatment group 
• By PT and greatest reported severity by treatment group 
• By PT and relationship to study drug by treatment group 
Detailed listings for all AEs, serious TEAEs, AEs leading to the discontinuation of study, 
AEs leading to the discontinuation of treatment, and death will also be generated.  
The severity will be based on Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.0. If an AE cannot be graded based on CTCAE, the investigator will assign a 
severity based on 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 = Death. 
8.8.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values and changes from the baseline values at 
each assessment time point will be presented by treatment group for laboratory parameters 
listed in Appendix 2. Shift table for iPTH at each scheduled visit will be provided to assess to 
the normality over time. Listings for all clinical laboratory parameters and all abnormal 
laboratory parameters will be provided for each subject. 


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8.8.3 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressures, systolic and 
diastolic blood pressure percentiles, pulse rate, and weight) and changes from baseline values 
at each visit and at the end of study will be presented by treatment group. 
The blood pressure will be summarized by study visit in mmHg and percentile to assess the 
blood pressure change over time.  
Heart rate and heart rate percentile category will be tabulated over time by treatment group. 
8.8.4 
Concomitant Medications 
Each medication will be coded to a preferred name and an Anatomic Therapeutic 
Classification (ATC) code using WHODrug. The number and percentage of subjects taking 
each concomitant medication will be displayed by medication class (anatomical 
classification) and preferred name for each treatment group. This display will be created for 
the safety analysis set.  A concomitant medication listing will also be made. Prior 
medications, e.g. medications that were stopped before the first dose of study therapy, will 
also be listed. 
8.8.5 
Physical Examination 
Physical exam results will include the assessment of general appearance; head, eyes, ears, 
nose, and throat (HEENT); the cardiovascular, dermatology, lymphatic, respiratory, 
gastrointestinal, genitourinary, musculoskeletal, neurological systems. The number and 
percentage of subjects with Normal/Abnormal assessment for each body system will be 
summarized by visit and treatment group.  All physical examination assessments will be 
listed. 
8.8.6 
Pregnancy Test 
Subject level listing for pregnancy test results will be created for those who had positive 
pregnancy test.  
8.8.7 
Renal Ultrasound 
Renal ultrasound will be conducted with findings of nephrocalcinosis graded on a 5-point 
scale by a central reader. These results will be summarized by time point and presented by 
treatment group. Furthermore, a grade shift table summarizing changes from baseline by time 
point will also be created.  
A listing of renal ultrasound/nephrocalcinosis scores will also be provided. 


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8.8.8 
ECG 
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS duration, 
QT interval, and QTc) and changes from baseline values at each assessment time point to the 
end of study will be presented by treatment group. The QTc will be calculated using both the 
Bazett and Fridericia corrections. 
ECG parameters will be summarized by study visit, by the maximum post-baseline value, 
change from baseline and maximum change from baseline. Shift from baseline to post-
baseline visits in overall ECG assessment (normal or abnormal) will also be provided.   
A listing of all ECG parameters including the overall assessment will also be created. 
8.8.9 
ECHO 
ECHO data will be read locally to assess for evidence of ectopic mineralization in the heart 
and aorta and to evaluate for signs of LVH or cardiac dysfunction. Descriptive statistics for 
the various continuous ECHO measurements will be reported by treatment group at the 
scheduled time points and will include the change from baseline value. The summary of the 
descriptive statistics will be displayed by visit. Shift table in presence of ectopic 
mineralization and aortic valve regurgitation from baseline to post-baseline visits will be 
provided. 
8.8.10 Anti-KRN23 Antibody Testing 
Anti-KRN23 antibody will be summarized descriptively by treatment group.  Shift table from 
baseline to post-baseline visit will also be provided. 
 


Protocol Number:  UX023-CL301  
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9 REFERENCES 
Bieri, D, Reeve, RA, Champion, GD, Addicoat, L, and Ziegler, JB. 1990. "The Faces Pain 
Scale for the self-assessment of the severity of pain experienced by children: 
development, initial validation, and preliminary investigation for ratio scale 
properties." Pain 41 (2):139-50. 
Broderick, JE, DeWitt, EM, Rothrock, N, Crane, PK, and Forrest, CB. 2013. "Advances in 
Patient-Reported Outcomes: The NIH PROMIS((R)) Measures." EGEMS (Wash DC) 
1 (1):1015. 
Carpenter, TO, Imel, EA, Holm, IA, Jan de Beur, SM, and Insogna, KL. 2011. "A clinician's 
guide to X-linked hypophosphatemia." J Bone Miner Res 26 (7):1381-8. 
Geiger, R, Strasak, A, Treml, B, Gasser, K, Kleinsasser, A, Fischer, V, Geiger, H, 
Loeckinger, A, and Stein, JI. 2007. "Six-minute walk test in children and 
adolescents." J Pediatr 150 (4):395-9. 
Hicks, CL, von Baeyer, CL, Spafford, PA, van Korlaar, I, and Goodenough, B. 2001. "The 
Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement." 
Pain 93 (2):173-83. 
Kuczmarski, RJ, Ogden, CL, Grummer-Strawn, LM, Flegal, KM, Guo, SS, Wei, R, Mei, Z, 
Curtin, LR, Roche, AF, and Johnson, CL. 2000. "CDC growth charts: United States." 
Adv Data (314):1-27. 
Linglart, A, Biosse-Duplan, M, Briot, K, Chaussain, C, Esterle, L, Guillaume-Czitrom, S, 
Kamenicky, P, Nevoux, J, Prie, D, Rothenbuhler, A, Wicart, P, and Harvengt, P. 
2014. "Therapeutic management of hypophosphatemic rickets from infancy to 
adulthood." Endocr Connect 3 (1). 
NHLBI. 2005. "The Fourth Report on the Diagnosis, Evaluation, and Treatment of High 
Blood Pressure in Children and Adolescents.  National Institutes of Health." National 
Heart, Lung, and Blood Institute. 
NIH. 2015. PROMIS  2015 [cited January 2015]. Available from 
http://www.nihpromis.org/default.aspx#6. 
Ostchega, Y, Porter, KS, Hughes, J, Dillon, CF, and Nwankwo, T. 2011. "Resting pulse rate 
reference data for children, adolescents, and adults: United States, 1999-2008." Natl 
Health Stat Report (41):1-16. 
Saris-Baglama, RN, DeRosa, MA, Raczek, AE, Bjorner, JB, and Turner-Bowker, DM. 2007. 
The SF-10TM Health Survey for Children: A User’s Guide: Lincoln: QualityMetric 
Incorporated. 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
Proprietary and Confidential 
Page 42 
Saris-Baglama, RN, DeRosa, MA, Raczek, AE, Bjorner, JB, and Ware, JE. 2006. 
"Development, validation, and norming of the SF-10 for Children Health Survey." 
Quality of Life Research 15 (S1):A-145. 
Tanner, JM, and Davies, PS. 1985. "Clinical longitudinal standards for height and height 
velocity for North American children." J Pediatr 107 (3):317-29. 
Thacher, TD, Fischer, PR, Pettifor, JM, Lawson, JO, Manaster, BJ, and Reading, JC. 2000. 
"Radiographic scoring method for the assessment of the severity of nutritional 
rickets." J Trop Pediatr 46 (3):132-9. 


Protocol Number:  UX023-CL301 
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10 APPENDICES 
APPENDIX 1 
SUMMARY OF STATISTICAL ANALYSIS APPROACHES ON EFFICACY ENDPOINTS 
Primary Efficacy Endpoint 
Endpoint 
Scale 
Analysis populations 
Comparisons 
Data Time Points 
Week 40 Analysis 
RGI-C global score 
Continuous 
Full Analysis Set 
KRN23 vs SOC 
Baseline, Week 40 
ANCOVA 
Key Secondary Efficacy Endpoint(s) 
Endpoints 
Scale 
Analysis 
populations 
Comparisons 
Data Time Points 
Week 40 Analysis 
Week 64 Analysis 
RGI-C long leg score 
Continuous 
Full Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 40, 
Week 64 
ANCOVA 
GEE 
Change from baseline 
in Recumbent 
length/standing height 
Z score 
Continuous 
Full Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 24, 
Week 40, Week 64 
GEE 
GEE 
Change from baseline 
in RSS total score 
Continuous 
Full Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 40, 
Week 64 
ANCOVA 
GEE 
Change in serum 
phosphorus from 
baseline to mean 
post-baseline values 
Continuous 
PD Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 1, Week 4, 
Week 8, Week 16, 
Week 24, Week 32, Week 
40, Week 52, and Week 64 
ANCOVA 
ANCOVA 
Change from baseline 
in ALP 
Continuous 
PD Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 4, Week 8, 
Week 16, Week 24, Week 
32, Week 40, Week 52 and 
Week 64  
GEE 
GEE 


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Other Secondary Efficacy Endpoint(s) 
Endpoints 
Scale 
Analysis 
populations 
Comparisons 
Data Time Points 
Week 40 Analysis 
Week 64 Analysis 
RGI-C responder 
Binary 
Full Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 40, 
Week 64 
Logistic Regression 
Repeated Measures 
Logistic Regression 
RGI-C knee and wrist 
scores 
Continuous 
Full Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 40, 
Week 64 
ANCOVA 
GEE 
Change from baseline 
in RSS knee and wrist 
scores 
Continuous 
Full Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 40, 
Week 64 
ANCOVA 
GEE 
Change from baseline 
in Growth velocity Z 
score  
Continuous 
Full Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 40, 
Week 64 
ANCOVA 
ANCOVA 
Change from baseline 
in PROMIS pain, 
fatigue and physical 
function scores 
Continuous 
Full Analysis 
Subset (Baseline 
age ≥ 5 years) 
KRN23 vs 
SOC 
Baseline, Week 24, 
Week 40, Week 64 
GEE 
GEE 
Change from baseline 
in FPS-R score 
Continuous 
Full Analysis 
Subset (Baseline 
age ≥ 5 years) 
KRN23 vs 
SOC 
Baseline, Week 24, 
Week 40, Week 64 
GEE 
GEE 
Change from baseline 
in 6MWT total 
distance and percent 
of predicted normal 
Continuous 
Full Analysis 
Subset (Baseline 
age ≥ 5 years) 
KRN23 vs 
SOC 
Baseline, Week 24, 
Week 40, Week 64 
GEE 
GEE 
Change from baseline 
in PD parameters 
Continuous 
PD Analysis Set 
KRN23 vs 
SOC 
Baseline, Week 1, Week 4, 
Week 8, Week 16, 
Week 24, Week 32, Week 
40, Week 52, and Week 64 
(whichever applies) 
GEE 
GEE 
Note: Week 64 GEE analysis will include the result for Week 40 and other study visits. 


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APPENDIX 2 
CLINICAL LABORATORY ASSESSMENTS FOR SAFETY 
Chemistry
Hematology 
Urinalysis
1,25(OH)2D* 
Hematocrit 
Appearance 
Alanine aminotransferase (ALT) 
Hemoglobin 
Color 
Alkaline phosphatase (ALP)*  
Platelet count 
pH 
Amylase 
Red blood cell (RBC) count 
Specific gravity 
Aspartate aminotransferase (AST) 
White blood cell (WBC) count 
Ketones 
Bilirubin (direct and total) 
Mean corpuscular volume (MCV) 
Protein 
Blood urea nitrogen (BUN) 
Mean corpuscular hemoglobin (MCH) 
Glucose 
Calcium (total) 
MCH concentration 
Chloride 
Cholesterol (total) 
24-hour Urine 
Creatinine 
Calcium 
Gamma-glutamyl transpeptidase (GGT) 
Calcium/creatinine ratio 
Glucose 
Creatinine 
Intact parathyroid hormone (iPTH) 
Phosphorus 
Lactate dehydrogenase (LDH)
Phosphorus/creatinine ratio 
Lipase 
Phosphorus* 
2-hour Urine 
Potassium 
Calcium 
Protein (albumin and total) 
Creatinine 
Sodium 
Phosphorus 
Uric acid 
Pregnancy test (if applicable) 
* Also designated as PD/efficacy parameter


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APPENDIX 3 
SCHEDULE OF EVENTS 
Table 10.1:  Schedule of Events – Treatment Period Weeks 1-30 
 
Screening/ 
Baseline1 
Treatment Period 
VISIT ID 
SV 
BL 
V1 
V2 
HH 
V3 
V4 
HH 
V5 
V6 
HH 
V7 
HH 
V8 
HH 
V9 
V10 
HH 
V11 
HH 
V12 
HH 
V13 
V14 
HH 
V15 
HH  
V16 
HH 
V17 
TIME (WEEK/DAY) 
W-8 
to BL 
W0 
W
1 
W2 
W4 
W6 
W
8 
W1
0 
W1
2 
W1
4 
W16 
W18 
W20 
W22 
W2
4 
W2
6 
W28 
W30 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parents’ Heights 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tanner Staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHEX mutation analysis2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KRN23 Administration3 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Active Control3,4 
 
Administered at the discretion of the treating Investigator 
EFFICACY MEASURES 
Growth (standing height [or 
length], sitting height)5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Growth velocity 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilateral AP knee x-rays1, 6, 
7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilateral PA hand/wrist 
x-rays1,6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standing long leg x-ray7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6MWT8 (aged ≥ 5 years at 
Screening Visit) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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Screening/ 
Baseline1 
Treatment Period 
VISIT ID 
SV 
BL 
V1 
V2 
HH 
V3 
V4 
HH 
V5 
V6 
HH 
V7 
HH 
V8 
HH 
V9 
V10 
HH 
V11 
HH 
V12 
HH 
V13 
V14 
HH 
V15 
HH  
V16 
HH 
V17 
TIME (WEEK/DAY) 
W-8 
to BL 
W0 
W
1 
W2 
W4 
W6 
W
8 
W1
0 
W1
2 
W1
4 
W16 
W18 
W20 
W22 
W2
4 
W2
6 
W28 
W30 
PROMIS Pediatric Pain 
Interference, Fatigue and 
Physical Function Mobility 
(aged ≥ 5 years at Screening 
Visit)9 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Faces Pain Scale – Revised 
(aged > 5years at Screening 
Visit) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
SF-10 (aged ≥ 5 years at 
Screening Visit)10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
PD MEASURES 
Serum Phosphorus11 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Serum 1,25(OH)2D11  
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
ALP12 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
PHARMACOKINETICS 
Serum Pre-dose KRN23 
 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
SAFETY MEASURES 
Vital Signs13 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Weight14 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Concomitant Medication15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Ultrasound1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ECG1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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Screening/ 
Baseline1 
Treatment Period 
VISIT ID 
SV 
BL 
V1 
V2 
HH 
V3 
V4 
HH 
V5 
V6 
HH 
V7 
HH 
V8 
HH 
V9 
V10 
HH 
V11 
HH 
V12 
HH 
V13 
V14 
HH 
V15 
HH  
V16 
HH 
V17 
TIME (WEEK/DAY) 
W-8 
to BL 
W0 
W
1 
W2 
W4 
W6 
W
8 
W1
0 
W1
2 
W1
4 
W16 
W18 
W20 
W22 
W2
4 
W2
6 
W28 
W30 
ECHO1 (ages ≥ 5 years) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry16, Hematology, 
Urinalysis11 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Serum 25(OH)D 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum Calcium11 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Serum Creatinine11 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Serum iPTH 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Serum iFGF23 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
2-hr Urine11,17 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
24-hr Urine11,17 (aged 
≥ 5 years) 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Dental assessment18 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Immunogenicity (HAHA)19 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Urine Pregnancy Test20 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
See footnotes after Table 10.2 


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Table 10.2:  Schedule of Events – Treatment Period Weeks 32-64 
 
Treatment Period 
Safety 
Visit21 
VISIT ID 
V18 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH  
V24 
HH 
V25 
HH  
V26 
HH 
V27 
HH  
V28 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
HH  
V33 
HH  
V34 
V35 
V36 
TIME 
(WEEK/DAY) 
W3
2 
W3
3 
W3
4 
W3
6 
W38 
W4
0 
W4
2 
W4
4 
W4
6 
W4
8 
W5
0 
W5
2 
W5
4 
W5
6 
W5
8 
W6
0 
W6
2 
W64/ 
ET 
W76 
Tanner staging 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
KRN23 
Administration3 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Active Control3,4 
Administered at the discretion of the treating Investigator 
EFFICACY MEASURES 
Growth 
(standing height 
[or length], 
sitting height)5 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Growth velocity 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Bilateral AP 
knee x-rays1, 6, 7 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Bilateral PA 
hand/wrist 
x-rays1, 6 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Standing long 
leg x-ray7 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
6MWT8 (aged 
≥5 years at 
Screening Visit) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 


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Treatment Period 
Safety 
Visit21 
VISIT ID 
V18 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH  
V24 
HH 
V25 
HH  
V26 
HH 
V27 
HH  
V28 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
HH  
V33 
HH  
V34 
V35 
V36 
TIME 
(WEEK/DAY) 
W3
2 
W3
3 
W3
4 
W3
6 
W38 
W4
0 
W4
2 
W4
4 
W4
6 
W4
8 
W5
0 
W5
2 
W5
4 
W5
6 
W5
8 
W6
0 
W6
2 
W64/ 
ET 
W76 
PROMIS 
Pediatric Pain 
Interference, 
Fatigue and 
Physical 
Function 
Mobility (aged 
≥5 years at 
Screening Visit)9 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Faces Pain Scale 
– Revised 
(FPS-R) (aged 
≥5 years at 
Screening Visit) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
SF-10 (aged 
≥5 years at 
Screening 
Visit)10 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PD MEASURES 
Serum 
Phosphorus11 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Serum 
1,25(OH)2D11  
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
ALP12 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PHARMACOKINETICS 
Serum Pre-dose 
KRN23 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
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Treatment Period 
Safety 
Visit21 
VISIT ID 
V18 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH  
V24 
HH 
V25 
HH  
V26 
HH 
V27 
HH  
V28 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
HH  
V33 
HH  
V34 
V35 
V36 
TIME 
(WEEK/DAY) 
W3
2 
W3
3 
W3
4 
W3
6 
W38 
W4
0 
W4
2 
W4
4 
W4
6 
W4
8 
W5
0 
W5
2 
W5
4 
W5
6 
W5
8 
W6
0 
W6
2 
W64/ 
ET 
W76 
SAFETY MEASURES 
Vital Signs13 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Weight14 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Physical 
Examination 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Concomitant 
Medication15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
Events15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal 
Ultrasound1 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECG1 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECHO1 (ages 
≥5 years) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Chemistry16, 
Hematology, 
Urinalysis11 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Serum 25(OH)D 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum 
Calcium11 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Serum 
Creatinine11 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Serum iPTH 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Serum iFGF23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
2-hr Urine11,17 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0 
 
 
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Page 52 
 
Treatment Period 
Safety 
Visit21 
VISIT ID 
V18 
HH 
V19 
HH 
V20 
HH 
V21 
HH 
V22 
V23 
HH  
V24 
HH 
V25 
HH  
V26 
HH 
V27 
HH  
V28 
V29 
HH 
V30 
HH 
V31 
HH 
V32 
HH  
V33 
HH  
V34 
V35 
V36 
TIME 
(WEEK/DAY) 
W3
2 
W3
3 
W3
4 
W3
6 
W38 
W4
0 
W4
2 
W4
4 
W4
6 
W4
8 
W5
0 
W5
2 
W5
4 
W5
6 
W5
8 
W6
0 
W6
2 
W64/ 
ET 
W76 
24-hr Urine11,17 
(aged ≥5 years) 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Dental 
assessment18 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Immunogenicity 
(HAHA)19 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy 
Test20 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
1. 
Renal ultrasound, ECG, ECHO, and x-rays may be performed within ± 3 days of clinic visit to accommodate scheduling availability. All Screening/Baseline 
assessments and inclusion/exclusion criteria must be satisfied prior to randomization and dosing. The Screening Visit window may be up to 8 weeks for 
PHEX mutation analysis and washout of oral phosphate and active vitamin D therapy.  
2. 
PHEX mutation analysis will be performed in all subjects. Potential subjects with prior confirmation of a PHEX mutation or variant of uncertain significance 
in either self or a family member with appropriate X-linked inheritance who meet other eligibility requirements may enroll before screening PHEX mutation 
results are returned. 
3. 
Patients will be randomized 1:1 to either the KRN23 treatment arm or the active control arm (oral phosphate/active vitamin D therapy). 
4. 
Active control will be administered at the discretion of the treating Investigator. Subjects randomized to the active control arm will visit the clinic at 
Weeks 1, 4, 8, 16, 24, 32, 40, 52, and 64.  
5. 
In subjects < 2 years old, length will be measured instead of standing height. 
6. 
Screening results will be treated as Baseline data. 
7. 
AP knee and PA hand/wrist x-rays will be acquired for all subjects and standing long leg x-rays will be acquired for all qualifying subjects. 
8. 
6MWT will be conducted only for subjects ≥5 years of age at the Screening Visit. If a subject is < 5 years of age at the Screening Visit, the 6MWT will not 
be assessed when the subject is over 5 years of age during the post-baseline visits. 
9. 
For the PROMIS Pediatric Pain Interference, Fatigue, and Physical Function Mobility scales, the parent or legal guardian will complete a Parent/Legal 
Guardian form for subjects ages 5 to < 8 years of age at the Screening Visit. Subjects ≥ 8 years of age at the Screening Visit will complete a pediatric 
self-report form. Parent/Legal Guardian forms will be used for the duration of the study for subjects < 8 years of age at the Screening Visit who had a 
baseline assessment, even when a subject turns 8 during the study.  
10. If a subject is < 5 years of age at the Screening Visit and therefore has no baseline data, SF-10 will not be administered even when the subject turns 5 during 
the study. 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
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Page 53 
11. Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug administration (if applicable). Record fasting duration on 
CRF. Serum phosphorus may be collected as an unscheduled lab if necessary. 
12. Alkaline phosphatase (ALP) 
13. Vital sign measurements consist of seated systolic/diastolic blood pressure (BP) measured in millimeters of mercury (mm Hg), heart rate (beats per minute), 
respiration rate (breaths per minute), and temperature in degrees Celsius (°C). Vital signs will be obtained at the beginning of each visit before any additional 
assessments are completed and after the subject has rested for 5 minutes. BP measurements will only be obtained at clinic visits and only for subjects 
≥3 years of age. At the Screening Visit and at Baseline, two sets of three BP measurements will be obtained – the first set will be done at the beginning of 
the visit and the second set at end of the visit after all site procedures are completed. BP measurements should be done after the subject has rested for 
5 minutes and a second and third BP measurement should be obtained, each performed 30 seconds apart.  
14. Weight from the previous in-clinic visit will be used to calculate KRN23 dose. 
15. At every Home Health visit for subjects in the KRN23 treatment arm, all subjects randomized to the active control arm will receive a phone call to assess 
adverse events and concomitant medications. Home Health visits are not applicable to subjects in Japan or Korea. 
16. Serum chemistry panels may include PD parameters (i.e. serum phosphorus and ALP), and safety parameters of interest (i.e. calcium) to avoid duplication of 
testing. 
17. Both 2-hr and 24-hr urine will be used for measurements of urinary phosphorus, creatinine, lipase, amylase, and calcium; 2-hr urine will be used for the 
derivation of TmP/GFR and TRP. For subjects <5 years of age, spot urine may be collected in place of the 2-hr urine samples for measurements of urinary 
calcium, phosphorus, and creatine.   
18. Separate dental assessments are not required and will be captured under AEs as dental issues arise. At each clinic visit, an oral examination will be 
conducted and subjects will be proactively asked if they had any dental events from dental caries, delay in eruption of the dentition, enamel hypoplasia, 
dental abscesses, and gingivitis. 
19. HAHA assessment will be performed only for subjects randomized to KRN23. If development of anti-KRN23 antibodies is suspected in a given subject, 
samples may be obtained at additional timepoints on a case by case basis. 
20. Pregnancy testing will be performed on any female subject of childbearing potential who has experienced menarche. 
21. An additional safety visit will take place 12 weeks ±1 week after the date of the last study drug administration for those subjects who discontinue treatment, 
or 12 weeks ±1 week after the Week 64 visit for subjects who complete the study and choose not to enroll in an extension study. This visit is not required for 
subjects who are eligible and choose to take part in an extension study. Every reasonable effort should be made to have required subjects return to the clinic 
for the final safety visit; however, subjects who are unable to return to the clinic for the final safety visit will be given the option of providing blood and 
urine samples as part of a Home Health visit. 
 
 
 
 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0 
 
 
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Page 54 
APPENDIX 4 
RSS DATA COLLECTION FORM 
 


Protocol Number:  UX023-CL301  
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APPENDIX 5 
RGI-C DATA COLLECTION FORM 
 


Protocol Number:  UX023-CL301  
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02 January 2018, Version 1.0 
 
 
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Page 56 
 
 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0 
 
 
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Page 57 
 
 
 
 
 
 
 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0 
 
 
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Page 58 
 
 
 


Protocol Number:  UX023-CL301 
Statistical Analysis Plan 
02 January 2018, Version 1.0  
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Page 59 
APPENDIX 6 
GROWTH VELOCITY MEAN AND SD VALUES BY AGE AND 
GENDER 
MALES 
FEMALES 
Age (years) 
Mean 
SD 
Mean 
SD 
2.5 
8.3 
1.3 
8.6 
1.3 
3 
7.8 
1.2 
8.1 
1.2 
3.5 
7.4 
1.1 
7.6 
1.2 
4 
7.1 
1.1 
7.2 
1.1 
4.5 
6.8 
1.0 
6.8 
1.0 
5 
6.6 
1.0 
6.6 
1.0 
5.5 
6.4 
1.0 
6.4 
0.9 
6 
6.2 
0.9 
6.2 
0.9 
6.5 
6.0 
0.9 
6.1 
0.9 
7 
5.9 
0.9 
6.0 
0.8 
7.5 
5.8 
0.9 
5.9 
0.8 
8 
5.6 
0.8 
5.8 
0.8 
8.5 
5.4 
0.8 
5.7 
0.8 
9 
5.3 
0.8 
5.8 
0.8 
9.5 
5.2 
0.7 
5.8 
0.8 
10 
5.1 
0.7 
6.2 
0.9 
10.5 
5.1 
0.7 
6.8 
1.1 
11 
5.2 
0.8 
7.7 
1.1 
11.5 
5.3 
0.7 
8.3 
1.1 
12 
5.7 
0.8 
7.3 
1.0 
12.5 
6.7 
0.9 
5.9 
1.1 
13 
8.6 
1.2 
4.3 
1.0 
13.5 
9.5 
1.2 
2.9 
0.7 
14 
8.4 
1.2 
1.8 
0.7 
14.5 
6.5 
1.2 
1.0 
0.5 
15 
4.7 
1.1 
15.5 
3.3 
1.0 
16 
2.2 
0.9 
16.5 
1.5 
0.8 
17 
0.9 
0.5 
17.5 
0.5 
0.4 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
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Page 60 
APPENDIX 7 
BLOOD PRESSURE PERCENTILES BY GENDER, AGE AND 
HEIGHT (NHLBI 2005) 
 
 
 


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02 January 2018, Version 1.0  
 
 
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Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
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Page 62 
APPENDIX 8 
HEART RATE PERCENTILES BY GENDER AND AGE 
 
 
 
 
 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
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Page 63 
APPENDIX 9 
ECG NORMAL RANGES 
 
 


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Page 64 
 
 
 


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APPENDIX 10 EVENTS TO MONITOR 
Injection site reactions: based on HLT “Injection site reaction” 
Category 
PT 
Injection site reaction 
Embolia cutis medicamentosa 
Injection site reaction 
Injected limb mobility decreased 
Injection site reaction 
Injection site abscess 
Injection site reaction 
Injection site abscess sterile 
Injection site reaction 
Injection site anaesthesia 
Injection site reaction 
Injection site atrophy 
Injection site reaction 
Injection site bruising 
Injection site reaction 
Injection site calcification 
Injection site reaction 
Injection site cellulitis 
Injection site reaction 
Injection site coldness 
Injection site reaction 
Injection site cyst 
Injection site reaction 
Injection site dermatitis 
Injection site reaction 
Injection site discharge 
Injection site reaction 
Injection site discolouration 
Injection site reaction 
Injection site discomfort 
Injection site reaction 
Injection site dryness 
Injection site reaction 
Injection site dysaesthesia 
Injection site reaction 
Injection site eczema 
Injection site reaction 
Injection site erosion 
Injection site reaction 
Injection site erythema 
Injection site reaction 
Injection site exfoliation 
Injection site reaction 
Injection site extravasation 
Injection site reaction 
Injection site fibrosis 
Injection site reaction 
Injection site granuloma 
Injection site reaction 
Injection site haematoma 
Injection site reaction 
Injection site haemorrhage 
Injection site reaction 
Injection site hyperaesthesia 
Injection site reaction 
Injection site hypersensitivity 
Injection site reaction 
Injection site hypertrichosis 
Injection site reaction 
Injection site hypertrophy 
Injection site reaction 
Injection site hypoaesthesia 
Injection site reaction 
Injection site induration 
Injection site reaction 
Injection site infection 
Injection site reaction 
Injection site inflammation 
Injection site reaction 
Injection site injury 
Injection site reaction 
Injection site irritation 
Injection site reaction 
Injection site ischaemia 
Injection site reaction 
Injection site joint discomfort 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
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Page 66 
Category 
PT 
Injection site reaction 
Injection site joint effusion 
Injection site reaction 
Injection site joint erythema 
Injection site reaction 
Injection site joint infection 
Injection site reaction 
Injection site joint inflammation 
Injection site reaction 
Injection site joint movement impairment 
Injection site reaction 
Injection site joint pain 
Injection site reaction 
Injection site joint swelling 
Injection site reaction 
Injection site joint warmth 
Injection site reaction 
Injection site laceration 
Injection site reaction 
Injection site lymphadenopathy 
Injection site reaction 
Injection site macule 
Injection site reaction 
Injection site mass 
Injection site reaction 
Injection site movement impairment 
Injection site reaction 
Injection site necrosis 
Injection site reaction 
Injection site nerve damage 
Injection site reaction 
Injection site nodule 
Injection site reaction 
Injection site oedema 
Injection site reaction 
Injection site pain 
Injection site reaction 
Injection site pallor 
Injection site reaction 
Injection site papule 
Injection site reaction 
Injection site paraesthesia 
Injection site reaction 
Injection site phlebitis 
Injection site reaction 
Injection site photosensitivity reaction 
Injection site reaction 
Injection site plaque 
Injection site reaction 
Injection site pruritus 
Injection site reaction 
Injection site pustule 
Injection site reaction 
Injection site rash 
Injection site reaction 
Injection site reaction 
Injection site reaction 
Injection site recall reaction 
Injection site reaction 
Injection site scab 
Injection site reaction 
Injection site scar 
Injection site reaction 
Injection site streaking 
Injection site reaction 
Injection site swelling 
Injection site reaction 
Injection site thrombosis 
Injection site reaction 
Injection site ulcer 
Injection site reaction 
Injection site urticaria 
Injection site reaction 
Injection site vasculitis 
Injection site reaction 
Injection site vesicles 
Injection site reaction 
Injection site warmth 
Injection site reaction 
Malabsorption from injection site 
 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
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Hypersensitivity: based on relevant PTs in the narrow SMQs for “Hypersensitivity”, 
Category 
PT 
Hypersensitivity 
Acute generalised exanthematous pustulosis 
Hypersensitivity 
Administration site dermatitis 
Hypersensitivity 
Administration site eczema 
Hypersensitivity 
Administration site hypersensitivity 
Hypersensitivity 
Administration site rash 
Hypersensitivity 
Administration site recall reaction 
Hypersensitivity 
Administration site urticaria 
Hypersensitivity 
Administration site vasculitis 
Hypersensitivity 
Allergic bronchitis 
Hypersensitivity 
Allergic colitis 
Hypersensitivity 
Allergic cough 
Hypersensitivity 
Allergic cystitis 
Hypersensitivity 
Allergic eosinophilia 
Hypersensitivity 
Allergic gastroenteritis 
Hypersensitivity 
Allergic granulomatous angiitis 
Hypersensitivity 
Allergic hepatitis 
Hypersensitivity 
Allergic keratitis 
Hypersensitivity 
Allergic myocarditis 
Hypersensitivity 
Allergic oedema 
Hypersensitivity 
Allergic otitis externa 
Hypersensitivity 
Allergic otitis media 
Hypersensitivity 
Allergic pharyngitis 
Hypersensitivity 
Allergic respiratory disease 
Hypersensitivity 
Allergic respiratory symptom 
Hypersensitivity 
Allergic sinusitis 
Hypersensitivity 
Allergic transfusion reaction 
Hypersensitivity 
Allergy alert test positive 
Hypersensitivity 
Allergy test positive 
Hypersensitivity 
Allergy to immunoglobulin therapy 
Hypersensitivity 
Allergy to vaccine 
Hypersensitivity 
Alveolitis allergic 
Hypersensitivity 
Anaphylactic reaction 
Hypersensitivity 
Anaphylactic shock 
Hypersensitivity 
Anaphylactic transfusion reaction 
Hypersensitivity 
Anaphylactoid reaction 
Hypersensitivity 
Anaphylactoid shock 
Hypersensitivity 
Anaphylaxis treatment 
Hypersensitivity 
Angioedema 
Hypersensitivity 
Antiallergic therapy 
Hypersensitivity 
Antiendomysial antibody positive 
Hypersensitivity 
Anti-neutrophil cytoplasmic antibody positive vasculitis 
Hypersensitivity 
Application site dermatitis 
Hypersensitivity 
Application site eczema 
Hypersensitivity 
Application site hypersensitivity 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
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Page 68 
Category 
PT 
Hypersensitivity 
Application site rash 
Hypersensitivity 
Application site recall reaction 
Hypersensitivity 
Application site urticaria 
Hypersensitivity 
Application site vasculitis 
Hypersensitivity 
Arthritis allergic 
Hypersensitivity 
Atopy 
Hypersensitivity 
Blepharitis allergic 
Hypersensitivity 
Blood immunoglobulin E abnormal 
Hypersensitivity 
Blood immunoglobulin E increased 
Hypersensitivity 
Bromoderma 
Hypersensitivity 
Bronchospasm 
Hypersensitivity 
Catheter site dermatitis 
Hypersensitivity 
Catheter site eczema 
Hypersensitivity 
Catheter site hypersensitivity 
Hypersensitivity 
Catheter site rash 
Hypersensitivity 
Catheter site urticaria 
Hypersensitivity 
Catheter site vasculitis 
Hypersensitivity 
Chronic eosinophilic rhinosinusitis 
Hypersensitivity 
Chronic hyperplastic eosinophilic sinusitis 
Hypersensitivity 
Circulatory collapse 
Hypersensitivity 
Circumoral oedema 
Hypersensitivity 
Conjunctival oedema 
Hypersensitivity 
Conjunctivitis allergic 
Hypersensitivity 
Corneal oedema 
Hypersensitivity 
Cutaneous vasculitis 
Hypersensitivity 
Dennie-Morgan fold 
Hypersensitivity 
Dermatitis 
Hypersensitivity 
Dermatitis acneiform 
Hypersensitivity 
Dermatitis allergic 
Hypersensitivity 
Dermatitis atopic 
Hypersensitivity 
Dermatitis bullous 
Hypersensitivity 
Dermatitis contact 
Hypersensitivity 
Dermatitis exfoliative 
Hypersensitivity 
Dermatitis exfoliative generalised 
Hypersensitivity 
Dermatitis herpetiformis 
Hypersensitivity 
Dermatitis infected 
Hypersensitivity 
Dermatitis psoriasiform 
Hypersensitivity 
Distributive shock 
Hypersensitivity 
Documented hypersensitivity to administered product 
Hypersensitivity 
Drug cross-reactivity 
Hypersensitivity 
Drug eruption 
Hypersensitivity 
Drug hypersensitivity 
Hypersensitivity 
Drug provocation test 
Hypersensitivity 
Drug reaction with eosinophilia and systemic symptoms 
Hypersensitivity 
Eczema 
Hypersensitivity 
Eczema infantile 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
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Page 69 
Category 
PT 
Hypersensitivity 
Eczema nummular 
Hypersensitivity 
Eczema vaccinatum 
Hypersensitivity 
Eczema vesicular 
Hypersensitivity 
Eczema weeping 
Hypersensitivity 
Encephalitis allergic 
Hypersensitivity 
Encephalopathy allergic 
Hypersensitivity 
Epidermal necrosis 
Hypersensitivity 
Epidermolysis 
Hypersensitivity 
Epidermolysis bullosa 
Hypersensitivity 
Epiglottic oedema 
Hypersensitivity 
Erythema multiforme 
Hypersensitivity 
Erythema nodosum 
Hypersensitivity 
Exfoliative rash 
Hypersensitivity 
Eye allergy 
Hypersensitivity 
Eye oedema 
Hypersensitivity 
Eye swelling 
Hypersensitivity 
Eyelid oedema 
Hypersensitivity 
Face oedema 
Hypersensitivity 
Giant papillary conjunctivitis 
Hypersensitivity 
Gingival oedema 
Hypersensitivity 
Gingival swelling 
Hypersensitivity 
Gleich's syndrome 
Hypersensitivity 
Haemorrhagic urticaria 
Hypersensitivity 
Hand dermatitis 
Hypersensitivity 
Henoch-Schonlein purpura 
Hypersensitivity 
Henoch-Schonlein purpura nephritis 
Hypersensitivity 
Hereditary angioedema 
Hypersensitivity 
Hypersensitivity 
Hypersensitivity 
Hypersensitivity vasculitis 
Hypersensitivity 
Idiopathic urticaria 
Hypersensitivity 
Immediate post-injection reaction 
Hypersensitivity 
Immune thrombocytopenic purpura 
Hypersensitivity 
Immune tolerance induction 
Hypersensitivity 
Infusion site dermatitis 
Hypersensitivity 
Infusion site eczema 
Hypersensitivity 
Infusion site hypersensitivity 
Hypersensitivity 
Infusion site rash 
Hypersensitivity 
Infusion site recall reaction 
Hypersensitivity 
Infusion site urticaria 
Hypersensitivity 
Infusion site vasculitis 
Hypersensitivity 
Injection site dermatitis 
Hypersensitivity 
Injection site eczema 
Hypersensitivity 
Injection site hypersensitivity 
Hypersensitivity 
Injection site rash 
Hypersensitivity 
Injection site recall reaction 
Hypersensitivity 
Injection site urticaria 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
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Page 70 
Category 
PT 
Hypersensitivity 
Injection site vasculitis 
Hypersensitivity 
Instillation site hypersensitivity 
Hypersensitivity 
Instillation site rash 
Hypersensitivity 
Instillation site urticaria 
Hypersensitivity 
Interstitial granulomatous dermatitis 
Hypersensitivity 
Intestinal angioedema 
Hypersensitivity 
Iodine allergy 
Hypersensitivity 
Kaposi's varicelliform eruption 
Hypersensitivity 
Kounis syndrome 
Hypersensitivity 
Laryngeal oedema 
Hypersensitivity 
Laryngitis allergic 
Hypersensitivity 
Laryngospasm 
Hypersensitivity 
Laryngotracheal oedema 
Hypersensitivity 
Limbal swelling 
Hypersensitivity 
Lip oedema 
Hypersensitivity 
Lip swelling 
Hypersensitivity 
Mast cell degranulation present 
Hypersensitivity 
Mouth swelling 
Hypersensitivity 
Mucocutaneous rash 
Hypersensitivity 
Multiple allergies 
Hypersensitivity 
Nephritis allergic 
Hypersensitivity 
Nikolsky's sign 
Hypersensitivity 
Nodular rash 
Hypersensitivity 
Oculomucocutaneous syndrome 
Hypersensitivity 
Oculorespiratory syndrome 
Hypersensitivity 
Oedema mouth 
Hypersensitivity 
Oral allergy syndrome 
Hypersensitivity 
Oropharyngeal blistering 
Hypersensitivity 
Oropharyngeal spasm 
Hypersensitivity 
Oropharyngeal swelling 
Hypersensitivity 
Palatal oedema 
Hypersensitivity 
Palatal swelling 
Hypersensitivity 
Palisaded neutrophilic granulomatous dermatitis 
Hypersensitivity 
Palpable purpura 
Hypersensitivity 
Pathergy reaction 
Hypersensitivity 
Periorbital oedema 
Hypersensitivity 
Pharyngeal oedema 
Hypersensitivity 
Pruritus allergic 
Hypersensitivity 
Radioallergosorbent test positive 
Hypersensitivity 
Rash 
Hypersensitivity 
Rash erythematous 
Hypersensitivity 
Rash follicular 
Hypersensitivity 
Rash generalised 
Hypersensitivity 
Rash macular 
Hypersensitivity 
Rash maculo-papular 
Hypersensitivity 
Rash maculovesicular 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
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Page 71 
Category 
PT 
Hypersensitivity 
Rash morbilliform 
Hypersensitivity 
Rash neonatal 
Hypersensitivity 
Rash papulosquamous 
Hypersensitivity 
Rash pruritic 
Hypersensitivity 
Rash pustular 
Hypersensitivity 
Rash rubelliform 
Hypersensitivity 
Rash scarlatiniform 
Hypersensitivity 
Rash vesicular 
Hypersensitivity 
Reaction to azo-dyes 
Hypersensitivity 
Reaction to colouring 
Hypersensitivity 
Reaction to drug excipients 
Hypersensitivity 
Reaction to preservatives 
Hypersensitivity 
Red man syndrome 
Hypersensitivity 
Rhinitis allergic 
Hypersensitivity 
Scleral oedema 
Hypersensitivity 
Scleritis allergic 
Hypersensitivity 
Scrotal oedema 
Hypersensitivity 
Serum sickness 
Hypersensitivity 
Serum sickness-like reaction 
Hypersensitivity 
Shock 
Hypersensitivity 
Shock symptom 
Hypersensitivity 
Skin necrosis 
Hypersensitivity 
Skin reaction 
Hypersensitivity 
Skin test positive 
Hypersensitivity 
Solar urticaria 
Hypersensitivity 
Solvent sensitivity 
Hypersensitivity 
Stevens-Johnson syndrome 
Hypersensitivity 
Stoma site hypersensitivity 
Hypersensitivity 
Stoma site rash 
Hypersensitivity 
Swelling face 
Hypersensitivity 
Swollen tongue 
Hypersensitivity 
Tongue oedema 
Hypersensitivity 
Toxic epidermal necrolysis 
Hypersensitivity 
Toxic skin eruption 
Hypersensitivity 
Tracheal oedema 
Hypersensitivity 
Type I hypersensitivity 
Hypersensitivity 
Type II hypersensitivity 
Hypersensitivity 
Type III immune complex mediated reaction 
Hypersensitivity 
Type IV hypersensitivity reaction 
Hypersensitivity 
Urticaria 
Hypersensitivity 
Urticaria cholinergic 
Hypersensitivity 
Urticaria chronic 
Hypersensitivity 
Urticaria contact 
Hypersensitivity 
Urticaria papular 
Hypersensitivity 
Urticaria physical 
Hypersensitivity 
Urticaria pigmentosa 


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Page 72 
Category 
PT 
Hypersensitivity 
Urticaria vesiculosa 
Hypersensitivity 
Vaginal exfoliation 
Hypersensitivity 
Vaginal ulceration 
Hypersensitivity 
Vasculitic rash 
Hypersensitivity 
Vessel puncture site rash 
Hypersensitivity 
Vulval ulceration 
Hypersensitivity 
Vulvovaginal rash 
Hypersensitivity 
Vulvovaginal ulceration 
 
Hyperphosphataemia: based on selected PTs below 
Category 
PT 
Hyperphosphataemia  
Hyperphosphataemia 
Hyperphosphataemia  
Blood phosphorus increased 
 
Ectopic mineralization: based on a MedDRA search of ‘calcification’ 
Category 
PT 
Ectopic calcification 
Adrenal calcification 
Ectopic calcification 
Aortic calcification 
Ectopic calcification 
Aortic valve calcification 
Ectopic calcification 
Aortic valve sclerosis 
Ectopic calcification 
Articular calcification 
Ectopic calcification 
Bladder wall calcification 
Ectopic calcification 
Breast calcifications 
Ectopic calcification 
Bursa calcification 
Ectopic calcification 
Calcific deposits removal 
Ectopic calcification 
Calcification metastatic 
Ectopic calcification 
Calcification of muscle 
Ectopic calcification 
Calcinosis 
Ectopic calcification 
Calculus bladder 
Ectopic calcification 
Calculus prostatic 
Ectopic calcification 
Calculus ureteric 
Ectopic calcification 
Calculus urethral 
Ectopic calcification 
Calculus urinary 
Ectopic calcification 
Cardiac valve sclerosis 
Ectopic calcification 
Cerebral calcification 
Ectopic calcification 
Chondrocalcinosis 
Ectopic calcification 
Chondrocalcinosis pyrophosphate 
Ectopic calcification 
Cutaneous calcification 
Ectopic calcification 
Dystrophic calcification 
Ectopic calcification 
Heart valve calcification 


Protocol Number:  UX023-CL301  
Statistical Analysis Plan 
02 January 2018, Version 1.0  
 
 
Proprietary and Confidential 
Page 73 
Category 
PT 
Ectopic calcification 
Heart valve stenosis 
Ectopic calcification 
Hepatic calcification 
Ectopic calcification 
Intervertebral disc calcification 
Ectopic calcification 
Intestinal calcification 
Ectopic calcification 
Ligament calcification 
Ectopic calcification 
Lymph node calcification 
Ectopic calcification 
Mitral valve calcification 
Ectopic calcification 
Mitral valve sclerosis 
Ectopic calcification 
Myocardial calcification 
Ectopic calcification 
Nephrocalcinosis 
Ectopic calcification 
Nephrolithiasis 
Ectopic calcification 
Ovarian calcification 
Ectopic calcification 
Pancreatic calcification 
Ectopic calcification 
Pericardial calcification 
Ectopic calcification 
Pleural calcification 
Ectopic calcification 
Prostatic calcification 
Ectopic calcification 
Pulmonary calcification 
Ectopic calcification 
Pulmonary valve calcification 
Ectopic calcification 
Pulmonary valve sclerosis 
Ectopic calcification 
Splenic calcification 
Ectopic calcification 
Stag horn calculus 
Ectopic calcification 
Tendon calcification 
Ectopic calcification 
Tracheal calcification 
Ectopic calcification 
Tricuspid valve calcification 
Ectopic calcification 
Tricuspid valve sclerosis 
Ectopic calcification 
Vascular calcification 
 
Restless legs syndrome 
Category 
PT 
Restless legs syndrome 
Restless legs syndrome 
Restless legs syndrome 
Restlessness 
Restless legs syndrome 
Akathisia 
Restless legs syndrome 
Psychomotor hyperactivity 
Restless legs syndrome 
Sensory disturbance 
Restless legs syndrome 
Muscle cramp 
Restless legs syndrome 
Limb discomfort 
Restless legs syndrome 
Neuromuscular pain 
Restless legs syndrome 
Formication