Clinical Trials Register

Summary
EudraCT Number:	2016-000600-29
Sponsor's Protocol Code Number:	UX023-CL301
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-06-20
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2016-000600-29

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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)

A.4.1

Sponsor's protocol code number

UX023-CL301

A.5.4

Other Identifiers

Name:

Unique product identifier (UPI)

Number:

EMA/902676

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/958/2016

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Ultragenyx Pharmaceuticals Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Ultragenyx Pharmaceuticals Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Icon Clinical research Ltd
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	100 Milton Park
B.5.3.2	Town/ city	Abingdon
B.5.3.3	Post code	OX14 4RY
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	441235451277
B.5.6	E-mail	markas.marriott@iconplc.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1351
D.3 Description of the IMP
D.3.1	Product name	Recombinant human IgG1 monoclonal antibody to fibroblast growth factor 23 [FGF23]
D.3.2	Product code	KRN23
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Burosumab
D.3.9.1	CAS number	1610833-03-8
D.3.9.2	Current sponsor code	KRN23
D.3.9.3	Other descriptive name	RECOMBINANT HUMAN IGG1 MONOCLONAL ANTIBODY TO FIBROBLAST GROWTH FACTOR 23
D.3.9.4	EV Substance Code	SUB130804
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Burosumab
D.3.9.1	CAS number	1610833-03-8
D.3.9.2	Current sponsor code	KRN23
D.3.9.3	Other descriptive name	RECOMBINANT HUMAN IGG1 MONOCLONAL ANTIBODY TO FIBROBLAST GROWTH FACTOR 23
D.3.9.4	EV Substance Code	SUB130804
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

X-linked hypophosphatemia (XLH) is a disorder of renal phosphate wasting, defective bone mineralisation, 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.

E.1.1.1

Medical condition in easily understood language

Inheritable form of rickets

E.1.1.2

Therapeutic area

Body processes [G] - Bones and nerves physological processes [G11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10016206
E.1.2	Term	Familial hypophosphataemic rickets
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

• Evaluate the effect of KRN23 therapy in improving rickets in children with XLH compared with active control (oral phosphate/active vitamin D)

E.2.2

Secondary objectives of the trial

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) 2 D, 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) (e.g., nephrocalcinosis), as compared with active control, and immunogenicity profile

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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 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 within age-adjusted normal range*
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) prior to the Screening 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. If sexually active, male and female subjects must be willing to use highly effective method(s) of contraception for the duration of the study.

E.4

Principal 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 through physical examination
2) Height percentile >50% based on country-specific norms
3) Use of aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit
4) Current or prior use of leuprorelin (e.g., 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 or recommended orthopedic surgery (implantation or removal), including staples, 8-plates or osteotomy, within 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 (parathyroid hormone [PTH] levels 2.5X upper limit of normal [ULN])
10) Use of medication to suppress PTH (e.g., 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.

E.5 End points

E.5.1

Primary end point(s)

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

E.5.1.1

Timepoint(s) of evaluation of this end point

week 40

E.5.2

Secondary end point(s)

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
• 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) 2 D, 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 (pre-dose level)
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)
• Chemistry, hematology, and urinalysis, including additional KRN23/XLH biochemical parameters of interest (serum 25(OH)D; lipase; amylase; creatinine; serum calcium and iPTH, and urinarycalcium 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 from dental caries, delay in eruption of the dentition, enamel hypoplasia, dental abscesses, and gingivitis
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.

E.5.2.1

Timepoint(s) of evaluation of this end point

weeks 24, 40 & 64

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

France

Germany

Ireland

Italy

Japan

Korea, Republic of

Spain

Sweden

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

current standard of care or post study extension for 96weeks or whenever the product is licenced

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-10-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-07-15

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