Clinical Trials Register

Summary
EudraCT Number:	2019-000469-19
Sponsor's Protocol Code Number:	BUR-CL207
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-10-28
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

France - ANSM

A.2

EudraCT number

2019-000469-19

A.3

Full title of the trial

A Phase 1/2, Open-label, Multicenter, Non-randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Burosumab in Pediatric Patients from Birth to Less than 1 Year of Age with X-linked Hypophosphatemia (XLH)

Étude de phase 1/2, en ouvert, multicentrique, non randomisée visant à évaluer la sécurité d’emploi, la tolérance, la pharmacocinétique et l’efficacité
du burosumab chez des patients pédiatriques depuis la naissance jusqu’à l’âge d’un an et atteints d’hypophosphatémie liée à l’X (XLH)

A.3.1

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

A Phase 1/2, Study to measure the safety, tolerability and the action of drugs in the body (method and rate of excretion; duration of effect on the body) and effectivity of Burosumab in children from birth to less than 1 year of age with inheritable form of rickets

Une étude de phase 1/2 visant à mesurer l'innocuité, la tolérabilité et l'action des médicaments dans l'organisme (méthode et vitesse d'excrétion; durée de l'effet sur l'organisme) et l'efficacité du burosumab chez l'enfant de la naissance à moins de 1 an avec une forme héréditaire de rachitisme

A.4.1

Sponsor's protocol code number

BUR-CL207

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/144/2016

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Kyowa Kirin Pharmaceutical Development Ltd.
B.1.3.4	Country	United Kingdom
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	Kyowa Kirin Pharmaceutical Development Ltd.
B.4.2	Country	United Kingdom
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 Rd
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	4407931653684
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	Yes
D.2.1.1.1	Trade name	CRYSVITA
D.2.1.1.2	Name of the Marketing Authorisation holder	Kyowa Kirin Holdings B.V. Bloemlaan2, 2132NP Hoofddorp, The Netherlands
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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
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.3.9.2	Current sponsor code	KRN23
D.3.9.3	Other descriptive name	FGF23
D.3.9.4	EV Substance Code	SUB184986
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 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	No
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

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). 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).

La HLX est une maladie génétique rare, grave, débilitante chronique et qui représente un besoin médical non satisfait. On estime que cette déficience génétique se produit dans environ 1/20 000 naissances vivantes (Burnett et al. 1964), (Imel et al. 2005). La HLX est la forme de rachitisme héréditaire la plus répandue et le défaut héréditaire le plus courant dans le transport du phosphate tubulaire rénal. La XLH est transmis comme un trouble dominant lié à l'X (Dixon et al. 1998)

E.1.1.1

Medical condition in easily understood language

Inheritable form of rickets

Forme héréditaire de rachitisme

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	20.0
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

To assess the safety and tolerability of burosumab in pediatric subjects with X-linked Hypophosphatemia (XLH)
starting treatment below 12 months of age with up to 64 weeks of exposure.

E.2.2

Secondary objectives of the trial

Secondary Objectives:
• To characterize the effect of burosumab on serum phosphate, 1,25-dihydroxyvitamin D (1,25[OH] 2 D), and
other pharmacodynamic (PD) markers of phosphate homeostasis in pediatric subjects with XLH starting
treatment below 12 months of age.
• To characterize the pharmacokinetics (PK) of burosumab following subcutaneous (SC) injection in pediatric
subjects with XLH below 12 months of age.
• To assess the clinical effects of burosumab on growth and prevention and/or healing of rickets and skeletal
deformities.
Exploratory Objectives:
• To evaluate presence and appearance of bone and skeletal XLH related abnormalities in pediatric subjects
starting treatment below 12 months of age.
• To evaluate anthropometric and motor development in pediatric subjects with XLH.
• To characterize the immunogenicity of burosumab following administration to pediatric subjects with XLH.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Main Criteria for Inclusion:
1. Male or female pediatric subjects, aged <12 months at burosumab treatment initiation.
2. Pediatric subjects with PHEX mutation or variant of uncertain significance in either the subject or a directly
related family member with appropriate X-linked inheritance.
3. Presenting serum phosphate levels below the age-specific LLN at Screening.
4. A legally authorized representative has provided written informed consent prior to any research-related procedures.
5. A legally authorized representative 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 required by the
study protocol, including providing access to prior medical records for the collection of historical growth,
biochemical, and radiographic data and disease history

E.4

Principal exclusion criteria

Main Criteria for Exclusion:
1. The pediatric subject’s legally authorized representative is unwilling or unable to stop the subject’s treatment
with oral phosphate and/or pharmacologic vitamin D metabolite or analogue (e.g. calcitriol, alfacalcidol) for
at least 1 week before planned treatment start and for the duration of the study.
2. Preterm pediatric patients (defined as born before 37 weeks of pregnancy) with a chronological age of
<6 months. Enrolment of preterm pediatric patients with a chronological age ≥6 months must be confirmed
by the Study Medical Monitor before study entry.
3. Impairment of renal function measured as serum creatinine above the age-adjusted normal range and
estimated GFR (calculated using the Bedside Schwartz equation) below the age-adjusted normal range.
4. Presence of nephrocalcinosis on renal ultrasound
5. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits.
6. Presence of a concurrent disease or condition that would interfere with study participation or affect subject safety.
7. Predisposition to infection or known immunodeficiency.
8. Severe dermatological conditions over the available injection sites.
9. 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.
10. Nutritional rickets and/or osteopenia to include exclusion of patients with metabolic
bone disease of other origin than XLH at Screening and/or Baseline.

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoints:
• Incidence, frequency, and severity of AEs and SAEs, including clinically significant changes in laboratory and imaging assessments, from Baseline to scheduled time points (measured throughout the study up to Week 64).

E.5.1.1

Timepoint(s) of evaluation of this end point

Even evaluation times to week 64/ followup week 70

E.5.2

Secondary end point(s)

Change from Baseline over time (Week 20, 32, 40,
48, 56 and 64) in:
• serum phosphate,
• 1,25(OH) 2 D.

Burosumab serum concentrations and PK
parameters, including CL/F, V/F, AUC, C max
and other parameters, as appropriate, following
SC administration.

Spot urine collection was added for measurement of calcium, creatinine,
calcium/creatinine ratio, phosphate and ratio of renal tubular maximum
reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) at baseline,
week 2, week 6, week 20, week 48 and week 64.

Change from Baseline over time and at
Week 40 and 64 in serum ALP.
• Change from Baseline or from time of
appearance in radiographic appearance of
rickets severity as assessed by the RGI-C
scoring system at Week 40 and 64.
• Change from Baseline or from time of
appearance in rickets severity assessed by total
RSS at Week 40 and 64.
• Change from Baseline in lower extremity
skeletal abnormalities, including genu varum
and genu valgus, as determined by the RGI-C
long leg score at Week 40 and 64.
• Change from Baseline in recumbent length at
Week 40 and Week 64 in cm, height-for-age z-
scores, and percentiles.

E.5.2.1

Timepoint(s) of evaluation of this end point

Change from Baseline over time (Week 20, 32, 40,
48, 56 and 64) in:
• serum phosphate,
• 1,25(OH) 2 D.
Change from Baseline over time and at
Week 40 and 64 in serum ALP.
• Change from Baseline or from time of
appearance in radiographic appearance of
rickets severity as assessed by the RGI-C
Spot urine -baseline,
week 2, week 6, week 20, week 48 and week 64.
scoring system at Week 40 and 64.
• Change from Baseline or from time of
appearance in rickets severity assessed by total
RSS at Week 40 and 64.
• Change from Baseline in lower extremity
skeletal abnormalities, as determined by the RGI-C
long leg score at Week 40 and 64.
• Change from Baseline in recumbent length at
Week 40 and Week 64 in cm, height-for-age z-
scores, and percentiles.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

PK in nunder 12 months population

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

France

Germany

Italy

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

dernière visite du dernier patient

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

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

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

infants under the age of 12 months

nourrissons de moins de 12 mois

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)

None

Aucun

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

2019-11-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-29

P. End of Trial
P.	End of Trial Status	Ongoing

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