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Clinical Trial Results:
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)

Summary
EudraCT number	2016-000600-29
Trial protocol	DK IE DE ES SE GB IT
Global end of trial date	15 Jul 2019

Results information
Results version number	v1(current)
This version publication date	31 Jan 2020
First version publication date	31 Jan 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

UX023-CL301

ISRCTN number

US NCT number

NCT02915705

WHO universal trial number (UTN)

Other trial identifiers

Unique product identifier (UPI): EMA/902676

Sponsor organisation name

Ultragenyx Pharmaceutical Inc.

Sponsor organisation address

60 Leveroni Court, Novato, California , United States, 94949

Public contact

Medical Information, Ultragenyx Pharmaceutical Inc., 1 8887568567, medinfo@ultragenyx.com

Scientific contact

Medical Information, Ultragenyx Pharmaceutical Inc., 1 8887568567, medinfo@ultragenyx.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001659-PIP01-15

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

15 Jul 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Jul 2019

Was the trial ended prematurely?

Main objective of the trial

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).

Protection of trial subjects

The trial was designed, conducted, recorded, and reported in accordance with the principles established by the 18th World Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and clarifications adopted by the General Assemblies. The investigators made every effort to ensure that the study was conducted in full conformance with Helsinki principles, International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, current Food and Drug Administration (FDA) regulations, EU Clinical Trial Directive 2001/20/EC, and local ethical and regulatory requirements. Each investigator was thoroughly familiar with the appropriate administration and potential risks of administration of the study drug, as described in the protocol and Investigator’s Brochure, prior to the initiation of the study. The method of obtaining and documenting informed consent and the contents of the informed consent form (ICF) complied with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human Subjects,” the Health Insurance Portability and Accountability Act regulations, and all other applicable regulatory requirements. Investigators were responsible for preparing the ICF and submitting it to the Sponsor for approval prior to submission to the Institutional Review Board (IRB). All ICFs were written in regional language and contained the minimum elements for consent as mandated by the ICH guidelines. An IRB-approved ICF was provided by the Sponsor prior to initiation of the study. Investigators obtained signed written informed consent from each potential study subject prior to the conduct of any study procedures and after the methods, objectives, requirements, and potential risks of the study were fully explained to each potential subject. Consent for participation could be withdrawn at any time for any reason by the subject.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 31

Country: Number of subjects enrolled

Australia: 9

Country: Number of subjects enrolled

Canada: 9

Country: Number of subjects enrolled

Japan: 5

Country: Number of subjects enrolled

Korea, Republic of: 2

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

United Kingdom: 4

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Eligible subjects discontinued oral phosphate and active vitamin D therapy for 7 days prior to randomization. Subjects were then randomized 1:1 to receive either open label burosumab administered by subcutaneous (SC) injection every 2 weeks (Q2W) or phosphate and active vitamin D therapy administered orally daily for a total of 64 weeks

Period 1 title

Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Active Control

Arm description

Arm type

Active comparator

Investigational medicinal product name

Oral Phosphate Supplement

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution, Oral powder

Routes of administration

Oral use

Dosage and administration details

Detailed information about the brand, starting dosages, and any changes in oral phosphate and active vitamin D therapy were determined by the treating Investigator within the expert guidelines and recorded at every site visit.

Investigational medicinal product name

Active Vitamin D

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution, Tablet

Routes of administration

Oral use

Dosage and administration details

Burosumab

Arm description

Burosumab 0.8 mg/kg starting dose, administered every 2 weeks by subcutaneous injection during the Treatment Period (up to Week 64).

Arm type

Experimental

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, UX023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Burosumab dosing should occur no sooner than 8 days after the last dose administered.

Number of subjects in period 1	Active Control	Burosumab
Started	32	29
Completed Week 40	32	29
Completed Week 64	32	29
Completed	32	29

Period 2 title

Long Term Extension Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Active Control

Arm description

During the Treatment Extension Period (Week 64 to Week 140), subjects crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Subjects in Japan and Korea did not enter the Treatment Extension Period.

Arm type

Experimental

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, UX023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Burosumab dosing should occur no sooner than 8 days after the last dose of oral phosphate and active vitamin D.

Burosumab

Arm description

During the Treatment Extension Period (Week 64 to Week 140), subjects continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Subjects in Japan and Korea did not enter the Treatment Extension Period.

Arm type

Experimental

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, UX023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Burosumab dosing should occur no sooner than 8 days after the last dose administered.

Number of subjects in period 2 ^[1]	Active Control	Burosumab
Started	26	25
Completed	26	25

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 7 subjects in Japan and Korea and 3 subjects who started treatment with commercially available burosumab did not enter the Treatment Extension Period.

Baseline characteristics

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Reporting group title

Active Control

Reporting group description

Reporting group title

Burosumab

Reporting group description

Burosumab 0.8 mg/kg starting dose, administered every 2 weeks by subcutaneous injection during the Treatment Period (up to Week 64).

Reporting group values	Active Control	Burosumab	Total
Number of subjects	32	29	61
Age categorical
Units: Subjects
Age continuous
age at first dose
Units: years
arithmetic mean (standard deviation)	6.50 ± 3.250	6.01 ± 3.408	-
Gender categorical
Units: Subjects
Female	18	16	34
Male	14	13	27
Ethnicity
Units: Subjects
Hispanic or Latino	3	3	6
Not Hispanic or Latino	29	26	55
Unknown or Not Reported	0	0	0
Race
Units: Subjects
Asian	6	2	8
White	25	25	50
Other/not specified	1	2	3
Rickets Severity Score (RSS) Total Score
The RSS system is a 10-point radiographic scoring method. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees (the total score is the sum of the wrist and knee score). Higher scores indicate greater rickets severity.
Units: score on a scale
arithmetic mean (standard deviation)	3.19 ± 1.141	3.17 ± 0.975	-
Height-For-Age Z Score
Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the Centers for Disease Control [CDC] growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. One subject in the burosumab group did not have a baseline measurement (n=28 for this group).
Units: Z score
arithmetic mean (standard deviation)	-2.05 ± 0.868	-2.32 ± 1.167	-
Growth Velocity Z Score From Pre-Treatment
The Z score indicates the number of standard deviations away from a reference population (from Tanner's standard) in the same age range and with the same sex. The baseline growth velocity was calculated for subjects who had data available from within 1.5 years prior to baseline. Children with a mid-point age under 2.25 years were excluded (younger ages are not available in Tanner's standard). A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome. n=22, 22 (active control, burosumab)
Units: Z score
arithmetic mean (standard deviation)	-2.14 ± 5.571	-1.37 ± 1.334	-
Serum Phosphorus
Units: mg/dL
arithmetic mean (standard deviation)	2.30 ± 0.257	2.42 ± 0.244	-
Serum 1,25(OH)D
n=30, 28 (active control, burosumab)
Units: pg/mL
arithmetic mean (standard deviation)	40.18 ± 14.886	46.00 ± 20.060	-
Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate(TmP/GFR)
Data for urinary phosphorus and tubular reabsorption of phosphate (TRP) were used in the calculation of TmP/GFR. n=30, 24 (active control, burosumab)
Units: mg/dL
arithmetic mean (standard deviation)	2.008 ± 0.3300	2.193 ± 0.3733	-
Serum Alkaline Phosphatase (ALP) Concentration
Units: U/L
arithmetic mean (standard deviation)	523.44 ± 154.419	510.76 ± 124.903	-
Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference Domain
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. For the Pain Interference Domain, decreases indicate less pain. n=20, 15 (active control, burosumab)
Units: T-score
arithmetic mean (standard deviation)	49.9 ± 12.05	53.1 ± 10.95	-
PROMIS Physical Function Mobility Domain
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. For the Physical Function Mobility Domain, increases indicate greater mobility. n=20, 15 (active control, burosumab)
Units: T-score
arithmetic mean (standard deviation)	45.5 ± 9.86	45.2 ± 9.05	-
PROMIS Fatigue Domain
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. For the Fatigue Domain, decreases indicate less fatigue. n=20, 15 (active control, burosumab)
Units: T-score
arithmetic mean (standard deviation)	47.0 ± 13.70	48.8 ± 9.60	-
Faces Pain Scale- Revised (FPS-R)
The FPS-R is a dimensionless 10 point Likert scale used to assess self-reported pain intensity on a scale from 0 (no pain) to 10 (most pain you can imagine). Greater pain scores are indicative of more severe pain. n=20, 15 (active control, burosumab)
Units: score on a scale
arithmetic mean (standard deviation)	0.7 ± 1.17	0.4 ± 1.12	-
Six Minute Walk Test (6MWT) Total Distance
The total distance walked (meters) in a 6-minute period was measured, and the percent predicted distance based on normative data for age and gender was estimated. n=20, 15 (active control, burosumab)
Units: meters
arithmetic mean (standard deviation)	450.50 ± 106.432	365.93 ± 118.083	-
Percent of Predicted Normal in the 6MWT Total Distance
The total distance walked (meters) in a 6-minute period was measured, and the percent predicted distance based on normative data for age and gender was estimated. n=20, 15 (active control, burosumab)
Units: meters
arithmetic mean (standard deviation)	76.20 ± 14.838	62.13 ± 18.629	-

End points

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Reporting group title

Active Control

Reporting group description

Reporting group title

Burosumab

Reporting group description

Burosumab 0.8 mg/kg starting dose, administered every 2 weeks by subcutaneous injection during the Treatment Period (up to Week 64).

Reporting group title

Active Control

Reporting group description

Reporting group title

Burosumab

Reporting group description

Subject analysis set title

Full Analysis Set: Active Control

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set: all randomized subjects who received at least one dose of assigned medication and had at least one post-baseline assessment.

Subject analysis set title

Full Analysis Set: Burosumab

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set: all randomized subjects who received at least one dose of assigned medication and had at least one post-baseline assessment.

Subject analysis set title

Pharmacodynamic Analysis Set: Active Control

Subject analysis set type

Full analysis

Subject analysis set description

Pharmacodynamic (PD) Analysis Set: all subjects who received at least one dose of study therapy and had evaluable serum data.

Subject analysis set title

Pharmacodynamic Analysis Set: Burosumab

Subject analysis set type

Full analysis

Subject analysis set description

Pharmacodynamic (PD) Analysis Set: all subjects who received at least one dose of study therapy and had evaluable serum data.

Primary: Radiographic Global Impression of Change (RGI-C) Global Score at Week 40

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End point title

Radiographic Global Impression of Change (RGI-C) Global Score at Week 40

End point description

Changes in the severity of rickets and bowing were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-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, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets).

End point type

Primary

End point timeframe

Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32	29
Units: score on a scale
least squares mean (standard error)	0.77 ± 0.107	1.92 ± 0.110

Statistical Analysis 1

Statistical analysis description

Least squares (LS) mean, standard error (SE), confidence interval (CI), and 2-sided p value per ANCOVA model, which included RGI-C as the dependent variable, treatment group and baseline age stratification factor as independent variables and baseline RSS score as a continuous covariate.

Comparison groups

Full Analysis Set: Burosumab v Full Analysis Set: Active Control

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.45

Secondary: Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40

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End point title

Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40

End point description

RGI-C responders are defined as subjects with a mean RGI-C global score >= +2.0. The RGI-C is a 7-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, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets).

End point type

Secondary

End point timeframe

Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32	29
Units: percentage of participants
number (not applicable)	6.3	72.4

Statistical Analysis 1

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

39.1

Confidence interval

level

95%

sides

2-sided

lower limit

7.2

upper limit

211.7

Notes
[1] - Odds ratio, CI, and 2-sided p-value were per logistic regression model, which included treatment group and baseline age stratification factor as independent variables and baseline RSS score as a continuous covariate.

Secondary: Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64

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End point title

Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64

End point description

End point type

Secondary

End point timeframe

Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32	29
Units: percentage of subjects
number (not applicable)	18.8	86.2

Statistical Analysis 1

Comparison groups

Full Analysis Set: Burosumab v Full Analysis Set: Active Control

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[2]

Method

generalized linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

34.1

Confidence interval

level

95%

sides

2-sided

lower limit

5.6

upper limit

206.3

Notes
[2] - Odds ratio, CI, and 2-sided p-value were per generalized linear mixed model, which includes treatment, visit, treatment by visit interaction and baseline age stratification factor as factors, baseline RSS total score as a continuous covariate.

Secondary: RGI-C Global Score at Week 64

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End point title

RGI-C Global Score at Week 64

End point description

End point type

Secondary

End point timeframe

Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32	29
Units: score on a scale
least squares mean (standard error)	1.03 ± 0.136	2.06 ± 0.072

Statistical Analysis 1

Statistical analysis description

Per generalized estimating equation (GEE) model, which included RGI-C as the dependent variable, treatment, visit, treatment by visit interaction and baseline age stratification factor as factors, baseline RSS score as a continuous covariate, with exchangeable covariate structure.

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

GEE model

Parameter type

difference in LS means

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.33

Secondary: Change From Baseline in RSS Total Score at Week 40

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End point title

Change From Baseline in RSS Total Score at Week 40

End point description

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, lucency, separation, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees (the total score is the sum of the wrist and knee score). Higher scores indicate greater rickets severity.

End point type

Secondary

End point timeframe

Baseline, Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32 ^[3]	28 ^[4]
Units: score on a scale
least squares mean (standard error)	-0.71 ± 0.138	-2.04 ± 0.145

Notes
[3] - subjects who had at least one post-baseline RSS Total Score assessment
[4] - subjects who had at least one post-baseline RSS Total Score assessment

Statistical Analysis 1

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1.34

Confidence interval

level

95%

sides

2-sided

lower limit

-1.74

upper limit

-0.94

Notes
[5] - LS mean, SE, CI, and 2-sided p value per ANCOVA model, which included treatment group and baseline age stratification factor as independent variables and baseline RSS score as a continuous covariate.

Secondary: Change From Baseline in RSS Total Score at Week 64

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End point title

Change From Baseline in RSS Total Score at Week 64

End point description

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 the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.

End point type

Secondary

End point timeframe

Baseline, Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32 ^[6]	29 ^[7]
Units: score on a scale
least squares mean (standard error)	-1.01 ± 0.151	-2.23 ± 0.117

Notes
[6] - subjects who had at least one post-baseline RSS Total Score assessment
[7] - subjects who had at least one post-baseline RSS Total Score assessment

Statistical Analysis 1

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

GEE model

Parameter type

difference in LS means

Point estimate

-1.21

Confidence interval

level

95%

sides

2-sided

lower limit

-1.59

upper limit

-0.83

Notes
[8] - LS mean, SE, CI, and 2-sided p value per GEE model, which included treatment, visit, treatment by visit interaction and baseline age stratification factor as factors, baseline RSS score as a continuous covariate.

Secondary: RGI-C Long Leg Score at Week 40

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End point title

RGI-C Long Leg Score at Week 40

End point description

Changes in the severity of lower extremity skeletal abnormalities, including genu varum and genu valgus, were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing), +2 = much better (substantial healing), +1 = minimally better (i.e., minimal healing), 0 = unchanged, -1 = minimally worse (minimal worsening), -2 = much worse (moderate worsening), -3 = very much worse (severe worsening).

End point type

Secondary

End point timeframe

Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32	29
Units: score on a scale
least squares mean (standard error)	0.22 ± 0.080	0.62 ± 0.153

Statistical Analysis 1

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0162 ^[9]

Method

GEE model

Parameter type

LS Mean Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.07

upper limit

0.72

Notes
[9] - LS mean, SE, CI, and 2-sided p value per GEE model, which included treatment, visit, treatment by visit interaction, and baseline age stratification factor as factors; and baseline RSS score as a continuous covariate.

Secondary: RGI-C Long Leg Score at Week 64

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End point title

RGI-C Long Leg Score at Week 64

End point description

End point type

Secondary

End point timeframe

Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32	29
Units: score on a scale
least squares mean (standard error)	0.29 ± 0.119	1.25 ± 0.170

Statistical Analysis 1

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[10]

Method

GEE model

Parameter type

difference in LS means

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.37

Notes
[10] - LS mean, SE, CI, and 2-sided p value per GEE model, which included treatment, visit, treatment by visit interaction, and baseline age stratification factor as factors; and baseline RSS score as a continuous covariate.

Secondary: Change From Baseline in Height-For-Age Z-Scores to Week 40

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End point title

Change From Baseline in Height-For-Age Z-Scores to Week 40

End point description

Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the Centers for Disease Control [CDC] growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.

End point type

Secondary

End point timeframe

Baseline, Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32	28 ^[11]
Units: Z score
least squares mean (standard error)	0.03 ± 0.031	0.16 ± 0.052

Notes
[11] - subjects with an assessment at Week 40

Statistical Analysis 1

Statistical analysis description

LS mean, SE, CI, and 2-sided p value per GEE model, which included change from baseline for recumbent length/standing height Z score as the dependent variable, treatment group, visit, interaction between treatment group by visit and baseline RSS stratification as factors, age and baseline recumbent length/standing height Z score as continuous covariates, with exchangeable covariance structure.

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0408

Method

GEE model

Parameter type

LS Mean Difference

Point estimate

0.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.24

Secondary: Change From Baseline in Height-For-Age Z-Scores to Week 64

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End point title

Change From Baseline in Height-For-Age Z-Scores to Week 64

End point description

Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.

End point type

Secondary

End point timeframe

Baseline, Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	32	28 ^[12]
Units: Z score
least squares mean (standard error)	0.02 ± 0.035	0.17 ± 0.066

Notes
[12] - subjects with an assessment at Week 64

Statistical Analysis 1

Statistical analysis description

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.049

Method

GEE model

Parameter type

difference in LS means

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.29

Secondary: Change in Growth Velocity Z Score From Baseline to Week 40

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End point title

Change in Growth Velocity Z Score From Baseline to Week 40

End point description

A growth velocity Z score was calculated based on Tanner’s standard. The Z score indicates the number of standard deviations away from a reference population (from Tanner's standard) in the same age range and with the same sex. The baseline growth velocity was calculated for participants who had data available from within 1.5 years prior to baseline. The Week 64 growth velocity was calculated using data between baseline and Week 64. The mid-point of the age interval was used to locate the closest reference age provided by Tanner’s Standard. Children with a mid-point age under 2.25 years were excluded, because younger ages are not available in Tanner’s standard. To smoothly transition from recumbent length to standing height, 0·8 cm was subtracted from recumbent length before pooling with standing height. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome.

End point type

Secondary

End point timeframe

Baseline, Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	22 ^[13]	22 ^[14]
Units: Z score
least squares mean (standard error)	0.73 ± 0.339	1.76 ± 0.337

Notes
[13] - subjects with Baseline growth velocity
[14] - subjects with Baseline growth velocity

Statistical Analysis 1

Statistical analysis description

LS mean, SE, CI, and 2-sided p value per ANCOVA model, which included change from baseline for growth velocity Z score as the dependent variable, treatment group and baseline RSS total score stratification as factors, baseline Z score and age as continuous covariates.

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0386

Method

ANCOVA

Parameter type

difference in LS means

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.06

upper limit

1.99

Secondary: Change in Growth Velocity Z Score From Baseline to Week 64

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End point title

Change in Growth Velocity Z Score From Baseline to Week 64

End point description

End point type

Secondary

End point timeframe

Baseline, Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	22 ^[15]	22 ^[16]
Units: Z score
least squares mean (standard error)	0.41 ± 0.265	1.53 ± 0.264

Notes
[15] - subjects with Baseline growth velocity
[16] - subjects with Baseline growth velocity

Statistical Analysis 1

Statistical analysis description

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0047

Method

ANCOVA

Parameter type

difference in LS means

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

1.88

Secondary: Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64

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End point title

Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64

End point description

The generalized estimation equation (GEE) model includes change from baseline for serum phosphorous measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and Baseline RSS stratification as factors, baseline phosphorous measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	32 ^[17]	29 ^[18]
Units: mg/dL
least squares mean (standard error)
Week 1; n=31, 28	0.22 ± 0.072	1.26 ± 0.094
Week 2; n=0, 26	99999 ± 99999	1.14 ± 0.098
Week 4; n=32, 29	0.18 ± 0.061	1.21 ± 0.102
Week 8; n=32, 29	0.21 ± 0.064	0.99 ± 0.074
Week 12; n=0, 26	99999 ± 99999	1.01 ± 0.072
Week 16; n=29, 29	0.24 ± 0.063	0.87 ± 0.072
Week 24; n=32, 29	0.27 ± 0.073	0.78 ± 0.077
Week 32; n=32, 29	0.23 ± 0.063	0.93 ± 0.073
Week 33; n=0, 27	99999 ± 99999	1.23 ± 0.106
Week 40; n=32, 29	0.20 ± 0.062	0.92 ± 0.080
Week 52; n=32, 29	0.30 ± 0.082	0.91 ± 0.075
Week 64; n=32, 29	0.21 ± 0.062	0.91 ± 0.078

Attachments

Untitled (Filename: Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64 stat analyses.docx)

Notes
[17] - n=subjects with an assessment at given time point; 99999=not applicable (n=0)
[18] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112

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End point title

Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 66, 68, 76, 88, 100, 112

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	26 ^[19]	22 ^[20]
Units: mg/dL
arithmetic mean (standard deviation)
Week 66; n=26, 0	0.05 ± 0.235	99999 ± 99999
Week 68; n=26, 1	1.17 ± 0.472	1.10 ± 999999
Week 76; n=22, 22	0.90 ± 0.324	0.92 ± 0.324
Week 88; n=16, 11	0.98 ± 0.433	1.00 ± 0.576
Week 100; n=7, 2	0.99 ± 0.445	1.00 ± 0.424
Week 112; n=5, 2	1.26 ± 0.508	1.10 ± 0.283

Notes
[19] - n=subjects with an assessment at given time point
[20] - n=subjects with an assessment at given time point; 99999=not applicable (NA; n=0); 999999=NA (n=1)

No statistical analyses for this end point

Secondary: Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64

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End point title

Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64

End point description

The ANCOVA model includes change in serum phosphorus from baseline to mean post-baseline as the dependent variable, treatment group, baseline age and baseline RSS stratification as factors, baseline phosphorous measure as a covariate.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	32	29
Units: mg/dL
least squares mean (standard error)	0.24 ± 0.058	0.98 ± 0.061

Statistical Analysis 1

Comparison groups

Pharmacodynamic Analysis Set: Active Control v Pharmacodynamic Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

difference in LS means

Point estimate

0.74

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

0.91

Secondary: Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment with Burosumab)

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End point title

Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment with Burosumab)

End point description

End point type

Secondary

End point timeframe

Burosumab arm: Baseline, Week 1, 4, 8, 16, 24, 32, 40, 52, 64, 66, 68, 76, 88, 100, 112, 124, 140; Active Control arm: Baseline, Week 68, 76, 88, 100, 112, 124, 140

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	26	29
Units: mg/dL
arithmetic mean (standard deviation)	1.05 ± 0.310	0.93 ± 0.336

No statistical analyses for this end point

Secondary: Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)

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End point title

Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)

End point description

End point type

Secondary

End point timeframe

Burosumab arm: Baseline, up to Week 140; Active Control arm: Baseline, Week 68 up to Week 140

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	32	29
Units: percentage of subjects
number (not applicable)	75.0	96.6

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64

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End point title

Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64

End point description

The GEE model includes change from baseline for 1, 25-Dihydroxyvitamin D measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline 1, 25-Dihydroxyvitamin D measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	30 ^[21]	28 ^[22]
Units: pg/mL
least squares mean (standard error)
Week 1; n=29, 27	19.81 ± 2.758	68.09 ± 5.251
Week 2; n=0, 24	99999 ± 99999	31.78 ± 5.130
Week 4; n=30, 27	12.77 ± 2.998	33.86 ± 3.561
Week 8; n=30, 28	15.10 ± 2.528	30.85 ± 3.830
Week 12; n=0, 24	99999 ± 99999	33.43 ± 3.176
Week 16; n=27, 28	19.41 ± 3.757	32.38 ± 3.032
Week 24; n=28, 27	17.46 ± 2.905	28.35 ± 3.113
Week 32; n=29, 28	17.25 ± 3.156	23.49 ± 2.439
Week 33; n=0, 24	99999 ± 99999	31.50 ± 3.423
Week 40; n=27, 25	18.42 ± 3.594	29.63 ± 3.721
Week 52; n=29, 27	8.74 ± 3.866	13.75 ± 2.862
Week 64; n=29, 27	1.19 ± 2.785	9.89 ± 2.235

Attachments

Untitled (Filename: Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64 stat analyses.docx)

Notes
[21] - n=subjects with an assessment at given time point; 99999=NA (n=0)
[22] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112

Top of page

End point title

Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 68, 76, 88, 100, 112

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	25 ^[23]	21 ^[24]
Units: pg/mL
arithmetic mean (standard deviation)
Week 68; n=25, 1	22.12 ± 23.950	-9.80 ± 99999
Week 76; n=21, 21	19.05 ± 22.612	12.80 ± 20.093
Week 88; n=14, 10	24.58 ± 17.787	11.76 ± 22.874
Week 100; n=6, 2	33.57 ± 16.591	13.25 ± 1.061
Week 112; n=5, 2	29.94 ± 15.402	31.05 ± 33.729

Notes
[23] - n=subjects with an assessment at given time point
[24] - n=subjects with an assessment at given time point; 99999=NA (n=1)

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in TmP/GFR, up to Week 64

Top of page

End point title

Change From Baseline Over Time in TmP/GFR, up to Week 64

End point description

Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR. The GEE model includes change from baseline for TmP/GFR measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline TmP/GFR measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

End point type

Secondary

End point timeframe

Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed
Units: mg/dL
least squares mean (standard error)
Week 4; n=28, 23	-0.17 ± 0.065	1.48 ± 0.173
Week 8; n=27, 24	-0.20 ± 0.057	1.22 ± 0.101
Week 16; n=26, 24	-0.15 ± 0.085	1.00 ± 0.139
Week 24; n=29, 23	-0.12 ± 0.072	0.99 ± 0.134
Week 32; n=29, 22	-0.10 ± 0.062	1.14 ± 0.115
Week 40; n=28, 23	-0.15 ± 0.053	1.20 ± 0.113
Week 52; n=28, 22	-0.12 ± 0.069	1.13 ± 0.124
Week 64; n=30, 23	-0.09 ± 0.070	1.16 ± 0.127

Attachments

Untitled (Filename: Change From Baseline Over Time in TmP_GFR, up to Week 64 stat analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in TmP/GFR, Week 68 to 112

Top of page

End point title

Change From Baseline Over Time in TmP/GFR, Week 68 to 112

End point description

Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR.

End point type

Secondary

End point timeframe

Baseline, Weeks 68, 76, 88, 112

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	24 ^[25]	7 ^[26]
Units: mg/dL
arithmetic mean (standard deviation)
Week 68; n=24, 1	1.61 ± 0.705	1.65 ± 99999
Week 76; n=4, 4	1.18 ± 0.758	0.59 ± 0.429
Week 88; n=14, 7	1.33 ± 0.480	0.95 ± 0.620
Week 112; n=3, 2	1.56 ± 0.233	1.32 ± 0.233

Notes
[25] - n=subjects with an assessment at given time point
[26] - n=subjects with an assessment at given time point; 99999=NA (n=1)

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in Serum ALP, up to Week 64

Top of page

End point title

Change From Baseline Over Time in Serum ALP, up to Week 64

End point description

The GEE model includes change from baseline for ALP measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline ALP measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

End point type

Secondary

End point timeframe

Baseline, Weeks 16, 24, 40, 52, 64

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	32	29
Units: U/L
least squares mean (standard error)
Week 16	-5.43 ± 17.885	-97.97 ± 11.281
Week 24	-22.43 ± 15.074	-108.00 ± 16.225
Week 40	-34.78 ± 18.132	-130.72 ± 12.365
Week 52	-50.03 ± 18.641	-161.31 ± 11.674
Week 64	-28.06 ± 19.980	-174.62 ± 13.427

Statistical Analysis 1

Statistical analysis description

Week 16

Comparison groups

Pharmacodynamic Analysis Set: Active Control v Pharmacodynamic Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

GEE model

Parameter type

difference

Point estimate

-92.53

Confidence interval

level

95%

sides

2-sided

lower limit

-131.4

upper limit

-53.66

Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Pharmacodynamic Analysis Set: Active Control v Pharmacodynamic Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

GEE model

Parameter type

difference

Point estimate

-85.57

Confidence interval

level

95%

sides

2-sided

lower limit

-126.37

upper limit

-44.76

Statistical Analysis 3

Statistical analysis description

Week 40

Comparison groups

Pharmacodynamic Analysis Set: Active Control v Pharmacodynamic Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

GEE model

Parameter type

difference

Point estimate

-95.95

Confidence interval

level

95%

sides

2-sided

lower limit

-136.05

upper limit

-55.84

Statistical Analysis 4

Statistical analysis description

Week 52

Comparison groups

Pharmacodynamic Analysis Set: Active Control v Pharmacodynamic Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

GEE model

Parameter type

difference

Point estimate

-111.28

Confidence interval

level

95%

sides

2-sided

lower limit

-152.08

upper limit

-70.49

Statistical Analysis 5

Statistical analysis description

Week 64

Comparison groups

Pharmacodynamic Analysis Set: Active Control v Pharmacodynamic Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

GEE model

Parameter type

difference

Point estimate

-146.56

Confidence interval

level

95%

sides

2-sided

lower limit

-191.61

upper limit

-101.52

Secondary: Change From Baseline Over Time in Serum ALP, Week 68 to 112

Top of page

End point title

Change From Baseline Over Time in Serum ALP, Week 68 to 112

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 68, 76, 88, 100, 112

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	26 ^[27]	22 ^[28]
Units: U/L
arithmetic mean (standard deviation)
Week 68; n=26, 1	-82.73 ± 83.683	-184.00 ± 99999
Week 76; n=22, 22	-106.73 ± 73.316	-166.73 ± 87.700
Week 88; n=16, 11	-146.56 ± 73.120	-154.55 ± 48.148
Week 100; n=7, 2	-83.14 ± 104.675	-184.00 ± 48.083
Week 112; n=5, 2	-104.80 ± 80.350	-172.00 ± 26.870

Notes
[27] - n=subjects with an assessment at given time point
[28] - n=subjects with an assessment at given time point; 99999=NA (n=1)

No statistical analyses for this end point

Secondary: Percent Change From Baseline Over Time in Serum ALP, up to Week 112

Top of page

End point title

Percent Change From Baseline Over Time in Serum ALP, up to Week 112

End point description

Decreases indicate improvement.

End point type

Secondary

End point timeframe

Baseline, Weeks 16, 24, 40, 52, 64, 68, 76, 88, 100, 112

End point values	Pharmacodynamic Analysis Set: Active Control	Pharmacodynamic Analysis Set: Burosumab
Number of subjects analysed	32 ^[29]	29 ^[30]
Units: percent change
arithmetic mean (standard deviation)
Week 16; n=29, 29	0.41 ± 21.021	-18.39 ± 10.815
Week 24; n=32, 29	-3.21 ± 15.827	-19.88 ± 17.642
Week 40; n=32, 29	-6.85 ± 16.493	-24.38 ± 13.498
Week 52; n=32, 29	-8.60 ± 19.027	-30.60 ± 11.852
Week 64; n=32, 29	-4.60 ± 20.711	-32.78 ± 13.095
Week 68; n=26, 1	-14.66 ± 14.760	-38.02 ± 99999
Week 76; n=22, 22	-20.49 ± 13.926	-31.42 ± 13.422
Week 88; n=16, 11	-28.77 ± 12.201	-32.02 ± 10.610
Week 100; n=7, 2	-16.06 ± 23.703	-39.29 ± 11.460
Week 112; n=5, 2	-21.00 ± 15.053	-36.67 ± 6.868

Notes
[29] - n=subjects with an assessment at given time point
[30] - n=subjects with an assessment at given time point; 99999=NA (n=1)

No statistical analyses for this end point

Secondary: Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40

Top of page

End point title

Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40

End point description

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. For the Pain Interference Domain, decreases indicate less pain, for the Physical Function Mobility Domain, increases indicate greater mobility and for the Fatigue Domain, decreases indicate less fatigue.

End point type

Secondary

End point timeframe

Baseline, Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	20 ^[31]	15 ^[32]
Units: T-score
least squares mean (standard error)
Pain Interference Domain Score	-0.29 ± 1.539	-5.31 ± 1.705
Physical Function Mobility Domain Score	0.10 ± 0.966	2.78 ± 1.336
Fatigue Domain Score	-1.05 ± 1.754	-4.29 ± 1.709

Notes
[31] - subjects with an assessment at Week 40
[32] - subjects with an assessment at Week 40

Statistical Analysis 1

Statistical analysis description

Pain Interference Domain. 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0212

Method

GEE model

Parameter type

difference in LS means

Point estimate

-5.02

Confidence interval

level

95%

sides

2-sided

lower limit

-9.29

upper limit

-0.75

Statistical Analysis 2

Statistical analysis description

Physical Function Mobility Domain. 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.

Comparison groups

Full Analysis Set: Burosumab v Full Analysis Set: Active Control

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1009

Method

GEE model

Parameter type

difference in LS means

Point estimate

2.68

Confidence interval

level

95%

sides

2-sided

lower limit

-0.52

upper limit

5.89

Statistical Analysis 3

Statistical analysis description

Fatigue Domain. 2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1676

Method

GEE model

Parameter type

difference in LS means

Point estimate

-3.25

Confidence interval

level

95%

sides

2-sided

lower limit

-7.86

upper limit

1.37

Secondary: Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64

Top of page

End point title

Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64

End point description

End point type

Secondary

End point timeframe

Baseline, Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	20 ^[33]	15 ^[34]
Units: T-score
least squares mean (standard error)
Pain Interference Domain Score	-1.29 ± 1.267	-3.55 ± 1.873
Physical Function Mobility Domain Score	0.92 ± 0.962	2.82 ± 1.648
Fatigue Domain Score	-2.57 ± 1.547	-3.65 ± 2.119

Notes
[33] - subjects with an assessment at Week 64
[34] - subjects with an assessment at Week 64

Statistical Analysis 1

Statistical analysis description

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3091

Method

GEE model

Parameter type

difference in LS means

Point estimate

-2.26

Confidence interval

level

95%

sides

2-sided

lower limit

-6.61

upper limit

2.09

Statistical Analysis 2

Statistical analysis description

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3145

Method

GEE model

Parameter type

difference in LS means

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

5.59

Statistical Analysis 3

Statistical analysis description

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.681

Method

GEE model

Parameter type

difference in LS means

Point estimate

-1.08

Confidence interval

level

95%

sides

2-sided

lower limit

-6.21

upper limit

4.06

Secondary: Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40

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End point title

Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40

End point description

The FPS-R is a dimensionless 10 point Likert scale used to assess self-reported pain intensity on a scale from 0 (no pain) to 10 (most pain you can imagine). Greater pain scores are indicative of more severe pain.

End point type

Secondary

End point timeframe

Baseline, Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	20 ^[35]	15 ^[36]
Units: units on a scale
least squares mean (standard error)	0.02 ± 0.323	0.03 ± 0.323

Notes
[35] - subjects with an assessment at Week 40
[36] - subjects with an assessment at Week 40

Statistical Analysis 1

Statistical analysis description

GEE model includes change from baseline for FPS-R as the dependent variable, treatment group, visit, interaction between treatment group by visit and baseline RSS stratification as factors, baseline FPS-R as a covariate, with exchangeable covariance structure. The LS Mean, SE, 95% CI and 2-sided p-value are from the GEE model.

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9862

Method

GEE model

Parameter type

difference in LS means

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.79

upper limit

0.8

Secondary: Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64

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End point title

Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64

End point description

End point type

Secondary

End point timeframe

Baseline, Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	19 ^[37]	15 ^[38]
Units: units on a scale
least squares mean (standard error)	0.04 ± 0.270	-0.01 ± 0.234

Notes
[37] - subjects with an assessment at Week 64
[38] - subjects with an assessment at Week 64

Statistical Analysis 1

Statistical analysis description

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8786

Method

GEE model

Parameter type

difference in LS means

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.58

upper limit

0.68

Secondary: Change From Baseline in the 6MWT Total Distance at Week 40

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End point title

Change From Baseline in the 6MWT Total Distance at Week 40

End point description

The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test.

End point type

Secondary

End point timeframe

Baseline, Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	20 ^[39]	13 ^[40]
Units: meters
least squares mean (standard error)	3.65 ± 14.060	47.10 ± 15.768

Notes
[39] - subjects with an assessment at Week 40 in subjects ≥ 5 years who were able to complete the test
[40] - subjects with an assessment at Week 40 in subjects ≥ 5 years who were able to complete the test

Statistical Analysis 1

Statistical analysis description

2-sided p value per GEE model, which included change from baseline for the parameter as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline parameter measure as a covariate, with exchangeable covariance structure.

Comparison groups

Full Analysis Set: Burosumab v Full Analysis Set: Active Control

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0514

Method

GEE model

Parameter type

difference in LS means

Point estimate

43.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

87.17

Secondary: Change From Baseline in the 6MWT Total Distance at Week 64

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End point title

Change From Baseline in the 6MWT Total Distance at Week 64

End point description

The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test.

End point type

Secondary

End point timeframe

Baseline, Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	20 ^[41]	13 ^[42]
Units: meters
least squares mean (standard error)	29.28 ± 16.834	74.83 ± 12.513

Notes
[41] - subjects with an assessment at Week 64
[42] - subjects with an assessment at Week 64

Statistical Analysis 1

Statistical analysis description

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0399

Method

GEE model

Parameter type

difference in LS means

Point estimate

45.55

Confidence interval

level

95%

sides

2-sided

lower limit

2.09

upper limit

89.02

Secondary: Percent of Predicted Normal in the 6MWT Total Distance at Week 40

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End point title

Percent of Predicted Normal in the 6MWT Total Distance at Week 40

End point description

The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test, and the percent predicted distance based on normative data for age and gender was estimated.

End point type

Secondary

End point timeframe

Baseline, Week 40

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	20 ^[43]	13 ^[44]
Units: percent of predicted meters
least squares mean (standard error)	-1.14 ± 2.224	5.59 ± 2.633

Notes
[43] - subjects with an assessment at Week 40
[44] - subjects with an assessment at Week 40

Statistical Analysis 1

Statistical analysis description

Comparison groups

Full Analysis Set: Active Control v Full Analysis Set: Burosumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0633

Method

GEE model

Parameter type

difference in LS means

Point estimate

6.72

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

13.82

Secondary: Percent of Predicted Normal in the 6MWT Total Distance at Week 64

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End point title

Percent of Predicted Normal in the 6MWT Total Distance at Week 64

End point description

End point type

Secondary

End point timeframe

Baseline, Week 64

End point values	Full Analysis Set: Active Control	Full Analysis Set: Burosumab
Number of subjects analysed	20 ^[45]	13 ^[46]
Units: percent of predicted meters
least squares mean (standard error)	1.88 ± 2.789	9.15 ± 2.056

Notes
[45] - subjects with an assessment at Week 64
[46] - subjects with an assessment at Week 64

Statistical Analysis 1

Statistical analysis description

Comparison groups

Full Analysis Set: Burosumab v Full Analysis Set: Active Control

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0496

Method

GEE model

Parameter type

difference in LS means

Point estimate

7.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

14.52

Adverse events

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Timeframe for reporting adverse events

Up to Week 64 in the Treatment Period and up to Week 140 in the Long Term Extension Period, plus up to 12 weeks ±1 week after the last dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Oral Phosphate/Active Vitamin D (Treatment Period)

Reporting group description

Reporting group title

Burosumab (Treatment Period)

Reporting group description

Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64).

Reporting group title

Oral Phosphate/Active Vitamin D->Burosumab (Extension Period)

Reporting group description

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), subjects crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Subjects in Japan and Korea did not enter the Treatment Extension Period.

Reporting group title

Burosumab->Burosumab (Treatment Period and Extension Period)

Reporting group description

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), subjects continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Subjects in Japan and Korea did not enter the Treatment Extension Period.

Reporting group title

Total Burosumab (Treatment Period and Extension Period)

Reporting group description

Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection at any time during the study.

Serious adverse events	Oral Phosphate/Active Vitamin D (Treatment Period)	Burosumab (Treatment Period)	Oral Phosphate/Active Vitamin D->Burosumab (Extension Period)	Burosumab->Burosumab (Treatment Period and Extension Period)	Total Burosumab (Treatment Period and Extension Period)
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 32 (9.38%)	3 / 29 (10.34%)	0 / 26 (0.00%)	4 / 29 (13.79%)	4 / 55 (7.27%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events
Congenital, familial and genetic disorders
Craniosynostosis
subjects affected / exposed	1 / 32 (3.13%)	1 / 29 (3.45%)	0 / 26 (0.00%)	1 / 29 (3.45%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Migraine
subjects affected / exposed	0 / 32 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	1 / 29 (3.45%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Papilloedema
subjects affected / exposed	0 / 32 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 32 (3.13%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Knee Deformity
subjects affected / exposed	1 / 32 (3.13%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Viral Infection
subjects affected / exposed	0 / 32 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	1 / 29 (3.45%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Oral Phosphate/Active Vitamin D (Treatment Period)	Burosumab (Treatment Period)	Oral Phosphate/Active Vitamin D->Burosumab (Extension Period)	Burosumab->Burosumab (Treatment Period and Extension Period)	Total Burosumab (Treatment Period and Extension Period)
Total subjects affected by non serious adverse events
subjects affected / exposed	23 / 32 (71.88%)	21 / 29 (72.41%)	9 / 26 (34.62%)	25 / 29 (86.21%)	34 / 55 (61.82%)
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 32 (6.25%)	1 / 29 (3.45%)	1 / 26 (3.85%)	2 / 29 (6.90%)	3 / 55 (5.45%)
occurrences all number	3	1	1	2	3
Injection Site Bruising
subjects affected / exposed	0 / 32 (0.00%)	0 / 29 (0.00%)	2 / 26 (7.69%)	1 / 29 (3.45%)	3 / 55 (5.45%)
occurrences all number	0	0	2	1	3
Injection Site Erosion
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	3	0	3	3
Injection Site Erythema
subjects affected / exposed	0 / 32 (0.00%)	9 / 29 (31.03%)	6 / 26 (23.08%)	9 / 29 (31.03%)	15 / 55 (27.27%)
occurrences all number	0	26	12	29	41
Injection Site Pruritus
subjects affected / exposed	0 / 32 (0.00%)	3 / 29 (10.34%)	2 / 26 (7.69%)	3 / 29 (10.34%)	5 / 55 (9.09%)
occurrences all number	0	10	2	11	13
Injection Site Rash
subjects affected / exposed	0 / 32 (0.00%)	3 / 29 (10.34%)	0 / 26 (0.00%)	3 / 29 (10.34%)	3 / 55 (5.45%)
occurrences all number	0	4	0	4	4
Injection Site Reaction
subjects affected / exposed	0 / 32 (0.00%)	7 / 29 (24.14%)	2 / 26 (7.69%)	8 / 29 (27.59%)	10 / 55 (18.18%)
occurrences all number	0	10	2	13	15
Injection Site Swelling
subjects affected / exposed	0 / 32 (0.00%)	3 / 29 (10.34%)	1 / 26 (3.85%)	3 / 29 (10.34%)	4 / 55 (7.27%)
occurrences all number	0	4	3	7	10
Injection Site Urticaria
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	5	0	5	5
Pain
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	0 / 26 (0.00%)	3 / 29 (10.34%)	3 / 55 (5.45%)
occurrences all number	0	3	0	4	4
Pyrexia
subjects affected / exposed	7 / 32 (21.88%)	16 / 29 (55.17%)	7 / 26 (26.92%)	17 / 29 (58.62%)	24 / 55 (43.64%)
occurrences all number	13	35	8	42	50
Immune system disorders
Hypersensitivity
subjects affected / exposed	2 / 32 (6.25%)	1 / 29 (3.45%)	0 / 26 (0.00%)	1 / 29 (3.45%)	1 / 55 (1.82%)
occurrences all number	2	1	0	1	1
Seasonal Allergy
subjects affected / exposed	2 / 32 (6.25%)	4 / 29 (13.79%)	1 / 26 (3.85%)	4 / 29 (13.79%)	5 / 55 (9.09%)
occurrences all number	3	6	1	7	8
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 32 (3.13%)	4 / 29 (13.79%)	0 / 26 (0.00%)	4 / 29 (13.79%)	4 / 55 (7.27%)
occurrences all number	2	7	0	7	7
Cough
subjects affected / exposed	6 / 32 (18.75%)	15 / 29 (51.72%)	4 / 26 (15.38%)	15 / 29 (51.72%)	19 / 55 (34.55%)
occurrences all number	7	31	4	35	39
Nasal Congestion
subjects affected / exposed	1 / 32 (3.13%)	5 / 29 (17.24%)	1 / 26 (3.85%)	7 / 29 (24.14%)	8 / 55 (14.55%)
occurrences all number	1	6	1	9	10
Oropharyngeal Pain
subjects affected / exposed	1 / 32 (3.13%)	5 / 29 (17.24%)	3 / 26 (11.54%)	6 / 29 (20.69%)	9 / 55 (16.36%)
occurrences all number	3	8	3	10	13
Rhinitis Allergic
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	3	0	4	4
Rhinorrhoea
subjects affected / exposed	2 / 32 (6.25%)	7 / 29 (24.14%)	3 / 26 (11.54%)	8 / 29 (27.59%)	11 / 55 (20.00%)
occurrences all number	2	16	5	17	22
Wheezing
subjects affected / exposed	0 / 32 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	1	0	2	2
Psychiatric disorders
Attention Deficit/Hyperactivity Disorder
subjects affected / exposed	0 / 32 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	0	0	2	2
Investigations
Vitamin D Decreased
subjects affected / exposed	1 / 32 (3.13%)	6 / 29 (20.69%)	1 / 26 (3.85%)	6 / 29 (20.69%)	7 / 55 (12.73%)
occurrences all number	1	6	1	6	7
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 32 (0.00%)	4 / 29 (13.79%)	0 / 26 (0.00%)	4 / 29 (13.79%)	4 / 55 (7.27%)
occurrences all number	0	4	0	4	4
Fall
subjects affected / exposed	0 / 32 (0.00%)	3 / 29 (10.34%)	0 / 26 (0.00%)	3 / 29 (10.34%)	3 / 55 (5.45%)
occurrences all number	0	3	0	4	4
Procedural Pain
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	2	0	2	2
Congenital, familial and genetic disorders
Tooth Hypoplasia
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	2	0	2	2
Nervous system disorders
Headache
subjects affected / exposed	6 / 32 (18.75%)	10 / 29 (34.48%)	3 / 26 (11.54%)	10 / 29 (34.48%)	13 / 55 (23.64%)
occurrences all number	42	23	24	25	49
Migraine
subjects affected / exposed	2 / 32 (6.25%)	1 / 29 (3.45%)	1 / 26 (3.85%)	1 / 29 (3.45%)	2 / 55 (3.64%)
occurrences all number	2	1	1	1	2
Ear and labyrinth disorders
Ear Discomfort
subjects affected / exposed	0 / 32 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	1	0	2	2
Ear Pain
subjects affected / exposed	1 / 32 (3.13%)	4 / 29 (13.79%)	2 / 26 (7.69%)	4 / 29 (13.79%)	6 / 55 (10.91%)
occurrences all number	3	6	3	6	9
Gastrointestinal disorders
Abdominal Discomfort
subjects affected / exposed	2 / 32 (6.25%)	2 / 29 (6.90%)	1 / 26 (3.85%)	2 / 29 (6.90%)	3 / 55 (5.45%)
occurrences all number	2	2	1	2	3
Abdominal Pain
subjects affected / exposed	1 / 32 (3.13%)	2 / 29 (6.90%)	1 / 26 (3.85%)	2 / 29 (6.90%)	3 / 55 (5.45%)
occurrences all number	1	3	1	3	4
Abdominal Pain Upper
subjects affected / exposed	3 / 32 (9.38%)	3 / 29 (10.34%)	2 / 26 (7.69%)	4 / 29 (13.79%)	6 / 55 (10.91%)
occurrences all number	5	3	2	4	6
Constipation
subjects affected / exposed	0 / 32 (0.00%)	5 / 29 (17.24%)	2 / 26 (7.69%)	5 / 29 (17.24%)	7 / 55 (12.73%)
occurrences all number	0	7	2	8	10
Dental Caries
subjects affected / exposed	2 / 32 (6.25%)	9 / 29 (31.03%)	0 / 26 (0.00%)	10 / 29 (34.48%)	10 / 55 (18.18%)
occurrences all number	3	25	0	26	26
Diarrhoea
subjects affected / exposed	2 / 32 (6.25%)	7 / 29 (24.14%)	1 / 26 (3.85%)	7 / 29 (24.14%)	8 / 55 (14.55%)
occurrences all number	3	7	1	8	9
Haematochezia
subjects affected / exposed	0 / 32 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	1	0	2	2
Nausea
subjects affected / exposed	1 / 32 (3.13%)	3 / 29 (10.34%)	2 / 26 (7.69%)	5 / 29 (17.24%)	7 / 55 (12.73%)
occurrences all number	1	3	3	5	8
Teething
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	1 / 26 (3.85%)	2 / 29 (6.90%)	3 / 55 (5.45%)
occurrences all number	0	2	1	2	3
Tooth Loss
subjects affected / exposed	0 / 32 (0.00%)	1 / 29 (3.45%)	1 / 26 (3.85%)	2 / 29 (6.90%)	3 / 55 (5.45%)
occurrences all number	0	2	1	3	4
Toothache
subjects affected / exposed	1 / 32 (3.13%)	4 / 29 (13.79%)	1 / 26 (3.85%)	5 / 29 (17.24%)	6 / 55 (10.91%)
occurrences all number	1	6	1	8	9
Vomiting
subjects affected / exposed	8 / 32 (25.00%)	12 / 29 (41.38%)	5 / 26 (19.23%)	14 / 29 (48.28%)	19 / 55 (34.55%)
occurrences all number	10	25	8	29	37
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	2	0	2	2
Rash
subjects affected / exposed	2 / 32 (6.25%)	3 / 29 (10.34%)	0 / 26 (0.00%)	4 / 29 (13.79%)	4 / 55 (7.27%)
occurrences all number	2	3	0	4	4
Skin Lesion
subjects affected / exposed	0 / 32 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	1	0	3	3
Swelling Face
subjects affected / exposed	0 / 32 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	1	0	2	2
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	2	0	2	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	10 / 32 (31.25%)	13 / 29 (44.83%)	3 / 26 (11.54%)	13 / 29 (44.83%)	16 / 55 (29.09%)
occurrences all number	28	39	6	42	48
Back Pain
subjects affected / exposed	3 / 32 (9.38%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	3	2	0	2	2
Pain In Extremity
subjects affected / exposed	10 / 32 (31.25%)	11 / 29 (37.93%)	3 / 26 (11.54%)	11 / 29 (37.93%)	14 / 55 (25.45%)
occurrences all number	29	33	4	37	41
Infections and infestations
Ear Infection
subjects affected / exposed	3 / 32 (9.38%)	2 / 29 (6.90%)	1 / 26 (3.85%)	3 / 29 (10.34%)	4 / 55 (7.27%)
occurrences all number	5	2	1	3	4
Gastroenteritis
subjects affected / exposed	3 / 32 (9.38%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	4	2	0	2	2
Gastroenteritis Viral
subjects affected / exposed	3 / 32 (9.38%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	3	2	0	2	2
Influenza
subjects affected / exposed	6 / 32 (18.75%)	4 / 29 (13.79%)	0 / 26 (0.00%)	4 / 29 (13.79%)	4 / 55 (7.27%)
occurrences all number	8	5	0	5	5
Nasopharyngitis
subjects affected / exposed	14 / 32 (43.75%)	11 / 29 (37.93%)	6 / 26 (23.08%)	15 / 29 (51.72%)	21 / 55 (38.18%)
occurrences all number	22	23	8	28	36
Otitis Externa
subjects affected / exposed	3 / 32 (9.38%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)	0 / 55 (0.00%)
occurrences all number	3	0	0	0	0
Otitis Media
subjects affected / exposed	4 / 32 (12.50%)	2 / 29 (6.90%)	0 / 26 (0.00%)	3 / 29 (10.34%)	3 / 55 (5.45%)
occurrences all number	4	5	0	6	6
Pharyngitis Streptococcal
subjects affected / exposed	1 / 32 (3.13%)	1 / 29 (3.45%)	1 / 26 (3.85%)	2 / 29 (6.90%)	3 / 55 (5.45%)
occurrences all number	2	1	1	2	3
Pneumonia
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	0	2	0	2	2
Rhinitis
subjects affected / exposed	2 / 32 (6.25%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)	2 / 55 (3.64%)
occurrences all number	6	7	0	8	8
Tooth Abscess
subjects affected / exposed	3 / 32 (9.38%)	8 / 29 (27.59%)	2 / 26 (7.69%)	9 / 29 (31.03%)	11 / 55 (20.00%)
occurrences all number	4	12	2	13	15
Upper Respiratory Tract Infection
subjects affected / exposed	3 / 32 (9.38%)	3 / 29 (10.34%)	0 / 26 (0.00%)	3 / 29 (10.34%)	3 / 55 (5.45%)
occurrences all number	3	4	0	4	4
Varicella
subjects affected / exposed	0 / 32 (0.00%)	2 / 29 (6.90%)	1 / 26 (3.85%)	2 / 29 (6.90%)	3 / 55 (5.45%)
occurrences all number	0	2	1	2	3
Viral Upper Respiratory Tract Infection
subjects affected / exposed	2 / 32 (6.25%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)	0 / 55 (0.00%)
occurrences all number	2	0	0	0	0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	2 / 32 (6.25%)	1 / 29 (3.45%)	0 / 26 (0.00%)	1 / 29 (3.45%)	1 / 55 (1.82%)
occurrences all number	2	1	0	1	1
Vitamin D Deficiency
subjects affected / exposed	1 / 32 (3.13%)	5 / 29 (17.24%)	0 / 26 (0.00%)	5 / 29 (17.24%)	5 / 55 (9.09%)
occurrences all number	1	5	0	5	5

More information

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Were there any global substantial amendments to the protocol? Yes

03 Nov 2017

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. All subjects who continue into the Treatment Extension Period will receive burosumab (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 burosumab at Week 62); subjects in these countries will be enrolled into a separate clinical trial of burosumab or will receive burosumab through another mechanism. For subjects in Europe, the US, Canada, and Australia, the study consists of the Treatment Period (last study visit Week 64) and the Treatment Extension Period (Weeks 66-140) 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 burosumab or will receive burosumab 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 burosumab is expected to be available; subjects will receive commercial burosumab or will receive burosumab 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

03 Nov 2017

(continued) b. Treatment in Treatment Extension Period (subjects in Europe, the US, Canada, and Australia only). After completion of the Treatment Period, subjects who were randomized to burosumab will continue treatment with burosumab, and subjects randomized to active control will cross over to receive open-label burosumab at the starting dose and regimen administered to subjects in the burosumab group. Subjects in the active control group 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 burosumab at Week 66 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 was clarified, and additional analyses time points were added for the Treatment Extension Period at Week 88, Week 112, and EOS. 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 burosumab, is treated with commercially available burosumab, or is treated with burosumab 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 burosumab protocol or per postapproval requirements for safety monitoring, as applicable) d. EOS: The description of the study periods was updated to describe the EOS procedures for different regions. For subjects in Japan and Korea, the EOS (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)

03 Nov 2017

(continued) e. Safety Follow-up: All subjects are expected to continue burosumab treatment poststudy in another clinical trial, through commercial use, or through another mechanism; poststudy safety follow-up calls and safety visits will occur only for subjects who are not documented to be continuing on burosumab 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 burosumab therapy has been started in another clinical trial, as commercial product, or through another mechanism; if burosumab 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 burosumab 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 HH 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 f. Clarified that “at least” (rather than “approximately”) 20 subjects age 1 to < 5 years will be included g. The maximum proportion of female subjects was increased from 60% to 70% 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 burosumab, and “active control” and “active control arm” refer to oral phosphate/active vitamin D therapy

03 Nov 2017

(continued) i. Added a substudy to assess pre- and postprandial serum phosphorus and calcium concentrations. Assessments for this substudy will occur at a single clinic visit anytime 10 to 14 days after a burosumab dose; this clinic visit may take the place of a HH 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 2. Selection of Study Population a. Inclusion Criterion #4 was revised to “Serum creatinine below age-adjusted upper normal limit” 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” 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 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 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”

03 Nov 2017

(continued) 3. Schedule of Events a. Added Table 2.3, Schedule of Events – Treatment Extension Period Weeks 66-140 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 were added to Urine Pregnancy Test for females administered burosumab who have reached menarche 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 burosumab dosing should occur no sooner than 8 days after the last dose administered, and that the Safety Follow-up Visit has an allowable variance of ±7 days 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 4. Study Drug a. Specified that subjects may resume burosumab at half of the last dose received (ie, half the dose of either 0.8 or 1.2 mg/kg) following withdrawal from burosumab due to increased serum phosphorus concentrations above the ULN, with a maximum dose of 40 mg. The maximum allowable dose of burosumab was defined as 90 mg per administration. Additional language was added to define the term “unscheduled serum phosphorus assessment” 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” c. Buttocks are included as a potential injection site for the administration of burosumab, and guidance provided to clarify the rotation of injection sites

03 Nov 2017

(continued) 5. Prohibited Medications a. Clarified that active vitamin D, not vitamin D supplementation, is prohibited in the burosumab treatment group 6. Efficacy Assessments a. Provided additional information regarding the collection of historical radiograph images and standing height/recumbent length data prior to Screening b. A new section, Change in Lower Extremity Abnormalities, was added to describe how this endpoint will be evaluated c. Provided greater clarity about how growth will be assessed. 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 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) e. Version 2.0 of the PROMIS instrument will be used (rather than Version 1.0) f. Clarified the process for a subject ≥ 8 years old at Screening who has difficulty completing 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 8. Safety Assessments a. Clarified the acceptable method for measuring blood pressure and updated the literature reference. 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

03 Nov 2017

(continued) c. Added the definition of a highly effective contraceptive method d. Clarified “dental events” as “dental caries, tooth extraction, root canal, dental abscesses, and gingivitis” to specify the events to be evaluated for the assessment of dental health e. Clarified SAE reporting for the active control group 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 group of this study f. Clarified the visits at which subject weight is determined g. Section 8.5.5.3, Pregnancy Reporting, was deleted because it 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.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Radiographic Global Impression of Change (RGI-C) Global Score at Week 40

Primary: Radiographic Global Impression of Change (RGI-C) Global Score at Week 40

Secondary: Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40

Secondary: Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40

Secondary: Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64

Secondary: Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64

Secondary: RGI-C Global Score at Week 64

Secondary: RGI-C Global Score at Week 64

Secondary: Change From Baseline in RSS Total Score at Week 40

Secondary: Change From Baseline in RSS Total Score at Week 40

Secondary: Change From Baseline in RSS Total Score at Week 64

Secondary: Change From Baseline in RSS Total Score at Week 64

Secondary: RGI-C Long Leg Score at Week 40

Secondary: RGI-C Long Leg Score at Week 40

Secondary: RGI-C Long Leg Score at Week 64

Secondary: RGI-C Long Leg Score at Week 64

Secondary: Change From Baseline in Height-For-Age Z-Scores to Week 40

Secondary: Change From Baseline in Height-For-Age Z-Scores to Week 40

Secondary: Change From Baseline in Height-For-Age Z-Scores to Week 64

Secondary: Change From Baseline in Height-For-Age Z-Scores to Week 64

Secondary: Change in Growth Velocity Z Score From Baseline to Week 40

Secondary: Change in Growth Velocity Z Score From Baseline to Week 40

Secondary: Change in Growth Velocity Z Score From Baseline to Week 64

Secondary: Change in Growth Velocity Z Score From Baseline to Week 64

Secondary: Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64

Secondary: Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64

Secondary: Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112

Secondary: Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112

Secondary: Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64

Secondary: Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64

Secondary: Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment with Burosumab)

Secondary: Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment with Burosumab)

Secondary: Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)

Secondary: Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)

Secondary: Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64

Secondary: Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64

Secondary: Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112

Secondary: Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112

Secondary: Change From Baseline Over Time in TmP/GFR, up to Week 64

Secondary: Change From Baseline Over Time in TmP/GFR, up to Week 64

Secondary: Change From Baseline Over Time in TmP/GFR, Week 68 to 112

Secondary: Change From Baseline Over Time in TmP/GFR, Week 68 to 112

Secondary: Change From Baseline Over Time in Serum ALP, up to Week 64

Secondary: Change From Baseline Over Time in Serum ALP, up to Week 64

Secondary: Change From Baseline Over Time in Serum ALP, Week 68 to 112

Secondary: Change From Baseline Over Time in Serum ALP, Week 68 to 112

Secondary: Percent Change From Baseline Over Time in Serum ALP, up to Week 112

Secondary: Percent Change From Baseline Over Time in Serum ALP, up to Week 112

Secondary: Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40

Secondary: Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40

Secondary: Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64

Secondary: Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64

Secondary: Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40

Secondary: Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40

Secondary: Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64

Secondary: Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64

Secondary: Change From Baseline in the 6MWT Total Distance at Week 40

Secondary: Change From Baseline in the 6MWT Total Distance at Week 40

Secondary: Change From Baseline in the 6MWT Total Distance at Week 64

Secondary: Change From Baseline in the 6MWT Total Distance at Week 64

Secondary: Percent of Predicted Normal in the 6MWT Total Distance at Week 40

Secondary: Percent of Predicted Normal in the 6MWT Total Distance at Week 40

Secondary: Percent of Predicted Normal in the 6MWT Total Distance at Week 64

Secondary: Percent of Predicted Normal in the 6MWT Total Distance at Week 64

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Clinical Trial Results:
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)