Study of the Safety, Pharmacodynamics (PD) and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT02750618

Recruitment Status : Completed

First Posted : April 25, 2016

Results First Posted : June 19, 2018

Last Update Posted : March 31, 2020

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Ultragenyx Pharmaceutical Inc

Study Type	Interventional
Study Design	Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	X-Linked Hypophosphatemia
Intervention	Biological: Burosumab
Enrollment	13

Participant Flow

Recruitment Details
Pre-assignment Details	The study enrolled pediatric participants between 1 and 4 years old, inclusive, with clinical findings consistent with XLH including hypophosphatemia and radiographic evidence of rickets, and a confirmed PHEX mutation or variant of uncertain significance.


Arm/Group Title	Burosumab Q2W
Arm/Group Description	Burosumab subcutaneous (SC) injecti...
Arm/Group Description	Burosumab subcutaneous (SC) injections every 2 weeks (Q2W) for a total of 160 weeks.
Period Title: Overall Study
Started	13
Completed Week 40	13
Completed Week 64	13
Completed	12
Not Completed	1
Reason Not Completed
Withdrawal by Subject	1

Baseline Characteristics

Arm/Group Title		Burosumab Q2W
Arm/Group Description		Burosumab SC injections Q2W for a t...
Arm/Group Description		Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Baseline Participants		13
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	13 participants
		2.94 (1.146)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	13 participants
	Female	4 30.8%
	Male	9 69.2%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	13 participants
	Hispanic or Latino	2 15.4%
	Not Hispanic or Latino	11 84.6%
	Unknown or Not Reported	0 0.0%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	13 participants
White		12 92.3%
Black or African American		1 7.7%
Serum Phosphorus Mean (Standard Deviation) Unit of measure: mg/dL
	Number Analyzed	13 participants
		2.51 (0.284)
Rickets Severity Score (RSS) Total Score ^[1] Mean (Standard Deviation) Unit of measure: Units on a scale
	Number Analyzed	13 participants
		2.92 (1.367)
		[1] Measure 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.
Recumbent length/Standing height ^[1] Mean (Standard Deviation) Unit of measure: Cm
	Number Analyzed	13 participants
		89.15 (7.597)
		[1] Measure Description: Growth is measured by recumbent length for subjects < 2 years of age or those unable or unwilling to stand for the measurement.
Recumbent length/Standing height (Z score) ^[1] Mean (Standard Deviation) Unit of measure: Z score
	Number Analyzed	13 participants
		-1.378 (1.1947)
		[1] Measure 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.
Recumbent length/Standing height (percentile) Mean (Standard Deviation) Unit of measure: Percentile
	Number Analyzed	13 participants
		18.044 (25.2644)
Serum Alkaline Phosphatase (ALP) Mean (Standard Deviation) Unit of measure: U/L
	Number Analyzed	13 participants
		548.5 (193.80)

Outcome Measures

1.Primary Outcome


Title	Change From Baseline at Week 40 in Serum Phosphorus
Description	The Generalized Estimation Equation (GEE) model includes the change fr...
Description	The Generalized Estimation Equation (GEE) model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: all participants who received at least one dose of study drug and had evaluable blood samples.


Arm/Group Title	Burosumab Q2W
Arm/Group Description:	Burosumab SC injections Q2W for a t...
Arm/Group Description:	Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed	13
Least Squares Mean (Standard Error) Unit of Measure: mg/dL
	0.96 (0.117)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95% 0.73 to 1.19
	Estimation Comments	[Not Specified]

2.Primary Outcome


Title	Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation
Description	An AE was defined as any untoward medical occurrence associated with t...
Description	An AE was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. A serious AE was defined as an AE that at any dose, in the view of either the Investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or disability, a congenital anomaly/birth defect, or other important medical events (according to the investigator). An AE was considered a TEAE if it occurred on or after the first dose and was not present prior to the first dose, or it was present prior to the first dose but increased in severity during the study. Events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death).
Time Frame	From first dose of study drug through the end of the study (Week 160). Maximum duration of exposure to study drug was 160 weeks.

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: all participants who received at least one dose of study drug.


Arm/Group Title	Burosumab Q2W
Arm/Group Description:	Burosumab SC injections Q2W for a t...
Arm/Group Description:	Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed	13
Measure Type: Count of Participants Unit of Measure: Participants
Adverse Event Starting during Screening Period	5 38.5%
TEAEs	13 100.0%
Related TEAEs	5 38.5%
Serious TEAEs	1 7.7%
Serious Related TEAEs	0 0.0%
Grade 3 or 4 TEAE	2 15.4%
TEAE Leading to Study Discontinuation	0 0.0%
TEAE Leading to Treatment Discontinuation	0 0.0%
TEAE Leading to Death	0 0.0%

3.Secondary Outcome


Title	Radiographic Global Impression of Change (RGI-C) Score at Week 40
Description	Changes in the severity of rickets and bowing were assessed centrally ...
Description	Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The Analysis of Covariance (ANCOVA) model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
Time Frame	Week 40

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.


Arm/Group Title	Burosumab Q2W
Arm/Group Description:	Burosumab SC injections Q2W for a t...
Arm/Group Description:	Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed	13
Least Squares Mean (Standard Error) Unit of Measure: units on a scale
	2.21 (0.071)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	2.21
	Confidence Interval	(2-Sided) 95% 2.07 to 2.35
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	RGI-C Score at Week 64
Description	Changes in the severity of rickets and bowing were assessed centrally ...
Description	Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
Time Frame	Week 64

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.


Arm/Group Title	Burosumab Q2W
Arm/Group Description:	Burosumab SC injections Q2W for a t...
Arm/Group Description:	Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed	13
Least Squares Mean (Standard Error) Unit of Measure: units on a scale
	2.23 (0.111)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure. The least squares (LS) mean, standard error (SE), 95% confidence interval (CI) and 2-sided p-value are from the GEE model.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	2.23
	Confidence Interval	(2-Sided) 95% 2.01 to 2.45
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score
Description	The RSS system is a 10-point radiographic scoring method that was deve...
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.The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.


Arm/Group Title	Burosumab Q2W
Arm/Group Description:	Burosumab SC injections Q2W for a t...
Arm/Group Description:	Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed	13
Least Squares Mean (Standard Error) Unit of Measure: units on a scale
	-1.75 (0.116)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-1.75
	Confidence Interval	(2-Sided) 95% -1.98 to -1.53
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score
Description	The RSS system is a 10-point radiographic scoring method that was deve...
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, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. The GEE model includes the change from baseline in RSS as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
Time Frame	Baseline, Week 64

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.


Arm/Group Title	Burosumab Q2W
Arm/Group Description:	Burosumab SC injections Q2W for a t...
Arm/Group Description:	Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed	13
Least Squares Mean (Standard Error) Unit of Measure: units on a scale
	-2.02 (0.115)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline in RSS as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-2.02
	Confidence Interval	(2-Sided) 95% -2.25 to -1.80
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	RGI-C Lower Limb Deformity Score at Week 40
Description	Changes in the severity of lower extremity skeletal abnormalities were...
Description	Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
Time Frame	Week 40

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.


Arm/Group Title	Burosumab Q2W
Arm/Group Description:	Burosumab SC injections Q2W for a t...
Arm/Group Description:	Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed	13
Least Squares Mean (Standard Error) Unit of Measure: units on a scale
	1.21 (0.155)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95% 0.90 to 1.51
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	RGI-C Lower Limb Deformity Score at Week 64
Description	Changes in the severity of lower extremity skeletal abnormalities were...
Description	Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
Time Frame	Week 64

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.


Arm/Group Title	Burosumab Q2W
Arm/Group Description:	Burosumab SC injections Q2W for a t...
Arm/Group Description:	Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed	13
Least Squares Mean (Standard Error) Unit of Measure: units on a scale
	1.51 (0.123)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure. The LS Mean, SE, 95% CI and 2-sided p-value are from the GEE model.
	Method	GEE
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95% 1.27 to 1.76
	Estimation Comments	[Not Specified]

9.Secondary Outcome


Title	Change From Baseline Over Time in Recumbent Length/Standing Height
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement at given time point.


Arm/Group Title		Burosumab Q2W
Arm/Group Description:		Burosumab SC injections Q2W for a t...
Arm/Group Description:		Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed		13
Mean (Standard Deviation) Unit of Measure: cm
Week 12	Number Analyzed	13 participants
Week 12		1.44 (2.009)
Week 24	Number Analyzed	13 participants
Week 24		2.52 (1.518)
Week 40	Number Analyzed	13 participants
Week 40		4.29 (2.451)
Week 64	Number Analyzed	13 participants
Week 64		7.22 (3.157)
Week 88	Number Analyzed	13 participants
Week 88		10.30 (3.400)
Week 112	Number Analyzed	13 participants
Week 112		13.25 (3.724)
Week 136	Number Analyzed	11 participants
Week 136		15.41 (3.699)
Week 160	Number Analyzed	12 participants
Week 160		18.96 (4.206)

10.Secondary Outcome


Title	Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores
Description	Recumbent length/Standing height z scores are measures of height adjus...
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.
Time Frame	Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement at given time point.


Arm/Group Title		Burosumab Q2W
Arm/Group Description:		Burosumab SC injections Q2W for a t...
Arm/Group Description:		Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed		13
Mean (Standard Deviation) Unit of Measure: Z score
Week 12	Number Analyzed	13 participants
Week 12		-0.082 (0.4964)
Week 24	Number Analyzed	13 participants
Week 24		-0.208 (0.4540)
Week 40	Number Analyzed	13 participants
Week 40		-0.276 (0.6647)
Week 64	Number Analyzed	13 participants
Week 64		-0.264 (0.8755)
Week 88	Number Analyzed	13 participants
Week 88		-0.212 (0.9115)
Week 112	Number Analyzed	13 participants
Week 112		-0.174 (0.9273)
Week 136	Number Analyzed	11 participants
Week 136		-0.321 (0.9123)
Week 160	Number Analyzed	12 participants
Week 160		-0.172 (0.9048)

11.Secondary Outcome


Title	Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement at given time point.


Arm/Group Title		Burosumab Q2W
Arm/Group Description:		Burosumab SC injections Q2W for a t...
Arm/Group Description:		Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed		13
Mean (Standard Deviation) Unit of Measure: percentiles
Week 12	Number Analyzed	13 participants
Week 12		-0.006 (11.6149)
Week 24	Number Analyzed	13 participants
Week 24		-4.940 (13.1323)
Week 40	Number Analyzed	13 participants
Week 40		-5.283 (20.1675)
Week 64	Number Analyzed	13 participants
Week 64		-4.980 (23.4412)
Week 88	Number Analyzed	13 participants
Week 88		-4.155 (23.9126)
Week 112	Number Analyzed	13 participants
Week 112		-3.000 (24.7569)
Week 136	Number Analyzed	11 participants
Week 136		-7.026 (24.8583)
Week 160	Number Analyzed	12 participants
Week 160		-3.628 (25.5113)

12.Secondary Outcome


Title	Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP)
Description	The GEE model includes the change from baseline as the dependent varia...
Description	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure.
Time Frame	Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160

Outcome Measure Data

Analysis Population Description

PK/PD Analysis Set: all participants who received at least one dose of study drug and had evaluable blood samples at given time point.


Arm/Group Title		Burosumab Q2W
Arm/Group Description:		Burosumab SC injections Q2W for a t...
Arm/Group Description:		Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed		13
Least Squares Mean (Standard Error) Unit of Measure: U/L
Week 4	Number Analyzed	13 participants
Week 4		-82.91 (23.348)
Week 12	Number Analyzed	13 participants
Week 12		-83.84 (45.263)
Week 20	Number Analyzed	13 participants
Week 20		-161.38 (12.924)
Week 40	Number Analyzed	13 participants
Week 40		-214.99 (13.628)
Week 48	Number Analyzed	12 participants
Week 48		-226.58 (11.491)
Week 56	Number Analyzed	13 participants
Week 56		-216.45 (16.165)
Week 64	Number Analyzed	13 participants
Week 64		-216.76 (12.705)
Week 76	Number Analyzed	13 participants
Week 76		-231.22 (15.964)
Week 88	Number Analyzed	12 participants
Week 88		-237.78 (12.837)
Week 100	Number Analyzed	13 participants
Week 100		-218.14 (15.340)
Week 112	Number Analyzed	13 participants
Week 112		-233.91 (11.098)
Week 124	Number Analyzed	12 participants
Week 124		-252.22 (8.312)
Week 136	Number Analyzed	12 participants
Week 136		-267.89 (13.124)
Week 148	Number Analyzed	12 participants
Week 148		-248.05 (12.653)
Week 160	Number Analyzed	12 participants
Week 160		-248.47 (10.990)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0004
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-82.91
	Confidence Interval	(2-Sided) 95% -128.68 to -37.15
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0640
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-83.84
	Confidence Interval	(2-Sided) 95% -172.55 to 4.88
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 20
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-161.38
	Confidence Interval	(2-Sided) 95% -186.70 to -136.05
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 40
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-214.99
	Confidence Interval	(2-Sided) 95% -241.70 to -188.28
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-226.58
	Confidence Interval	(2-Sided) 95% -249.11 to -204.06
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 56
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-216.45
	Confidence Interval	(2-Sided) 95% -248.13 to -184.77
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 64
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-216.76
	Confidence Interval	(2-Sided) 95% -241.66 to -191.86
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 76
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-231.22
	Confidence Interval	(2-Sided) 95% -262.51 to -199.93
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 88
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-237.78
	Confidence Interval	(2-Sided) 95% -262.94 to -212.62
	Estimation Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 100
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-218.14
	Confidence Interval	(2-Sided) 95% -248.21 to -188.08
	Estimation Comments	[Not Specified]

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 112
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-233.91
	Confidence Interval	(2-Sided) 95% -255.66 to -212.16
	Estimation Comments	[Not Specified]

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 124
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-252.22
	Confidence Interval	(2-Sided) 95% -268.51 to -235.93
	Estimation Comments	[Not Specified]

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 136
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-267.89
	Confidence Interval	(2-Sided) 95% -293.61 to -242.16
	Estimation Comments	[Not Specified]

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 148
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-248.05
	Confidence Interval	(2-Sided) 95% -272.85 to -223.25
	Estimation Comments	[Not Specified]

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Burosumab Q2W
	Comments	Week 160
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	GEE
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-248.47
	Confidence Interval	(2-Sided) 95% -270.01 to -226.93
	Estimation Comments	[Not Specified]

13.Secondary Outcome


Title	Percent Change From Baseline Over Time in Serum ALP
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160

Outcome Measure Data

Analysis Population Description

PK/PD Analysis Set: all participants who received at least one dose of study drug and had evaluable blood samples at given time point.


Arm/Group Title		Burosumab Q2W
Arm/Group Description:		Burosumab SC injections Q2W for a t...
Arm/Group Description:		Burosumab SC injections Q2W for a total of 160 weeks.
Overall Number of Participants Analyzed		13
Mean (Standard Deviation) Unit of Measure: percent change
Week 4	Number Analyzed	13 participants
Week 4		-12.47 (16.620)
Week 12	Number Analyzed	13 participants
Week 12		-5.00 (60.124)
Week 20	Number Analyzed	13 participants
Week 20		-24.76 (18.883)
Week 40	Number Analyzed	13 participants
Week 40		-36.25 (12.787)
Week 48	Number Analyzed	13 participants
Week 48		-37.29 (13.936)
Week 56	Number Analyzed	13 participants
Week 56		-35.80 (16.568)
Week 64	Number Analyzed	13 participants
Week 64		-35.95 (14.851)
Week 76	Number Analyzed	13 participants
Week 76		-38.36 (15.621)
Week 88	Number Analyzed	12 participants
Week 88		-39.08 (12.987)
Week 100	Number Analyzed	13 participants
Week 100		-37.42 (12.466)
Week 112	Number Analyzed	13 participants
Week 112		-39.05 (13.808)
Week 124	Number Analyzed	12 participants
Week 124		-43.11 (12.493)
Week 136	Number Analyzed	12 participants
Week 136		-47.01 (11.752)
Week 148	Number Analyzed	12 participants
Week 148		-43.47 (11.321)
Week 160	Number Analyzed	12 participants
Week 160		-42.35 (13.574)

Adverse Events

Time Frame	From first dose of study drug through the end of the study (at Week 160). Maximum duration of exposure to study drug was 160 weeks.
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Burosumab Q2W
Arm/Group Description	Burosumab SC injections Q2W for a t...
Arm/Group Description	Burosumab SC injections Q2W for a total of 160 weeks.
All-Cause Mortality
	Burosumab Q2W
	Affected / at Risk (%)
Total	0/13 (0.00%)
Serious Adverse Events Serious Adverse Events
	Burosumab Q2W
	Affected / at Risk (%)
Total	1/13 (7.69%)
Infections and infestations
Tooth Abscess ^† 1	1/13 (7.69%)
1 Term from vocabulary, MedDRA 18.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Burosumab Q2W
	Affected / at Risk (%)
Total	13/13 (100.00%)
Congenital, familial and genetic disorders
Skull Malformation ^† 1	1/13 (7.69%)
Syringomyelia ^† 1	1/13 (7.69%)
Ear and labyrinth disorders
Deafness Unilateral ^† 1	1/13 (7.69%)
Ear Haemorrhage ^† 1	1/13 (7.69%)
Ear Pain ^† 1	4/13 (30.77%)
Excessive Cerumen Production ^† 1	1/13 (7.69%)
Hypoacusis ^† 1	1/13 (7.69%)
Motion Sickness ^† 1	1/13 (7.69%)
Otorrhoea ^† 1	1/13 (7.69%)
Tinnitus ^† 1	1/13 (7.69%)
Eye disorders
Ocular Hyperaemia ^† 1	1/13 (7.69%)
Gastrointestinal disorders
Abdominal Discomfort ^† 1	3/13 (23.08%)
Abdominal Pain Upper ^† 1	5/13 (38.46%)
Aphthous Ulcer ^† 1	2/13 (15.38%)
Constipation ^† 1	2/13 (15.38%)
Dental Caries ^† 1	1/13 (7.69%)
Diarrhoea ^† 1	6/13 (46.15%)
Epigastric Discomfort ^† 1	1/13 (7.69%)
Gingival Blister ^† 1	1/13 (7.69%)
Gingival Erythema ^† 1	1/13 (7.69%)
Gingival Pain ^† 1	1/13 (7.69%)
Haematochezia ^† 1	1/13 (7.69%)
Loose Tooth ^† 1	1/13 (7.69%)
Nausea ^† 1	1/13 (7.69%)
Oral Pain ^† 1	4/13 (30.77%)
Post-Tussive Vomiting ^† 1	1/13 (7.69%)
Stomatitis ^† 1	1/13 (7.69%)
Teething ^† 1	1/13 (7.69%)
Toothache ^† 1	3/13 (23.08%)
Vomiting ^† 1	7/13 (53.85%)
Vomiting Projectile ^† 1	1/13 (7.69%)
General disorders
Fatigue ^† 1	2/13 (15.38%)
Injection Site Bruising ^† 1	1/13 (7.69%)
Injection Site Erythema ^† 1	2/13 (15.38%)
Injection Site Pain ^† 1	1/13 (7.69%)
Injection Site Pruritus ^† 1	2/13 (15.38%)
Injection Site Reaction ^† 1	1/13 (7.69%)
Non-Cardiac Chest Pain ^† 1	1/13 (7.69%)
Pain ^† 1	1/13 (7.69%)
Pyrexia ^† 1	11/13 (84.62%)
Vaccination Site Reaction ^† 1	1/13 (7.69%)
Immune system disorders
Food Allergy ^† 1	1/13 (7.69%)
Hypersensitivity ^† 1	3/13 (23.08%)
Infections and infestations
Atypical Pneumonia ^† 1	1/13 (7.69%)
Conjunctivitis ^† 1	1/13 (7.69%)
Croup Infectious ^† 1	1/13 (7.69%)
Ear Infection ^† 1	6/13 (46.15%)
Enterobiasis ^† 1	1/13 (7.69%)
Eye Infection ^† 1	1/13 (7.69%)
Gastroenteritis ^† 1	1/13 (7.69%)
Gastrointestinal Viral Infection ^† 1	1/13 (7.69%)
Genital Candidiasis ^† 1	1/13 (7.69%)
Gingival Abscess ^† 1	1/13 (7.69%)
Hand-Foot-And-Mouth Disease ^† 1	1/13 (7.69%)
Hordeolum ^† 1	1/13 (7.69%)
Impetigo ^† 1	2/13 (15.38%)
Influenza ^† 1	3/13 (23.08%)
Molluscum Contagiosum ^† 1	3/13 (23.08%)
Nasopharyngitis ^† 1	3/13 (23.08%)
Otitis Media ^† 1	1/13 (7.69%)
Pharyngitis Streptococcal ^† 1	8/13 (61.54%)
Pneumonia ^† 1	2/13 (15.38%)
Sinusitis ^† 1	1/13 (7.69%)
Tooth Abscess ^† 1	10/13 (76.92%)
Upper Respiratory Tract Infection ^† 1	9/13 (69.23%)
Urinary Tract Infection ^† 1	1/13 (7.69%)
Viral Infection ^† 1	2/13 (15.38%)
Viral Upper Respiratory Tract Infection ^† 1	3/13 (23.08%)
Injury, poisoning and procedural complications
Arthropod Bite ^† 1	3/13 (23.08%)
Contusion ^† 1	2/13 (15.38%)
Fall ^† 1	4/13 (30.77%)
Laceration ^† 1	1/13 (7.69%)
Lip Injury ^† 1	1/13 (7.69%)
Skin Abrasion ^† 1	4/13 (30.77%)
Tooth Fracture ^† 1	1/13 (7.69%)
Tooth Injury ^† 1	1/13 (7.69%)
Traumatic Tooth Displacement ^† 1	1/13 (7.69%)
Investigations
Amylase Increased ^† 1	2/13 (15.38%)
Blood 25-Hydroxycholecalciferol Decreased ^† 1	1/13 (7.69%)
Blood Parathyroid Hormone Increased ^† 1	1/13 (7.69%)
Blood Phosphorus Decreased ^† 1	1/13 (7.69%)
Heart Rate Abnormal ^† 1	1/13 (7.69%)
Lipase Increased ^† 1	1/13 (7.69%)
Vitamin D Decreased ^† 1	2/13 (15.38%)
White Blood Cell Count Increased ^† 1	1/13 (7.69%)
Metabolism and nutrition disorders
Decreased Appetite ^† 1	1/13 (7.69%)
Increased Appetite ^† 1	1/13 (7.69%)
Polydipsia ^† 1	1/13 (7.69%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	4/13 (30.77%)
Back Pain ^† 1	1/13 (7.69%)
Bone Pain ^† 1	3/13 (23.08%)
Foot Deformity ^† 1	1/13 (7.69%)
Knee Deformity ^† 1	3/13 (23.08%)
Myalgia ^† 1	1/13 (7.69%)
Pain In Extremity ^† 1	9/13 (69.23%)
Nervous system disorders
Dizziness ^† 1	1/13 (7.69%)
Dysarthria ^† 1	1/13 (7.69%)
Headache ^† 1	6/13 (46.15%)
Hypersomnia ^† 1	2/13 (15.38%)
Lethargy ^† 1	1/13 (7.69%)
Periodic Limb Movement Disorder ^† 1	1/13 (7.69%)
Psychiatric disorders
Insomnia ^† 1	1/13 (7.69%)
Renal and urinary disorders
Dysuria ^† 1	1/13 (7.69%)
Polyuria ^† 1	1/13 (7.69%)
Urinary Incontinence ^† 1	1/13 (7.69%)
Reproductive system and breast disorders
Penile Erythema ^† 1	1/13 (7.69%)
Penile Pain ^† 1	1/13 (7.69%)
Respiratory, thoracic and mediastinal disorders
Adenoidal Disorder ^† 1	1/13 (7.69%)
Chronic Throat Clearing ^† 1	1/13 (7.69%)
Cough ^† 1	11/13 (84.62%)
Epistaxis ^† 1	3/13 (23.08%)
Nasal Congestion ^† 1	8/13 (61.54%)
Nasal Discharge Discolouration ^† 1	1/13 (7.69%)
Oropharyngeal Pain ^† 1	3/13 (23.08%)
Productive Cough ^† 1	3/13 (23.08%)
Respiratory Tract Congestion ^† 1	2/13 (15.38%)
Rhinorrhoea ^† 1	7/13 (53.85%)
Sinus Congestion ^† 1	1/13 (7.69%)
Sneezing ^† 1	2/13 (15.38%)
Throat Irritation ^† 1	1/13 (7.69%)
Wheezing ^† 1	2/13 (15.38%)
Skin and subcutaneous tissue disorders
Dermatitis Contact ^† 1	1/13 (7.69%)
Pruritus ^† 1	2/13 (15.38%)
Rash ^† 1	2/13 (15.38%)
Rash Papular ^† 1	1/13 (7.69%)
Skin Disorder ^† 1	1/13 (7.69%)
Swelling Face ^† 1	1/13 (7.69%)
Urticaria ^† 1	4/13 (30.77%)
Urticaria Papular ^† 1	1/13 (7.69%)
Vascular disorders
Flushing ^† 1	1/13 (7.69%)
Haematoma ^† 1	1/13 (7.69%)
1 Term from vocabulary, MedDRA 18.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Medical Information
Organization:	Ultragenyx Pharmaceutical Inc
Phone:	1-888-756-8657
EMail:	medinfo@ultragenyx.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mao M, Carpenter TO, Whyte MP, Skrinar A, Chen CY, San Martin J, Rogol AD. Growth Curves for Children with X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2020 Oct 1;105(10):3243-9. doi: 10.1210/clinem/dgaa495.

Whyte MP, Carpenter TO, Gottesman GS, Mao M, Skrinar A, San Martin J, Imel EA. Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019 Mar;7(3):189-199. doi: 10.1016/S2213-8587(18)30338-3. Epub 2019 Jan 9.

Layout table for additonal information

Responsible Party:	Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier:	NCT02750618
Other Study ID Numbers:	UX023-CL205
First Submitted:	December 6, 2015
First Posted:	April 25, 2016
Results First Submitted:	April 19, 2018
Results First Posted:	June 19, 2018
Last Update Posted:	March 31, 2020

To Top