Efficacy and Safety of Burosumab (KRN23) Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With X Linked Hypophosphatemia (XLH)

• ClinicalTrials.gov Identifier: NCT02915705
• Recruitment Status: Completed
• First Posted: September 27, 2016
• Results First Posted: April 11, 2019
• Last Update Posted: January 23, 2020
• Sponsor: Ultragenyx Pharmaceutical Inc
• Collaborator: Kyowa Kirin Co., Ltd.
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: X-Linked Hypophosphatemia
• Interventions: Biological: burosumab; Drug: Oral Phosphate Supplement; Drug: active vitamin D
• Enrollment: 61

Participant Flow

Recruitment Details
Pre-assignment Details	Eligible participants discontinued oral phosphate and active vitamin D therapy for 7 days prior to randomization. Participants 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.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Period Title: Treatment Period
Started	32	29
Completed Week 40	32	29
Completed Week 64	32	29
Completed	32	29
Not Completed	0	0
Period Title: Long Term Extension Period
Started	26 [1]	25 [2]
Completed	26	25
Not Completed	0	0
[1] 6 participants did not enter the extension period; [2] 4 participants did not enter the extension period

Baseline Characteristics

Arm/Group Title		Active Control	Burosumab	Total
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Total of all reporting groups
Overall Number of Baseline Participants		32	29	61
Baseline Analysis Population Description		[Not Specified]
Age, Continuous [1]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	32 participants	29 participants	61 participants
		6.50 (3.250)	6.01 (3.408)	6.27 (3.307)
		[1] Measure Description: age at first dose
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	32 participants	29 participants	61 participants
	Female	18 56.3%	16 55.2%	34 55.7%
	Male	14 43.8%	13 44.8%	27 44.3%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	32 participants	29 participants	61 participants
	Hispanic or Latino	3 9.4%	3 10.3%	6 9.8%
	Not Hispanic or Latino	29 90.6%	26 89.7%	55 90.2%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Asian	Number Analyzed	32 participants	29 participants	61 participants
		6 18.8%	2 6.9%	8 13.1%
White	Number Analyzed	32 participants	29 participants	61 participants
		25 78.1%	25 86.2%	50 82.0%
Other (Not Specified)	Number Analyzed	32 participants	29 participants	61 participants
		1 3.1%	2 6.9%	3 4.9%
Rickets Severity Score (RSS) Total Score [1]; Mean (Standard Deviation); Unit of measure: Score on a scale
	Number Analyzed	32 participants	29 participants	61 participants
		3.19 (1.141)	3.17 (0.975)	3.18 (1.057)
		[1] Measure Description: 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.
Height-For-Age Z-Score [1] [2]; Mean (Standard Deviation); Unit of measure: Z score
	Number Analyzed	32 participants	28 participants	60 participants
		-2.05 (0.868)	-2.32 (1.167)	-2.17 (1.018)
		[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.; [2] Measure Analysis Population Description: 1 participant in the burosumab group did not have a baseline measurement
Growth Velocity Z Score From Pre-Treatment [1] [2]; Mean (Standard Deviation); Unit of measure: Z score
	Number Analyzed	22 participants	22 participants	44 participants
		-2.14 (5.571)	-1.37 (1.334)	-1.75 (4.022)
		[1] Measure Description: 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. Children with a mid-point age under 2.25 years were excluded, because 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.; [2] Measure Analysis Population Description: participants with a baseline measurement
Serum Phosphorus; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	32 participants	29 participants	61 participants
		2.30 (0.257)	2.42 (0.244)	2.36 (0.256)
Serum 1,25(OH)D [1]; Mean (Standard Deviation); Unit of measure: pg/mL
	Number Analyzed	30 participants	28 participants	58 participants
		40.18 (14.886)	46.00 (20.060)	42.99 (17.663)
		[1] Measure Analysis Population Description: participants with a baseline measurement
Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate(TmP/GFR) [1] [2]; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	30 participants	24 participants	54 participants
		2.008 (0.3300)	2.193 (0.3733)	2.091 (0.3587)
		[1] Measure Description: Data for urinary phosphorus and tubular reabsorption of phosphate (TRP) were used in the calculation of TmP/GFR.; [2] Measure Analysis Population Description: participants with a baseline measurement
Serum Alkaline Phosphatase (ALP) Concentration; Mean (Standard Deviation); Unit of measure: U/L
	Number Analyzed	32 participants	29 participants	61 participants
		523.44 (154.419)	510.76 (124.903)	517.4 (140.15)
Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference Domain [1] [2]; Mean (Standard Deviation); Unit of measure: T-score
	Number Analyzed	20 participants	15 participants	35 participants
		49.9 (12.05)	53.1 (10.95)	51.3 (11.54)
		[1] Measure 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.; [2] Measure Analysis Population Description: participants with a baseline assessment
PROMIS Physical Function Mobility Domain [1] [2]; Mean (Standard Deviation); Unit of measure: T-score
	Number Analyzed	20 participants	15 participants	35 participants
		45.5 (9.86)	45.2 (9.05)	45.3 (9.39)
		[1] Measure 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 Physical Function Mobility Domain, increases indicate greater mobility.; [2] Measure Analysis Population Description: participants with a baseline assessment
PROMIS Fatigue Domain [1] [2]; Mean (Standard Deviation); Unit of measure: T-score
	Number Analyzed	20 participants	15 participants	35 participants
		47.0 (13.70)	48.8 (9.60)	47.8 (11.98)
		[1] Measure 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 Fatigue Domain, decreases indicate less fatigue.; [2] Measure Analysis Population Description: participants with a baseline assessment
Faces Pain Scale-Revised (FPS-R) [1] [2]; Mean (Standard Deviation); Unit of measure: Score on a scale
	Number Analyzed	20 participants	15 participants	35 participants
		0.7 (1.17)	0.4 (1.12)	0.6 (1.14)
		[1] Measure 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.; [2] Measure Analysis Population Description: participants with a baseline assessment
Six Minute Walk Test (6MWT) Total Distance [1] [2]; Mean (Standard Deviation); Unit of measure: Meters
	Number Analyzed	20 participants	15 participants	35 participants
		450.50 (106.432)	365.93 (118.083)	414.26 (117.790)
		[1] Measure Description: 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.; [2] Measure Analysis Population Description: participants with a baseline measurement
Percent of Predicted Normal in the 6MWT Total Distance [1] [2]; Mean (Standard Deviation); Unit of measure: Perecent of predicted meters
	Number Analyzed	20 participants	15 participants	35 participants
		76.20 (14.838)	62.13 (18.629)	70.17 (17.771)
		[1] Measure Description: 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.; [2] Measure Analysis Population Description: participants with a baseline measurement

Outcome Measures

1. Primary Outcome

Title	Radiographic Global Impression of Change (RGI-C) Global Score at Week 40
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).
Time Frame	Week 40

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.77 (0.107)	1.92 (0.110)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.45
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40
Description	RGI-C responders are defined as participants 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).
Time Frame	Week 40

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Measure Type: Number; Unit of Measure: percentage of participants
	6.3	72.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	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.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	39.1
	Confidence Interval	(2-Sided) 95%; 7.2 to 211.7
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64
Description	RGI-C responders are defined as participants 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).
Time Frame	Week 64

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Measure Type: Number; Unit of Measure: percentage of participants
	18.8	86.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	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.
	Method	generalized linear mixed model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	34.1
	Confidence Interval	(2-Sided) 95%; 5.6 to 206.3
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	RGI-C Global Score at Week 64
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).
Time Frame	Week 64

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	1.03 (0.136)	2.06 (0.072)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	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	1.02
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.33
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Change From Baseline in RSS Total Score at Week 40
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.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	28
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-0.71 (0.138)	-2.04 (0.145)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	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.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.34
	Confidence Interval	(2-Sided) 95%; -1.74 to -0.94
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Change From Baseline in RSS Total Score at Week 64
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.
Time Frame	Baseline, Week 64

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-1.01 (0.151)	-2.23 (0.117)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	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.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-1.21
	Confidence Interval	(2-Sided) 95%; -1.59 to -0.83
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	RGI-C Long Leg Score at Week 40
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).
Time Frame	Week 40

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.22 (0.080)	0.62 (0.153)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0162
	Comments	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.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.07 to 0.72
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	RGI-C Long Leg Score at Week 64
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).
Time Frame	Week 64

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.29 (0.119)	1.25 (0.170)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	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.
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.37
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Change From Baseline in Height-For-Age Z-Scores to Week 40
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.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	28
Least Squares Mean (Standard Error); Unit of Measure: Z score
	0.03 (0.031)	0.16 (0.052)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0408
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.24
	Estimation Comments	[Not Specified]

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	28
Least Squares Mean (Standard Error); Unit of Measure: Z score
	0.02 (0.035)	0.17 (0.066)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0490
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; 0.00 to 0.29
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Change in Growth Velocity Z Score From Baseline to Week 40
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.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with Baseline growth velocity.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	22	22
Least Squares Mean (Standard Error); Unit of Measure: Z score
	0.73 (0.339)	1.76 (0.337)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0386
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.06 to 1.99
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Change in Growth Velocity Z Score From Baseline to Week 64
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.
Time Frame	Baseline, Week 64

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with Baseline growth velocity.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	22	22
Least Squares Mean (Standard Error); Unit of Measure: Z score
	0.41 (0.265)	1.53 (0.264)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0047
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.37 to 1.88
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64
Description	The 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.
Time Frame	Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with data at given time point.

Arm/Group Title		Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed		32	29
Least Squares Mean (Standard Error); Unit of Measure: mg/dL
Week 1	Number Analyzed	31 participants	28 participants
		0.22 (0.072)	1.26 (0.094)
Week 2	Number Analyzed	0 participants	26 participants
			1.14 (0.098)
Week 4	Number Analyzed	32 participants	29 participants
		0.18 (0.061)	1.21 (0.102)
Week 8	Number Analyzed	32 participants	29 participants
		0.21 (0.064)	0.99 (0.074)
Week 12	Number Analyzed	0 participants	26 participants
			1.01 (0.072)
Week 16	Number Analyzed	29 participants	29 participants
		0.24 (0.063)	0.87 (0.072)
Week 24	Number Analyzed	32 participants	29 participants
		0.27 (0.073)	0.78 (0.077)
Week 32	Number Analyzed	32 participants	29 participants
		0.23 (0.063)	0.93 (0.073)
Week 33	Number Analyzed	0 participants	27 participants
			1.23 (0.106)
Week 40	Number Analyzed	32 participants	29 participants
		0.20 (0.062)	0.92 (0.080)
Week 52	Number Analyzed	32 participants	29 participants
		0.30 (0.082)	0.91 (0.075)
Week 64	Number Analyzed	32 participants	29 participants
		0.21 (0.062)	0.91 (0.078)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 1
	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
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.27
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 4
	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
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.27
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 8
	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
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.97
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 16
	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
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.81
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 24
	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
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.30 to 0.72
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 32
	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
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.89
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	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
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.91
	Estimation Comments	Difference (burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 52
	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
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.82
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	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
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.90
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112
Description	[Not Specified]
Time Frame	Baseline, Weeks 66, 68, 76, 88, 100, 112

Outcome Measure Data

Analysis Population Description

PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with an assessment at given time point.

Arm/Group Title		Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed		26	22
Mean (Standard Deviation); Unit of Measure: mg/dL
Week 66	Number Analyzed	26 participants	0 participants
		0.05 (0.235)
Week 68	Number Analyzed	26 participants	1 participants
		1.17 (0.472)	1.10 [1] (NA)
Week 76	Number Analyzed	22 participants	22 participants
		0.90 (0.324)	0.92 (0.324)
Week 88	Number Analyzed	16 participants	11 participants
		0.98 (0.433)	1.00 (0.576)
Week 100	Number Analyzed	7 participants	2 participants
		0.99 (0.445)	1.00 (0.424)
Week 112	Number Analyzed	5 participants	2 participants
		1.26 (0.508)	1.10 (0.283)

[1]

1 participant analyzed

15. Secondary Outcome

Title	Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64
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.
Time Frame	Baseline, Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Least Squares Mean (Standard Error); Unit of Measure: mg/dL
	0.24 (0.058)	0.98 (0.061)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.91
	Estimation Comments	Difference (KRN23 - Oral Phosphate/Active Vitamin D)

16. Secondary Outcome

Title	Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab)
Description	[Not Specified]
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	26	29
Mean (Standard Deviation); Unit of Measure: mg/dL
	1.05 (0.310)	0.93 (0.336)

17. Secondary Outcome

Title	Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)
Description	[Not Specified]
Time Frame	Burosumab arm: Baseline, up to Week 140; Active Control arm: Baseline, Week 68 up to Week 140

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Measure Type: Number; Unit of Measure: percentage of participants
	75.0	96.6

18. Secondary Outcome

Title	Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64
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.
Time Frame	Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64

Outcome Measure Data

Analysis Population Description

PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with an assessment at given time point.

Arm/Group Title		Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed		30	28
Least Squares Mean (Standard Error); Unit of Measure: pg/mL
Week 1	Number Analyzed	29 participants	27 participants
		19.81 (2.758)	68.09 (5.251)
Week 2	Number Analyzed	0 participants	24 participants
			31.78 (5.130)
Week 4	Number Analyzed	30 participants	27 participants
		12.77 (2.998)	33.86 (3.561)
Week 8	Number Analyzed	30 participants	28 participants
		15.10 (2.528)	30.85 (3.830)
Week 12	Number Analyzed	0 participants	24 participants
			33.43 (3.176)
Week 16	Number Analyzed	27 participants	28 participants
		19.41 (3.757)	32.38 (3.032)
Week 24	Number Analyzed	28 participants	27 participants
		17.46 (2.905)	28.35 (3.113)
Week 32	Number Analyzed	29 participants	28 participants
		17.25 (3.156)	23.49 (2.439)
Week 33	Number Analyzed	0 participants	24 participants
			31.50 (3.423)
Week 40	Number Analyzed	27 participants	25 participants
		18.42 (3.594)	29.63 (3.721)
Week 52	Number Analyzed	29 participants	27 participants
		8.74 (3.866)	13.75 (2.862)
Week 64	Number Analyzed	29 participants	27 participants
		1.19 (2.785)	9.89 (2.235)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 1
	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
	Estimated Value	48.27
	Confidence Interval	(2-Sided) 95%; 36.53 to 60.02
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 4
	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
	Estimated Value	21.09
	Confidence Interval	(2-Sided) 95%; 12.01 to 30.16
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0010
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference
	Estimated Value	15.75
	Confidence Interval	(2-Sided) 95%; 6.35 to 25.15
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0078
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference
	Estimated Value	12.97
	Confidence Interval	(2-Sided) 95%; 3.41 to 22.53
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0101
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference
	Estimated Value	10.89
	Confidence Interval	(2-Sided) 95%; 2.59 to 19.19
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 32
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1165
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference
	Estimated Value	6.23
	Confidence Interval	(2-Sided) 95%; -1.55 to 14.02
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 40
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0317
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference
	Estimated Value	11.21
	Confidence Interval	(2-Sided) 95%; 0.98 to 21.44
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 52
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3044
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference
	Estimated Value	5.01
	Confidence Interval	(2-Sided) 95%; -4.55 to 14.56
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 64
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0145
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference
	Estimated Value	8.70
	Confidence Interval	(2-Sided) 95%; 1.72 to 15.68
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D

19. Secondary Outcome

Title	Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112
Description	[Not Specified]
Time Frame	Baseline, Weeks 68, 76, 88, 100, 112

Outcome Measure Data

Analysis Population Description

PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with an assessment at given time point.

Arm/Group Title		Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed		25	21
Mean (Standard Deviation); Unit of Measure: pg/mL
Week 68	Number Analyzed	25 participants	1 participants
		22.12 (23.950)	-9.80 [1] (NA)
Week 76	Number Analyzed	21 participants	21 participants
		19.05 (22.612)	12.80 (20.093)
Week 88	Number Analyzed	14 participants	10 participants
		24.58 (17.787)	11.76 (22.874)
Week 100	Number Analyzed	6 participants	2 participants
		33.57 (16.591)	13.25 (1.061)
Week 112	Number Analyzed	5 participants	2 participants
		29.94 (15.402)	31.05 (33.729)

[1]

1 participant analyzed

20. Secondary Outcome

Title	Change From Baseline Over Time in TmP/GFR, up to Week 64
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.
Time Frame	Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64

Outcome Measure Data

Analysis Population Description

PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with an assessment at given time point.

Arm/Group Title		Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed		30	24
Least Squares Mean (Standard Error); Unit of Measure: mg/dL
Week 4	Number Analyzed	28 participants	23 participants
		-0.17 (0.065)	1.48 (0.173)
Week 8	Number Analyzed	27 participants	24 participants
		-0.20 (0.057)	1.22 (0.101)
Week 16	Number Analyzed	26 participants	24 participants
		-0.15 (0.085)	1.00 (0.139)
Week 24	Number Analyzed	29 participants	23 participants
		-0.12 (0.072)	0.99 (0.134)
Week 32	Number Analyzed	29 participants	22 participants
		-0.10 (0.062)	1.14 (0.115)
Week 40	Number Analyzed	28 participants	23 participants
		-0.15 (0.053)	1.20 (0.113)
Week 52	Number Analyzed	28 participants	22 participants
		-0.12 (0.069)	1.13 (0.124)
Week 64	Number Analyzed	30 participants	23 participants
		-0.09 (0.070)	1.16 (0.127)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 4
	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
	Estimated Value	1.65
	Confidence Interval	(2-Sided) 95%; 1.28 to 2.02
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 8
	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
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; 1.19 to 1.64
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 16
	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
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.48
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 24
	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
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.41
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 32
	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
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.51
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	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
	Estimated Value	1.35
	Confidence Interval	(2-Sided) 95%; 1.10 to 1.60
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 52
	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
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.97 to 1.54
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	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
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 95%; 0.96 to 1.54
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

21. Secondary Outcome

Title	Change From Baseline Over Time in TmP/GFR, Week 68 to 112
Description	Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR.
Time Frame	Baseline, Weeks 68, 76, 88, 112

Outcome Measure Data

Analysis Population Description

PD Analysis Set: all participants who received at least one dose of study therapy and had evaluable serum data. Participants with data at given time point.

Arm/Group Title		Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed		24	7
Mean (Standard Deviation); Unit of Measure: mg/dL
Week 68	Number Analyzed	24 participants	1 participants
		1.61 (0.705)	1.65 [1] (NA)
Week 76	Number Analyzed	4 participants	4 participants
		1.18 (0.758)	0.59 (0.429)
Week 88	Number Analyzed	14 participants	7 participants
		1.33 (0.480)	0.95 (0.620)
Week 112	Number Analyzed	3 participants	2 participants
		1.56 (0.233)	1.32 (0.233)

[1]

1 participant analyzed

22. Secondary Outcome

Title	Change From Baseline Over Time in Serum ALP, up to Week 64
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.
Time Frame	Baseline, Weeks 16, 24, 40, 52, 64

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	32	29
Least Squares Mean (Standard Error); Unit of Measure: U/L
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 Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 16
	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
	Estimated Value	-92.53
	Confidence Interval	(2-Sided) 95%; -131.40 to -53.66
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 24
	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
	Estimated Value	-85.57
	Confidence Interval	(2-Sided) 95%; -126.37 to -44.76
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	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
	Estimated Value	-95.95
	Confidence Interval	(2-Sided) 95%; -136.05 to -55.84
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	Week 52
	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
	Estimated Value	-111.28
	Confidence Interval	(2-Sided) 95%; -152.08 to -70.49
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	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
	Estimated Value	-146.56
	Confidence Interval	(2-Sided) 95%; -191.61 to -101.52
	Estimation Comments	Difference (Burosumab - Oral Phosphate/Active Vitamin D)

23. Secondary Outcome

Title	Change From Baseline Over Time in Serum ALP, Week 68 to 112
Description	[Not Specified]
Time Frame	Baseline, Weeks 68, 76, 88, 100, 112

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed		26	22
Mean (Standard Deviation); Unit of Measure: U/L
Week 68	Number Analyzed	26 participants	1 participants
		-82.73 (83.683)	-184.00 [1] (NA)
Week 76	Number Analyzed	22 participants	22 participants
		-106.73 (73.316)	-166.73 (87.700)
Week 88	Number Analyzed	16 participants	11 participants
		-146.56 (73.120)	-154.55 (48.148)
Week 100	Number Analyzed	7 participants	2 participants
		-83.14 (104.675)	-184.00 (48.083)
Week 112	Number Analyzed	5 participants	2 participants
		-104.80 (80.350)	-172.00 (26.870)

[1]

1 participant analyzed

24. Secondary Outcome

Title	Percent Change From Baseline Over Time in Serum ALP, up to Week 112
Description	Decreases indicate improvement.
Time Frame	Baseline, Weeks 16, 24, 40, 52, 64, 68, 76, 88, 100, 112

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed		32	29
Mean (Standard Deviation); Unit of Measure: percent change
Week 16	Number Analyzed	29 participants	29 participants
		0.41 (21.021)	-18.39 (10.815)
Week 24	Number Analyzed	32 participants	29 participants
		-3.21 (15.827)	-19.88 (17.642)
Week 40	Number Analyzed	32 participants	29 participants
		-6.85 (16.493)	-24.38 (13.498)
Week 52	Number Analyzed	32 participants	29 participants
		-8.60 (19.027)	-30.60 (11.852)
Week 64	Number Analyzed	32 participants	29 participants
		-4.60 (20.711)	-32.78 (13.095)
Week 68	Number Analyzed	26 participants	1 participants
		-14.66 (14.760)	-38.02 [1] (NA)
Week 76	Number Analyzed	22 participants	22 participants
		-20.49 (13.926)	-31.42 (13.422)
Week 88	Number Analyzed	16 participants	11 participants
		-28.77 (12.201)	-32.02 (10.610)
Week 100	Number Analyzed	7 participants	2 participants
		-16.06 (23.703)	-39.29 (11.460)
Week 112	Number Analyzed	5 participants	2 participants
		-21.00 (15.053)	-36.67 (6.868)

[1]

1 participant analyzed

25. Secondary Outcome

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
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.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	20	15
Least Squares Mean (Standard Error); Unit of Measure: T-score
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0212
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-5.02
	Confidence Interval	(2-Sided) 95%; -9.29 to -0.75
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1009
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	2.68
	Confidence Interval	(2-Sided) 95%; -0.52 to 5.89
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1676
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-3.25
	Confidence Interval	(2-Sided) 95%; -7.86 to 1.37
	Estimation Comments	[Not Specified]

26. Secondary Outcome

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
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.
Time Frame	Baseline, Week 64

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	20	15
Least Squares Mean (Standard Error); Unit of Measure: T-score
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3091
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-2.26
	Confidence Interval	(2-Sided) 95%; -6.61 to 2.09
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3145
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	1.90
	Confidence Interval	(2-Sided) 95%; -1.80 to 5.59
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6810
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-1.08
	Confidence Interval	(2-Sided) 95%; -6.21 to 4.06
	Estimation Comments	[Not Specified]

27. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	20	15
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	0.02 (0.323)	0.03 (0.323)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9862
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.80
	Estimation Comments	[Not Specified]

28. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	19	15
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	0.04 (0.270)	-0.01 (0.234)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8786
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.58 to 0.68
	Estimation Comments	[Not Specified]

29. Secondary Outcome

Title	Change From Baseline in the 6MWT Total Distance at Week 40
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.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40 in subjects ≥ 5 years who were able to complete the test.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	20	13
Least Squares Mean (Standard Error); Unit of Measure: meters
	3.65 (14.060)	47.10 (15.768)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0514
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	43.46
	Confidence Interval	(2-Sided) 95%; -0.26 to 87.17
	Estimation Comments	[Not Specified]

30. Secondary Outcome

Title	Change From Baseline in the 6MWT Total Distance at Week 64
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.
Time Frame	Baseline, Week 64

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	20	13
Least Squares Mean (Standard Error); Unit of Measure: meters
	29.28 (16.834)	74.83 (12.513)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0399
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	45.55
	Confidence Interval	(2-Sided) 95%; 2.09 to 89.02
	Estimation Comments	[Not Specified]

31. Secondary Outcome

Title	Percent of Predicted Normal in the 6MWT Total Distance at Week 40
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.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 40.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	20	13
Least Squares Mean (Standard Error); Unit of Measure: percent of predicted meters
	-1.14 (2.224)	5.59 (2.633)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0633
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	6.72
	Confidence Interval	(2-Sided) 95%; -0.37 to 13.82
	Estimation Comments	[Not Specified]

32. Secondary Outcome

Title	Percent of Predicted Normal in the 6MWT Total Distance at Week 64
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.
Time Frame	Baseline, Week 64

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least one dose of assigned medication and had at least one post-baseline assessment. Participants with an assessment at Week 64.

Arm/Group Title	Active Control	Burosumab
Arm/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), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
Overall Number of Participants Analyzed	20	13
Least Squares Mean (Standard Error); Unit of Measure: percent of predicted meters
	1.88 (2.789)	9.15 (2.056)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Control, Burosumab
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0496
	Comments	[Not Specified]
	Method	GEE model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	7.27
	Confidence Interval	(2-Sided) 95%; 0.01 to 14.52
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	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)
Arm/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).	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64).	Multiple daily doses of oral phosphate and one or more daily doses of active vitamin D therapy, titrated and individualized by the investigator based on published recommendations during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.	Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection at any time during the study.
All-Cause Mortality
	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)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/32 (0.00%)	0/29 (0.00%)	0/26 (0.00%)	0/29 (0.00%)	0/55 (0.00%)
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)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	3/32 (9.38%)	3/29 (10.34%)	0/26 (0.00%)	4/29 (13.79%)	4/55 (7.27%)
Congenital, familial and genetic disorders
Craniosynostosis † 1	1/32 (3.13%)	1/29 (3.45%)	0/26 (0.00%)	1/29 (3.45%)	1/55 (1.82%)
Eye disorders
Papilloedema † 1	0/32 (0.00%)	0/29 (0.00%)	0/26 (0.00%)	1/29 (3.45%)	1/55 (1.82%)
Infections and infestations
Viral Infection † 1	0/32 (0.00%)	1/29 (3.45%)	0/26 (0.00%)	1/29 (3.45%)	1/55 (1.82%)
Musculoskeletal and connective tissue disorders
Knee Deformity † 1	1/32 (3.13%)	0/29 (0.00%)	0/26 (0.00%)	0/29 (0.00%)	0/55 (0.00%)
Nervous system disorders
Migraine † 1	0/32 (0.00%)	1/29 (3.45%)	0/26 (0.00%)	1/29 (3.45%)	1/55 (1.82%)
Renal and urinary disorders
Haematuria † 1	1/32 (3.13%)	0/29 (0.00%)	0/26 (0.00%)	0/29 (0.00%)	0/55 (0.00%)
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%
	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)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	23/32 (71.88%)	21/29 (72.41%)	9/26 (34.62%)	25/29 (86.21%)	34/55 (61.82%)
Congenital, familial and genetic disorders
Tooth Hypoplasia † 1	0/32 (0.00%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Ear and labyrinth disorders
Ear Discomfort † 1	0/32 (0.00%)	1/29 (3.45%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Ear Pain † 1	1/32 (3.13%)	4/29 (13.79%)	2/26 (7.69%)	4/29 (13.79%)	6/55 (10.91%)
Gastrointestinal disorders
Abdominal Discomfort † 1	2/32 (6.25%)	2/29 (6.90%)	1/26 (3.85%)	2/29 (6.90%)	3/55 (5.45%)
Abdominal Pain † 1	1/32 (3.13%)	2/29 (6.90%)	1/26 (3.85%)	2/29 (6.90%)	3/55 (5.45%)
Abdominal Pain Upper † 1	3/32 (9.38%)	3/29 (10.34%)	2/26 (7.69%)	4/29 (13.79%)	6/55 (10.91%)
Constipation † 1	0/32 (0.00%)	5/29 (17.24%)	2/26 (7.69%)	5/29 (17.24%)	7/55 (12.73%)
Dental Caries † 1	2/32 (6.25%)	9/29 (31.03%)	0/26 (0.00%)	10/29 (34.48%)	10/55 (18.18%)
Diarrhoea † 1	2/32 (6.25%)	7/29 (24.14%)	1/26 (3.85%)	7/29 (24.14%)	8/55 (14.55%)
Haematochezia † 1	0/32 (0.00%)	1/29 (3.45%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Nausea † 1	1/32 (3.13%)	3/29 (10.34%)	2/26 (7.69%)	5/29 (17.24%)	7/55 (12.73%)
Teething † 1	0/32 (0.00%)	2/29 (6.90%)	1/26 (3.85%)	2/29 (6.90%)	3/55 (5.45%)
Tooth Loss † 1	0/32 (0.00%)	1/29 (3.45%)	1/26 (3.85%)	2/29 (6.90%)	3/55 (5.45%)
Toothache † 1	1/32 (3.13%)	4/29 (13.79%)	1/26 (3.85%)	5/29 (17.24%)	6/55 (10.91%)
Vomiting † 1	8/32 (25.00%)	12/29 (41.38%)	5/26 (19.23%)	14/29 (48.28%)	19/55 (34.55%)
General disorders
Fatigue † 1	2/32 (6.25%)	1/29 (3.45%)	1/26 (3.85%)	2/29 (6.90%)	3/55 (5.45%)
Injection Site Bruising † 1	0/32 (0.00%)	0/29 (0.00%)	2/26 (7.69%)	1/29 (3.45%)	3/55 (5.45%)
Injection Site Erosion † 1	0/32 (0.00%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Injection Site Erythema † 1	0/32 (0.00%)	9/29 (31.03%)	6/26 (23.08%)	9/29 (31.03%)	15/55 (27.27%)
Injection Site Pruritus † 1	0/32 (0.00%)	3/29 (10.34%)	2/26 (7.69%)	3/29 (10.34%)	5/55 (9.09%)
Injection Site Rash † 1	0/32 (0.00%)	3/29 (10.34%)	0/26 (0.00%)	3/29 (10.34%)	3/55 (5.45%)
Injection Site Reaction † 1	0/32 (0.00%)	7/29 (24.14%)	2/26 (7.69%)	8/29 (27.59%)	10/55 (18.18%)
Injection Site Swelling † 1	0/32 (0.00%)	3/29 (10.34%)	1/26 (3.85%)	3/29 (10.34%)	4/55 (7.27%)
Injection Site Urticaria † 1	0/32 (0.00%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Pain † 1	0/32 (0.00%)	2/29 (6.90%)	0/26 (0.00%)	3/29 (10.34%)	3/55 (5.45%)
Pyrexia † 1	7/32 (21.88%)	16/29 (55.17%)	7/26 (26.92%)	17/29 (58.62%)	24/55 (43.64%)
Immune system disorders
Hypersensitivity † 1	2/32 (6.25%)	1/29 (3.45%)	0/26 (0.00%)	1/29 (3.45%)	1/55 (1.82%)
Seasonal Allergy † 1	2/32 (6.25%)	4/29 (13.79%)	1/26 (3.85%)	4/29 (13.79%)	5/55 (9.09%)
Infections and infestations
Ear Infection † 1	3/32 (9.38%)	2/29 (6.90%)	1/26 (3.85%)	3/29 (10.34%)	4/55 (7.27%)
Gastroenteritis † 1	3/32 (9.38%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Gastroenteritis Viral † 1	3/32 (9.38%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Influenza † 1	6/32 (18.75%)	4/29 (13.79%)	0/26 (0.00%)	4/29 (13.79%)	4/55 (7.27%)
Nasopharyngitis † 1	14/32 (43.75%)	11/29 (37.93%)	6/26 (23.08%)	15/29 (51.72%)	21/55 (38.18%)
Otitis Externa † 1	3/32 (9.38%)	0/29 (0.00%)	0/26 (0.00%)	0/29 (0.00%)	0/55 (0.00%)
Otitis Media † 1	4/32 (12.50%)	2/29 (6.90%)	0/26 (0.00%)	3/29 (10.34%)	3/55 (5.45%)
Pharyngitis Streptococcal † 1	1/32 (3.13%)	1/29 (3.45%)	1/26 (3.85%)	2/29 (6.90%)	3/55 (5.45%)
Pneumonia † 1	0/32 (0.00%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Rhinitis † 1	2/32 (6.25%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Tooth Abscess † 1	3/32 (9.38%)	8/29 (27.59%)	2/26 (7.69%)	9/29 (31.03%)	11/55 (20.00%)
Upper Respiratory Tract Infection † 1	3/32 (9.38%)	3/29 (10.34%)	0/26 (0.00%)	3/29 (10.34%)	3/55 (5.45%)
Varicella † 1	0/32 (0.00%)	2/29 (6.90%)	1/26 (3.85%)	2/29 (6.90%)	3/55 (5.45%)
Viral Upper Respiratory Tract Infection † 1	2/32 (6.25%)	0/29 (0.00%)	0/26 (0.00%)	0/29 (0.00%)	0/55 (0.00%)
Injury, poisoning and procedural complications
Contusion † 1	0/32 (0.00%)	4/29 (13.79%)	0/26 (0.00%)	4/29 (13.79%)	4/55 (7.27%)
Fall † 1	0/32 (0.00%)	3/29 (10.34%)	0/26 (0.00%)	3/29 (10.34%)	3/55 (5.45%)
Procedural Pain † 1	0/32 (0.00%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Investigations
Vitamin D Decreased † 1	1/32 (3.13%)	6/29 (20.69%)	1/26 (3.85%)	6/29 (20.69%)	7/55 (12.73%)
Metabolism and nutrition disorders
Decreased Appetite † 1	2/32 (6.25%)	1/29 (3.45%)	0/26 (0.00%)	1/29 (3.45%)	1/55 (1.82%)
Vitamin D Deficiency † 1	1/32 (3.13%)	5/29 (17.24%)	0/26 (0.00%)	5/29 (17.24%)	5/55 (9.09%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	10/32 (31.25%)	13/29 (44.83%)	3/26 (11.54%)	13/29 (44.83%)	16/55 (29.09%)
Back Pain † 1	3/32 (9.38%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Pain In Extremity † 1	10/32 (31.25%)	11/29 (37.93%)	3/26 (11.54%)	11/29 (37.93%)	14/55 (25.45%)
Nervous system disorders
Headache † 1	6/32 (18.75%)	10/29 (34.48%)	3/26 (11.54%)	10/29 (34.48%)	13/55 (23.64%)
Migraine † 1	2/32 (6.25%)	1/29 (3.45%)	1/26 (3.85%)	1/29 (3.45%)	2/55 (3.64%)
Psychiatric disorders
Attention Deficit/Hyperactivity Disorder † 1	0/32 (0.00%)	0/29 (0.00%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Renal and urinary disorders
Dysuria † 1	0/32 (0.00%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Respiratory, thoracic and mediastinal disorders
Asthma † 1	1/32 (3.13%)	4/29 (13.79%)	0/26 (0.00%)	4/29 (13.79%)	4/55 (7.27%)
Cough † 1	6/32 (18.75%)	15/29 (51.72%)	4/26 (15.38%)	15/29 (51.72%)	19/55 (34.55%)
Nasal Congestion † 1	1/32 (3.13%)	5/29 (17.24%)	1/26 (3.85%)	7/29 (24.14%)	8/55 (14.55%)
Oropharyngeal Pain † 1	1/32 (3.13%)	5/29 (17.24%)	3/26 (11.54%)	6/29 (20.69%)	9/55 (16.36%)
Rhinitis Allergic † 1	0/32 (0.00%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Rhinorrhoea † 1	2/32 (6.25%)	7/29 (24.14%)	3/26 (11.54%)	8/29 (27.59%)	11/55 (20.00%)
Wheezing † 1	0/32 (0.00%)	1/29 (3.45%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Skin and subcutaneous tissue disorders
Erythema † 1	0/32 (0.00%)	2/29 (6.90%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Rash † 1	2/32 (6.25%)	3/29 (10.34%)	0/26 (0.00%)	4/29 (13.79%)	4/55 (7.27%)
Skin Lesion † 1	0/32 (0.00%)	1/29 (3.45%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
Swelling Face † 1	0/32 (0.00%)	1/29 (3.45%)	0/26 (0.00%)	2/29 (6.90%)	2/55 (3.64%)
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

• Name/Title: Medical Information
• Organization: Ultragenyx Pharmaceutical Inc
• Phone: 1-888-756-8567
• EMail: medinfo@ultragenyx.com

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

Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019 Jun 15;393(10189):2416-2427. doi: 10.1016/S0140-6736(19)30654-3. Epub 2019 May 16. Erratum in: Lancet. 2019 Jul 13;394(10193):120.

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT02915705
• Other Study ID Numbers: UX023-CL301
• First Submitted: May 23, 2016
• First Posted: September 27, 2016
• Results First Submitted: February 28, 2019
• Results First Posted: April 11, 2019
• Last Update Posted: January 23, 2020