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Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Efficacy and Safety of KRN23 in Adults with X-linked Hypophosphatemia (XLH)

Summary
EudraCT number	2014-005529-11
Trial protocol	GB IE FR DK IT
Global end of trial date	06 Dec 2018

Results information
Results version number	v2(current)
This version publication date	31 Jan 2021
First version publication date	20 Dec 2019
Other versions	v1
Version creation reason	Correction of full data set Minor corrections to full data set

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

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Trial information

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Sponsor protocol code

UX023-CL303

ISRCTN number

US NCT number

NCT02526160

WHO universal trial number (UTN)

Other trial identifiers

na: EMA/902676

Sponsor organisation name

Ultragenyx Pharmaceutical Inc.

Sponsor organisation address

60 Leveroni Court, Novato, United States, California 94949

Public contact

Medical Information, Ultragenyx Pharmaceutical Inc., 1 888- 756-8567, medinfo@ultragenyx.com

Scientific contact

Medical Information, Ultragenyx Pharmaceutical Inc., 1 888- 756-8567, medinfo@ultragenyx.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

06 Dec 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Dec 2018

Was the trial ended prematurely?

Main objective of the trial

To establish the effect of burosumab treatment compared with placebo on increasing serum phosphorus levels in adults with XLH.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Oct 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 69

Country: Number of subjects enrolled

Japan: 11

Country: Number of subjects enrolled

Korea, Republic of: 7

Country: Number of subjects enrolled

United Kingdom: 11

Country: Number of subjects enrolled

France: 30

Country: Number of subjects enrolled

Ireland: 3

Country: Number of subjects enrolled

Italy: 3

Worldwide total number of subjects

134

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

133

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Potential subjects came in to the site to sign informed consent and complete the initial Screening procedures (SV1). Individuals who successfully passed the initial screening requirements returned for the site for a second Screening visit (SV2) to complete the remaining screening assessments and confirm eligibility.

Period 1 title

Double-Blind (Placebo Controlled) Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

The study was conducted as a randomized, double-blind, placebo-controlled study through Week 24. Double-blind conditions were established so that neither the sponsor, subject, or site personnel involved in study conduct knew the identity of a subject’s treatment.

Are arms mutually exclusive

Yes

Placebo

Arm description

Subcutaneous (SC) injection of placebo every 4 weeks (Q4W) for 24 weeks (double-blind placebo-controlled Treatment Period)

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects began treatment with an SC injection of placebo administered Q4W.

Burosumab

Arm description

SC injection of 1.0 mg/kg burosumab Q4W for 24 weeks (double-blind placebo-controlled Treatment Period)

Arm type

Experimental

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, ux023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

The amount of drug administered was calculated based on Baseline body weight and a 1.0 mg/kg burosumab dose level (rounded to the nearest 10 mg), up to a maximum dose of 90 mg.

Number of subjects in period 1	Placebo	Burosumab
Started	66	68
Completed	66	67
Not completed	0	1
Consent withdrawn by subject	-	1

Period 2 title

Treatment Continuation Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo -> Burosumab

Arm description

SC injection of placebo Q4W for 24 weeks (double-blind placebo-controlled Treatment Period), SC injection of burosumab 1 mg/kg Q4W for 24 weeks (open-label Treatment Continuation Period)

Arm type

Placebo

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, ux023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

The amount of drug administered was calculated based on Baseline body weight and a 1.0 mg/kg burosumab dose level (rounded to the nearest 10 mg), up to a maximum dose of 90 mg.

Burosumab -> Burosumab

Arm description

SC injection of 1.0 mg/kg burosumab Q4W for 24 weeks (double-blind placebo-controlled Treatment Period), SC injection of burosumab 1 mg/kg Q4W for 24 weeks (open-label Treatment Continuation Period)

Arm type

Experimental

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, ux023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

The amount of drug administered was calculated based on Baseline body weight and a 1.0 mg/kg burosumab dose level (rounded to the nearest 10 mg), up to a maximum dose of 90 mg.

Number of subjects in period 2	Placebo -> Burosumab	Burosumab -> Burosumab
Started	66	67
Completed	63	63
Not completed	3	4
Consent withdrawn by subject	-	1
Other, not specified	3	3

Period 3 title

Treatment Extension Period I

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo -> Burosumab

Arm description

SC injection of placebo Q4W for 24 weeks (double-blind placebo-controlled Treatment Period), SC injection of burosumab 1 mg/kg Q4W for 24 weeks (open-label Treatment Continuation Period), SC injection of burosumab 1 mg/kg Q4W for 48 weeks (open label Treatment Extension Period I)

Arm type

Experimental

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, ux023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

The amount of drug administered was calculated based on Baseline body weight and a 1.0 mg/kg burosumab dose level (rounded to the nearest 10 mg), up to a maximum dose of 90 mg.

Burosumab -> Burosumab

Arm description

SC injection of 1.0 mg/kg burosumab Q4W for 24 weeks (double-blind Placebo-controlled Treatment Period), SC injection of burosumab 1 mg/kg Q4W for 24 weeks (open-label Treatment Continuation Period), SC injection of burosumab 1 mg/kg Q4W for 48 weeks (open-label Treatment Extension Period I)

Arm type

Experimental

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, ux023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

The amount of drug administered was calculated based on Baseline body weight and a 1.0 mg/kg burosumab dose level (rounded to the nearest 10 mg), up to a maximum dose of 90 mg.

Number of subjects in period 3	Placebo -> Burosumab	Burosumab -> Burosumab
Started	63	63
Completed	60	59
Not completed	3	4
Consent withdrawn by subject	-	1
Death	-	1
Not specified	3	-
Other, not specified	-	1
Lost to follow-up	-	1

Period 4 title

Treatment Extension Period II

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo -> Burosumab

Arm description

Arm type

Experimental

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, ux023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

The amount of drug administered was calculated based on Baseline body weight and a 1.0 mg/kg burosumab dose level (rounded to the nearest 10 mg), up to a maximum dose of 90 mg.

Burosumab -> Burosumab

Arm description

SC injection of 1.0 mg/kg burosumab Q4W for 24 weeks (double-blind placebo-controlled Treatment Period), SC injection of burosumab 1 mg/kg Q4W for 24 weeks (open-label Treatment Continuation Period), SC injection of burosumab 1 mg/kg Q4W for 48 weeks (open-label Treatment Extension Period I), and SC injection of burosumab 1 mg/kg Q4W up to 53 weeks (open-label Treatment Extension Period II).

Arm type

Experimental

Investigational medicinal product name

burosumab

Investigational medicinal product code

Other name

KRN23, Crysvita®, ux023

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

The amount of drug administered was calculated based on Baseline body weight and a 1.0 mg/kg burosumab dose level (rounded to the nearest 10 mg), up to a maximum dose of 90 mg.

Number of subjects in period 4 ^[1]	Placebo -> Burosumab	Burosumab -> Burosumab
Started	52	49
Completed	51	49
Not completed	1	0
Other, not specified	1	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Treatment Extension Period II (US and EU subjects only).

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Subcutaneous (SC) injection of placebo every 4 weeks (Q4W) for 24 weeks (double-blind placebo-controlled Treatment Period)

Reporting group title

Burosumab

Reporting group description

SC injection of 1.0 mg/kg burosumab Q4W for 24 weeks (double-blind placebo-controlled Treatment Period)

Reporting group values	Placebo	Burosumab	Total
Number of subjects	66	68	134
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	38.65 ( 12.756 )	41.29 ( 11.582 )	-
Gender categorical
Units: Subjects
Female	43	44	87
Male	23	24	47
Primary Race
Units: Subjects
Asian	9	12	21
Black or African American	3	0	3
White	53	55	108
Other, Not Specified	1	1	2
Ethnicity
Units: Subjects
Hispanic or Latino	5	7	12
Not Hispanic or Latino	61	61	122
Brief Pain Inventory (BPI) Worst Pain Score
The BPI evaluates the condition of all pain over the previous 24 hours. Question 3 of the short-form BPI (BPI-Q3) asks subjects to rate their pain at its worst in the last 24 hours on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The baseline BPI Worst Pain is defined as the mean of the BPI Worst Pain for 8 days including the 7 days of diary scores prior to baseline visit and the baseline visit score.
Units: score on a scale
arithmetic mean (standard deviation)	6.54 ( 1.433 )	6.81 ( 1.308 )	-
BPI Pain Severity Score
The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). The severity of pain in the last 24 hours is rated on a scale of 0 (no pain) to 10 (pain as bad as you can imagine).
Units: score on a scale
arithmetic mean (standard deviation)	4.92 ( 1.547 )	5.18 ( 1.531 )	-
BPI Pain Interference Score
The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Pain interference in the last 24 hours is rated on a scale of 0 (does not interfere) to 10 (completely interferes).
Units: score on a scale
arithmetic mean (standard deviation)	4.76 ( 2.174 )	5.23 ( 2.237 )	-
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Score
The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst.
Units: score on a scale
arithmetic mean (standard deviation)	61.36 ( 20.770 )	64.71 ( 20.253 )	-
WOMAC Physical Function Score
The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst.
Units: score on a scale
arithmetic mean (standard deviation)	43.89 ( 19.938 )	50.79 ( 19.660 )	-
Brief Fatigue Inventory (BFI) Worst Fatigue Score
The BFI is a self-reported questionnaire consisting of 9 items related to fatigue rated on a 0 to 10 numerical scale with a recall period of 24 hours. Two dimensions are measured: fatigue severity and the interference of fatigue on daily life (activity, mood, walking ability, work, relations with others, and enjoyment of life). Participants are asked to rate their worst fatigue over the past 24 hours from 0 (no fatigue) to 10 (as bad a you can imagine).
Units: score on a scale
arithmetic mean (standard deviation)	6.74 ( 1.526 )	6.94 ( 1.657 )	-
BFI Global Fatigue Score
The BFI is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a numerical scale with a recall period of 24 hours. Two dimensions are measured: fatigue severity and the interference of fatigue on daily life (activity, mood, walking ability, work, relations with others, and enjoyment of life). BFI Global Fatigue score was calculated by averaging all 9 items on the BFI. Global scores range from 0 to 10, with higher score indicating worse fatigue severity and interference.
Units: score on a scale
arithmetic mean (standard deviation)	4.86 ( 1.932 )	5.37 ( 2.044 )	-
Serum Procollagen Type 1 N- Propeptide (P1NP)
Subjects with a baseline assessment are n=66, 67 for placebo and burosumab, respectively.
Units: ng/mL
arithmetic mean (standard deviation)	87.6 ( 53.41 )	87.5 ( 53.60 )	-
Serum Carboxy-Terminal Cross-Linked Telopeptide of Type I Collagen (CTx)
Subjects with a baseline assessment are n=66, 67 for placebo and burosumab, respectively.
Units: pg/mL
arithmetic mean (standard deviation)	719.2 ( 419.24 )	718.4 ( 413.71 )	-
Serum Bone-Specific Alkaline Phosphatase (BALP)
Subjects with a baseline assessment: n=66, 66 for placebo and burosumab arms, respectively.
Units: µg/L
arithmetic mean (standard deviation)	24.6 ( 17.30 )	25.1 ( 21.55 )	-
Serum Phosphorus
Units: mmol/L
arithmetic mean (standard deviation)	0.617 ( 0.1001 )	0.653 ( 0.1072 )	-
Serum 1, 25 (OH)2 D
Subjects with a baseline assessment: n=64, 66 for placebo and burosumab arms, respectively.
Units: pg/mL
arithmetic mean (standard deviation)	33.5 ( 15.61 )	32.4 ( 12.96 )	-
24-Hour Urinary Phosphorus
Subjects with a baseline assessment: n=65, 68 for placebo and burosumab arms, respectively.
Units: g/24hr
arithmetic mean (standard deviation)	0.81 ( 0.262 )	0.72 ( 0.241 )	-
Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate(TmP/GFR)
Subjects with a baseline assessment: n=64, 66 for placebo and burosumab arms, respectively.
Units: mg/dL
arithmetic mean (standard deviation)	1.598 ( 0.3693 )	1.678 ( 0.4004 )	-
Tubular Reabsorption of Phosphate (TRP)
Subjects with a baseline assessment: n=64, 67 for placebo and burosumab arms, respectively.
Units: fraction of phosphate reabsorbed
arithmetic mean (standard deviation)	0.812 ( 0.0842 )	0.807 ( 0.0832 )	-

End points

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Reporting group title

Placebo

Reporting group description

Subcutaneous (SC) injection of placebo every 4 weeks (Q4W) for 24 weeks (double-blind placebo-controlled Treatment Period)

Reporting group title

Burosumab

Reporting group description

SC injection of 1.0 mg/kg burosumab Q4W for 24 weeks (double-blind placebo-controlled Treatment Period)

Reporting group title

Placebo -> Burosumab

Reporting group description

SC injection of placebo Q4W for 24 weeks (double-blind placebo-controlled Treatment Period), SC injection of burosumab 1 mg/kg Q4W for 24 weeks (open-label Treatment Continuation Period)

Reporting group title

Burosumab -> Burosumab

Reporting group description

SC injection of 1.0 mg/kg burosumab Q4W for 24 weeks (double-blind placebo-controlled Treatment Period), SC injection of burosumab 1 mg/kg Q4W for 24 weeks (open-label Treatment Continuation Period)

Reporting group title

Placebo -> Burosumab

Reporting group description

Reporting group title

Burosumab -> Burosumab

Reporting group description

Reporting group title

Placebo -> Burosumab

Reporting group description

Reporting group title

Burosumab -> Burosumab

Reporting group description

Subject analysis set title

Primary Analysis Set-Placebo

Subject analysis set type

Full analysis

Subject analysis set description

The Primary Analysis Set included all randomized subjects who received at least 1 dose of study drug during the Placebo-Controlled Treatment Period.

Subject analysis set title

Primary Analysis Set-Burosumab

Subject analysis set type

Full analysis

Subject analysis set description

The Primary Analysis Set included all randomized subjects who received at least 1 dose of study drug during the Placebo-Controlled Treatment Period.

Primary: Percentage of Subjects Who Achieved Mean Serum Phosphorus Above the Lower Limit of Normal (LLN; 2.5 mg/dL [0.81 mmol/L]) Across Midpoints of Dose Intervals Through Week 24

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End point title

Percentage of Subjects Who Achieved Mean Serum Phosphorus Above the Lower Limit of Normal (LLN; 2.5 mg/dL [0.81 mmol/L]) Across Midpoints of Dose Intervals Through Week 24

End point description

End point type

Primary

End point timeframe

Baseline through Week 24

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66	68
Units: percentage of subjects
arithmetic mean (confidence interval 95%)	7.6 (3.3 to 16.5)	92.6 (83.9 to 96.8)

Statistical Analysis 1

Comparison groups

Primary Analysis Set-Placebo v Primary Analysis Set-Burosumab

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[1] - The p-value is from Cochran-Mantel-Haenszel (CMH) testing for association between achieving mean serum phosphorus levels above the LLN and treatment group, adjusting for the actual randomization stratification of BPI Average Pain and region.

Secondary: Change From Baseline to Week 24 in BPI Worst Pain Score

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End point title

Change From Baseline to Week 24 in BPI Worst Pain Score

End point description

The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Question 3 of the short-form BPI (BPI-Q3) asks subjects to rate their pain at its worst in the last 24 hours on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). From the generalized estimating equation (GEE) model, which includes the change from Baseline for the endpoint of interest as the dependent variable; region, visit, treatment, actual randomization stratification (not included for analysis of BPI Worst Pain), and visit by treatment as fixed factors; and Baseline value for the endpoint of interest as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	Burosumab
Number of subjects analysed	66	68
Units: score on a scale
least squares mean (standard error)	-0.32 ( 0.222 )	-0.79 ( 0.211 )

Statistical Analysis 1

Statistical analysis description

placebo vs burosumab

Comparison groups

Placebo v Burosumab

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0919 ^[2]

Method

GEE

Parameter type

Least squares (LS) mean difference

Point estimate

-0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.275

Notes
[2] - Prespecified significance level for test after Hochberg adjustment: 0.05

Secondary: Change From Baseline to Week 24 in WOMAC Stiffness Score

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End point title

Change From Baseline to Week 24 in WOMAC Stiffness Score

End point description

The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE Estimates are from the GEE model which includes the change from baseline for WOMAC Stiffness as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of WOMAC Stiffness as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	Burosumab
Number of subjects analysed	66	68
Units: score on a scale
least squares mean (standard error)	0.46 ( 3.139 )	-7.85 ( 3.034 )

Statistical Analysis 1

Statistical analysis description

placebo vs burosumab

Comparison groups

Placebo v Burosumab

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0106 ^[3]

Method

GEE

Parameter type

LS mean difference

Point estimate

-8.31

Confidence interval

level

95%

sides

2-sided

lower limit

-14.68

upper limit

-1.94

Variability estimate

Standard error of the mean

Dispersion value

3.251

Notes
[3] - Prespecified significance level for test after Hochberg adjustment: 0.0167

Secondary: Change From Baseline to Week 24 in WOMAC Physical Function Score

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End point title

Change From Baseline to Week 24 in WOMAC Physical Function Score

End point description

The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE Estimates are from the GEE model which includes the change from baseline for WOMAC Physical Function as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of WOMAC Physical Function as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	Burosumab
Number of subjects analysed	66	68
Units: score on a scale
least squares mean (standard error)	1.79 ( 2.722 )	-3.11 ( 2.553 )

Statistical Analysis 1

Statistical analysis description

placebo vs burosumab

Comparison groups

Placebo v Burosumab

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0478 ^[4]

Method

GEE

Parameter type

LS mean difference

Point estimate

-4.9

Confidence interval

level

95%

sides

2-sided

lower limit

-9.76

upper limit

-0.05

Variability estimate

Standard error of the mean

Dispersion value

2.479

Notes
[4] - Prespecified significance level for test after Hochberg adjustment: 0.025

Secondary: Change From Baseline Over Time in BPI Worst Pain Score

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End point title

Change From Baseline Over Time in BPI Worst Pain Score

End point description

The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Question 3 of the short-form BPI (BPI-Q3) asks subjects to rate their pain at its worst in the last 24 hours on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The GEE Estimates are from the GEE model which includes the change from baseline for BPI worst pain as the dependent variable, region, visit, treatment and visit by treatment as fixed factors, and baseline of BPI Worst Pain as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[5]	68 ^[6]
Units: score on a scale
least squares mean (standard error)
Week 12; n=66, 68	-0.37 ( 0.216 )	-0.62 ( 0.208 )
Week 24; n=65, 67	-0.31 ( 0.242 )	-0.77 ( 0.228 )
Week 36; n=65, 65	-1.25 ( 0.234 )	-0.95 ( 0.228 )
Week 48; n=66, 66	-1.49 ( 0.243 )	-1.05 ( 0.230 )
Week 72; n=60, 59	-1.28 ( 0.283 )	-1.21 ( 0.316 )
Week 96; 59, 59	-0.99 ( 0.265 )	-1.48 ( 0.299 )

Notes
[5] - n=subjects with an assessment at given time point
[6] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in BPI Pain Severity Score

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End point title

Change From Baseline Over Time in BPI Pain Severity Score

End point description

The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). The severity of pain in the last 24 hours is rated on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The GEE Estimates are from the GEE model which includes the change from baseline for each BPI endpoint as the dependent variable, region, visit, treatment, and visit by treatment as fixed factors, and baseline of each BPI endpoint as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[7]	68 ^[8]
Units: score on a scale
least squares mean (standard error)
Week 12; n=66, 68	-0.32 ( 0.166 )	-0.43 ( 0.163 )
Week 24; n=65, 67	-0.10 ( 0.211 )	-0.53 ( 0.172 )
Week 36; n=65, 65	-0.97 ( 0.214 )	-0.62 ( 0.184 )
Week 48; n=66, 66	-1.13 ( 0.205 )	-0.79 ( 0.162 )
Week 72; n=60, 59	-1.36 ( 0.216 )	-1.24 ( 0.231 )
Week 96; n=59, 59	-1.18 ( 0.195 )	-1.42 ( 0.229 )

Notes
[7] - n=subjects with an assessment
[8] - n=subjects with an assessment

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in BPI Pain Interference Score

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End point title

Change From Baseline Over Time in BPI Pain Interference Score

End point description

The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Pain interference in the last 24 hours is rated on a scale of 0 (does not interfere) to 10 (completely interferes). The GEE Estimates are from the GEE model which includes the change from baseline for each BPI endpoint as the dependent variable, region, visit, treatment, and visit by treatment as fixed factors, and baseline of each BPI endpoint as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[9]	68 ^[10]
Units: score on a scale
least squares mean (standard error)
Week 12; n=66, 68	-0.29 ( 0.215 )	-0.51 ( 0.207 )
Week 24; n=65, 67	-0.28 ( 0.242 )	-0.41 ( 0.207 )
Week 36; n=65, 65	-1.30 ( 0.260 )	-0.79 ( 0.221 )
Week 48; n=66, 66	-1.28 ( 0.251 )	-1.04 ( 0.235 )
Week 72; n=60, 60	-1.22 ( 0.247 )	-1.24 ( 0.263 )
Week 96; n=59, 59	-1.08 ( 0.260 )	-1.43 ( 0.234 )

Notes
[9] - n=subjects with an assessment at given time point
[10] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in WOMAC Stiffness Score

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End point title

Change From Baseline Over Time in WOMAC Stiffness Score

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96, 120, 144

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[11]	68 ^[12]
Units: score on a scale
least squares mean (standard error)
Week 12; n=66, 68	-1.24 ( 2.929 )	-7.86 ( 3.622 )
Week 24; n=65, 67	0.20 ( 3.289 )	-8.01 ( 2.968 )
Week 36; n=65, 65	-13.50 ( 3.422 )	-12.58 ( 3.411 )
Week 48; n=66, 66	-15.83 ( 3.488 )	-16.63 ( 3.302 )
Week 72; n=61, 60	-18.02 ( 3.613 )	-15.47 ( 3.111 )
Week 96; n=59, 59	-17.67 ( 3.737 )	-15.32 ( 3.577 )
Week 120; n=49, 46	-19.23 ( 3.404 )	-20.57 ( 3.371 )
Week 144; n=9, 12	-30.64 ( 4.407 )	-25.88 ( 4.501 )

Notes
[11] - n=subjects with an assessment at given time point
[12] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in WOMAC Physical Function Score

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End point title

Change From Baseline Over Time in WOMAC Physical Function Score

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96, 120, 144

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[13]	68 ^[14]
Units: score on a scale
least squares mean (standard error)
Week 12; n=66, 68	-1.40 ( 2.418 )	-3.96 ( 1.787 )
Week 24; n=65, 66	1.14 ( 2.531 )	-3.45 ( 2.193 )
Week 36; n=63, 65	-5.47 ( 2.694 )	-7.14 ( 2.133 )
Week 48; n=66, 66	-7.15 ( 2.801 )	-8.42 ( 2.057 )
Week 72; n=61, 60	-8.68 ( 2.835 )	-8.66 ( 2.523 )
Week 96; n=59, 59	-8.41 ( 2.752 )	-9.02 ( 2.270 )
Week 120; n=49, 46	-11.93 ( 2.685 )	-11.98 ( 2.291 )
Week 144; n=9, 11	-19.49 ( 3.892 )	-17.67 ( 4.061 )

Notes
[13] - n=subjects with an assessment at given time point
[14] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in BFI Worst Fatigue Score

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End point title

Change From Baseline Over Time in BFI Worst Fatigue Score

End point description

The BFI is a self-reported questionnaire consisting of 9 items related to fatigue rated on a 0 to 10 numerical scale with a recall period of 24 hours. Two dimensions are measured: fatigue severity and the interference of fatigue on daily life (activity, mood, walking ability, work, relations with others, and enjoyment of life). Participants are asked to rate their worst fatigue over the past 24 hours from 0 (no fatigue) to 10 (as bad a you can imagine). The GEE Estimates are from the GEE model which includes the change from baseline for each BFI endpoint as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of each BFI endpoint as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[15]	68 ^[16]
Units: score on a scale
least squares mean (standard error)
Week 12; n=66, 68	-0.53 ( 0.266 )	-0.44 ( 0.261 )
Week 24; n=65, 67	-0.45 ( 0.298 )	-0.65 ( 0.280 )
Week 36; n=65, 65	-1.23 ( 0.305 )	-0.90 ( 0.271 )
Week 48; n=66, 66	-1.21 ( 0.317 )	-0.99 ( 0.295 )
Week 72; n=60, 60	-0.79 ( 0.352 )	-0.58 ( 0.309 )
Week 96; n=59, 58	-0.82 ( 0.362 )	-0.75 ( 0.306 )

Notes
[15] - n=subjects with an assessment at given time point
[16] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in BFI Global Fatigue Score

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End point title

Change From Baseline Over Time in BFI Global Fatigue Score

End point description

The BFI is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a numerical scale with a recall period of 24 hours. Two dimensions are measured: fatigue severity and the interference of fatigue on daily life (activity, mood, walking ability, work, relations with others, and enjoyment of life). BFI Global Fatigue score was calculated by averaging all 9 items on the BFI. Global scores range from 0 to 10, with higher score indicating worse fatigue severity and interference. The GEE Estimates are from the GEE model which includes the change from baseline for each BFI endpoint as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of each BFI endpoint as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[17]	68 ^[18]
Units: score on a scale
least squares mean (standard error)
Week 12; n=66, 68	-0.14 ( 0.262 )	-0.18 ( 0.261 )
Week 24; n= 65, 67	-0.08 ( 0.292 )	0.05 ( 0.261 )
Week 36; n=65, 65	-0.69 ( 0.315 )	-0.54 ( 0.283 )
Week 48; n=66, 66	-0.75 ( 0.303 )	-0.45 ( 0.275 )
Week 72; n=60, 60	-0.72 ( 0.304 )	-0.78 ( 0.266 )
Week 96; n=59, 58	-0.86 ( 0.291 )	-0.80 ( 0.285 )

Notes
[17] - n=subjects with an assessment at given time point
[18] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in P1NP

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End point title

Change From Baseline Over Time in P1NP

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[19]	67 ^[20]
Units: ng/mL
least squares mean (standard error)
Week 12; n=66, 67	-1.86 ( 5.958 )	96.22 ( 14.264 )
Week 24; n=65, 66	2.95 ( 6.423 )	63.50 ( 7.239 )
Week 36; n=65, 64	100.00 ( 10.562 )	49.71 ( 6.786 )
Week 48; n=66, 63	85.12 ( 11.037 )	40.07 ( 7.292 )
Week 72; n=60, 59	48.98 ( 7.286 )	18.04 ( 9.186 )
Week 96; n=59, 59	22.98 ( 7.075 )	12.48 ( 8.661 )

Notes
[19] - n=subjects with an assessment at given time point
[20] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Percent Change From Baseline Over Time in P1NP

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End point title

Percent Change From Baseline Over Time in P1NP

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[21]	67 ^[22]
Units: percentage change
least squares mean (standard error)
Week 12; n=66, 67	2.30 ( 6.318 )	91.78 ( 10.787 )
Week 24; n=65, 66	7.83 ( 7.076 )	72.43 ( 8.519 )
Week 36; n=65, 64	116.39 ( 9.726 )	63.58 ( 8.562 )
Week 48; n=66, 63	99.10 ( 11.442 )	56.51 ( 8.771 )
Week 72; n=60, 59	72.56 ( 10.055 )	38.82 ( 10.225 )
Week 96; n=59, 59	41.62 ( 8.163 )	31.04 ( 8.126 )

Notes
[21] - n=subjects with an assessment at given time point
[22] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in CTx

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End point title

Change From Baseline Over Time in CTx

End point description

The GEE Estimates are from the GEE model which includes the change from baseline for CTx as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of CTx as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[23]	67 ^[24]
Units: pg/mL
least squares mean (standard error)
Week 12; n=66, 67	26.96 ( 35.689 )	322.09 ( 56.924 )
Week 24; n=64, 66	-4.20 ( 34.835 )	184.56 ( 39.213 )
Week 36; n=65, 63	350.89 ( 53.131 )	193.50 ( 39.461 )
Week 48; n=66, 63	310.67 ( 45.003 )	138.61 ( 37.886 )
Week 72; n=60, 59	178.03 ( 42.702 )	51.59 ( 42.863 )
Week 96; n=59, 59	79.04 ( 45.622 )	10.84 ( 40.761 )

Notes
[23] - n=subjects with an assessment at given time point
[24] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Percent Change From Baseline Over Time in CTx

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End point title

Percent Change From Baseline Over Time in CTx

End point description

The GEE Estimates are from the GEE model which includes the percent change from baseline for CTx as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of CTx as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[25]	67 ^[26]
Units: percentage change
least squares mean (standard error)
Week 12; n=66, 67	9.64 ( 5.671 )	45.40 ( 7.267 )
Week 24; n=64, 66	4.75 ( 5.280 )	32.48 ( 6.414 )
Week 36; n=65, 63	61.31 ( 10.653 )	34.07 ( 6.250 )
Week 48; n=66, 63	50.35 ( 6.464 )	28.33 ( 5.354 )
Week 72; n=60, 59	34.78 ( 7.007 )	17.09 ( 5.957 )
Week 96; n=59, 59	27.38 ( 7.783 )	13.47 ( 5.952 )

Notes
[25] - n=subjects with an assessment at given time point
[26] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in Serum BALP

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End point title

Change From Baseline Over Time in Serum BALP

End point description

The GEE Estimates are from the GEE model which includes the change from baseline for Bone ALP as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of Bone ALP as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[27]	66 ^[28]
Units: µg/L
least squares mean (standard error)
Week 12; n=66, 66	-2.11 ( 1.529 )	6.52 ( 2.832 )
Week 24; n=64, 65	1.03 ( 1.801 )	5.70 ( 2.038 )
Week 36; n=65, 63	10.42 ( 2.017 )	4.46 ( 1.607 )
Week 48; n=66, 61	6.69 ( 1.929 )	0.23 ( 1.830 )
Week 72; n=61, 58	-0.92 ( 1.779 )	-3.39 ( 1.739 )
Week 96; n=59, 58	-2.49 ( 1.887 )	-2.76 ( 1.640 )

Notes
[27] - n=subjects with an assessment at given time point
[28] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Percent Change From Baseline Over Time in Serum BALP

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End point title

Percent Change From Baseline Over Time in Serum BALP

End point description

The GEE Estimates are from the GEE model which includes the percent change from baseline for Bone ALP as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of Bone ALP as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[29]	66 ^[30]
Units: percent change
least squares mean (standard error)
Week 12; n=66, 66	7.85 ( 9.867 )	30.29 ( 13.476 )
Week 24; n=64, 65	27.56 ( 10.339 )	39.13 ( 10.902 )
Week 36; n=65, 63	64.41 ( 11.669 )	43.13 ( 11.473 )
Week 48; n=66, 61	50.65 ( 11.317 )	23.46 ( 10.041 )
Week 72; n=61, 58	19.79 ( 11.755 )	14.40 ( 11.618 )
Week 96; n=59, 58	16.46 ( 11.027 )	21.21 ( 9.688 )

Notes
[29] - subjects with an assessment at given time point
[30] - subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in Serum Phosphorus

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End point title

Change From Baseline Over Time in Serum Phosphorus

End point description

The GEE Estimates are from the GEE model which includes the change from baseline for serum phosphorus as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of serum phosphorus as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 4, 6, 10, 12, 14, 18, 20, 21, 22, 24, 26, 28, 34, 36, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[31]	68 ^[32]
Units: mmol/L
least squares mean (standard error)
Week 1; n=60, 61	-0.01 ( 0.024 )	0.44 ( 0.031 )
Week 2; n=64, 64	-0.03 ( 0.023 )	0.43 ( 0.032 )
Week 4; n=65, 67	-0.03 ( 0.022 )	0.27 ( 0.034 )
Week 6; n=65, 65	-0.00 ( 0.023 )	0.45 ( 0.036 )
Week 10; n=64, 64	0.01 ( 0.022 )	0.37 ( 0.033 )
Week 12; n=64, 68	-0.01 ( 0.023 )	0.17 ( 0.032 )
Week 14; n=66, 65	0.02 ( 0.022 )	0.32 ( 0.032 )
Week 18; n=62, 68	0.02 ( 0.023 )	0.32 ( 0.031 )
Week 20; n=65, 65	-0.01 ( 0.023 )	0.18 ( 0.028 )
Week 21; n=61, 65	-0.00 ( 0.024 )	0.31 ( 0.033 )
Week 22; n= 65, 64	-0.02 ( 0.022 )	0.25 ( 0.033 )
Week 24; n=66, 68	-0.00 ( 0.023 )	0.13 ( 0.028 )
Week 26; n=62, 66	0.47 ( 0.035 )	0.31 ( 0.032 )
Week 28; n=66, 67	0.28 ( 0.028 )	0.18 ( 0.028 )
Week 34; n=65, 62	0.36 ( 0.029 )	0.28 ( 0.031 )
Week 36; n=66, 64	0.17 ( 0.026 )	0.13 ( 0.027 )
Week 46; n=66, 65	0.31 ( 0.026 )	0.27 ( 0.030 )
Week 48; n=66, 64	0.13 ( 0.027 )	0.11 ( 0.027 )
Week 60; n=62, 61	0.14 ( 0.028 )	0.11 ( 0.028 )
Week 70; n=55, 57	0.30 ( 0.029 )	0.30 ( 0.030 )
Week 72; n=61, 60	0.13 ( 0.025 )	0.11 ( 0.027 )
Week 84; n=60, 59	0.12 ( 0.025 )	0.14 ( 0.027 )
Week 94; n=59, 58	0.25 ( 0.029 )	0.30 ( 0.029 )
Week 96; n=60, 59	0.07 ( 0.026 )	0.13 ( 0.025 )
Week 108; n=49, 48	0.11 ( 0.028 )	0.13 ( 0.031 )
Week 120; n=44, 41	0.09 ( 0.027 )	0.13 ( 0.033 )
Week 132; n=19, 19	0.12 ( 0.033 )	0.15 ( 0.036 )
Week 144; n=2, 0	0.05 ( 0.064 )	99999 ( 99999 )

Notes
[31] - n=subjects with an assessment at given time point
[32] - n=subjects with an assessment at given time point; 99999=not applicable (n=0 for this time point)

No statistical analyses for this end point

Secondary: Percent Change From Baseline Over Time in Serum Phosphorus

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End point title

Percent Change From Baseline Over Time in Serum Phosphorus

End point description

The GEE Estimates are from the GEE model which includes the percent change from baseline for serum phosphorus as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of serum phosphorus as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 4, 6, 10, 12, 14, 18, 20, 21, 22, 24, 26, 28, 34, 36, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	66 ^[33]	68 ^[34]
Units: percentage change
least squares mean (standard error)
Week 1; n=60,61	-1.11 ( 3.936 )	69.24 ( 4.762 )
Week 2; n=64, 64	-5.91 ( 3.969 )	69.39 ( 4.881 )
Week 4; n=65, 67	-4.84 ( 3.792 )	42.89 ( 5.325 )
Week 6; n=65, 65	-0.41 ( 3.951 )	72.96 ( 5.944 )
Week 10; n=64, 64	2.40 ( 3.680 )	59.96 ( 5.356 )
Week 12; n=64, 68	-2.14 ( 3.798 )	29.50 ( 5.087 )
Week 14; n=66, 65	3.58 ( 3.691 )	52.14 ( 5.194 )
Week 18; n=62, 68	3.93 ( 3.857 )	53.22 ( 5.106 )
Week 20; n=65, 65	-1.81 ( 3.759 )	31.28 ( 4.472 )
Week 21; n=61, 65	0.21 ( 4.011 )	50.59 ( 5.123 )
Week 22; n=65, 64	-3.42 ( 3.709 )	40.98 ( 5.196 )
Week 24; n=66, 68	-0.61 ( 3.802 )	22.01 ( 4.523 )
Week 26; n=62, 66	78.30 ( 5.993 )	51.51 ( 5.204 )
Week 28; n=66, 67	46.07 ( 4.766 )	31.32 ( 4.415 )
Week 34; n=65, 62	59.18 ( 4.959 )	45.83 ( 4.871 )
Week 36; n=66, 64	28.03 ( 4.424 )	22.34 ( 4.256 )
Week 46; n=66, 65	51.49 ( 4.380 )	45.39 ( 5.018 )
Week 48; n=66, 64	21.58 ( 4.365 )	19.12 ( 4.190 )
Week 60; n=62, 61	22.90 ( 4.338 )	19.60 ( 4.436 )
Week 70; n=55, 57	50.22 ( 4.916 )	47.81 ( 4.768 )
Week 72; n=61, 60	21.59 ( 4.155 )	19.45 ( 4.344 )
Week 84; n=60, 59	21.47 ( 4.089 )	23.58 ( 4.200 )
Week 94; n=59, 58	43.67 ( 4.834 )	49.36 ( 4.501 )
Week 96; n=60, 59	12.97 ( 4.216 )	21.65 ( 3.854 )
Week 108; n=49, 48	19.21 ( 4.665 )	23.39 ( 4.749 )
Week 120; n=44, 41	15.13 ( 4.365 )	21.50 ( 5.268 )
Week 132; n=19, 19	20.43 ( 5.362 )	25.34 ( 5.847 )
Week 144; n=2, 0	5.49 ( 12.212 )	99999 ( 99999 )

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

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in Serum 1,25(OH)2D

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End point title

Change From Baseline Over Time in Serum 1,25(OH)2D

End point description

The GEE Estimates are from the GEE model which includes the change from baseline for 1, 25 (OH)2 D as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of 1, 25 (OH)2 D as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 4, 20, 21, 22, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	64 ^[35]	66 ^[36]
Units: pg/mL
least squares mean (standard error)
Week 1; n=58, 59	2.04 ( 2.251 )	87.23 ( 5.500 )
Week 2; n=63, 65	1.40 ( 2.113 )	58.20 ( 3.931 )
Week 4; n=63, 66	2.61 ( 2.300 )	20.55 ( 2.828 )
Week 20; n=64, 63	2.88 ( 2.163 )	8.11 ( 2.294 )
Week 21; n=59, 64	3.09 ( 2.177 )	33.95 ( 3.019 )
Week 22; n=64, 65	3.45 ( 2.289 )	26.10 ( 2.952 )
Week 46; n=64, 64	25.23 ( 2.576 )	23.08 ( 3.243 )
Week 48; n=64, 63	10.50 ( 2.418 )	7.24 ( 2.449 )
Week 60; n=59, 60	9.29 ( 2.336 )	5.69 ( 2.583 )
Week 70; n=54, 60	24.20 ( 2.529 )	18.82 ( 2.486 )
Week 72; n=59, 58	7.12 ( 2.424 )	5.52 ( 2.607 )
Week 84; n=58, 57	5.13 ( 2.388 )	1.16 ( 2.549 )
Week 94; n=57, 58	18.96 ( 2.655 )	15.26 ( 2.502 )
Week 96; n=56, 58	3.43 ( 2.348 )	1.95 ( 2.356 )
Week 108; n=48, 48	4.76 ( 2.349 )	4.29 ( 2.672 )
Week 120; n=43, 42	4.64 ( 2.496 )	5.37 ( 2.935 )
Week 132; n=18, 19	4.08 ( 3.142 )	8.05 ( 4.227 )
Week 144; n=2, 0	-0.38 ( 4.677 )	99999 ( 99999 )

Notes
[35] - n=subjects with an assessment at given time point
[36] - n=subjects with an assessment at given time point; 99999=not applicable (n=0 for this time point)

No statistical analyses for this end point

Secondary: Percent Change From Baseline Over Time in Serum 1,25(OH)2D

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End point title

Percent Change From Baseline Over Time in Serum 1,25(OH)2D

End point description

The GEE Estimates are from the GEE model which includes the percent change from baseline for 1, 25 (OH)2 D as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of 1, 25 (OH)2 D as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 4, 20, 21, 22, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	64 ^[37]	66 ^[38]
Units: percentage change
least squares mean (standard error)
Week 1; n=58, 59	10.45 ( 13.041 )	310.72 ( 23.225 )
Week 2; n=63, 65	10.53 ( 12.760 )	207.90 ( 16.728 )
Week 4; n=63, 66	16.07 ( 12.810 )	76.22 ( 12.147 )
Week 20; n=64, 63	21.36 ( 12.424 )	41.08 ( 11.943 )
Week 21; n=59, 64	21.51 ( 12.825 )	131.76 ( 14.862 )
Week 22; n=64, 65	21.07 ( 12.725 )	102.81 ( 14.619 )
Week 46; n=64, 64	130.29 ( 22.718 )	96.63 ( 16.909 )
Week 48; n=64, 63	70.09 ( 17.114 )	34.47 ( 12.903 )
Week 60; n=59, 60	65.46 ( 13.083 )	32.32 ( 12.230 )
Week 70; n=54, 60	123.58 ( 17.315 )	82.03 ( 12.604 )
Week 72; n=59, 58	58.45 ( 13.957 )	31.14 ( 13.070 )
Week 84; n=58, 57	55.67 ( 15.323 )	18.83 ( 12.801 )
Week 94; n=57, 58	111.25 ( 21.970 )	71.30 ( 12.280 )
Week 96; n=56, 58	50.17 ( 18.857 )	22.15 ( 10.487 )
Week 108; n=48, 48	44.78 ( 14.219 )	29.16 ( 13.326 )
Week 120; n=43, 42	58.37 ( 19.621 )	36.09 ( 13.089 )
Week 132; n=18, 19	67.59 ( 35.770 )	42.55 ( 15.925 )
Week 144; n=2, 0	22.65 ( 19.297 )	99999 ( 99999 )

Notes
[37] - n=subjects with an assessment at given time point
[38] - n=subjects with an assessment at given time point; 99999=not applicable (n=0 for this time point)

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in 24-Hour Urinary Phosphorus

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End point title

Change From Baseline Over Time in 24-Hour Urinary Phosphorus

End point description

The GEE Estimates are from the GEE model which includes the change from baseline for 24-Hour urinary phosphorus as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of urinary phosphorus as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	65 ^[39]	67 ^[40]
Units: g/24hr
least squares mean (standard error)
Week 12; n=63, 63	0.06 ( 0.052 )	0.05 ( 0.046 )
Week 24; n=65, 67	0.07 ( 0.065 )	0.05 ( 0.046 )
Week 36; n=64, 64	0.04 ( 0.054 )	0.07 ( 0.045 )
Week 48; n=63, 63	0.07 ( 0.060 )	0.13 ( 0.067 )
Week 72; n=57, 57	0.08 ( 0.065 )	0.05 ( 0.052 )
Week 96; n=58, 59	0.10 ( 0.075 )	0.10 ( 0.054 )

Notes
[39] - n=subjects with an assessment at given time point
[40] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Percent Change From Baseline Over Time in 24-Hour Urinary Phosphorus

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End point title

Percent Change From Baseline Over Time in 24-Hour Urinary Phosphorus

End point description

The GEE Estimates are from the GEE model which includes the percent change from baseline for 24-Hour urinary phosphorus as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of urinary phosphorus as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 48, 72, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	65 ^[41]	67 ^[42]
Units: percentage change
least squares mean (standard error)
Week 12; n=63, 63	21.91 ( 11.844 )	21.40 ( 11.453 )
Week 24; n=65, 67	28.45 ( 15.518 )	20.35 ( 11.567 )
Week 36; n=64, 64	18.19 ( 11.784 )	28.31 ( 12.173 )
Week 48; n=63, 63	27.32 ( 14.328 )	37.50 ( 14.687 )
Week 72; n=57, 57	29.53 ( 14.485 )	25.80 ( 15.476 )
Week 96; n=58, 59	31.17 ( 17.248 )	30.64 ( 10.420 )

Notes
[41] - n=subjects with an assessment at given time point
[42] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in TmP/GFR

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End point title

Change From Baseline Over Time in TmP/GFR

End point description

The GEE Estimates are from the GEE model which includes the change from baseline for TmP/GFR as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of TmP/GFR as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	63 ^[43]	66 ^[44]
Units: mg/dL
least squares mean (standard error)
Week 2; n=60, 60	-0.02 ( 0.072 )	1.60 ( 0.121 )
Week 4; n=61, 63	-0.03 ( 0.070 )	0.91 ( 0.117 )
Week 12; n=61, 64	0.11 ( 0.082 )	0.70 ( 0.107 )
Week 22; n=63, 62	0.02 ( 0.069 )	1.01 ( 0.123 )
Week 24; n=62, 66	0.07 ( 0.071 )	0.51 ( 0.093 )
Week 48; n=62, 61	0.55 ( 0.087 )	0.48 ( 0.091 )
Week 60; n=58, 58	0.57 ( 0.097 )	0.43 ( 0.086 )
Week 72; n=57, 57	0.55 ( 0.086 )	0.43 ( 0.091 )
Week 84; n=57, 56	0.49 ( 0.078 )	0.42 ( 0.092 )
Week 96; n= 58, 57	0.29 ( 0.086 )	0.46 ( 0.084 )

Notes
[43] - n=subjects with an assessment at given time point
[44] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Percent Change From Baseline Over Time in TmP/GFR

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End point title

Percent Change From Baseline Over Time in TmP/GFR

End point description

The GEE Estimates are from the GEE model which includes the percent change from baseline for TmP/GFR as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of TmP/GFR as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	63 ^[45]	66 ^[46]
Units: percentage change
least squares mean (standard error)
Week 2; n=60, 60	-2.15 ( 4.515 )	100.10 ( 7.222 )
Week 4; n=-61, 63	-2.73 ( 4.416 )	56.53 ( 6.816 )
Week 12; n=61, 64	6.28 ( 4.900 )	43.65 ( 6.206 )
Week 22; n=63, 62	1.38 ( 4.252 )	62.38 ( 7.144 )
Week 24; n=62, 66	3.63 ( 4.460 )	33.02 ( 5.464 )
Week 48; n=62, 61	35.52 ( 5.390 )	31.02 ( 5.489 )
Week 60; n=58, 58	37.13 ( 5.855 )	27.49 ( 5.002 )
Week 72; n=57, 57	35.89 ( 5.492 )	28.98 ( 5.513 )
Week 84; n=57, 56	33.15 ( 4.924 )	27.69 ( 5.527 )
Week 96; n=58, 57	19.95 ( 5.417 )	29.67 ( 4.759 )

Notes
[45] - n=subjects with an assessment at given time point
[46] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Change From Baseline Over Time in TRP

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End point title

Change From Baseline Over Time in TRP

End point description

The GEE Estimates are from the GEE model which includes the change from baseline for TRP as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of TRP as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	64 ^[47]	67 ^[48]
Units: fraction of phosphate reabsorbed
least squares mean (standard error)
Week 2; n=62, 63	-0.02 ( 0.013 )	0.07 ( 0.008 )
Week 4; n=63, 65	-0.03 ( 0.012 )	0.03 ( 0.009 )
Week 12; n=62, 64	-0.00 ( 0.010 )	0.04 ( 0.008 )
Week 22; n=63, 64	-0.01 ( 0.009 )	0.05 ( 0.011 )
Week 24; n=63; 67	-0.02 ( 0.012 )	0.03 ( 0.009 )
Week 48; n=64, 63	0.02 ( 0.012 )	0.03 ( 0.009 )
Week 60; n=60, 60	0.03 ( 0.009 )	0.02 ( 0.009 )
Week 72; n=60, 59	0.02 ( 0.011 )	0.02 ( 0.011 )
Week 84; n=58, 58	0.02 ( 0.010 )	0.01 ( 0.012 )
Week 96; n=59, 58	-0.01 ( 0.014 )	0.03 ( 0.009 )

Notes
[47] - n=subjects with an assessment at given time point
[48] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Percent Change From Baseline Over Time in TRP

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End point title

Percent Change From Baseline Over Time in TRP

End point description

The GEE Estimates are from the GEE model which includes the percent change from baseline for TRP as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of TRP as a covariate, with compound symmetry covariance structure.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96

End point values	Primary Analysis Set-Placebo	Primary Analysis Set-Burosumab
Number of subjects analysed	64 ^[49]	67 ^[50]
Units: percentage change
least squares mean (standard error)
Week 2; n=62, 63	-2.00 ( 1.530 )	9.81 ( 1.111 )
Week 4; n=63, 65	-3.75 ( 1.486 )	4.86 ( 1.114 )
Week 12; n=62, 64	0.56 ( 1.261 )	5.45 ( 1.079 )
Week 22; n=63, 64	-0.01 ( 1.163 )	7.03 ( 1.451 )
Week 24; n=63, 67	-1.56 ( 1.579 )	4.21 ( 1.141 )
Week 48; n=64, 63	3.95 ( 1.547 )	4.70 ( 1.183 )
Week 60; n=60, 60	3.99 ( 1.096 )	3.00 ( 1.123 )
Week 72; n=60, 59	3.90 ( 1.427 )	3.24 ( 1.414 )
Week 84; n=58, 58	3.78 ( 1.276 )	1.97 ( 1.516 )
Week 96; n=59, 58	-0.09 ( 1.582 )	4.44 ( 1.116 )

Notes
[49] - n=subjects with an assessment at given time point
[50] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Percentage of Subjects Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

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End point title

Percentage of Subjects Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

End point description

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	Burosumab
Number of subjects analysed	66	68
Units: percentage of subjects
number (confidence interval 95%)	6.1 (2.4 to 14.6)	67.6 (55.8 to 77.6)

No statistical analyses for this end point

Secondary: Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

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End point title

Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

End point description

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	Burosumab
Number of subjects analysed	66	68
Units: mg/dL
arithmetic mean (standard deviation)	0.16 ( 0.272 )	1.21 ( 0.513 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

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End point title

Percent Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

End point description

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	Burosumab
Number of subjects analysed	66	68
Units: percentage change
arithmetic mean (standard deviation)	9.85 ( 15.292 )	61.44 ( 28.961 )

No statistical analyses for this end point

Secondary: Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

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End point title

Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

End point description

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	Burosumab
Number of subjects analysed	66	68
Units: mg/dL
arithmetic mean (standard deviation)	0.13 ( 0.265 )	0.69 ( 0.392 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

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End point title

Percent Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

End point description

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	Burosumab
Number of subjects analysed	66	68
Units: percentage change
arithmetic mean (standard deviation)	7.83 ( 14.755 )	35.18 ( 20.731 )

No statistical analyses for this end point

Secondary: Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24

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End point title

Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24

End point description

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	Burosumab
Number of subjects analysed	66	68
Units: mg/dL
arithmetic mean (standard deviation)	2.08 ( 0.292 )	3.08 ( 0.477 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug through the end of study plus 4 weeks (+ 5 days).

Adverse event reporting additional description

Mean (SE) duration of exposure to burosumab for all periods combined through EOS II was 771.3 (21.97) days (range: 167 – 957) in the burosumab->burosumab group and 625.7 (19.40) days (range: 165 – 844) in the placebo->burosumab group.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Placebo (Double Blind [DB] Period)

Reporting group description

SC injection of placebo Q4W for 24 weeks (double-blind placebo-controlled Treatment Period)

Reporting group title

Placebo -> Burosumab (Open Label [OL] Period)

Reporting group description

Reporting group title

Burosumab -> Burosumab (Combined DB and OL Period)

Reporting group description

Reporting group title

Total Burosumab (Combined DB and OL Period)

Reporting group description

SC injection of 1.0 mg/kg burosumab at any time during the study

Serious adverse events	Placebo (Double Blind [DB] Period)	Placebo -> Burosumab (Open Label [OL] Period)	Burosumab -> Burosumab (Combined DB and OL Period)	Total Burosumab (Combined DB and OL Period)
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 66 (1.52%)	10 / 66 (15.15%)	12 / 68 (17.65%)	22 / 134 (16.42%)
number of deaths (all causes)	0	0	1	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive Ductal Breast Carcinoma
subjects affected / exposed	1 / 66 (1.52%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 134 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Parathyroid Tumour Benign
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural Nausea
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural Vomiting
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road Traffic Accident
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Subdural Haematoma
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrospinal Fluid Leakage
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical Radiculopathy
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myelopathy
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	2 / 68 (2.94%)	2 / 134 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Partial Seizures
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal Ulcer
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Irritable Bowel Syndrome
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periodontal Disease
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal Adhesions
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	1 / 68 (1.47%)	2 / 134 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back Pain
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical Spinal Stenosis
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint Range Of Motion Decreased
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Knee Deformity
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal Pain
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pseudarthrosis
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Column Stenosis
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Site Infection
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	1 / 134 (0.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo (Double Blind [DB] Period)	Placebo -> Burosumab (Open Label [OL] Period)	Burosumab -> Burosumab (Combined DB and OL Period)	Total Burosumab (Combined DB and OL Period)
Total subjects affected by non serious adverse events
subjects affected / exposed	57 / 66 (86.36%)	63 / 66 (95.45%)	68 / 68 (100.00%)	131 / 134 (97.76%)
Vascular disorders
Hot Flush
subjects affected / exposed	0 / 66 (0.00%)	2 / 66 (3.03%)	6 / 68 (8.82%)	8 / 134 (5.97%)
occurrences all number	0	2	8	10
Hypertension
subjects affected / exposed	2 / 66 (3.03%)	5 / 66 (7.58%)	8 / 68 (11.76%)	13 / 134 (9.70%)
occurrences all number	2	5	9	14
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 66 (3.03%)	1 / 66 (1.52%)	5 / 68 (7.35%)	6 / 134 (4.48%)
occurrences all number	4	1	11	12
Fatigue
subjects affected / exposed	7 / 66 (10.61%)	14 / 66 (21.21%)	16 / 68 (23.53%)	30 / 134 (22.39%)
occurrences all number	7	19	21	40
Injection Site Erythema
subjects affected / exposed	2 / 66 (3.03%)	6 / 66 (9.09%)	6 / 68 (8.82%)	12 / 134 (8.96%)
occurrences all number	2	22	9	31
Injection Site Pruritus
subjects affected / exposed	0 / 66 (0.00%)	8 / 66 (12.12%)	3 / 68 (4.41%)	11 / 134 (8.21%)
occurrences all number	0	17	11	28
Injection Site Reaction
subjects affected / exposed	2 / 66 (3.03%)	8 / 66 (12.12%)	7 / 68 (10.29%)	15 / 134 (11.19%)
occurrences all number	2	40	35	75
Pain
subjects affected / exposed	6 / 66 (9.09%)	9 / 66 (13.64%)	12 / 68 (17.65%)	21 / 134 (15.67%)
occurrences all number	6	10	18	28
Pyrexia
subjects affected / exposed	0 / 66 (0.00%)	4 / 66 (6.06%)	5 / 68 (7.35%)	9 / 134 (6.72%)
occurrences all number	0	5	5	10
Immune system disorders
Seasonal Allergy
subjects affected / exposed	1 / 66 (1.52%)	6 / 66 (9.09%)	5 / 68 (7.35%)	11 / 134 (8.21%)
occurrences all number	1	7	6	13
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 66 (0.00%)	5 / 66 (7.58%)	2 / 68 (2.94%)	7 / 134 (5.22%)
occurrences all number	0	5	2	7
Cough
subjects affected / exposed	3 / 66 (4.55%)	11 / 66 (16.67%)	10 / 68 (14.71%)	21 / 134 (15.67%)
occurrences all number	4	12	13	25
Nasal Congestion
subjects affected / exposed	2 / 66 (3.03%)	5 / 66 (7.58%)	5 / 68 (7.35%)	10 / 134 (7.46%)
occurrences all number	2	6	8	14
Oropharyngeal Pain
subjects affected / exposed	7 / 66 (10.61%)	8 / 66 (12.12%)	4 / 68 (5.88%)	12 / 134 (8.96%)
occurrences all number	8	10	7	17
Rhinorrhoea
subjects affected / exposed	3 / 66 (4.55%)	2 / 66 (3.03%)	4 / 68 (5.88%)	6 / 134 (4.48%)
occurrences all number	3	2	4	6
Psychiatric disorders
Depression
subjects affected / exposed	1 / 66 (1.52%)	3 / 66 (4.55%)	9 / 68 (13.24%)	12 / 134 (8.96%)
occurrences all number	1	4	10	14
Insomnia
subjects affected / exposed	1 / 66 (1.52%)	6 / 66 (9.09%)	9 / 68 (13.24%)	15 / 134 (11.19%)
occurrences all number	1	7	10	17
Investigations
Blood 25-Hydroxycholecalciferol Decreased
subjects affected / exposed	1 / 66 (1.52%)	3 / 66 (4.55%)	6 / 68 (8.82%)	9 / 134 (6.72%)
occurrences all number	1	5	8	13
Blood Glucose Increased
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	5 / 68 (7.35%)	6 / 134 (4.48%)
occurrences all number	0	1	6	7
Blood Parathyroid Hormone Increased
subjects affected / exposed	1 / 66 (1.52%)	1 / 66 (1.52%)	5 / 68 (7.35%)	6 / 134 (4.48%)
occurrences all number	1	1	5	6
Blood Pressure Increased
subjects affected / exposed	1 / 66 (1.52%)	1 / 66 (1.52%)	6 / 68 (8.82%)	7 / 134 (5.22%)
occurrences all number	1	1	9	10
Lipase Increased
subjects affected / exposed	0 / 66 (0.00%)	0 / 66 (0.00%)	4 / 68 (5.88%)	4 / 134 (2.99%)
occurrences all number	0	0	5	5
Vitamin D Decreased
subjects affected / exposed	0 / 66 (0.00%)	9 / 66 (13.64%)	8 / 68 (11.76%)	17 / 134 (12.69%)
occurrences all number	0	9	8	17
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 66 (1.52%)	5 / 66 (7.58%)	4 / 68 (5.88%)	9 / 134 (6.72%)
occurrences all number	1	6	5	11
Fall
subjects affected / exposed	0 / 66 (0.00%)	7 / 66 (10.61%)	6 / 68 (8.82%)	13 / 134 (9.70%)
occurrences all number	0	9	7	16
Ligament Sprain
subjects affected / exposed	6 / 66 (9.09%)	2 / 66 (3.03%)	4 / 68 (5.88%)	6 / 134 (4.48%)
occurrences all number	6	2	4	6
Procedural Pain
subjects affected / exposed	0 / 66 (0.00%)	6 / 66 (9.09%)	9 / 68 (13.24%)	15 / 134 (11.19%)
occurrences all number	0	7	16	23
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 66 (6.06%)	5 / 66 (7.58%)	11 / 68 (16.18%)	16 / 134 (11.94%)
occurrences all number	4	5	20	25
Headache
subjects affected / exposed	5 / 66 (7.58%)	18 / 66 (27.27%)	22 / 68 (32.35%)	40 / 134 (29.85%)
occurrences all number	6	36	46	82
Hypoaesthesia
subjects affected / exposed	1 / 66 (1.52%)	3 / 66 (4.55%)	7 / 68 (10.29%)	10 / 134 (7.46%)
occurrences all number	1	3	8	11
Migraine
subjects affected / exposed	1 / 66 (1.52%)	2 / 66 (3.03%)	7 / 68 (10.29%)	9 / 134 (6.72%)
occurrences all number	1	2	8	10
Restless Legs Syndrome
subjects affected / exposed	5 / 66 (7.58%)	10 / 66 (15.15%)	11 / 68 (16.18%)	21 / 134 (15.67%)
occurrences all number	5	13	14	27
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 66 (1.52%)	4 / 66 (6.06%)	3 / 68 (4.41%)	7 / 134 (5.22%)
occurrences all number	2	4	5	9
Gastrointestinal disorders
Abdominal Discomfort
subjects affected / exposed	0 / 66 (0.00%)	3 / 66 (4.55%)	4 / 68 (5.88%)	7 / 134 (5.22%)
occurrences all number	0	3	6	9
Abdominal Pain
subjects affected / exposed	2 / 66 (3.03%)	2 / 66 (3.03%)	6 / 68 (8.82%)	8 / 134 (5.97%)
occurrences all number	3	5	15	20
Abdominal Pain Upper
subjects affected / exposed	0 / 66 (0.00%)	6 / 66 (9.09%)	3 / 68 (4.41%)	9 / 134 (6.72%)
occurrences all number	0	9	3	12
Constipation
subjects affected / exposed	0 / 66 (0.00%)	4 / 66 (6.06%)	10 / 68 (14.71%)	14 / 134 (10.45%)
occurrences all number	0	4	13	17
Diarrhoea
subjects affected / exposed	5 / 66 (7.58%)	5 / 66 (7.58%)	13 / 68 (19.12%)	18 / 134 (13.43%)
occurrences all number	8	5	15	20
Nausea
subjects affected / exposed	6 / 66 (9.09%)	5 / 66 (7.58%)	11 / 68 (16.18%)	16 / 134 (11.94%)
occurrences all number	7	10	20	30
Toothache
subjects affected / exposed	1 / 66 (1.52%)	10 / 66 (15.15%)	12 / 68 (17.65%)	22 / 134 (16.42%)
occurrences all number	1	12	21	33
Vomiting
subjects affected / exposed	2 / 66 (3.03%)	4 / 66 (6.06%)	6 / 68 (8.82%)	10 / 134 (7.46%)
occurrences all number	2	8	6	14
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 66 (0.00%)	1 / 66 (1.52%)	5 / 68 (7.35%)	6 / 134 (4.48%)
occurrences all number	0	1	5	6
Rash
subjects affected / exposed	3 / 66 (4.55%)	1 / 66 (1.52%)	4 / 68 (5.88%)	5 / 134 (3.73%)
occurrences all number	3	1	5	6
Renal and urinary disorders
Nephrocalcinosis
subjects affected / exposed	0 / 66 (0.00%)	4 / 66 (6.06%)	2 / 68 (2.94%)	6 / 134 (4.48%)
occurrences all number	0	4	2	6
Endocrine disorders
Hyperparathyroidism Secondary
subjects affected / exposed	0 / 66 (0.00%)	3 / 66 (4.55%)	4 / 68 (5.88%)	7 / 134 (5.22%)
occurrences all number	0	3	7	10
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	16 / 66 (24.24%)	23 / 66 (34.85%)	27 / 68 (39.71%)	50 / 134 (37.31%)
occurrences all number	22	37	48	85
Back Pain
subjects affected / exposed	6 / 66 (9.09%)	17 / 66 (25.76%)	18 / 68 (26.47%)	35 / 134 (26.12%)
occurrences all number	6	23	23	46
Bone Pain
subjects affected / exposed	4 / 66 (6.06%)	6 / 66 (9.09%)	8 / 68 (11.76%)	14 / 134 (10.45%)
occurrences all number	4	6	12	18
Joint Stiffness
subjects affected / exposed	0 / 66 (0.00%)	4 / 66 (6.06%)	4 / 68 (5.88%)	8 / 134 (5.97%)
occurrences all number	0	5	4	9
Joint Swelling
subjects affected / exposed	0 / 66 (0.00%)	7 / 66 (10.61%)	5 / 68 (7.35%)	12 / 134 (8.96%)
occurrences all number	0	7	6	13
Muscle Spasms
subjects affected / exposed	2 / 66 (3.03%)	9 / 66 (13.64%)	11 / 68 (16.18%)	20 / 134 (14.93%)
occurrences all number	2	15	14	29
Muscular Weakness
subjects affected / exposed	1 / 66 (1.52%)	2 / 66 (3.03%)	6 / 68 (8.82%)	8 / 134 (5.97%)
occurrences all number	4	2	6	8
Musculoskeletal Chest Pain
subjects affected / exposed	0 / 66 (0.00%)	4 / 66 (6.06%)	3 / 68 (4.41%)	7 / 134 (5.22%)
occurrences all number	0	5	3	8
Musculoskeletal Pain
subjects affected / exposed	4 / 66 (6.06%)	10 / 66 (15.15%)	12 / 68 (17.65%)	22 / 134 (16.42%)
occurrences all number	4	15	12	27
Musculoskeletal Stiffness
subjects affected / exposed	3 / 66 (4.55%)	4 / 66 (6.06%)	4 / 68 (5.88%)	8 / 134 (5.97%)
occurrences all number	6	4	4	8
Myalgia
subjects affected / exposed	1 / 66 (1.52%)	5 / 66 (7.58%)	8 / 68 (11.76%)	13 / 134 (9.70%)
occurrences all number	1	5	9	14
Neck Pain
subjects affected / exposed	1 / 66 (1.52%)	5 / 66 (7.58%)	3 / 68 (4.41%)	8 / 134 (5.97%)
occurrences all number	1	5	5	10
Pain In Extremity
subjects affected / exposed	10 / 66 (15.15%)	10 / 66 (15.15%)	18 / 68 (26.47%)	28 / 134 (20.90%)
occurrences all number	12	17	18	35
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 66 (1.52%)	6 / 66 (9.09%)	4 / 68 (5.88%)	10 / 134 (7.46%)
occurrences all number	1	6	5	11
Gastroenteritis
subjects affected / exposed	2 / 66 (3.03%)	4 / 66 (6.06%)	2 / 68 (2.94%)	6 / 134 (4.48%)
occurrences all number	2	4	2	6
Influenza
subjects affected / exposed	3 / 66 (4.55%)	6 / 66 (9.09%)	9 / 68 (13.24%)	15 / 134 (11.19%)
occurrences all number	3	6	11	17
Nasopharyngitis
subjects affected / exposed	6 / 66 (9.09%)	24 / 66 (36.36%)	28 / 68 (41.18%)	52 / 134 (38.81%)
occurrences all number	8	34	53	87
Oral Herpes
subjects affected / exposed	0 / 66 (0.00%)	4 / 66 (6.06%)	4 / 68 (5.88%)	8 / 134 (5.97%)
occurrences all number	0	5	7	12
Pharyngitis
subjects affected / exposed	1 / 66 (1.52%)	0 / 66 (0.00%)	4 / 68 (5.88%)	4 / 134 (2.99%)
occurrences all number	1	0	4	4
Rhinitis
subjects affected / exposed	1 / 66 (1.52%)	4 / 66 (6.06%)	1 / 68 (1.47%)	5 / 134 (3.73%)
occurrences all number	1	6	1	7
Sinusitis
subjects affected / exposed	2 / 66 (3.03%)	2 / 66 (3.03%)	6 / 68 (8.82%)	8 / 134 (5.97%)
occurrences all number	2	3	9	12
Tooth Abscess
subjects affected / exposed	6 / 66 (9.09%)	5 / 66 (7.58%)	19 / 68 (27.94%)	24 / 134 (17.91%)
occurrences all number	7	7	33	40
Upper Respiratory Tract Infection
subjects affected / exposed	6 / 66 (9.09%)	2 / 66 (3.03%)	12 / 68 (17.65%)	14 / 134 (10.45%)
occurrences all number	6	2	16	18
Urinary Tract Infection
subjects affected / exposed	4 / 66 (6.06%)	6 / 66 (9.09%)	5 / 68 (7.35%)	11 / 134 (8.21%)
occurrences all number	5	9	9	18
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 66 (1.52%)	0 / 66 (0.00%)	4 / 68 (5.88%)	4 / 134 (2.99%)
occurrences all number	1	0	4	4
Hyperphosphataemia
subjects affected / exposed	0 / 66 (0.00%)	4 / 66 (6.06%)	1 / 68 (1.47%)	5 / 134 (3.73%)
occurrences all number	0	4	1	5
Vitamin D Deficiency
subjects affected / exposed	3 / 66 (4.55%)	7 / 66 (10.61%)	15 / 68 (22.06%)	22 / 134 (16.42%)
occurrences all number	3	9	17	26

More information

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Were there any global substantial amendments to the protocol? Yes

21 Jul 2016

(continued) • Efficacy Measures: Enthesopathy was added as an efficacy measure in the study. Enthesopathy would be measured in all subjects by lateral foot x rays (bilateral) at Baseline (obtained as skeletal survey) and at Weeks 24, 48, and 96, and, if applicable, at the end of Treatment Extension Period II to assess the change from Baseline in enthesopathy at the calcaneus as an exploratory endpoint. - A statement was added to Section 7.5.3.1 that 2 questions from the short-form BPI about the use of pain medications and relief from pain medications would not be administered. Use of pain medications was captured separately in the diary. • General Assessments: A provision was added to allow additional testing for mutations consistent with syndromes with overlapping clinical and biochemical characteristics as XLH if the initial PHEX mutation analysis was negative or inconclusive and informed consent was provided by the subject. Testing would include, but not necessarily be limited to, genes for autosomal dominant hypophosphatemic rickets (FGF23), autosomal recessive hypophosphatemic rickets (DMP1, ENPP1), x-linked recessive hypophosphatemic rickets (CLCN5), and hereditary hypophosphatemic rickets with hypercalciuria (SLC34A3). The Investigator would communicate any additional genetic testing results to the subject. • Safety Assessments: Several changes were made to the safety assessments. - Sections 7.4.5 and 7.5.7.6 were updated to indicate echocardiogram (ECHO) would no longer be read locally at the study site. All ECHO assessments would be centrally read by individuals blinded to treatment assignment and subject data. - In Section 7.5.7, electrocardiogram (ECG) was listed as a general safety assessment. Previously it was listed within the safety assessments for ectopic mineralization. - Blood pressure (Section 7.5.7.2) would be obtained twice (2 measurements within 15 minutes) at indicated clinic visits.

21 Jul 2016

(continued) - Section 7.5.7.8 was updated to add assessment of lipase in all subjects and reflexive testing for amylase isoenzymes if serum amylase levels were elevated to ≥ 1.5 × upper limit of normal (ULN). - Descriptions of FGF23 measurements were removed consistent with changes to the Schedule of Events. • Statistical Methods: The following changes were made to Section 7.6. - A final analysis was planned at Week 96 to coincide with the end of the Extension Period (Section 7.6.4). - Section 7.6.4.2 was clarified to state the key secondary endpoint would be derived from the average of daily diary scores recorded over 1 week and the study visit score. - Section 7.6.4.3 was updated to clarify that the endpoints for BPI pain severity and pain interference would be evaluated separately. The endpoints for BFI would be based on BF-Q3, Worst Fatigue, and a BFI Global Fatigue score calculated by averaging all 9 items on the BFI, rather than separate BFI Severity and BFI Interference scores. • Ethics: Section 8.1.2 was updated to state that both the Sponsor and Investigator would make every effort to ensure the study described in the protocol was conducted in full conformance with those principles, current Food and Drug Administration (FDA) regulations, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice (ICH GCP) guidelines, and local ethical and regulatory requirements. • Record Retention: Section 8.4.3 was updated to state that all study records must be retained for at least 25 years after the end of the clinical trial or in accordance with national law. • Safety Contact Information: The medical monitor information for the study was updated in Section 8.5.4.7.

21 Jul 2016

• Overall Study Design: A 48-week Extension Period was added to the study design. The study title was modified with the open-label extension as a descriptor, and the corresponding Schedule of Events for this period was provided. • Study Population: Several changes were made to the inclusion and exclusion criteria as indicated below: - Inclusion criterion #5 was modified to correct a duplicative value of 60 mL/min. The estimated glomerular filtration rate (eGFR) was to be ≥ 60 mL/min; OR eGFR of 45 to < 60 mL/min at SV2 with confirmation that the renal insufficiency was not due to nephrocalcinosis. - Inclusion criterion #10 was updated as follows (bolded text indicates newly added text): “Participants of child‐bearing potential or with partners of child-bearing potential who have not undergone a total hysterectomy or bilateral salpingo oophorectomy and are sexually active must consent to use 2 effective methods of contraception as determined by the site Investigator (ie, oral hormonal contraceptives, patch hormonal contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation, or true abstinence) from the period following the signing of the informed consent through 12 weeks after last dose of study drug.” - Exclusion criterion #4 was changed to specify timing around screening visit (SV)1. - Exclusion criterion # 8 was modified to remove “oral” and restrict use of any bisphosphonates in the 2 years prior to SV1. - Additional criteria were inserted to exclude individuals who had used denosumab in the 6 months prior to SV1 and teriparatide in the 2 months prior to SV1. These medications were also added to the list of prohibited medications for consistency. - A provision was added to Exclusion criterion #19 to allow individuals to participate who may have had a history of recurrent dental abscesses, which are known to be associated with XLH.

21 Jul 2016

(continued) • Schedule of Events: Several changes were made to the Schedule of Events: - The timing of assessments for intact fibroblast growth factor 23 (iFGF23), phosphate regulating gene with homology to endopeptidases located on the X chromosome (PHEX) mutation analysis, and pregnancy testing during Screening/Baseline was modified and/or clarified. PHEX mutation analysis was only to be performed once (either at SV2 or the Baseline Visit). A provision was added to allow for a screening period > 31 days. - Additional pharmacokinetic assessments were added at Weeks 34, 36, 46, and 70. The skeletal survey was moved from SV1 to the Baseline Visit in Table 2.1 to align with the description in Section 7.5.6.1. Serum 1,25(OH)2D was also to be assayed at Week 24. - Footnote 12 to the Schedules of Events and Section 7.5.3.3 were updated to clarify that the full 24-item WOMAC would be administered. - The TUG test was added to the Schedules of Events and Section 7.5.5 as an exploratory endpoint. The TUG was to be performed at Weeks 24, 36, 48, and 72. • Treatments: Two changes were made regarding study drug. Section 7.4.1 was modified to provide additional flexibility in SC dosing sites; subjects could receive study drug via SC injection to the abdomen, upper arms or thighs. Section 7.4.2 was updated to state the composition of the placebo solution is the same as burosumab investigational product except placebo contains no active substance. • Blinding: Language discussing blinding was clarified to state that the study was double blind and placebo controlled through Week 24 and that unblinding of serum phosphorus levels and treatment assignment referred to the placebo-controlled portion of the study. The section also stated subjects and Investigators would remain blinded to original treatment assignment until the Week 48 analysis was completed. Previously it had stated that Investigator and site personnel would remain blinded during the study.

08 Sep 2016

(continued) • Exploratory Endpoints: In Section 7.6.4.4, language describing the exploratory endpoint of pseudofracture healing was modified to read: Healing of pre-existing pseudofractures and/or Looser zones, as defined by skeletal survey at Baseline and subsequent targeted radiography. Previously this endpoint had indicated “time to healing” of pre-existing pseudofractures and/or Looser zones.

08 Sep 2016

• Schedules of Events: Numbering was added to the footnotes for the Schedules of Events. In addition, a duplicative Visit 34 was corrected and the study visits renumbered and an unintended anti-burosumab antibody assessment at Week 70 was removed. • Study Objectives: In Section 6, the pharmacokinetic (PK) Objective was clarified as: Assess the PK of burosumab throughout the dosing cycle following the first doses and at steady state. It had previously stated, “…following single and multiple doses.” • Genetic Testing: In Section 7.5.8, 1 gene, for Raine Syndrome (FAM20C), was added to the list of genes that may be assessed for mutation in subjects whose initial PHEX mutation analysis was negative or inconclusive and who provided informed consent. The wording “not necessarily limited to” regarding the list of genes was removed. • 6 Minute Walk Test (6MWT): Section 7.5.4 and the Schedules of Events were updated to indicate that the 6MWT would be performed at Week 72 and at Early Termination if the subject discontinued on or before Week 72. • Timed Up and Go (TUG): Section 7.5.5 and the Schedules of Events were updated to indicate that the TUG test would be performed at the Early Termination visit if it occurred between Weeks 24 and 72. • Drug Concentration Measurements: The description of drug concentration measurements was placed under Section 7.5.7. Previously it was misplaced within the heading of Enthesopathy. • Vital Signs: A discrepancy regarding the timing of blood pressure assessments was clarified in Section 7.5.8.2. Seated systolic blood pressure and diastolic blood pressure would be measured twice with the measurements separated by 15 minutes at indicated study visits. Previously this had stated 2 measurements within 15 minutes. • Secondary Endpoints: Language in Section 7.6.4.3 was updated to specify that statistical methods of analysis for additional secondary endpoints including any adjustment for multiplicity would be described in the SAP.

31 Mar 2017

• Randomization Stratification: Section 7.4.4 (and elsewhere throughout the protocol as relevant) was updated to clarify that randomization is stratified not only by baseline pain intensity, but also by region (North America/European Union, Japan, and South Korea). • Pregnancy Testing and Contraception: In Section 7.5.3.9, the list of examples of effective contraception methods was updated. • Study Design and Duration: In Sections 7.1 and 7.4.3.1 and other relevant sections, a second Treatment Extension Period that included up to approximately 53 additional weeks of burosumab treatment, until end of September 2018, was added for subjects enrolled at sites in the US only. (The duration of this period will vary for individual subjects and will be determined by the time from start of Week 97 through final visit scheduled before 30 September 2018.) In addition, in these sections and Section 8.5.4.1 and other relevant sections, Safety Follow-up telephone calls (TCs) over an interval of up to 8 weeks following the End of Study or Early Termination Visit were added for subjects not immediately continuing burosumab treatment under commercial use or another mechanism upon completion of study drug treatment or early withdrawal from this study. The maximum study duration consequently was changed to up to approximately 157 weeks. For subjects outside of the US, the duration of study treatment remained 96 weeks, followed by Safety Follow-up TCs over an interval of up to 8 weeks if not continuing burosumab treatment under commercial use or another mechanism upon completion of study drug or early withdrawal from this study. The end of study was defined as the last day that protocol-specified assessments (including telephone contact) were conducted for the last subject in the study.

31 Mar 2017

• Study Objectives: In Section 6, the objectives were modified to elevate 2 “other” secondary objectives to “key” objectives (in addition to the previously specified single key secondary objective involving effect on skeletal pain), as follows: “To establish the effect of KRN23 treatment compared with placebo on skeletal pain, stiffness, and physical functioning.” • Key Secondary Efficacy Endpoints: In Section 7.6.4.2, 2 other endpoints were identified as key secondary efficacy endpoints in addition to change from baseline to Week 24 in BPI-Q3 (Worst Pain) score. These included change from baseline to Week 24 in the WOMAC Stiffness score and change from baseline to Week 24 in the WOMAC Physical Function score. • Additional Secondary Efficacy Endpoints: Section 7.6.4.3 was updated to a) clarify that additional secondary endpoints include change from baseline to post-Baseline visits (other than Week 24) in BPI Worst Pain score and WOMAC Physical Function score, b) clarify that change and percent change from baseline to post-baseline visits in serum phosphorus will be assessed, and c) clarify the descriptions of other endpoints. • Exploratory Efficacy Endpoints: In Section 7.6.4.4, the exploratory endpoint of healing of pre-existing pseudofractures and/or Looser zones, as defined by skeletal survey at baseline and subsequent targeted radiography was updated to clarify that it comprised the following components: the number of active pseudofractures and/or fractures as defined by skeletal survey at baseline and the numbers and percentages of the baseline active pseudofractures/fractures that were healed, partially healed, unchanged, and worsened at post-baseline visits, and the number of subjects with baseline active pseudofractures and/or fractures at baseline and the numbers of subjects who had changes from baseline to healed, partially healed, unchanged, and worsened at post-baseline visits. Descriptions of other exploratory endpoints were updated for clarity.

31 Mar 2017

(continued) • Study Drug Administration: Sections 7.4.1 and 7.4.6 were updated to indicate that for subjects in the US, after proper training by study personnel in SC injection technique, the subject could self-administer burosumab, or a caregiver could administer burosumab to the subject, in the home setting. Subjects or caregivers were instructed to follow the directions provided in the Instructions for Use. The dosing schedule remained the same. Additional instructions regarding the timing of the training and implementation of the subject/caregiver administration were provided in Section 7.4.6.

29 Sep 2017

• Study Design: Section 7.1 and related sections were updated to indicate that subjects at study sites in Europe would continue study into Treatment Extension Period II until availability of another mechanism of burosumab treatment and not later than September 2018, to avoid a potential treatment interruption for subjects. • Safety Monitoring: Section 7.6.7 and Section 8.5.4.6 were updated to describe safety monitoring during Treatment Extension Periods I and II of the study. Specifically, the DMC would monitor safety through Week 48. During the Treatment Extension Periods I and II, safety would be monitored on an ongoing basis by the Study Safety Review Team (SSRT), an internal safety review team that was defined and in place since the original protocol. • Study Assessments: Section 7.5.1.2 was updated to indicate that the Brief Pain Inventory and Brief Fatigue Inventory would not be assessed after Week 96. This change was made as results from the Placebo-controlled Treatment Period suggested that pain and fatigue in XLH are multi-systemic syndromes, making it difficult to isolate and measure a direct impact of burosumab. Therefore, these assessments were removed in Treatment Extension Period II.

26 Jan 2018

• Overall Study Design and Plan: Section 7.1, Section 7.5.3.8, Table 2.2, and Table 2.3 were updated to include a substudy to assess pre- and postprandial serum phosphorus and calcium levels following 2 different meals on the same day, when burosumab serum concentration was at steady state. The effect of burosumab on postprandial physiological excursions of serum phosphorus has not been studied. The substudy was added to evaluate the postprandial increases in serum phosphorus during burosumab treatment. • Treatments: Section 7.4.1, Section 7.4.6, and Table 2.1 – Table 2.3 were updated to remove the provision for administration of burosumab by subjects or their caregivers in the US. Given that the end of the study was approaching, the implementation of self administration of burosumab, including the requisite training on SC injection techniques, were not feasible. • The Schedule of Events table for Treatment Extension Period II (Table 2.3) was updated to clarify that the WOMAC, 6MWT and TUG test would be assessed for those subjects who discontinued from the study early to ensure that the above assessments were fully captured for all subjects enrolled in Treatment Extension Period II, including those who discontinued from the study early. • In Section 7.5.3.8.2 and Table 2.1 – Table 2.3, the parenthetical explanation of anti burosumab antibodies was changed from human anti-human antibodies (HAHA) to anti-drug antibodies (ADAs). This change was a clarification. While the study protocol previously used the term “HAHA” for this assessment, it was replaced with the more correct and specific term, ADA.

Were there any global interruptions to the trial? No

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/31165191
http://www.ncbi.nlm.nih.gov/pubmed/29947083

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Efficacy and Safety of KRN23 in Adults with X-linked Hypophosphatemia (XLH)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects Who Achieved Mean Serum Phosphorus Above the Lower Limit of Normal (LLN; 2.5 mg/dL [0.81 mmol/L]) Across Midpoints of Dose Intervals Through Week 24

Primary: Percentage of Subjects Who Achieved Mean Serum Phosphorus Above the Lower Limit of Normal (LLN; 2.5 mg/dL [0.81 mmol/L]) Across Midpoints of Dose Intervals Through Week 24

Secondary: Change From Baseline to Week 24 in BPI Worst Pain Score

Secondary: Change From Baseline to Week 24 in BPI Worst Pain Score

Secondary: Change From Baseline to Week 24 in WOMAC Stiffness Score

Secondary: Change From Baseline to Week 24 in WOMAC Stiffness Score

Secondary: Change From Baseline to Week 24 in WOMAC Physical Function Score

Secondary: Change From Baseline to Week 24 in WOMAC Physical Function Score

Secondary: Change From Baseline Over Time in BPI Worst Pain Score

Secondary: Change From Baseline Over Time in BPI Worst Pain Score

Secondary: Change From Baseline Over Time in BPI Pain Severity Score

Secondary: Change From Baseline Over Time in BPI Pain Severity Score

Secondary: Change From Baseline Over Time in BPI Pain Interference Score

Secondary: Change From Baseline Over Time in BPI Pain Interference Score

Secondary: Change From Baseline Over Time in WOMAC Stiffness Score

Secondary: Change From Baseline Over Time in WOMAC Stiffness Score

Secondary: Change From Baseline Over Time in WOMAC Physical Function Score

Secondary: Change From Baseline Over Time in WOMAC Physical Function Score

Secondary: Change From Baseline Over Time in BFI Worst Fatigue Score

Secondary: Change From Baseline Over Time in BFI Worst Fatigue Score

Secondary: Change From Baseline Over Time in BFI Global Fatigue Score

Secondary: Change From Baseline Over Time in BFI Global Fatigue Score

Secondary: Change From Baseline Over Time in P1NP

Secondary: Change From Baseline Over Time in P1NP

Secondary: Percent Change From Baseline Over Time in P1NP

Secondary: Percent Change From Baseline Over Time in P1NP

Secondary: Change From Baseline Over Time in CTx

Secondary: Change From Baseline Over Time in CTx

Secondary: Percent Change From Baseline Over Time in CTx

Secondary: Percent Change From Baseline Over Time in CTx

Secondary: Change From Baseline Over Time in Serum BALP

Secondary: Change From Baseline Over Time in Serum BALP

Secondary: Percent Change From Baseline Over Time in Serum BALP

Secondary: Percent Change From Baseline Over Time in Serum BALP

Secondary: Change From Baseline Over Time in Serum Phosphorus

Secondary: Change From Baseline Over Time in Serum Phosphorus

Secondary: Percent Change From Baseline Over Time in Serum Phosphorus

Secondary: Percent Change From Baseline Over Time in Serum Phosphorus

Secondary: Change From Baseline Over Time in Serum 1,25(OH)2D

Secondary: Change From Baseline Over Time in Serum 1,25(OH)2D

Secondary: Percent Change From Baseline Over Time in Serum 1,25(OH)2D

Secondary: Percent Change From Baseline Over Time in Serum 1,25(OH)2D

Secondary: Change From Baseline Over Time in 24-Hour Urinary Phosphorus

Secondary: Change From Baseline Over Time in 24-Hour Urinary Phosphorus

Secondary: Percent Change From Baseline Over Time in 24-Hour Urinary Phosphorus

Secondary: Percent Change From Baseline Over Time in 24-Hour Urinary Phosphorus

Secondary: Change From Baseline Over Time in TmP/GFR

Secondary: Change From Baseline Over Time in TmP/GFR

Secondary: Percent Change From Baseline Over Time in TmP/GFR

Secondary: Percent Change From Baseline Over Time in TmP/GFR

Secondary: Change From Baseline Over Time in TRP

Secondary: Change From Baseline Over Time in TRP

Secondary: Percent Change From Baseline Over Time in TRP

Secondary: Percent Change From Baseline Over Time in TRP

Secondary: Percentage of Subjects Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Percentage of Subjects Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Percent Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Percent Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Percent Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Percent Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24

Secondary: Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24

Secondary: Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Efficacy and Safety of KRN23 in Adults with X-linked Hypophosphatemia (XLH)