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Clinical Trial Results:
A Randomized, open Label, Dose Finding, Phase 2 Study to Assess the Pharmacodynamics and Safety of the anti-FGF23 antibody, KRN23, in Pediatric Patients with X-linked Hypophosphatemia (XLH)

Summary
EudraCT number	2014-000406-35
Trial protocol	GB NL FR
Global end of trial date	30 Oct 2018

Results information
Results version number	v1(current)
This version publication date	15 May 2019
First version publication date	15 May 2019
Other versions

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

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Trial information

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Sponsor protocol code

UX023-CL201

ISRCTN number

US NCT number

NCT02163577

WHO universal trial number (UTN)

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)

Yes

EMA paediatric investigation plan number(s)

EMEA-001659-PIP01-15

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

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

Analysis stage

Final

Date of interim/final analysis

30 Oct 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Oct 2018

Was the trial ended prematurely?

Main objective of the trial

The objectives of the study are to: • Identify a dose and dosing regimen of burosumab (KRN23), based on safety and PD effect, in pediatric XLH patients • Establish the safety profile of burosumab for the treatment of children with XLH including ectopic mineralization risk, cardiovascular effects, and immunogenicity profile • Characterize the PK/PD of the burosumab doses tested in the monthly (Q4) and biweekly (Q2) dose regimens in pediatric XLH patients • Determine the PD effects of burosumab treatment on markers of bone health in pediatric XLH patients • Obtain a preliminary assessment of the clinical effects of burosumab on bone health and deformity, muscle strength, and motor function • Obtain a preliminary assessment of the effects of burosumab on patient-reported outcomes, including pain, disability, and quality of life in pediatric XLH patients • Evaluate the long-term safety and efficacy of burosumab

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

02 Jul 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

United States: 36

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Potential subjects provided informed consent at an Screening Visit 1 at the study site. Screening Visit 2 was conducted 14 to 35 days following Screening Visit 1, and the remaining screening assessments to confirm eligibility were performed. Screening Visit 2 and Baseline visits were conducted no more than 7 days apart.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Burosumab Q2W

Arm description

Burosumab subcutaneous (SC) injections every 2 weeks (Q2W). Dose was determined by the subject's weight and prescribed dose by their study doctor.

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 KRN23 administered was calculated based on the subject’s weight.

Burosumab Q4W Then Q2W

Arm description

Burosumab SC injections every 4 weeks (Q4W). Dose was determined by the subject's weight and prescribed dose by their study doctor. Subjects in Q4W were to switch to Q2W beginning with Week 64 dosing.

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 KRN23 administered was calculated based on the subject’s weight.

Number of subjects in period 1	Burosumab Q2W	Burosumab Q4W Then Q2W
Started	26	26
Completed	26	26

Baseline characteristics

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Reporting group title

Burosumab Q2W

Reporting group description

Burosumab subcutaneous (SC) injections every 2 weeks (Q2W). Dose was determined by the subject's weight and prescribed dose by their study doctor.

Reporting group title

Burosumab Q4W Then Q2W

Reporting group description

Reporting group values	Burosumab Q2W	Burosumab Q4W Then Q2W	Total
Number of subjects	26	26	52
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	8.7 ( 1.72 )	8.3 ( 2.04 )	-
Gender categorical
Units: Subjects
Female	14	14	28
Male	12	12	24
Race
Units: Subjects
Black or African American	2	0	2
White	23	23	46
Other, Not Specified	1	3	4
Ethnicity
Units: Subjects
Hispanic or Latino	0	2	2
Not Hispanic or Latino	26	24	50
Rickets Severity Score (RSS) Total Score
The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.
Units: score on a scale
arithmetic mean (standard deviation)	1.92 ( 1.172 )	1.67 ( 0.999 )	-
Serum Phosphorus
Units: mg/dL
arithmetic mean (standard deviation)	2.38 ( 0.405 )	2.28 ( 0.299 )	-
Serum 1, 25- Dihydroxyvitamin D
Units: pg/mL
arithmetic mean (standard deviation)	41.28 ( 21.967 )	41.37 ( 15.293 )	-
Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate(TmP/GFR)
Data for urinary phosphorus and tubular reabsorption of phosphate (TRP) were used in the calculation of TmP/GFR. Analysis Population Description: subjects with a Baseline measurement (n=25, 25)
Units: mg/dL
arithmetic mean (standard deviation)	2.176 ( 0.4925 )	1.978 ( 0.3474 )	-
RSS Knee Scores
The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.
Units: score on a scale
arithmetic mean (standard deviation)	1.21 ( 0.681 )	1.19 ( 0.601 )	-
RSS Wrist Scores
The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.
Units: score on a scale
arithmetic mean (standard deviation)	0.71 ( 0.619 )	0.48 ( 0.519 )	-
Growth Velocity
Baseline growth velocity was calculated based on the standing height measured within 2 years prior to Baseline. Analysis Population Description: Data presented for subjects with evaluable growth velocity data at Baseline. Growth velocity could not be calculated for 3 subjects for whom pretreatment height data were not available within 2 years prior to Baseline (n=25, 24).
Units: cm/year
arithmetic mean (standard deviation)	5.45 ( 1.171 )	5.24 ( 1.402 )	-
Standing Height Z Score
Standing height Z scores are measures of height adjusted for a child's age and sex. The Z score indicates the number of standard deviations away from a reference population (from the Centers for Disease Control [CDC] growth charts) in the same age range and with the same sex. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome.
Units: Z score
arithmetic mean (standard deviation)	-1.72 ( 1.026 )	-2.05 ( 0.957 )	-
Growth (Standing Height)
Units: cm
arithmetic mean (standard deviation)	123.28 ( 10.326 )	119.42 ( 12.623 )	-
Growth (Sitting Height)
Units: cm
arithmetic mean (standard deviation)	70.10 ( 5.632 )	67.04 ( 5.691 )	-
Growth (Arm Length)
Units: cm
arithmetic mean (standard deviation)	54.80 ( 4.930 )	52.59 ( 6.129 )	-
Growth (Leg Length)
Units: cm
arithmetic mean (standard deviation)	66.06 ( 7.027 )	63.71 ( 8.322 )	-
6-Minute Walk Test (6MWT) Distance (Predicted Percent of Normal)
The total distance walked (meters) in a 6-minute period was measured. The percent of predicted values were calculated using published normative data based on age, gender, and height (Geiger et al. 2007).
Units: percentage of predicted distance
arithmetic mean (standard deviation)	79.32 ( 13.257 )	81.42 ( 15.101 )	-
POSNA-PODCI Normative Scores: Upper Extremity Scale
The Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI) yields 4 functional assessment scores: Upper Extremity Function, Transfers and Basic Mobility, Sports/Physical Function, and Comfort/Pain. Also a Global Function score, an average of the 4 functional assessments, and a Happiness score are calculated. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. (n=26, 25)
Units: score on a scale
arithmetic mean (standard deviation)	52.1 ( 6.77 )	48.5 ( 13.04 )	-
POSNA-PODCI: Transfer and Basic Mobility Scale
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function, Transfers and Basic Mobility, Sports/Physical Function, and Comfort/Pain. Also a Global Function score, an average of the 4 functional assessments, and a Happiness score are calculated. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. (n=26, 25)
Units: score on a scale
arithmetic mean (standard deviation)	45.7 ( 10.88 )	46.0 ( 10.53 )	-
POSNA-PODCI: Sports/Physical Functioning Scale
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function, Transfers and Basic Mobility, Sports/Physical Function, and Comfort/Pain. Also a Global Function score, an average of the 4 functional assessments, and a Happiness score are calculated. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. (n=26, 25)
Units: score on a scale
arithmetic mean (standard deviation)	34.6 ( 15.70 )	32.2 ( 19.29 )	-
POSNA-PODCI: Pain/Comfort Scale
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function, Transfers and Basic Mobility, Sports/Physical Function, and Comfort/Pain. Also a Global Function score, an average of the 4 functional assessments, and a Happiness score are calculated. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. (n=26, 25)
Units: score on a scale
arithmetic mean (standard deviation)	35.2 ( 15.26 )	34.8 ( 16.76 )	-
POSNA-PODCI: Happiness Scale
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function, Transfers and Basic Mobility, Sports/Physical Function, and Comfort/Pain. Also a Global Function score, an average of the 4 functional assessments, and a Happiness score are calculated. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. (n=26, 25)
Units: score on a scale
arithmetic mean (standard deviation)	43.6 ( 13.75 )	43.4 ( 13.69 )	-
POSNA-PODCI: Global Functioning Scale
The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function, Transfers and Basic Mobility, Sports/Physical Function, and Comfort/Pain. Also a Global Function score, an average of the 4 functional assessments, and a Happiness score are calculated. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10. (n=26, 25)
Units: score on a scale
arithmetic mean (standard deviation)	37.5 ( 13.96 )	35.6 ( 17.24 )	-
Fractional Excretion of Phosphorus (FEP)
FEP is defined as 100% × (urine phosphorus × serum creatinine)/(urine creatinine × serum phosphorus), where the 2-hour urine sample was used for urine phosphorus and urine creatinine. Analysis Population Description: subjects with a Baseline assessment (n=25,26).
Units: percentage of phosphorus excreted
arithmetic mean (standard deviation)	13.91 ( 6.775 )	15.42 ( 7.373 )	-
Procollagen Type 1 N Propeptide (P1NP)
Analysis Population Description: subjects with a Baseline assessment (n=24, 26)
Units: ng/mL
arithmetic mean (standard deviation)	843.11 ( 214.367 )	742.35 ( 209.727 )	-
Carboxy-Terminal Crosslinked Telopeptide of Type I Collagen (CTx)
Units: ng/mL
arithmetic mean (standard deviation)	2.23 ( 0.642 )	2.10 ( 0.679 )	-
Alkaline Phosphatase (ALP)
Units: U/L
arithmetic mean (standard deviation)	461.92 ( 110.209 )	456.08 ( 101.157 )	-
Bone Specific Alkaline Phosphatase (BALP)
Analysis Population Description: subjects with a baseline assessment (n=20, 20).
Units: mcg/L
arithmetic mean (standard deviation)	163.54 ( 58.610 )	165.62 ( 45.534 )	-
Burosumab Concentration
For the lower limit of quantitation (< 50), the value 25 was used.
Units: ng/mL
arithmetic mean (standard deviation)	25.00 ( 0.000 )	25.00 ( 0.000 )	-

End points

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Reporting group title

Burosumab Q2W

Reporting group description

Burosumab subcutaneous (SC) injections every 2 weeks (Q2W). Dose was determined by the subject's weight and prescribed dose by their study doctor.

Reporting group title

Burosumab Q4W Then Q2W

Reporting group description

Subject analysis set title

Intent to Treat Analysis Set: Burosumab Q2W

Subject analysis set type

Intention-to-treat

Subject analysis set description

Burosumab SC injections Q2W. Dose was determined by the subject's weight and prescribed dose by their study doctor. Intent to Treat Analysis Set: All subjects who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.

Subject analysis set title

Intent to Treat Analysis Set: Burosumab Q4W Then Q2W

Subject analysis set type

Intention-to-treat

Subject analysis set description

Burosumab SC injections Q4W. Dose was determined by the subject's weight and prescribed dose by their study doctor. Subjects in Q4W were to switch to Q2W beginning with Week 64 dosing. Intent to Treat Analysis Set: All subjects who received at least 1 dose of study therapy and had at least 1 post-dose measurement at given time point.

Subject analysis set title

PK/PD Analysis Set: Burosumab Q2W

Subject analysis set type

Full analysis

Subject analysis set description

Burosumab SC injections Q2W. Dose was determined by the subject's weight and prescribed dose by their study doctor. Pharmacokinetic/Pharamcodynamic (PK/PD) Analysis Set: all subjects who received at least 1 dose of therapy and had evaluable serum data at given time point.

Subject analysis set title

PK/PD Analysis Set: Burosumab Q4W Then Q2W

Subject analysis set type

Full analysis

Subject analysis set description

Burosumab SC injections Q4W. Dose was determined by the subject's weight and prescribed dose by their study doctor. Subjects in Q4W were to switch to Q2W beginning with Week 64 dosing. Pharmacokinetic/Pharamcodynamic (PK/PD) Analysis Set: all subjects who received at least 1 dose of therapy and had evaluable serum data at given time point.

Subject analysis set title

Safety Analysis Set: Burosumab Q2W

Subject analysis set type

Safety analysis

Subject analysis set description

Burosumab SC injections Q2W. Dose was determined by the subject's weight and prescribed dose by their study doctor. Safety Analysis Set: All subjects who received at least 1 dose of study therapy.

Subject analysis set title

Safety Analysis Set: Burosumab Q4W Then Q2W

Subject analysis set type

Safety analysis

Subject analysis set description

Burosumab SC injections Q4W. Dose was determined by the subject's weight and prescribed dose by their study doctor. Subjects in Q4W were to switch to Q2W beginning with Week 64 dosing. Safety Analysis Set: All subjects who received at least 1 dose of study therapy and had an assessment at given time point.

Primary: Change From Baseline in RSS Total Score Over Time

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End point title

Change From Baseline in RSS Total Score Over Time ^[1]

End point description

The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.

End point type

Primary

End point timeframe

Baseline, Week 40, 64, 160

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses are attached as a separate document (see zip file below) since they couldn't be entered due to formatting restrictions in EudraCT.

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[2]	26 ^[3]
Units: score on a scale
least squares mean (standard error)
Change to Week 40; n=26, 26	-1.06 ( 0.100 )	-0.73 ( 0.100 )
Change to Week 64; n=26, 26	-1.00 ( 0.110 )	-0.84 ( 0.098 )
Change to Week 160; n=19, 22	-0.98 ( 0.129 )	-0.83 ( 0.122 )

Attachments

Untitled (Filename: RSS Total Score Statistical Analysis.docx)

Notes
[2] - n=subjects who had at least 1 post-dose measurement at given time point.
[3] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Primary: Change From Baseline in Serum Phosphorus Over Time

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End point title

Change From Baseline in Serum Phosphorus Over Time ^[4]

End point description

End point type

Primary

End point timeframe

Baseline, Week 40, 64, 160

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses are attached as a separate document (see zip file below) since they couldn't be entered due to formatting restrictions in EudraCT.

End point values	PK/PD Analysis Set: Burosumab Q2W	PK/PD Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[5]	26 ^[6]
Units: mg/dL
arithmetic mean (standard deviation)
Change at Week 40; n=26, 26	0.92 ( 0.480 )	0.57 ( 0.265 )
Change at Week 64; n=24, 23	0.99 ( 0.502 )	0.69 ( 0.370 )
Change at Week 160; n=26, 26	0.97 ( 0.338 )	1.08 ( 0.377 )

Attachments

Untitled (Filename: Serum Phosphorus Statistical Analysis.docx)

Notes
[5] - n=subjects who had evaluable serum data at given time point.
[6] - n=subjects who had evaluable serum data at given time point.

No statistical analyses for this end point

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

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End point title

Change From Baseline in Serum 1,25(OH)2D Over Time ^[7]

End point description

End point type

Primary

End point timeframe

Baseline, Week 40, 64, 160

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses are attached as a separate document (see zip file below) since they couldn't be entered due to formatting restrictions in EudraCT.

End point values	PK/PD Analysis Set: Burosumab Q2W	PK/PD Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[8]	26 ^[9]
Units: pg/mL
arithmetic mean (standard deviation)
Change at Week 40; n=26, 26	28.27 ( 29.312 )	17.62 ( 18.802 )
Change at Week 64; n=26, 24	23.58 ( 24.502 )	11.50 ( 16.522 )
Change at Week 160; n=26, 26	17.03 ( 24.889 )	19.64 ( 22.857 )

Attachments

Untitled (Filename: Serum 1,25(OH)2D Statistical Analysis.docx)

Notes
[8] - n=subjects who had evaluable serum data at given time point.
[9] - n=subjects who had evaluable serum data at given time point.

No statistical analyses for this end point

Primary: Change From Baseline in TmP/GFR Over Time

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End point title

Change From Baseline in TmP/GFR Over Time ^[10]

End point description

Data for urinary phosphorus and TRP were used in calculation TmP/GFR.

End point type

Primary

End point timeframe

Baseline, Week 40, 64, 160

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses are attached as a separate document (see zip file below) since they couldn't be entered due to formatting restrictions in EudraCT.

End point values	PK/PD Analysis Set: Burosumab Q2W	PK/PD Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[11]	26 ^[12]
Units: mg/dL
arithmetic mean (standard deviation)
Change at Week 40; n=24, 23	1.14 ( 0.686 )	0.80 ( 0.506 )
Change at Week 64; n=20, 19	1.11 ( 0.626 )	0.90 ( 0.632 )
Change at Week 160; n=23, 24	1.24 ( 0.548 )	1.45 ( 0.653 )

Attachments

Untitled (Filename: TmP_GFR Statistical Analysis.docx)

Notes
[11] - n=subjects who had evaluable serum data at given time point.
[12] - n=subjects had evaluable serum data at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in RSS Knee Scores Over Time

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End point title

Change From Baseline in RSS Knee Scores Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[13]	26 ^[14]
Units: score on a scale
least squares mean (standard error)
Change at Week 40; n=26, 26	-0.62 ( 0.08 )	-0.55 ( 0.08 )
Change at Week 64; n=26, 26	-0.70 ( 0.087 )	-0.61 ( 0.072 )
Change at Week 160; n=19, 22	-0.70 ( 0.105 )	-0.62 ( 0.093 )

Attachments

Untitled (Filename: RSS Knee Score Statistical Analysis.docx)

Notes
[13] - n=subjects who had at least 1 post-dose measurement at given time point.
[14] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in RSS Wrist Scores Over Time

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End point title

Change From Baseline in RSS Wrist Scores Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[15]	26 ^[16]
Units: score on a scale
least squares mean (standard error)
Change at Week 40; n=26, 26	-0.44 ( 0.05 )	-0.18 ( 0.05 )
Change at Week 64; n=26, 26	-0.30 ( 0.057 )	-0.24 ( 0.051 )
Change at Week 160; n=19, 21	-0.27 ( 0.065 )	-0.20 ( 0.047 )

Attachments

Untitled (Filename: RSS Wrist Score Statistical Analysis.docx)

Notes
[15] - n=subjects who had at least 1 post-dose measurement at given time point.
[16] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Radiographic Global Impression of Change (RGI-C) Global Scores Over Time

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End point title

Radiographic Global Impression of Change (RGI-C) Global Scores Over Time

End point description

Changes in the severity of rickets and bowing were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets).

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26	26
Units: score on a scale
least squares mean (standard error)
Change at Week 40	1.67 ( 0.12 )	1.46 ( 0.12 )
Change at Week 64	1.56 ( 0.112 )	1.58 ( 0.112 )
Change at Week 160	1.92 ( 0.111 )	1.86 ( 0.119 )

Attachments

Untitled (Filename: RGIC Global Score Statistical Analysis.docx)

No statistical analyses for this end point

Secondary: RGI-C Knee Scores Over Time

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End point title

RGI-C Knee Scores Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26	26
Units: scores on a scale
least squares mean (standard error)
Change at Week 40	1.60 ( 0.13 )	1.34 ( 0.13 )
Change at Week 64	1.57 ( 0.104 )	1.53 ( 0.099 )
Change at Week 160	2.01 ( 0.106 )	1.85 ( 0.118 )

Attachments

Untitled (Filename: RGIC Knee Score Statistical Analysis.docx)

No statistical analyses for this end point

Secondary: RGI-C Wrist Scores Over Time

Top of page

End point title

RGI-C Wrist Scores Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[17]	26
Units: scores on a scale
least squares mean (standard error)
Change at Week 40; n=26, 26	1.64 ( 0.14 )	1.45 ( 0.14 )
Change at Week 64; n=26, 26	1.65 ( 0.153 )	1.55 ( 0.124 )
Change at Week 160; n=26, 25	1.78 ( 0.133 )	1.83 ( 0.132 )

Attachments

Untitled (Filename: RGIC Wrist Score Statistical Analysis.docx)

Notes
[17] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in Growth Velocity Over Time

Top of page

End point title

Change From Baseline in Growth Velocity Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	25	24
Units: cm/year
arithmetic mean (standard deviation)
Week 0 to Week 40: Change from Baseline	0.96 ( 1.677 )	0.39 ( 2.559 )
Week 0 to Week 64: Change from Baseline	0.73 ( 1.399 )	0.37 ( 2.164 )
Week 64 to Week 112: Change from Baseline	0.29 ( 2.284 )	0.09 ( 2.523 )
Week 112 to Week 160: Change from Baseline	0.67 ( 2.318 )	0.54 ( 3.158 )

Attachments

Untitled (Filename: Growth Velocity Statistical Analysis.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Standing Height Z Score Over Time

Top of page

End point title

Change From Baseline in Standing Height Z Score Over Time

End point description

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

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[18]	26 ^[19]
Units: Z Score
least squares mean (standard error)
Change to Week 40; n=24, 23	0.17 ( 0.042 )	0.10 ( 0.051 )
Change to Week 64; n=26, 26	0.19 ( 0.051 )	0.12 ( 0.061 )
Change to Week 160; n=26, 26	0.35 ( 0.084 )	0.19 ( 0.089 )

Attachments

Untitled (Filename: Standing Height Z Score Statistical Analysis.docx)

Notes
[18] - n=subjects who had at least 1 post-dose measurement at given time point.
[19] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in Growth (Standing Height) Over Time

Top of page

End point title

Change From Baseline in Growth (Standing Height) Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[20]	26 ^[21]
Units: cm
arithmetic mean (standard deviation)
Change at Week 40; n=24, 23	5.03 ( 1.232 )	4.49 ( 1.455 )
Change at Week 64; n=26, 26	7.48 ( 1.934 )	6.98 ( 1.594 )
Change at Week 160; n=26, 26	18.38 ( 2.958 )	17.22 ( 2.653 )

Notes
[20] - n=subjects who had at least 1 post-dose measurement at given time point.
[21] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in Growth (Sitting Height) Over Time

Top of page

End point title

Change From Baseline in Growth (Sitting Height) Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[22]	26 ^[23]
Units: cm
arithmetic mean (standard deviation)
Change at Week 40; n=23, 23	2.66 ( 5.496 )	2.39 ( 1.486 )
Change at Week 64; n=26, 26	3.08 ( 2.405 )	3.45 ( 1.390 )
Change at Week 160; n=26, 26	8.29 ( 2.928 )	8.62 ( 2.163 )

Notes
[22] - n=subjects who had at least 1 post-dose measurement at given time point.
[23] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in Growth (Arm Length) Over Time

Top of page

End point title

Change From Baseline in Growth (Arm Length) Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[24]	26 ^[25]
Units: cm
arithmetic mean (standard deviation)
Change at Week 40; n=24, 23	2.36 ( 1.058 )	2.08 ( 0.905 )
Change at Week 64; n=26, 26	3.99 ( 1.556 )	4.77 ( 7.382 )
Change at Week 160; n=26, 26	8.50 ( 1.537 )	8.32 ( 1.798 )

Notes
[24] - n=subjects who had at least 1 post-dose measurement at given time point.
[25] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in Growth (Leg Length) Over Time

Top of page

End point title

Change From Baseline in Growth (Leg Length) Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[26]	26 ^[27]
Units: cm
arithmetic mean (standard deviation)
Change to Week 40; n=24, 23	2.90 ( 1.365 )	2.82 ( 1.270 )
Change at Week 64; n=26, 26	5.03 ( 1.879 )	5.16 ( 1.283 )
Change at Week 160; n=26, 26	11.78 ( 3.040 )	11.67 ( 2.338 )

Notes
[26] - n=subjects who had at least 1 post-dose measurement at given time point.
[27] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: 6MWT Distance (Predicted Percent of Normal) Change from Baseline Over Time

Top of page

End point title

6MWT Distance (Predicted Percent of Normal) Change from Baseline Over Time

End point description

The total distance walked (meters) in a 6-minute period was measured. The percent of predicted values were calculated using published normative data based on age, gender, and height (Geiger et al. 2007).

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26	26
Units: percentage of predicted distance
least squares mean (standard error)
Change at Week 40	3.25 ( 1.841 )	0.24 ( 2.153 )
Change at Week 64	5.29 ( 1.568 )	3.70 ( 1.731 )
Change at Week 160	1.96 ( 1.483 )	2.15 ( 1.932 )

Attachments

Untitled (Filename: 6MWT Statistical Analysis.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time

Top of page

End point title

Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time

End point description

The POSNA-PODCI yields 4 functional assessment scores: Upper Extremity Function,Transfers and Basic Mobility, Sports and Physical Function, and Comfort/Pain. In addition, a Global Function score, which is an average of the 4 functional assessments, and a Happiness score are calculated. Raw, mean, standardized, and normative scores are calculated for each scale. Normative scores are calculated so that higher scores indicate better functioning. All scores are referenced to the general, healthy population with a normative mean score of 50 and a standard deviation of 10.

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[28]	25 ^[29]
Units: score on a scale
least squares mean (standard error)
Change at Week 40; n=25, 24	2.97 ( 0.710 )	2.97 ( 1.212 )
Change at Week 64; n=26, 25	1.89 ( 0.914 )	3.20 ( 0.829 )
Change at Week 160; n=26, 25	-0.02 ( 0.740 )	1.82 ( 1.449 )

Attachments

Untitled (Filename: POSNA-PODCI Upper Extremity Scale Scores Statistical Analysis.docx)

Notes
[28] - n=subjects who had at least 1 post-dose measurement at given time point.
[29] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time

Top of page

End point title

Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[30]	25 ^[31]
Units: score on a scale
least squares mean (standard error)
Change at Week 40; n=25, 24	4.04 ( 0.827 )	3.69 ( 1.648 )
Change at Week 64; n=26, 25	-0.34 ( 3.123 )	4.32 ( 1.364 )
Change at Week 160; n=26, 25	1.88 ( 3.285 )	5.44 ( 1.113 )

Attachments

Untitled (Filename: POSNA-PODCI Transfer and Basic Mobility Scale Scores Statistical Analysis.docx)

Notes
[30] - n=subjects who had at least 1 post-dose measurement at given time point.
[31] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time

Top of page

End point title

Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[32]	25 ^[33]
Units: score on a scale
least squares mean (standard error)
Change at Week 40; n=25, 24	9.78 ( 1.679 )	9.15 ( 2.249 )
Change at Week 64; n=26, 25	7.74 ( 2.636 )	9.84 ( 2.534 )
Change at Week 160; n=26, 25	12.04 ( 2.102 )	14.33 ( 1.834 )

Attachments

Untitled (Filename: POSNA-PODCI Sports_Physical Functioning Scale Scores Statistical Analysis.docx)

Notes
[32] - n=subjects who had at least 1 post-dose measurement at given time point.
[33] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time

Top of page

End point title

Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[34]	25 ^[35]
Units: score on a scale
least squares mean (standard error)
Change at Week 40; n=25, 24	7.67 ( 2.399 )	7.39 ( 2.477 )
Change at Week 64; n=26, 25	5.60 ( 2.904 )	7.74 ( 2.077 )
Change at Week 160; n=26, 25	13.06 ( 2.187 )	12.38 ( 2.265 )

Attachments

Untitled (Filename: POSNA-PODCI Pain_Comfort Scale Scores Statistical Analysis.docx)

Notes
[34] - n=subjects who had at least 1 post-dose measurement at given time point.
[35] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time

Top of page

End point title

Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[36]	25 ^[37]
Units: score on a scale
least squares mean (standard error)
Change at Week 40; n=25, 24	2.84 ( 2.328 )	3.01 ( 1.902 )
Change at Week 64; n=26, 25	2.18 ( 1.914 )	3.34 ( 1.914 )
Change at Week 160; n=26, 25	6.46 ( 2.486 )	9.19 ( 1.075 )

Attachments

Untitled (Filename: POSNA-PODCI Happiness Scale Scores Statistical Analysis.docx)

Notes
[36] - n=subjects who had at least 1 post-dose measurement at given time point.
[37] - n=subjects who had at least 1 post-dose measurement at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time

Top of page

End point title

Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Intent to Treat Analysis Set: Burosumab Q2W	Intent to Treat Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26	26
Units: score on a scale
least squares mean (standard error)
Change at Week 40; n=25, 24	9.06 ( 1.560 )	8.12 ( 2.351 )
Change at Week 64; n=26, 25	6.02 ( 2.706 )	8.72 ( 2.019 )
Change at Week 160; n=25, 25	11.37 ( 1.804 )	11.94 ( 2.024 )

Attachments

Untitled (Filename: POSNA-PODCI Global Functioning Scale Scores Statistical Analysis.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in FEP Over Time

Top of page

End point title

Change From Baseline in FEP Over Time

End point description

FEP is defined as 100% × (urine phosphorus × serum creatinine)/(urine creatinine × serum phosphorus), where the 2-hour urine sample was used for urine phosphorus and urine creatinine.

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	Safety Analysis Set: Burosumab Q2W	Safety Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	25 ^[38]	26 ^[39]
Units: percentage of phosphorus excreted
arithmetic mean (standard deviation)
Change at Week 40; n=25, 26	-3.97 ( 7.161 )	-4.85 ( 7.170 )
Change at Week 64; n=20, 22	-2.63 ( 4.446 )	-3.96 ( 7.522 )
Change at Week 160; n=23, 26	-5.43 ( 6.985 )	-6.47 ( 8.072 )

Notes
[38] - n=subjects who had an assessment at given time point.
[39] - n=subjects who had an assessment at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in P1NP Over Time

Top of page

End point title

Change From Baseline in P1NP Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64

End point values	PK/PD Analysis Set: Burosumab Q2W	PK/PD Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	24 ^[40]	26 ^[41]
Units: ng/mL
arithmetic mean (standard deviation)
Change at Week 40; n=24, 26	275.98 ( 329.587 )	224.91 ( 161.053 )
Change at Week 64; n=22, 23	137.35 ( 354.315 )	133.56 ( 192.306 )

Notes
[40] - n=subjects who had evaluable serum data at given time point.
[41] - n=subjects who had evaluable serum data at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in CTx Over Time

Top of page

End point title

Change From Baseline in CTx Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64

End point values	PK/PD Analysis Set: Burosumab Q2W	PK/PD Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[42]	26 ^[43]
Units: ng/mL
arithmetic mean (standard deviation)
Change at Week 40; n=26, 26	1.01 ( 0.802 )	0.64 ( 0.578 )
Change at Week 64; n=25, 25	1.08 ( 0.870 )	0.81 ( 0.706 )

Notes
[42] - n=subjects who had evaluable serum data at given time point.
[43] - n=subjects who had evaluable serum data at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in ALP Over Time

Top of page

End point title

Change From Baseline in ALP Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	PK/PD Analysis Set: Burosumab Q2W	PK/PD Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26 ^[44]	26 ^[45]
Units: U/L
arithmetic mean (standard deviation)
Change at Week 40; n=26, 26	-79.4 ( 97.40 )	-47.8 ( 70.86 )
Change at Week 64: n=24, 23	-113.9 ( 81.28 )	-80.9 ( 67.11 )
Change at Week 160; n=26, 26	-153.1 ( 132.45 )	-140.0 ( 115.82 )

Attachments

Untitled (Filename: ALP Statistical Analysis.docx)

Notes
[44] - n=subjects who had evaluable serum data at given time point.
[45] - n=subjects who had evaluable serum data at given time point.

No statistical analyses for this end point

Secondary: Change From Baseline in BALP Over Time

Top of page

End point title

Change From Baseline in BALP Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Week 40, 64, 160

End point values	PK/PD Analysis Set: Burosumab Q2W	PK/PD Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	20 ^[46]	20 ^[47]
Units: mcg/L
arithmetic mean (standard deviation)
Change at Week 40; n=20, 20	-35.55 ( 46.738 )	-27.80 ( 31.409 )
Change at Week 64; n=19, 20	-50.40 ( 36.478 )	-47.13 ( 28.822 )
Change at Week 160; n=20, 20	-67.25 ( 59.309 )	-56.73 ( 52.284 )

Notes
[46] - n=subjects who had evaluable serum data at given time point.
[47] - n=subjects who had evaluable serum data at given time point.

No statistical analyses for this end point

Secondary: Serum Pre-Dose Concentrations of Burosumab

Top of page

End point title

Serum Pre-Dose Concentrations of Burosumab

End point description

End point type

Secondary

End point timeframe

Week 40, 64, 160

End point values	PK/PD Analysis Set: Burosumab Q2W	PK/PD Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26	26
Units: ng/mL
arithmetic mean (standard deviation)
Week 40; n=26, 26	13188.81 ( 7188.588 )	6443.08 ( 3266.215 )
Week 64; n= 26, 24	15846.65 ( 9385.393 )	8525.63 ( 3968.821 )
Week 160; n=26, 26	13975.27 ( 8168.877 )	13163.96 ( 6593.120 )

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs)

Top of page

End point title

Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs)

End point description

An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE is defined as an AE or suspected adverse reaction that at any dose results in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect. Severity was graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). TEAEs are defined as AEs with onset on or after the time of initiation of study drug administration.

End point type

Secondary

End point timeframe

Up to 216 weeks

End point values	Safety Analysis Set: Burosumab Q2W	Safety Analysis Set: Burosumab Q4W Then Q2W
Number of subjects analysed	26	26
Units: subjects
All TEAEs	26	26
Serious TEAE	0	1
Related TEAE	17	21
Serious Related TEAE	0	1
Grade 3 or 4 TEAE	1	1
TEAE Leading to Study Discontinuation	0	0
TEAE Leading to Treatment Discontinuation	0	0
TEAE Leading to Death	0	0

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Up to 216 weeks

Adverse event reporting additional description

TEAEs, defined as AEs with onset on or after the time of initiation of study drug administration, are presented.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Burosumab Q2W

Reporting group description

Burosumab SC injections Q2W. Dose was determined by the subject's weight and prescribed dose by their study doctor.

Reporting group title

Burosumab Q4W Then Q2W

Reporting group description

Burosumab SC injections Q4W. Dose was determined by the subject's weight and prescribed dose by their study doctor. Subjects in Q4W were to switch to Q2W beginning with Week 64 dosing.

Serious adverse events	Burosumab Q2W	Burosumab Q4W Then Q2W
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 26 (0.00%)	1 / 26 (3.85%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Burosumab Q2W	Burosumab Q4W Then Q2W
Total subjects affected by non serious adverse events
subjects affected / exposed	26 / 26 (100.00%)	26 / 26 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin Papilloma
subjects affected / exposed	3 / 26 (11.54%)	0 / 26 (0.00%)
occurrences all number	3	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	5 / 26 (19.23%)	3 / 26 (11.54%)
occurrences all number	7	5
Influenza Like Illness
subjects affected / exposed	2 / 26 (7.69%)	1 / 26 (3.85%)
occurrences all number	2	1
Injection Site Bruising
subjects affected / exposed	5 / 26 (19.23%)	4 / 26 (15.38%)
occurrences all number	6	5
Injection Site Erythema
subjects affected / exposed	14 / 26 (53.85%)	9 / 26 (34.62%)
occurrences all number	78	92
Injection Site Pain
subjects affected / exposed	3 / 26 (11.54%)	3 / 26 (11.54%)
occurrences all number	6	3
Injection Site Pruritus
subjects affected / exposed	2 / 26 (7.69%)	4 / 26 (15.38%)
occurrences all number	2	8
Injection Site Rash
subjects affected / exposed	2 / 26 (7.69%)	2 / 26 (7.69%)
occurrences all number	4	4
Injection Site Reaction
subjects affected / exposed	13 / 26 (50.00%)	13 / 26 (50.00%)
occurrences all number	48	38
Injection Site Swelling
subjects affected / exposed	5 / 26 (19.23%)	1 / 26 (3.85%)
occurrences all number	7	2
Malaise
subjects affected / exposed	3 / 26 (11.54%)	3 / 26 (11.54%)
occurrences all number	7	3
Medical Device Pain
subjects affected / exposed	3 / 26 (11.54%)	2 / 26 (7.69%)
occurrences all number	5	2
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	4
Pain
subjects affected / exposed	6 / 26 (23.08%)	4 / 26 (15.38%)
occurrences all number	6	5
Peripheral Swelling
subjects affected / exposed	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	1	2
Pyrexia
subjects affected / exposed	12 / 26 (46.15%)	13 / 26 (50.00%)
occurrences all number	37	36
Immune system disorders
Seasonal Allergy
subjects affected / exposed	6 / 26 (23.08%)	11 / 26 (42.31%)
occurrences all number	12	18
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	3 / 26 (11.54%)	1 / 26 (3.85%)
occurrences all number	7	2
Menorrhagia
subjects affected / exposed	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	6	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	6	0
Cough
subjects affected / exposed	21 / 26 (80.77%)	15 / 26 (57.69%)
occurrences all number	60	34
Dyspnoea
subjects affected / exposed	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	3	0
Epistaxis
subjects affected / exposed	6 / 26 (23.08%)	2 / 26 (7.69%)
occurrences all number	9	3
Nasal Congestion
subjects affected / exposed	10 / 26 (38.46%)	10 / 26 (38.46%)
occurrences all number	20	24
Nasal Obstruction
subjects affected / exposed	3 / 26 (11.54%)	1 / 26 (3.85%)
occurrences all number	3	1
Oropharyngeal Pain
subjects affected / exposed	14 / 26 (53.85%)	12 / 26 (46.15%)
occurrences all number	36	24
Respiratory Tract Congestion
subjects affected / exposed	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	2	0
Rhinorrhoea
subjects affected / exposed	12 / 26 (46.15%)	10 / 26 (38.46%)
occurrences all number	24	28
Sinus Congestion
subjects affected / exposed	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	3	0
Sneezing
subjects affected / exposed	6 / 26 (23.08%)	6 / 26 (23.08%)
occurrences all number	8	16
Throat Irritation
subjects affected / exposed	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	1	4
Upper Respiratory Tract Congestion
subjects affected / exposed	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	1	2
Wheezing
subjects affected / exposed	3 / 26 (11.54%)	2 / 26 (7.69%)
occurrences all number	4	3
Psychiatric disorders
Anxiety
subjects affected / exposed	3 / 26 (11.54%)	0 / 26 (0.00%)
occurrences all number	4	0
Initial Insomnia
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Insomnia
subjects affected / exposed	4 / 26 (15.38%)	1 / 26 (3.85%)
occurrences all number	4	3
Investigations
Blood 1,25-Dihydroxycholecalciferol Increased
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Blood 25-Hydroxycholecalciferol Decreased
subjects affected / exposed	2 / 26 (7.69%)	1 / 26 (3.85%)
occurrences all number	3	1
Blood Parathyroid Hormone Increased
subjects affected / exposed	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	1	2
Vitamin D Decreased
subjects affected / exposed	6 / 26 (23.08%)	5 / 26 (19.23%)
occurrences all number	7	6
Injury, poisoning and procedural complications
Arthropod Bite
subjects affected / exposed	1 / 26 (3.85%)	3 / 26 (11.54%)
occurrences all number	3	4
Contusion
subjects affected / exposed	6 / 26 (23.08%)	5 / 26 (19.23%)
occurrences all number	8	7
Fall
subjects affected / exposed	3 / 26 (11.54%)	3 / 26 (11.54%)
occurrences all number	3	4
Joint Injury
subjects affected / exposed	2 / 26 (7.69%)	2 / 26 (7.69%)
occurrences all number	3	2
Laceration
subjects affected / exposed	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	2	0
Ligament Sprain
subjects affected / exposed	3 / 26 (11.54%)	2 / 26 (7.69%)
occurrences all number	3	2
Procedural Pain
subjects affected / exposed	0 / 26 (0.00%)	6 / 26 (23.08%)
occurrences all number	0	8
Skin Abrasion
subjects affected / exposed	3 / 26 (11.54%)	4 / 26 (15.38%)
occurrences all number	3	4
Thermal Burn
subjects affected / exposed	3 / 26 (11.54%)	0 / 26 (0.00%)
occurrences all number	3	0
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 26 (7.69%)	7 / 26 (26.92%)
occurrences all number	3	7
Headache
subjects affected / exposed	20 / 26 (76.92%)	19 / 26 (73.08%)
occurrences all number	139	91
Lethargy
subjects affected / exposed	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	2	2
Migraine
subjects affected / exposed	5 / 26 (19.23%)	1 / 26 (3.85%)
occurrences all number	19	1
Post-Traumatic Headache
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Ear and labyrinth disorders
Ear Pain
subjects affected / exposed	10 / 26 (38.46%)	8 / 26 (30.77%)
occurrences all number	12	13
Eye disorders
Dry Eye
subjects affected / exposed	0 / 26 (0.00%)	3 / 26 (11.54%)
occurrences all number	0	3
Eye Pain
subjects affected / exposed	2 / 26 (7.69%)	2 / 26 (7.69%)
occurrences all number	3	2
Eye Pruritus
subjects affected / exposed	3 / 26 (11.54%)	2 / 26 (7.69%)
occurrences all number	3	3
Lacrimation Increased
subjects affected / exposed	1 / 26 (3.85%)	3 / 26 (11.54%)
occurrences all number	1	3
Gastrointestinal disorders
Abdominal Discomfort
subjects affected / exposed	4 / 26 (15.38%)	2 / 26 (7.69%)
occurrences all number	4	5
Abdominal Pain
subjects affected / exposed	2 / 26 (7.69%)	7 / 26 (26.92%)
occurrences all number	3	15
Abdominal Pain Upper
subjects affected / exposed	10 / 26 (38.46%)	8 / 26 (30.77%)
occurrences all number	29	22
Constipation
subjects affected / exposed	2 / 26 (7.69%)	4 / 26 (15.38%)
occurrences all number	2	5
Dental Caries
subjects affected / exposed	0 / 26 (0.00%)	3 / 26 (11.54%)
occurrences all number	0	4
Diarrhoea
subjects affected / exposed	7 / 26 (26.92%)	11 / 26 (42.31%)
occurrences all number	28	23
Gingival Pain
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Lip Swelling
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Mouth Ulceration
subjects affected / exposed	3 / 26 (11.54%)	1 / 26 (3.85%)
occurrences all number	4	2
Nausea
subjects affected / exposed	9 / 26 (34.62%)	8 / 26 (30.77%)
occurrences all number	22	15
Oral Pain
subjects affected / exposed	2 / 26 (7.69%)	3 / 26 (11.54%)
occurrences all number	2	5
Toothache
subjects affected / exposed	6 / 26 (23.08%)	11 / 26 (42.31%)
occurrences all number	6	23
Vomiting
subjects affected / exposed	13 / 26 (50.00%)	16 / 26 (61.54%)
occurrences all number	41	28
Skin and subcutaneous tissue disorders
Dermatitis Contact
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Dry Skin
subjects affected / exposed	1 / 26 (3.85%)	4 / 26 (15.38%)
occurrences all number	1	5
Eczema
subjects affected / exposed	1 / 26 (3.85%)	3 / 26 (11.54%)
occurrences all number	1	4
Erythema
subjects affected / exposed	1 / 26 (3.85%)	3 / 26 (11.54%)
occurrences all number	2	4
Pruritus
subjects affected / exposed	4 / 26 (15.38%)	5 / 26 (19.23%)
occurrences all number	4	6
Rash
subjects affected / exposed	7 / 26 (26.92%)	8 / 26 (30.77%)
occurrences all number	8	12
Swelling Face
subjects affected / exposed	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	1	4
Renal and urinary disorders
Glycosuria
subjects affected / exposed	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 26 (42.31%)	17 / 26 (65.38%)
occurrences all number	41	40
Back Pain
subjects affected / exposed	4 / 26 (15.38%)	4 / 26 (15.38%)
occurrences all number	15	5
Bone Pain
subjects affected / exposed	2 / 26 (7.69%)	3 / 26 (11.54%)
occurrences all number	2	3
Groin Pain
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	3
Musculoskeletal Pain
subjects affected / exposed	3 / 26 (11.54%)	4 / 26 (15.38%)
occurrences all number	3	5
Myalgia
subjects affected / exposed	4 / 26 (15.38%)	7 / 26 (26.92%)
occurrences all number	7	10
Neck Pain
subjects affected / exposed	4 / 26 (15.38%)	2 / 26 (7.69%)
occurrences all number	4	3
Pain In Extremity
subjects affected / exposed	10 / 26 (38.46%)	17 / 26 (65.38%)
occurrences all number	30	35
Scoliosis
subjects affected / exposed	3 / 26 (11.54%)	1 / 26 (3.85%)
occurrences all number	4	1
Infections and infestations
Conjunctivitis
subjects affected / exposed	3 / 26 (11.54%)	0 / 26 (0.00%)
occurrences all number	3	0
Ear Infection
subjects affected / exposed	4 / 26 (15.38%)	3 / 26 (11.54%)
occurrences all number	5	6
Enterobiasis
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Gastroenteritis
subjects affected / exposed	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	4	0
Gastroenteritis Viral
subjects affected / exposed	2 / 26 (7.69%)	4 / 26 (15.38%)
occurrences all number	3	6
Gingival Abscess
subjects affected / exposed	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	1	2
Infectious Mononucleosis
subjects affected / exposed	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2
Influenza
subjects affected / exposed	6 / 26 (23.08%)	4 / 26 (15.38%)
occurrences all number	9	4
Lice Infestation
subjects affected / exposed	2 / 26 (7.69%)	1 / 26 (3.85%)
occurrences all number	3	1
Nasopharyngitis
subjects affected / exposed	13 / 26 (50.00%)	15 / 26 (57.69%)
occurrences all number	35	43
Pharyngitis Streptococcal
subjects affected / exposed	4 / 26 (15.38%)	6 / 26 (23.08%)
occurrences all number	4	7
Rhinitis
subjects affected / exposed	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	4	0
Sinusitis
subjects affected / exposed	3 / 26 (11.54%)	3 / 26 (11.54%)
occurrences all number	3	4
Tooth Abscess
subjects affected / exposed	3 / 26 (11.54%)	6 / 26 (23.08%)
occurrences all number	6	10
Upper Respiratory Tract Infection
subjects affected / exposed	12 / 26 (46.15%)	13 / 26 (50.00%)
occurrences all number	17	16
Viral Infection
subjects affected / exposed	3 / 26 (11.54%)	2 / 26 (7.69%)
occurrences all number	3	2
Viral Upper Respiratory Tract Infection
subjects affected / exposed	5 / 26 (19.23%)	3 / 26 (11.54%)
occurrences all number	8	4
Metabolism and nutrition disorders
Vitamin D Deficiency
subjects affected / exposed	4 / 26 (15.38%)	6 / 26 (23.08%)
occurrences all number	5	8

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

07 May 2014

Key changes impacting the conduct of the study were: • Pregnancy testing (for female subjects of childbearing potential who had experienced menarche), contraception requirements, and follow up for pregnancies were incorporated into the protocol. Although the study enrolled pre-pubertal subjects of Tanner Stage 2 or less, contraception requirements and regular pregnancy testing for subjects entering puberty during trial participation was included as an added safety precaution, given that burosumab has been found to be associated with premature births, embryo/fetal deaths, and abortions in cynomolgus monkeys. • Subjects were to be discontinued from study drug if they experienced new or clinically significant worsening in mineralization that was considered clinically meaningful by the investigator and/or sponsor and was related was to study drug. Ectopic mineralization is a characteristic feature of patients with XLH and is also related to the current conventional therapy treatment with oral phosphate and active forms of vitamin D. It is unknown whether burosumab may increase the risk of ectopic mineralization including nephrocalcinosis. • The standing height inclusion criterion was broadened from < 25th percentile to < 50th percentile to include pediatric XLH subjects with significant bone disease who met all other eligibility criteria and who would previously have been excluded from participation in the study based on their stature alone.

02 Jul 2014

Key changes impacting the conduct of the study were: • The number of study sites was increased from 8 to 9. • Tanner staging criteria was to be assessed for all subjects, for consistency of data collection and to ensure that any subjects with early pubertal status due to underlying conditions were identified. • Subjects receiving growth hormone therapy within 3 months (previously: 12 months) of screening were excluded from the study.

02 Mar 2015

Key changes impacting the conduct of the study were: • The number of study sites was increased from 9 to 12. • Dose Cohort 3 was expanded to include up to 30 subjects for a total study population of up to 50 subjects. “Pre-expansion subjects” (n = 36) were fully enrolled under the earlier versions of the protocol; Dose Cohort 3 “expansion subjects” (n = approximately 15) were to be enrolled under the Amendment 3. • Added assessment of changes in rickets severity by the RSS method to complement assessments by RGI C. Methods for blinding of radiographic assessments also were added. • RSS at the knee of at least 1.5, as determined by a central reader, was required for inclusion in the expansion group. Requiring subjects in the expansion group to have an RSS of at least 1.5 at the knee increases the probability of seeing a meaningful reduction in rickets severity with burosumab. • Because the enrollment criteria were adjusted to require a specific level of rickets severity, gender-related differences in the severity of skeletal disease were minimized and the requirement for gender balance was removed for the expansion group.

22 Apr 2015

Key changes impacting the conduct of the study were: • The upper limit of the target serum phosphorus range was updated to 5.0 mg/dL (1.61 mmol/L) from 4.5 mg/dL (1.45 mmol/L). The normal reference serum phosphorus range for children aged 5 to 12 years is approximately 3.2 to 6.1 mg/dL (1.03 to 1.97 mmol/L). Increasing the upper limit of the target fasting serum phosphorus range for this study maintained the target within the low- to mid- normal range and would avoid unnecessary fluctuations in dose levels. • Dose titration adjustments, whether upward or downward, could be made in increments of 0.3 mg/kg for the Q2W regimen (vs 0.1 mg/kg previously) and in increments of 0.4 mg/kg for the Q4W regimen (vs 0.2 mg/kg previously). The dose increments in the initial version of the protocol were selected to slowly increase the dose to prevent any unexpected or exaggerated increases in serum phosphorus. Available data showed small proportional increases in serum phosphorus with the previous titration scheme, and many dose cycles were required to reach a dose that produced serum phosphorus levels in the target range. Therefore, in the absence of any safety signal and to allow subjects to achieve their serum phosphorus target range earlier, the dose titration scheme was modified. • Unscheduled blood draws for peak serum phosphorus measurements could be obtained at study visits if titration continues into the Treatment Period to enable appropriate dose management.

22 Apr 2015

(continued) • The maximum dose of burosumab in regimen Q2W was increased to 2.0 mg/kg. In addition, the maximum allowable dose was capped at 90 mg (for both the Q2W and Q4W groups). The target therapeutic goal remained the same, ie, peak serum phosphorus levels between 3.5 and 5.0 mg/dL (1.13 and 1.62 mmol/L). This change was based on the finding that some subjects needed doses higher than 1.0 mg/dL (0.32 mmol/L) to achieve the serum phosphorus target, regardless of whether the dose was given at the Q2W or Q4W dose regimen. Approximately half of the subjects in the Q4W regimen were already receiving doses above 1.0 mg/dL (0.32 mmol/L) to achieve the proposed target serum phosphorus range, and no safety concerns were raised. The increases in serum phosphorus were proportional to the dose administered, independently of the whether the subject is receiving burosumab monthly or biweekly. No cumulative dose effect in the Q2W regimen group was observed. The maximum dose was set at 90 mg because there is limited experience in adults with burosumab doses above 90 mg. • Changes were made in the timing of serum phosphorus, calcium, and 1,25(OH)2D measurements at Weeks 48 through 62 to better characterize the longer-term PD effects of burosumab by assessing both peak and trough measurements toward the end of the study. • The dosing window was changed so that subjects will be dosed at Q2W or Q4W week intervals (±3 days) and no fewer than 8 days apart (previously: no fewer than 12 days apart). Adjusting the dosing window provided additional convenience to subjects and study sites without impacting safety.

28 Aug 2015

• A 96-week Treatment Extension Period was incorporated into the study design to evaluate the long-term safety and efficacy of burosumab. It is expected that the maintenance of phosphate control will allow for continued healing of rickets and bowing and maximize growth outcomes. Changes in growth and correction of lower extremity bowing may take longer to observe than the healing of rickets, and these outcomes continued to be followed in the Treatment Extension Period. • During the Treatment Extension Period, all subjects receive Q2W administration of burosumab. The transition of subjects to Q2W dosing reflects interim Week 40 findings related to serum phosphorus levels, rickets, and dose. Subjects in the Q2W dosing regimen showed a more stable and consistent increase in serum phosphorus levels with less fluctuation over time than in subjects who received burosumab Q4W for whom serum phosphorus levels increased at the middle of the dose cycle (week 2) but tended to return to baseline at the end of the dose interval (week 4). - Subjects who had been receiving Q2W dosing continued receiving the same dose at the same dose interval. - Subjects who had been receiving the Q4W regimen switched to the Q2W regimen beginning with the Week 64 dose. The dose was 60% of the most recent monthly dose (rounded to the nearest 10 mg), the total dose was approximately 20% higher per month compared with the subject’s Q4W dose. • Vital signs measurements were required to be performed before any additional assessments were completed and after the subject had rested for 5 minutes. A second BP measurement was required to be obtained at the end of the study visit after all procedures have been performed.

07 Jul 2016

(continued) Statistical Analyses • In Section 7.6.4.3, the statistical methodology for the Week 40 analysis was updated to include the GEE model rather than the Mixed Model for Repeated Measures. 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. Definition of Adverse Events • In Section 8.5.1, language was added to clarify that hospitalizations planned prior to study enrollment (eg, for elective surgeries) are not considered SAEs but hospitalizations that occur for pre existing conditions that are scheduled after study enrollment are considered SAEs.

07 Jul 2016

Key changes impacting the conduct of the study were: Drug Administration • In Section 7.1 and Section 7.2, language and procedures regarding dose adjustment were updated and clarified. The information was also reorganized for easier reference to dosing for a specific period of the study (eg, Titration Period or Treatment Extension Period). Specifically, the protocol states that after the initial dose titration is complete, during the Treatment Period and Treatment Extension Period dose adjustments may be made in any subject if specific serum phosphorus criteria are met. When post-titration dose adjustment is needed, doses should be adjusted in 10 mg total dose increments (eg, a 20 mg rounded total dose would be increased to a 30 mg total dose). • Section 7.4.1 was updated to state that “At the discretion of the investigator and after proper training by study personnel in SC injection technique, a subject’s parent or non-healthcare provider caregiver may administer burosumab to the subject under the supervision of a Home Health (HH) nurse where local regulations permit and where logistically feasible. Parents or caregivers will be instructed to follow the directions provided in the Instructions for Use. The dosing schedule will remain the same.” Inclusion Criteria • In Section 7.3.1, inclusion criterion #10 was updated to state that sexually active male and female subjects must be willing to use 2 highly effective methods of contraception during the study. Previously it stated, “an acceptable method.”

07 Jul 2016

(continued) Removal of Subjects • In Section 7.3.3, language was added to indicate that orthopedic surgery will be permitted during the Treatment Extension Period if recommended by the investigator or consulting physician and that subjects who develop hyperparathyroidism may remain on study but use of medication to suppress PTH (eg, Sensipar®, cinacalcet, calcimimetics) is not permitted at any time. Subjects should be removed from study if treatment for hyperparathyroidism becomes medically necessary. Study Procedures and Assessments • The Schedule of Events was updated to add serum phosphorus and serum 1,25(OH)2D measurements at Weeks 124 and 148. • Section 7.5.3.2 was modified to add a 6MWT assessment at Week 160 and to indicate the POSNA-PODCI instrument will be administered at Weeks 88 and 160 but not at Weeks 112 and 136. • Measurement of pre-dose serum burosumab concentration at Week 24 using retrospective samples was added to Section 7.5.4 and the Schedule of Events. • The Schedule of Events was updated to indicate post-treatment Tanner staging will be performed beginning at Week 64 and every 6 months thereafter during the extension phase of the study. • Bilateral AP knee X-rays were added at Week 160 to the Schedule of Events and in Section 7.5.3.1. In addition, it is noted that beginning at Week 64 and during the extension, radiographs will be evaluated for epiphyseal closure, and that RGI C assessment of radiographs will occur at Weeks 88 and 160.

07 Jul 2016

(continued) Genetic Testing • Section 7.5.5 was modified to add that genetic testing for mutations in genes consistent with syndromes that have clinical and biochemical phenotypic overlap with XLH will be performed if the initial PHEX mutation analysis result is negative or inconclusive and informed consent is provided. This testing will 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 will be provided the genetic testing results and will determine when and whether the information should be shared with the subject. Central Reads of Echocardiograms • Section 7.5.5.6 was updated to state that ECHOs will be read centrally rather than locally. The central core lab will provide a study specific protocol to be followed by the sites to ensure adequate image acquisition for the assessment of mineralization. Safety Measures • In Section 7.5.5, ECG is listed as a general safety assessment. Previously it was listed within the safety assessments for ectopic mineralization. • Section 7.5.5.8 was updated to add assessment of lipase in all subjects and specify additional laboratory analyses will be performed reflexively if serum amylase levels are elevated to ≥ 1.5 times the upper limit of the reference range (ULRR). • Language in Section 7.5.5.8 regarding FGF23 assays was updated to indicate testing will be performed by a contract laboratory and not the sponsor’s development partner, Kyowa Hakko Kirin Pharma, Inc Ethics • Section 8.1.2 was updated to state that both the sponsor and investigator will make every effort to assure the study described in this protocol is conducted in full conformance with those principles, current FDA regulations, ICH GCP guidelines, and local ethical and regulatory requirements.

08 May 2017

Treatment Duration • The study treatment period was extended for subjects at study sites in the US for up to an additional 56 weeks until September 2018; therefore, the total treatment duration varied by region. The study consisted of an individual dose Titration Period (16 weeks), a Treatment Period (48 weeks), and a Treatment Extension Period I (up to 96 weeks), for a total treatment duration of up to 160 weeks for subjects at study sites outside the US. In the US, the study also included a Treatment Extension Period II (up to 56 weeks) until September 2018 for a maximum total treatment duration of up to 216 weeks. The total duration of treatment varied for the individual US subjects based on their initial time of enrollment but was not to exceed 216 weeks. For subjects at study sites in Europe, Week 160 was the final efficacy visit for the study. Additional safety follow-up phone calls and visits occurred for certain subjects. End of Study Definition, Timing, and Procedures • In Section 7.1 and related sections, the description of the study periods was updated to indicate that the study duration would vary by region. The study consisted of an individual dose Titration Period (16 weeks), a Treatment Period (48 weeks), and a Treatment Extension Period I (up to 96 weeks), for a total treatment duration of up to 160 weeks for subjects at study sites outside the US. For subjects at study sites outside the US, the Week 160 visit was their end of study (EOS) efficacy visit (referred to as EOSI). In the US, the study also included a Treatment Extension Period II (up to 56 weeks) until September 2018, at which time subjects had their EOS efficacy visit (referred to as EOS II), for a maximum total treatment duration of up to 216 weeks.

08 May 2017

(continued) A safety follow-up telephone call was to occur at 5 weeks (+ 5 days) after the EOS (I or II) efficacy visit, and a final safety visit was to occur at 10 weeks (± 1 week) after the EOS (I or II) efficacy visit for subjects who were not continuing on burosumab treatment through commercial use or another mechanism. The end of study was defined as the date of the last protocol-specified procedures (including telephone contact) for the last subject in the study. 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 subcutaneous injection technique, the subject’s parent or caregiver may administer KRN23 to the subject, in the home setting without the supervision of a home health nurse during Treatment Extension Period II. Parents or caregivers were to be 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 are provided in Section 7.4.6. In addition, in Section 7.4.1, the language was updated to indicate that 1.5 mL is the maximum volume that should be administered at a single injection site, and that rotation of injections may include rotation to a different quadrant of the abdomen. Dose Limiting Toxicity • In Section 7.5.5.13 the definition of dose limiting toxicity (DLT) for serum phosphorus was corrected to be a confirmed serum phosphorus level of ≥ 6.5 mg/dL rather than ≥ 6.1 mg/dL.

08 May 2017

(continued) Statistical Analyses • In Section 7.6.4.5, Treatment Extension Period Analysis, language was updated to account for the addition of Treatment Extension Period II. Efficacy analysis was to be performed at the completion of Treatment Extension Period I for the overall population and a final analysis was to be performed at the end of the study, which is defined as the date of the last protocol-specified procedures (including telephone contact) for the last subject in the study. Pregnancy Testing and Contraception • Section 7.5.5.10 and the Schedule of Events were updated to indicate that during Treatment Extension Period II, pregnancy testing will be conducted at study site visits every 12 weeks for subjects of childbearing potential. In addition, the acceptable methods of contraception were updated. Anti-Burosumab Antibodies • In Section 5.3, Section 7.5.5.9, and the Schedule of Events, the term HAHA (human anti-human antibody) in reference to anti- burosumab antibody testing, was replaced with the term ADA (anti-drug antibody).

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Randomized, open Label, Dose Finding, Phase 2 Study to Assess the Pharmacodynamics and Safety of the anti-FGF23 antibody, KRN23, in Pediatric Patients with X-linked Hypophosphatemia (XLH)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in RSS Total Score Over Time

Primary: Change From Baseline in RSS Total Score Over Time

Primary: Change From Baseline in Serum Phosphorus Over Time

Primary: Change From Baseline in Serum Phosphorus Over Time

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

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

Primary: Change From Baseline in TmP/GFR Over Time

Primary: Change From Baseline in TmP/GFR Over Time

Secondary: Change From Baseline in RSS Knee Scores Over Time

Secondary: Change From Baseline in RSS Knee Scores Over Time

Secondary: Change From Baseline in RSS Wrist Scores Over Time

Secondary: Change From Baseline in RSS Wrist Scores Over Time

Secondary: Radiographic Global Impression of Change (RGI-C) Global Scores Over Time

Secondary: Radiographic Global Impression of Change (RGI-C) Global Scores Over Time

Secondary: RGI-C Knee Scores Over Time

Secondary: RGI-C Knee Scores Over Time

Secondary: RGI-C Wrist Scores Over Time

Secondary: RGI-C Wrist Scores Over Time

Secondary: Change From Baseline in Growth Velocity Over Time

Secondary: Change From Baseline in Growth Velocity Over Time

Secondary: Change From Baseline in Standing Height Z Score Over Time

Secondary: Change From Baseline in Standing Height Z Score Over Time

Secondary: Change From Baseline in Growth (Standing Height) Over Time

Secondary: Change From Baseline in Growth (Standing Height) Over Time

Secondary: Change From Baseline in Growth (Sitting Height) Over Time

Secondary: Change From Baseline in Growth (Sitting Height) Over Time

Secondary: Change From Baseline in Growth (Arm Length) Over Time

Secondary: Change From Baseline in Growth (Arm Length) Over Time

Secondary: Change From Baseline in Growth (Leg Length) Over Time

Secondary: Change From Baseline in Growth (Leg Length) Over Time

Secondary: 6MWT Distance (Predicted Percent of Normal) Change from Baseline Over Time

Secondary: 6MWT Distance (Predicted Percent of Normal) Change from Baseline Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Upper Extremity Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Transfer and Basic Mobility Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Sports/Physical Functioning Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Pain/Comfort Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Happiness Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time

Secondary: Change From Baseline in POSNA-PODCI (Normative Score) Global Functioning Scale Scores Over Time

Secondary: Change From Baseline in FEP Over Time

Secondary: Change From Baseline in FEP Over Time

Secondary: Change From Baseline in P1NP Over Time

Secondary: Change From Baseline in P1NP Over Time

Secondary: Change From Baseline in CTx Over Time

Secondary: Change From Baseline in CTx Over Time

Secondary: Change From Baseline in ALP Over Time

Secondary: Change From Baseline in ALP Over Time

Secondary: Change From Baseline in BALP Over Time

Secondary: Change From Baseline in BALP Over Time

Secondary: Serum Pre-Dose Concentrations of Burosumab

Secondary: Serum Pre-Dose Concentrations of Burosumab

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs)

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Randomized, open Label, Dose Finding, Phase 2 Study to Assess the Pharmacodynamics and Safety of the anti-FGF23 antibody, KRN23, in Pediatric Patients with X-linked Hypophosphatemia (XLH)