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    Clinical Trial Results:
    An Open-Label, Phase 2 Study to Assess the Safety, Pharmacodynamics, and Efficacy of KRN23 in Children from 1 to 4 Years Old with X-linked Hypophosphatemia (XLH)

    Summary
    EudraCT number
    2018-001983-49
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    10 Sep 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Mar 2020
    First version publication date
    22 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UX023-CL205
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02750618
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ultragenyx Pharmaceutical Inc.
    Sponsor organisation address
    60 Leveroni Court, Novato, California, United States, 94949
    Public contact
    Medical Information, Ultragenyx Pharmaceutical Inc, 1 8887568567, medinfo@ultragenyx.com
    Scientific contact
    Medical Information, Ultragenyx Pharmaceutical Inc, 1 8887568567, medinfo@ultragenyx.com
    Paediatric regulatory details
    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?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are to: • Establish the safety profile of KRN23 for the treatment of XLH in children between 1 and 4 years old • Determine the pharmacodynamic (PD) effects of KRN23 treatment on serum phosphorus and other PD markers that reflect the status of phosphate homeostasis in children between 1 and 4 years old 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
    05 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    3
    Children (2-11 years)
    10
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study enrolled approximately 10 pediatric subjects between 1 and 4 years old, inclusive, with clinical findings consistent with XLH including hypophosphatemia and radiographic evidence of rickets, and a confirmed PHEX mutation or variant of uncertain significance.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Burosumab Q2W
    Arm description
    Burosumab subcutaneous (SC) injections every 2 weeks (Q2W) for a total of 160 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    burosumab
    Investigational medicinal product code
    UX023
    Other name
    KRN23, Crysvita®, UX023
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The amount of drug administered will be calculated based on a subject’s weight. All subjects will receive KRN23 at a Q2W dosing regimen.

    Number of subjects in period 1
    Burosumab Q2W
    Started
    13
    Completed Week 40
    13
    Completed Week 64
    13
    Completed
    12
    Not completed
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Burosumab Q2W
    Reporting group description
    Burosumab subcutaneous (SC) injections every 2 weeks (Q2W) for a total of 160 weeks.

    Reporting group values
    Burosumab Q2W Total
    Number of subjects
    13 13
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    2.94 ± 1.146 -
    Gender categorical
    Units: Subjects
        Female
    4 4
        Male
    9 9
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2 2
        Not Hispanic or Latino
    11 11
        Unknown or Not Reported
    0 0
    Race
    Units: Subjects
        White
    12 12
        Black or African American
    1 1
    Serum Phosphorus
    Units: mg/dL
        arithmetic mean (standard deviation)
    2.51 ± 0.284 -
    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: units on a scale
        arithmetic mean (standard deviation)
    2.92 ± 1.367 -
    Recumbent length/ Standing height
    Growth is measured by recumbent length for subjects < 2 years of age or those unable or unwilling to stand for the measurement.
    Units: cm
        arithmetic mean (standard deviation)
    89.15 ± 7.597 -
    Recumbent length/ Standing height (Z score)
    Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the Centers for Disease Control [CDC] growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.
    Units: Z score
        arithmetic mean (standard deviation)
    -1.378 ± 1.1947 -
    Recumbent length/ Standing height (percentile)
    Units: percentile
        arithmetic mean (standard deviation)
    18.044 ± 25.2644 -
    Serum Alkaline Phosphatase (ALP)
    Units: U/L
        arithmetic mean (standard deviation)
    548.5 ± 193.80 -

    End points

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    End points reporting groups
    Reporting group title
    Burosumab Q2W
    Reporting group description
    Burosumab subcutaneous (SC) injections every 2 weeks (Q2W) for a total of 160 weeks.

    Primary: Change From Baseline at Week 40 in Serum Phosphorus

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    End point title
    Change From Baseline at Week 40 in Serum Phosphorus [1]
    End point description
    The Generalized Estimation Equation (GEE) model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure. Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set: all participants who received at least one dose of study drug and had evaluable blood samples.
    End point type
    Primary
    End point timeframe
    Baseline, Week 40
    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: GEE statistical analysis is presented in the data table.
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: mg/dL
        least squares mean (standard error)
    0.96 ± 0.117
    Attachments
    Untitled (Filename: Statistical Analysis 1 for Change From Baseline at Week 40 in Serum Phosphorus.docx)
    No statistical analyses for this end point

    Primary: Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation

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    End point title
    Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation [2]
    End point description
    An AE was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. A serious AE was defined as an AE that at any dose, in the view of either the Investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or disability, a congenital anomaly/birth defect, or other important medical events (according to the investigator). An AE was considered a TEAE if it occurred on or after the first dose and was not present prior to the first dose, or it was present prior to the first dose but increased in severity during the study. Events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death).
    End point type
    Primary
    End point timeframe
    From first dose of study drug through the end of the study (at Week 160). Maximum duration of exposure to study drug was 160 weeks.
    Notes
    [2] - 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: Descriptive statistics are presented per protocol.
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: participants
        Adverse Event Starting during Screening Period
    5
        TEAEs
    13
        Related TEAEs
    5
        Serious TEAEs
    1
        Serious Related TEAEs
    0
        Grade 3 or 4 TEAEs
    2
        TEAE Leading to Study Discontinuation
    0
        TEAE Leading to Treatment Discontinuation
    0
        TEAE Leading to Death
    0
    No statistical analyses for this end point

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

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    End point title
    Radiographic Global Impression of Change (RGI-C) Score at Week 40
    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). The Analysis of Covariance (ANCOVA) model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates.
    End point type
    Secondary
    End point timeframe
    Week 40
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: units on a scale
        least squares mean (standard error)
    2.21 ± 0.071
    Attachments
    Untitled (Filename: Statistical Analysis 1 for Radiographic Global Impression of Change (RGI-C) Score at Week 40.docx)
    No statistical analyses for this end point

    Secondary: RGI-C Score at Week 64

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    End point title
    RGI-C Score at Week 64
    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). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure. Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
    End point type
    Secondary
    End point timeframe
    Week 64
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: units on a scale
        least squares mean (standard error)
    2.23 ± 0.111
    Attachments
    Untitled (Filename: Statistical Analysis 1 for RGI-C Score at Week 64.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score

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    End point title
    Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score
    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. The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates. Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: units on a scale
        least squares mean (standard error)
    -1.75 ± 0.116
    Attachments
    Untitled (Filename: Statistical Analysis 1 for Change From Baseline in Rickets at Week 40 as Assessed by the RSS Total Score.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score

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    End point title
    Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score
    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, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity. The GEE model includes the change from baseline in RSS as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 64
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: units on a scale
        least squares mean (standard error)
    -2.02 ± 0.115
    Attachments
    Untitled (Filename: Change From Baseline in Rickets at Week 64 as Assessed by the RSS Total Score.docx)
    No statistical analyses for this end point

    Secondary: RGI-C Lower Limb Deformity Score at Week 40

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    End point title
    RGI-C Lower Limb Deformity Score at Week 40
    End point description
    Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The ANCOVA model includes the RGI-C score as the dependent variable, age and RSS at baseline as covariates. Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
    End point type
    Secondary
    End point timeframe
    Week 40
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: units on a scale
        least squares mean (standard error)
    1.21 ± 0.155
    Attachments
    Untitled (Filename: Statistical Analysis 1 for RGI-C Lower Limb Deformity Score at Week 40.docx)
    No statistical analyses for this end point

    Secondary: RGI-C Lower Limb Deformity Score at Week 64

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    End point title
    RGI-C Lower Limb Deformity Score at Week 64
    End point description
    Changes in the severity of lower extremity skeletal abnormalities were assessed centrally by three independent pediatric radiologists contracted by a central imaging facility using a disease specific qualitative RGI-C scoring system. The RGI-C is a seven point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets). The GEE model includes the RGI-C score as the dependent variable, visit as a factor, age and RSS at baseline as covariates, with exchangeable covariance structure. Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement.
    End point type
    Secondary
    End point timeframe
    Week 64
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: units on a scale
        least squares mean (standard error)
    1.51 ± 0.123
    Attachments
    Untitled (Filename: Statistical Analysis 1 for RGI-C Lower Limb Deformity Score at Week 64.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Recumbent Length/Standing Height

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    End point title
    Change From Baseline Over Time in Recumbent Length/Standing Height
    End point description
    Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13 [3]
    Units: cm
    arithmetic mean (standard deviation)
        Week 12; n=13
    1.44 ± 2.009
        Week 24; n=13
    2.52 ± 1.518
        Week 40; n=13
    4.29 ± 2.451
        Week 64; n=13
    7.22 ± 3.157
        Week 88; n=13
    10.30 ± 3.400
        Week 112; n=13
    13.25 ± 3.724
        Week 136; n=11
    15.41 ± 3.699
        Week 160; n=12
    18.96 ± 4.206
    Notes
    [3] - n=participants with an assessment at given time point
    No statistical analyses for this end point

    Secondary: Change from Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores

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    End point title
    Change from Baseline Over Time in Recumbent Length/Standing Height as Assessed by Height-for-Age Z-Scores
    End point description
    Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13 [4]
    Units: Z score
    arithmetic mean (standard deviation)
        Week 12; n=13
    -0.082 ± 0.4964
        Week 24; n=13
    -0.208 ± 0.4540
        Week 40; n=13
    -0.276 ± 0.6647
        Week 64; n=13
    -0.264 ± 0.8755
        Week 88; n=13
    -0.212 ± 0.9115
        Week 112; n=13
    -0.174 ± 0.9273
        Week 136; n=11
    -0.321 ± 0.9123
        Week 160; n=12
    -0.172 ± 0.9048
    Notes
    [4] - n=participants with an assessment at given time point
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles

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    End point title
    Change From Baseline Over Time in Recumbent Length/Standing Height as Assessed by Percentiles
    End point description
    Efficacy Analysis Set: all participants who received at least one dose of study drug and had at least one post-study drug measurement at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 40, 64, 88, 112, 136, 160
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: percentiles
    arithmetic mean (standard deviation)
        Week 12; n=13
    -0.006 ± 11.6149
        Week 24; n=13
    -4.940 ± 13.1323
        Week 40; n=13
    -5.283 ± 20.1675
        Week 64; n=13
    -4.980 ± 23.4412
        Week 88; n=13
    -4.155 ± 23.9126
        Week 112; n=13
    -3.000 ± 24.7569
        Week 136; n=11
    -7.026 ± 24.8583
        Week 160; n=12
    -3.628 ± 25.5113
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP)

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    End point title
    Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP)
    End point description
    The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with exchangeable covariance structure. PK/PD Analysis Set: all participants who received at least one dose of study drug and had evaluable blood samples at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: U/L
    least squares mean (standard error)
        Week 4; n=13
    -82.91 ± 23.348
        Week 12; n=13
    -83.84 ± 45.263
        Week 20; n=13
    -161.38 ± 12.924
        Week 40; n=13
    -214.99 ± 13.628
        Week 48; n=12
    -226.58 ± 11.491
        Week 56; n=13
    -216.45 ± 16.165
        Week 64; n=13
    -216.76 ± 12.705
        Week 76; n=13
    -231.22 ± 15.964
        Week 88; n=12
    -237.78 ± 12.837
        Week 100; n=13
    -218.14 ± 15.340
        Week 112; n=13
    -233.91 ± 11.098
        Week 124; n=12
    -252.22 ± 8.312
        Week 136; n=12
    -267.89 ± 13.124
        Week 148; n=12
    -248.05 ± 12.653
        Week 160; n=12
    -248.47 ± 10.990
    Attachments
    Untitled (Filename: Statistical Analysis 15 for Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP).docx)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline Over Time in Serum ALP

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    End point title
    Percent Change From Baseline Over Time in Serum ALP
    End point description
    PK/PD Analysis Set: all participants who received at least one dose of study drug and had evaluable blood samples at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 12, 20, 40, 48, 56, 64, 76, 88, 100, 112, 124, 136, 148, 160
    End point values
    Burosumab Q2W
    Number of subjects analysed
    13
    Units: percent change
    arithmetic mean (standard deviation)
        Week 4; n=13
    -12.47 ± 16.620
        Week 12; n=13
    -5.00 ± 60.124
        Week 20; n=13
    -24.76 ± 18.883
        Week 40; n=13
    -36.25 ± 12.787
        Week 48; n=13
    -37.29 ± 13.936
        Week 56; n=13
    -35.80 ± 16.568
        Week 64; n=13
    -35.95 ± 14.851
        Week 76; n=13
    -38.36 ± 15.621
        Week 88; n=12
    -39.08 ± 12.987
        Week 100; n=13
    -37.42 ± 12.466
        Week 112; n=13
    -39.05 ± 13.808
        Week 124; n=12
    -43.11 ± 12.493
        Week 136; n=12
    -47.01 ± 11.752
        Week 148; n=12
    -43.47 ± 11.321
        Week 160; n=12
    -42.35 ± 13.574
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through the end of the study (at Week 160). Maximum duration of exposure to study drug was 160 weeks.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Burosumab Q2W
    Reporting group description
    Burosumab SC injections Q2W for a total of 160 weeks.

    Serious adverse events
    Burosumab Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Infections and infestations
    Tooth Abscess
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Burosumab Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Haematoma
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Immune system disorders
    Food Allergy
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Hypersensitivity
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Injection Site Bruising
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    3
    Injection Site Erythema
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    4
    Injection Site Pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Injection Site Pruritus
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Injection Site Reaction
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    11 / 13 (84.62%)
         occurrences all number
    54
    Vaccination Site Reaction
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Penile Erythema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Penile Pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Arthropod Bite
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    8
    Contusion
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Fall
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    6
    Laceration
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Lip Injury
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Skin Abrasion
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    5
    Tooth Fracture
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Tooth Injury
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Traumatic Tooth Displacement
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Investigations
    Amylase Increased
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Blood 25-Hydroxycholecalciferol Decreased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood Parathyroid Hormone Increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood Phosphorus Decreased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Heart Rate Abnormal
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Lipase Increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Vitamin D Decreased
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    White Blood Cell Count Increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Skull Malformation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Syringomyelia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Adenoidal Disorder
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Chronic Throat Clearing
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    11 / 13 (84.62%)
         occurrences all number
    40
    Epistaxis
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    11
    Nasal Congestion
         subjects affected / exposed
    8 / 13 (61.54%)
         occurrences all number
    9
    Nasal Discharge Discolouration
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Oropharyngeal Pain
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    10
    Productive Cough
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    4
    Respiratory Tract Congestion
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    4
    Rhinorrhoea
         subjects affected / exposed
    7 / 13 (53.85%)
         occurrences all number
    35
    Sinus Congestion
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Sneezing
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    3
    Throat Irritation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Dysarthria
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    6 / 13 (46.15%)
         occurrences all number
    15
    Hypersomnia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Lethargy
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    4
    Periodic Limb Movement Disorder
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Eye disorders
    Ocular Hyperaemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Deafness Unilateral
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Ear Haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Ear Pain
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    17
    Excessive Cerumen Production
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Hypoacusis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Motion Sickness
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Otorrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Tinnitus
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    4
    Abdominal Pain Upper
         subjects affected / exposed
    5 / 13 (38.46%)
         occurrences all number
    12
    Aphthous Ulcer
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    5
    Constipation
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    3
    Dental Caries
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    6 / 13 (46.15%)
         occurrences all number
    9
    Epigastric Discomfort
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gingival Blister
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gingival Erythema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gingival Pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Haematochezia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Loose Tooth
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Oral Pain
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    6
    Post-Tussive Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Teething
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    6
    Vomiting
         subjects affected / exposed
    7 / 13 (53.85%)
         occurrences all number
    15
    Vomiting Projectile
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Polyuria
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Urinary Incontinence
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermatitis Contact
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    3
    Rash Papular
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Skin Disorder
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Swelling Face
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    8
    Urticaria Papular
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    13
    Back Pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Bone Pain
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    6
    Foot Deformity
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Knee Deformity
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Pain In Extremity
         subjects affected / exposed
    9 / 13 (69.23%)
         occurrences all number
    40
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Increased Appetite
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Polydipsia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Infections and infestations
    Atypical Pneumonia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Croup Infectious
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Ear Infection
         subjects affected / exposed
    6 / 13 (46.15%)
         occurrences all number
    7
    Enterobiasis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Eye Infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrointestinal Viral Infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Genital Candidiasis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gingival Abscess
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Hand-Foot-And-Mouth Disease
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Hordeolum
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Impetigo
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    3
    Influenza
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Molluscum Contagiosum
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    5
    Otitis Media
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Pharyngitis Streptococcal
         subjects affected / exposed
    8 / 13 (61.54%)
         occurrences all number
    22
    Pneumonia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Tooth Abscess
         subjects affected / exposed
    10 / 13 (76.92%)
         occurrences all number
    24
    Upper Respiratory Tract Infection
         subjects affected / exposed
    9 / 13 (69.23%)
         occurrences all number
    11
    Urinary Tract Infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Viral Infection
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    6
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    15

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Mar 2016
    1. Burosumab dose and dose justification: As a result of additional clinical data available since the time the original protocol was written, the dose of burosumab was changed. The starting dose of burosumab was changed to 0.8 mg/kg Q2W. The dose may then be increased to 1.2 mg/kg at any time during the study if a subject met the following dose adjustment criteria: 1) 2 consecutive serum phosphorus measurements were below the normal range; 2) serum phosphorus had increased by < 0.5 mg/dL from Baseline; and 3) the subject had not missed a dose of study drug that would have accounted for the decrease in serum phosphorus. Previously the protocol had specified a starting dose of 0.3 mg/kg Q2W for the first 2 doses and a target dose of 0.6 mg/kg Q2W. 2. Study Population: The inclusion criteria were modified to add PHEX mutation or VUS in either the patient or in a directly related family member with appropriate X-linked inheritance to confirm presence of XLH and to avoid including patients with syndromes that have clinical and biochemical phenotypic overlap with XLH. The criterion of intact fibroblast growth factor 23 (iFGF23) level ≥ 30 pg/mL by Kainos assay was eliminated because it was unnecessary in addition to genetic confirmation. The exclusion criteria were modified to add presence of nephrocalcinosis grade 4 on renal ultrasound (ie, stone formation). Presence of stone formation was added as an exclusion criterion based on regulatory agency request.
    28 Mar 2016
    (continued) 3. Prohibited Medications: The washout period required for subjects receiving oral phosphate and active vitamin D standard therapy was reduced from 14 days to 7 days. Oral phosphate is typically given 4–5 times daily in XLH due to its rapid clearance from the body (Carpenter et al. 2011). Prescribing information for oral calcitriol notes a half life of 27.4 hours in children (Rocaltrol 2008); therefore, a 7-day washout was deemed sufficient to remove phosphate and active vitamin D from the body and minimizes the duration of time that a patient is off therapy. 4. Study Procedures and Assessments: a. Screening Visit 2 was removed from the Schedule of Events. Assessments previously indicated to be performed at Screening Visit 2 were rescheduled to be performed at the Baseline visit. This change was made to reduce the burden of multiple visits on subjects and their families. b. The Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument was removed as an assessment in the study because the questionnaire could be administered to subjects less than 2 years of age and most of the items were only relevant for subjects 5 years of age or older. Therefore, the amount of data to be collected from this instrument in this study of children 1 to 4 years old was likely minimal. c. The frequency and schedule of renal ultrasounds was modified. Renal ultrasounds were to be conducted at Screening, Week 40, and Week 64. Renal ultrasound assessment was moved from Baseline to Screening because renal stone formation had been added as an exclusion criterion. The Week 12 renal ultrasound was removed to minimize patient burden in these young patients. d. The frequency and schedule for measurement of FGF23 levels was modified to Baseline, Week 24, and Week 64. This change was made to minimize blood volumes collected and to align with the Phase 3 pediatric protocol.
    28 Mar 2016
    (continued) e. Assessment of ADA was added at the Baseline Visit. ADA assessment was needed both before and after burosumab administration to distinguish between background signal and ADAs induced by administration of burosumab. f. The instructions for the measurement of BP were updated. BP was to be measured only in subjects who were ≥ 3 years of age. Previously, PB was measured one time each at the beginning and end of site visits in all subjects. At the Screening Visit, BP was to be measured 3 times, 30 seconds apart at the beginning of each visit; 3 additional BP measurements, 30 seconds apart, were to be obtained at the end of the study visit after all procedures had been performed. Elevated BP measurements were noted in some subjects in the Phase 2 pediatric UX023-CL201 study prior to administration of burosumab and in some subjects post administration of burosumab. To help ensure accurate pre-treatment and post-treatment BP measurements in this study, multiple assessments of BP were to be obtained at each site visit. The United States Department of Health and Human Services guidelines for Blood Pressure Measurement in Children was used as a reference. 5. Safety Measurements: Assessment of serum lipase in addition to serum amylase was added for all subjects. Amylase is produced by several organs including the pancreas and salivary gland and so elevated amylase levels are not diagnostic in the absence of other information. In ongoing and completed burosumab studies at Baseline, mild elevations of amylase (<2x the upper limit of the reference range [ULRR]) have been noted. Post treatment mild shifts in amylase elevation (< 2xULRR) has been noted without association with GI symptoms. No AEs of pancreatitis have been observed. The additional testing of serum lipase were to aid in a determination of whether the elevations were from pancreatic or salivary gland sources.
    28 Mar 2016
    (continued) 6. Data Monitoring Committee: Details of the DMC were updated. Specifically, the amended protocol stated that the independent DMC was to include members with expertise in metabolic bone disease, cardiology, and nephrology and the conduct of clinical trials in children. The FDA requested the inclusion of DMC members with expertise in pediatric cardiology and nephrology in addition to metabolic bone disease. 7. Record Retention: The record retention language was updated to state that all study records must have been retained for at least 25 years after the end of the clinical trial or in accordance with national law. This administrative change was made to reflect changes to European Union clinical trial regulations and current regulations by other health authorities.
    12 Jun 2017
    1. Study Objectives: The additional study objective was modified from “Pre-dose KRN23 drug concentration levels” to “KRN23 drug concentration levels (PK)” to clarify that burosumab drug concentration levels were to be assessed throughout the study. 2. Overall Study Design and Plan: The provision to maintain gender balance was modified from “no more than 7 subjects” to “no more than 70% of subjects”. The original protocol planned sample size was 10 subjects, therefore 7 subjects (ie, 70% of the study population) were originally selected. The change more accurately reflected the total enrollment of 13 subjects (9 male; 69%). 3. Study Duration: An Extension Period of 96 weeks was added for continued assessment of the long-term safety and efficacy of burosumab in younger children. 4. Removal of Subjects: Language was added to allow orthopedic surgery during the Extension Period if recommended by the investigator or consulting physician. In addition, subjects who developed hyperparathyroidism were allowed to remain on study, but use of medication to suppress parathyroid hormone (eg, Sensipar®, cinacalcet, calcimimetics) was not permitted at any time. Subjects were to be removed from study if treatment for hyperparathyroidism became medically necessary.
    12 Jun 2017
    (continued) 5. Treatment: Updates were made to allow for a parent or caregiver to administer burosumab to the subject after proper training by study personnel in SC injection technique and documentation of proficiency. Additional updates were made to describe the timing of dose adjustments during the Extension Period and to describe methods for monitoring treatment compliance in the home setting via telephone contact and physical inventory of empty vials at site visits for study drug accountability. Allowing subjects’ parents or caregivers to administer burosumab in the home setting was expected to reduce the burden on the subjects. Instructions for Use (IFU) were thoughtfully developed with input from XLH patients and were used to guide parents and caregivers through the injection process. The IFU was provided to sites and IRBs for approval prior to the initiation of parent/caregiver administration. To avoid potential errors with any dose adjustments, dose changes during the Extension Period were to be initially implemented at the clinic visits. Site personnel collected information on treatment compliance in the home setting and monitored the home administration via telephone contact. 6. Study Procedures and Assessments: Changes to study procedures are described below; a new Schedule of Events table was included to describe visits and assessments during the Extension Period.
    12 Jun 2017
    (continued) a. During the Extension Period, clinic visits were to occur at approximately 12-week intervals (±5 days). Home health or telephone visits were to occur every 2 weeks. For telephone visits, study sites scheduled biweekly telephone calls with the subjects’ parent/caregiver to confirm administration of study drug, and for collection of AEs and concomitant medication information. Site personnel initiated a safety follow-up telephone call 5 weeks (+5 days) after the Week 160 visit to determine if the subject was receiving burosumab therapy under commercial use or another mechanism and to collect information on any ongoing or new AEs, serious TEAEs, and concomitant medications for subjects not receiving burosumab. The additional safety visit (10 weeks ± 5 days after Week 160) applied to subjects who discontinued treatment early or chose not to continue burosumab therapy as commercial product or through another mechanism once the study ended. These additional clinic visits and telephone calls were included in the Extension Period to monitor long-term safety, compliance, and efficacy at an interval deemed appropriate for the age of the population and duration of treatment. b. As previously communicated by memorandum (20 October 2016), updates were made to remove TmP/GFR and TRP (tubular reabsorption of phosphate) as estimates of renal phosphate reabsorption due to the breadth of available data and burden of obtaining urine samples in this study population (under 5 years of age). c. As previously communicated by memorandum (20 October 2016), the Week 22 serum calcium assessment was removed from the Schedule of Events. d. As previously communicated by memorandum (05 April 2016), updates were made such that blood pressure was to be obtained for subjects aged 3 years or above (at study entry or beginning when the subject turned 3 years of age). The provision for training on blood pressure measurements at the site initiation visit was removed.
    12 Jun 2017
    (continued) e. As previously communicated by memorandum (13 December 2016), updates were made to indicate that the scope of the genitourinary exam should have been noninvasive and as per age-appropriate standard of care, at the investigator’s discretion based on clinical judgement. f. ECG was changed from an ectopic mineralization assessment to a general safety assessment. ECG was performed to evaluate for changes associated with left ventricular hypertrophy. Ectopic mineralization was not expected to affect ECG parameters and ECG was inadvertently listed in that section in the original protocol. g. Updates were made such that concomitant medications and therapies were reviewed between site visits by telephone call from the study site every 2 weeks and recorded in the subject’s CRF. Inclusion of telephone calls provided a mechanism to track use of concomitant medications and therapies at a consistent frequency during the Extension Period. 7. Statistical Analysis and Data Monitoring Committee: The statistical models for efficacy analysis were updated to incorporate Baseline adjustment and repeated measures at multiple time points. A newly added section described the timing of planned analyses for the study and more precisely defined the end of the study. Updates were made to stipulate that the Data Monitoring Committee was to review safety data through the Treatment Period (Week 64); long-term safety during the Extension Period was to be reviewed by the Ultragenyx SSRT on an ongoing basis. 8. Investigators and Study Administrative Structure: As previously communicated by memorandum (30 September 2016), updates were made to include language describing the Coordinating Investigator for the study. The Coordinating Investigator is Erik Imel, MD, Indiana University School of Medicine.
    12 Jun 2017
    (continued) 9. Reporting and Follow-up of Adverse Events: Language was revised to reflect the revised study design and safety follow-up procedures. The reporting periods of AEs were defined as those from the time the subjects signs informed consent through “the final protocol-defined safety follow-up telephone call or safety visit”. Previously, these were defined as those through “12 weeks (approximately 5 times the elimination half-life) following the last dose of study drug.” 10. Nomenclature: Clarification was made in the Schedules of Events to change the explanation of anti-burosumab antibodies from human anti-human antibodies (HAHA) to the more correct and specific term, anti-drug antibodies (ADA).

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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