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    Clinical Trial Results:
    A Phase 3b Open-label Study of the Anti-FGF23 Antibody, Burosumab (KRN23) in Adult Patients with X-linked Hypophosphatemia (XLH)

    Summary
    EudraCT number
    		 2018-000202-37
    Trial protocol
    		 FR   GB   IT  
    Global end of trial date
    07 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2023
    First version publication date
    06 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BUR02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03920072
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kyowa Kirin Pharmaceutical Development Ltd
    Sponsor organisation address
    Galabank Business Park, Galashiels, United Kingdom, TD1 1QH
    Public contact
    Kyowa Kirin Pharmaceutical Development Ltd, Kyowa Kirin Pharmaceutical Development Ltd, kkd.clintrial.82@kyowakirin.com
    Scientific contact
    Kyowa Kirin Pharmaceutical Development Ltd, Kyowa Kirin Pharmaceutical Development Ltd, kkd.clintrial.82@kyowakirin.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    26 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To continue to evaluate the long-term efficacy and safety of burosumab as a treatment for adult patients with XLH and to provide continued treatment for subjects previously enrolled in UX023-CL303 and UX023-CL304 clinical trials.
    Protection of trial subjects
    This protocol was written 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 Sponsor and investigator made every effort to assure the study described in this protocol was conducted in full conformance with those principles, current Food and Drug Administration (FDA) regulations, ICH Good Clinical Practices (GCP) guidelines and local ethical and regulatory requirements. The investigator made sure he or she was thoroughly familiar with the appropriate administration and potential risks of administration of the study drug, as described in the protocol and the IB, prior to the initiation of the study. It was the investigator's responsibility to obtain signed written informed consent from each potential study subject prior to the conduct of any study procedures. This written informed consent was obtained after the methods, objectives, requirements and potential risks of the study had been fully explained to each potential subject. The investigator explained to each subject that the subject was completely free to refuse to enter the study or to withdraw from it at any time.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jul 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 2
    Worldwide total number of subjects
    35
    EEA total number of subjects
    26
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    35
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult XLH patients (18 to 70 years) from Europe who had participated in either study UX023-CL303 or UX023-CL304. Subjects were moved to this study as soon as possible after completion of UX023-CL303 or UX023 CL304.

    Pre-assignment
    Screening details
    		 Screening visits could occur up to 4 weeks before the baseline visit. Informed consent, Inclusion/Exclusion criteria, medical history, demographics and height were collected. Clinical labs were collected as well as a lateral foot x-ray and patient reported outcomes.

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

    Arms
    Arm title
    		 Overall trial
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Burosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Burosumab was supplied as a sterile, clear, colorless and preservative-free solution in single-use 5 mL vials containing 1 mL of burosumab at a concentration of 30 mg/mL. Burosumab was administered via SC injection, without dilution, to the abdomen, upper arms or thighs, at the same dose as the last administered during UX023-CL303 or UX023-CL304. The dose remained fixed for the duration of the study, provided serum phosphate levels did not exceed the upper limit of normal (ULN), as measured by the central laboratory, and body weight did not change by >20% from the baseline measurement. The dose was to be recalculated to account for the new body weight if it changed by >20%. The dose was increased stepwise by 0.4 mg/kg up to a maximum dose of 2.0 mg/kg (maximum dose of 90 mg) if the trough serum phosphate concentration remained below the lower limit of normal (LLN).

    Number of subjects in period 1
    		Overall trial
    Started
    35
    Completed
    25
    Not completed
    10
         Consent withdrawn by subject
    4
         Transfer to commercial burosumab
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 35 35
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 35 35
    Gender categorical
    Units: Subjects
        Female
    		 23 23
        Male
    		 12 12
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0
        Not Hispanic or Latino
    		 35 35
        Unknown or Not reported
    		 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0
        Asian
    		 1 1
        Native Hawaiian or Other Pacific Islander
    		 0
        Black or African American
    		 0
        White
    		 34 34
        More than one race
    		 0
        Unknown or not reported
    		 0
    Subject analysis sets

    Subject analysis set title
    Placebo in the Double-blinded Period - UX023-CL303
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Thirty-five subjects who completed study UX023-CL303 or UX023-CL304 were screened for this study (34 subjects from UX023-CL303 and 1 subject from UX023-CL304). All 35 subjects met the eligibility criteria and were enrolled. Of the 35 subjects, 18 subjects had received placebo during the double-blind period of UX023-CL303 (following the double-blind period, they received burosumab in the open-label periods of that study). This is the Placebo in the Double-blinded Period - UX023-CL303 Analysis set

    Subject analysis set title
    Burosumab in Double-blinded Period - UX023-CL303 and CL304
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Thirty-five subjects who completed study UX023-CL303 or UX023-CL304 were screened for this study (34 subjects from UX023-CL303 and 1 subject from UX023-CL304). All 35 subjects met the eligibility criteria and were enrolled. Of the 35 subjects, 17 subjects had either received burosumab during the double-blind period of UX023-CL303 or were from study UX023-CL304 (a single-arm study on burosumab). This is the Burosumab in the double-blinded period from UX023-CL303 and CL304 analysis set.

    Subject analysis set title
    All (Placebo + Burosumab)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Thirty-five subjects who completed study UX023-CL303 or UX023-CL304 were screened for this study (34 subjects from UX023-CL303 and 1 subject from UX023-CL304). All 35 subjects met the eligibility criteria and were enrolled. All 35 subjects received at least one dose of burosumab and were included in this analysis set.

    Subject analysis sets values
    		 Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects
    18
    17
    35
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    18
    17
    35
    Age continuous
    Units:
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    10
    13
    23
        Male
    8
    4
    12
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0
    0
    0
        Not Hispanic or Latino
    18
    17
    35
        Unknown or Not reported
    0
    0
    0
    Race
    Units: Subjects
        American Indian or Alaska Native
    0
    0
    0
        Asian
    1
    0
    1
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
        Black or African American
    0
    0
    0
        White
    17
    17
    34
        More than one race
    0
    0
    0
        Unknown or not reported
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Subject analysis set title
    Placebo in the Double-blinded Period - UX023-CL303
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Thirty-five subjects who completed study UX023-CL303 or UX023-CL304 were screened for this study (34 subjects from UX023-CL303 and 1 subject from UX023-CL304). All 35 subjects met the eligibility criteria and were enrolled. Of the 35 subjects, 18 subjects had received placebo during the double-blind period of UX023-CL303 (following the double-blind period, they received burosumab in the open-label periods of that study). This is the Placebo in the Double-blinded Period - UX023-CL303 Analysis set

    Subject analysis set title
    Burosumab in Double-blinded Period - UX023-CL303 and CL304
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Thirty-five subjects who completed study UX023-CL303 or UX023-CL304 were screened for this study (34 subjects from UX023-CL303 and 1 subject from UX023-CL304). All 35 subjects met the eligibility criteria and were enrolled. Of the 35 subjects, 17 subjects had either received burosumab during the double-blind period of UX023-CL303 or were from study UX023-CL304 (a single-arm study on burosumab). This is the Burosumab in the double-blinded period from UX023-CL303 and CL304 analysis set.

    Subject analysis set title
    All (Placebo + Burosumab)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Thirty-five subjects who completed study UX023-CL303 or UX023-CL304 were screened for this study (34 subjects from UX023-CL303 and 1 subject from UX023-CL304). All 35 subjects met the eligibility criteria and were enrolled. All 35 subjects received at least one dose of burosumab and were included in this analysis set.

    Primary: Number of Subjects Achieving Mean Trough Serum Phosphate Level Above the LLN as Assessed by Central Laboratories

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    End point title
    		 Number of Subjects Achieving Mean Trough Serum Phosphate Level Above the LLN as Assessed by Central Laboratories [1]
    End point description
    Number of subjects achieving mean trough serum phosphate level above the LLN (as assessed by the central or local laboratory as a result of the COVID-19 pandemic) in adults with X linked Hypophosphatemia (XLH) at EOS/ET.
    End point type
    Primary
    End point timeframe
    Baseline through to end of study/end of trial.
    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: Descriptive statistics only for this study due to number of patients enrolled. Based on central laboratory data, 28 of the 35 subjects (80.0%) achieved mean trough serum phosphate level above the LLN.
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    35
    18
    17
    35
    Units: Count of participant
    28
    12
    16
    28
    No statistical analyses for this end point

    Primary: Proportion of Subjects Achieving Mean Trough Serum Phosphate Level Above the LLN as Assessed by Local Laboratories

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    End point title
    		 Proportion of Subjects Achieving Mean Trough Serum Phosphate Level Above the LLN as Assessed by Local Laboratories [2]
    End point description
    Proportion of subjects achieving mean trough serum phosphate level above the LLN as assessed by local laboratories (due to the COVID-19 pandemic)
    End point type
    Primary
    End point timeframe
    From Baseline through to end of study/end of treatment
    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 only for this study due to number of patients enrolled. Overall, the results from local laboratories were consistent with the central laboratory: 14 of the 17 subjects (82.4%) had mean trough serum phosphate level above the LLN.
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    17
    12
    5
    17
    Units: Count of Participants
    14
    9
    5
    14
    No statistical analyses for this end point

    Secondary: Calcaneal Enthesopathy

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    End point title
    		 Calcaneal Enthesopathy
    End point description
    Total Calcaneal enthesopathy burden at EOS/ET.
    End point type
    Secondary
    End point timeframe
    From baseline to end of study/end of treatment.
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    29
    15
    14
    29
    Units: units on a scale
        arithmetic mean (standard deviation)
    100.74 ± 48.250
    93.97 ± 39.910
    107.99 ± 56.476
    100.74 ± 48.250
    No statistical analyses for this end point

    Secondary: Change from baseline to EOS/ET in Calcaneal enthesopathy

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    End point title
    		 Change from baseline to EOS/ET in Calcaneal enthesopathy
    End point description
    Change from baseline to EOS/ET in Calcaneal enthesopathy
    End point type
    Secondary
    End point timeframe
    From Baseline to end of study/end of treatment
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    29
    15
    14
    29
    Units: score on a scale
        arithmetic mean (standard deviation)
    100.74 ± 48.250
    93.97 ± 39.910
    107.99 ± 56.476
    100.74 ± 48.250
    No statistical analyses for this end point

    Secondary: Timed Up and Go (TUG) test, change from baseline (seconds)

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    End point title
    		 Timed Up and Go (TUG) test, change from baseline (seconds)
    End point description
    Timed Up and Go (TUG) test, change from baseline (seconds) to end of study/end of treatment
    End point type
    Secondary
    End point timeframe
    Baseline to end of study/end of treatment
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    31
    18
    13
    31
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -1.36 ± 3.156
    -1.54 ± 2.571
    -1.12 ± 3.927
    -1.36 ± 3.156
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory (BPI) Worst Pain, Change From Baseline.

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    End point title
    		 Brief Pain Inventory (BPI) Worst Pain, Change From Baseline.
    End point description
    Brief Pain Inventory (BPI) Worst Pain, change from baseline to Week 96
    End point type
    Secondary
    End point timeframe
    From baseline to Week 96
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    22
    10
    12
    22
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.58 ± 1.820
    -0.39 ± 1.554
    -0.73 ± 2.072
    -0.58 ± 1.820
    No statistical analyses for this end point

    Secondary: BPI Pain Severity Score, Change From Baseline

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    End point title
    		 BPI Pain Severity Score, Change From Baseline
    End point description
    BPI Pain Severity score, change from baseline to Week 96.
    End point type
    Secondary
    End point timeframe
    From baseline to week 96
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    21
    10
    11 [3]
    21
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.42 ± 1.907
    -0.33 ± 1.663
    -0.50 ± 2.185
    -0.42 ± 1.907
    Notes
    [3] - 11
    No statistical analyses for this end point

    Secondary: Brief Fatigue Inventory (BFI), Change From Baseline

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    End point title
    		 Brief Fatigue Inventory (BFI), Change From Baseline
    End point description
    Brief Fatigue Inventory (BFI), change from baseline to Week 96
    End point type
    Secondary
    End point timeframe
    From baseline to Week 96
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    21
    9
    12
    21
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.64 ± 1.726
    0.34 ± 1.013
    -1.38 ± 1.817
    -0.64 ± 1.726
    No statistical analyses for this end point

    Secondary: WOMAC Stiffness Score, Change From Baseline

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    End point title
    		 WOMAC Stiffness Score, Change From Baseline
    End point description
    WOMAC Stiffness score, change from baseline to end of study to end of treatment
    End point type
    Secondary
    End point timeframe
    From baseline to end of study/end of treatment
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    31
    17
    14
    31
    Units: score on a scale
        arithmetic mean (standard deviation)
    -14.52 ± 22.615
    -19.85 ± 23.410
    -8.04 ± 20.573
    -14.52 ± 22.615
    No statistical analyses for this end point

    Secondary: Trough Serum Phosphate

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    End point title
    		 Trough Serum Phosphate
    End point description
    Trough serum phosphate at end of study/end of treatment
    End point type
    Secondary
    End point timeframe
    Trough serum phosphate at end of study/end of treatment
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    33
    18
    15
    33
    Units: units on a scale(mmol/L)
        arithmetic mean (standard deviation)
    0.787 ± 0.1529
    0.754 ± 0.1768
    0.826 ± 0.1116
    0.787 ± 0.1529
    No statistical analyses for this end point

    Secondary: Serum Burosumab Concentrations (Pharmacokinetics)

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    End point title
    		 Serum Burosumab Concentrations (Pharmacokinetics)
    End point description
    Serum burosumab concentrations (Pharmacokinetics) at end of study/end of treatment
    End point type
    Secondary
    End point timeframe
    end of study/end of treatment
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    33
    18
    15
    33
    Units: units on a scale (ng/mL)
        arithmetic mean (standard deviation)
    6153.69 ± 2469.532
    6056.40 ± 2703.828
    6270.45 ± 2244.012
    6153.69 ± 2469.532
    No statistical analyses for this end point

    Secondary: BPI Pain Interference Score, Change From Baseline

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    End point title
    		 BPI Pain Interference Score, Change From Baseline
    End point description
    BPI Pain Interference score, change from baseline to Week 96.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 96
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    22
    10
    12
    22
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.27 ± 2.115
    -0.23 ± 2.381
    -0.31 ± 1.975
    -0.27 ± 2.115
    No statistical analyses for this end point

    Other pre-specified: Actual Walking Distance, Change From Baseline (Meters)

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    End point title
    		 Actual Walking Distance, Change From Baseline (Meters)
    End point description
    Actual Walking Distance, Change From Baseline (Meters) to end of study/end of treatment
    End point type
    Other pre-specified
    End point timeframe
    Baseline to end of study/end of treatment
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    30
    18
    12
    30
    Units: score on a scale
        arithmetic mean (standard deviation)
    23.80 ± 78.208
    22.78 ± 70.863
    25.33 ± 91.435
    23.80 ± 78.208
    No statistical analyses for this end point

    Other pre-specified: Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Treatment-emergent Adverse Events (TEAEs)
    End point description
    Treatment-emergent adverse events (TEAEs) Baseline to EOS/ET
    End point type
    Other pre-specified
    End point timeframe
    From baseline to end of study/to end of treatment
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    35
    18
    17
    35
    Units: Count of participants
    34
    17
    17
    34
    No statistical analyses for this end point

    Other pre-specified: Treatment-emergent Adverse Events (TEAEs) Related to Burosomab

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    End point title
    		 Treatment-emergent Adverse Events (TEAEs) Related to Burosomab
    End point description
    Treatment-emergent adverse events (TEAEs) related to burosomab Baseline to end of study/end of treatment
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to end of study/end of treatment
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    35
    18
    17
    35
    Units: count of participants
    16
    9
    7
    16
    No statistical analyses for this end point

    Other pre-specified: Treatment-emergent Hyperphosphatemia Adverse Events

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    End point title
    		 Treatment-emergent Hyperphosphatemia Adverse Events
    End point description
    Baseline to end of study/end of treatment
    End point type
    Other pre-specified
    End point timeframe
    Treatment-emergent hyperphosphatemia Adverse Events Baseline to end of study/end of treatment
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    35
    18
    17
    35
    Units: Count of participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Anti-burosumab Antibody

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    End point title
    		 Anti-burosumab Antibody
    End point description
    Anti-burosumab antibody Week 0 to EOS
    End point type
    Other pre-specified
    End point timeframe
    From week 0 to EOS
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    35
    18
    17
    35
    Units: Count of Participants
    3
    1
    2
    3
    No statistical analyses for this end point

    Other pre-specified: Increase in Ectopic Mineralization Grade in Echocardiogram

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    End point title
    		 Increase in Ectopic Mineralization Grade in Echocardiogram
    End point description
    Increase in ectopic mineralization grade in echocardiogram Baseline to EOT
    End point type
    Other pre-specified
    End point timeframe
    Baseline to End of trial
    End point values
    		 Overall trial Placebo in the Double-blinded Period - UX023-CL303 Burosumab in Double-blinded Period - UX023-CL303 and CL304 All (Placebo + Burosumab)
    Number of subjects analysed
    22
    13
    9
    22
    Units: Count of participants
    1
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from Baseline visit through to the safety follow up call
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Placebo in Double blinded Period from UX023-CL303
    Reporting group description
    		 18 subjects received placebo during the double-blind period of UX023-CL303.

    Reporting group title
    Burosumab in Double-blinded Period From UX023-CL303 & CL304
    Reporting group description
    		 17 subjects either received burosumab during the double-blind period of UX023 CL303 or were from study UX023-CL304 (a single-arm study on burosumab, 1 subject).

    Reporting group title
    All (Placebo + Burosumab)
    Reporting group description
    		 All 35 subjects received at least one dose of burosumab and were included in the Full analysis set (FAS).

    Serious adverse events
    		 Placebo in Double blinded Period from UX023-CL303 Burosumab in Double-blinded Period From UX023-CL303 & CL304 All (Placebo + Burosumab)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 18 (16.67%)
    3 / 17 (17.65%)
    6 / 35 (17.14%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Procedural failure
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum intestinal
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo in Double blinded Period from UX023-CL303 Burosumab in Double-blinded Period From UX023-CL303 & CL304 All (Placebo + Burosumab)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 18 (94.44%)
    17 / 17 (100.00%)
    34 / 35 (97.14%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 17 (5.88%)
    4 / 35 (11.43%)
         occurrences all number
    4
    1
    5
    injection site hematoma
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 17 (5.88%)
    3 / 35 (8.57%)
         occurrences all number
    2
    1
    3
    Injection site hypersensitivity
         subjects affected / exposed
    3 / 18 (16.67%)
    3 / 17 (17.65%)
    6 / 35 (17.14%)
         occurrences all number
    14
    7
    21
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 17 (5.88%)
    3 / 35 (8.57%)
         occurrences all number
    3
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 17 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    3
    0
    3
    Rhinorrhea
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    2
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    2
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    2
    0
    2
    Blood cholesterol increased
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 17 (11.76%)
    3 / 35 (8.57%)
         occurrences all number
    1
    2
    3
    Blood parathyroid hormone increased
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    2
    Lipase increased
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    2
    Vitamin D decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 17 (11.76%)
    3 / 35 (8.57%)
         occurrences all number
    1
    2
    3
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 17 (5.88%)
    3 / 35 (8.57%)
         occurrences all number
    3
    1
    4
    Post vaccination syndrome
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    Headache
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 17 (17.65%)
    5 / 35 (14.29%)
         occurrences all number
    5
    3
    8
    Hypoesthesia
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    2
    Migraine
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
    2 / 35 (5.71%)
         occurrences all number
    0
    5
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 17 (11.76%)
    3 / 35 (8.57%)
         occurrences all number
    2
    3
    5
    Toothache
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 17 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    4
    0
    4
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    3
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 18 (38.89%)
    6 / 17 (35.29%)
    13 / 35 (37.14%)
         occurrences all number
    10
    10
    20
    Arthritis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    2
    1
    3
    Back pain
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 17 (17.65%)
    5 / 35 (14.29%)
         occurrences all number
    2
    4
    6
    Enthesopathy
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    2
    0
    2
    Muscular weakness
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    2
    1
    3
    Myalgia
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 17 (5.88%)
    3 / 35 (8.57%)
         occurrences all number
    2
    1
    3
    Osteoarthritis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 17 (17.65%)
    3 / 35 (8.57%)
         occurrences all number
    0
    4
    4
    COVID-19
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    2
    Cystitis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    Ear infection
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    Influenza
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 17 (5.88%)
    3 / 35 (8.57%)
         occurrences all number
    2
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    2 / 18 (11.11%)
    4 / 17 (23.53%)
    6 / 35 (17.14%)
         occurrences all number
    2
    5
    7
    Rhinitis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    Tooth abscess
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 17 (17.65%)
    5 / 35 (14.29%)
         occurrences all number
    2
    4
    6
    Amylase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 17 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 17 (11.76%)
    3 / 35 (8.57%)
         occurrences all number
    1
    4
    5
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    3 / 18 (16.67%)
    6 / 17 (35.29%)
    9 / 35 (25.71%)
         occurrences all number
    3
    7
    10
    Vitamin D deficiency
         subjects affected / exposed
    9 / 18 (50.00%)
    10 / 17 (58.82%)
    19 / 35 (54.29%)
         occurrences all number
    14
    13
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2019
    Amendment 2: Duration of treatment was extended. An Inclusion criterion was updated. Collection of patient reported outcome data frequency was increased. An interim analysis was included. Pharmacokinetic samples were added.
    24 Apr 2020
    Amendment 3: Additional blood sampling of peak serum phosphate was added. Clarification on central versus local reading of ECHO, ECG and renal ultra sounds was added. Details on data cuts were added. Collection of details of PHEX analysis was removed. The specific serum phosphate lower limit of normal value used by the central laboratory was updated. Data retention timelines were updated.
    25 Jun 2021
    Amendment 4: Amendment 4 was to reduce the burden on the patients and hospital staff during the COVID-19 pandemic. The frequency of some assessments was reduced from every 3 months to every 6 months, and the Six Minute Walk Test and Timed Up and Go test were made optional. Investigators following discussion with the Sponsor could transition patients off the study sooner than the study end date of December 2021 or before commercial product was reimbursed. This was only considered if there was a clear mechanism via which the patient could continue, if they wished, to access burosumab until reimbursement was complete in their country.

    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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