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    Clinical Trial Results:
    An Open-Label, Multicenter, Multinational Study of the Safety, Efficacy and Pharmacokinetics of Asfotase alfa (human recombinant tissue nonspecific alkaline phosphatase fusion protein) in Infants and Children ≤5 Years of Age with Hypophosphatasia (HPP)

    Summary
    EudraCT number
    2010-019850-42
    Trial protocol
    DE   GB   IT   ES   FR  
    Global end of trial date
    26 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Nov 2017
    First version publication date
    11 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENB-010-10
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01176266
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals
    Sponsor organisation address
    100 College Street, New Haven, United States, 06510
    Public contact
    European Clinical Trial Information, ALEXION EUROPE SAS, +33 14710 0606, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, ALEXION EUROPE SAS, +33 14710 0606, clinicaltrials.eu@alexion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000987-PIP01-10
    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 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the following: • Effect of Asfotase alfa treatment on skeletal manifestations of HPP as measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale for all treated patients • Safety and tolerability of repeated subcutaneous (SC) injections of Asfotase alfa for all treated patients
    Protection of trial subjects
    No specific measure
    Background therapy
    -
    Evidence for comparator
    No comparator was used
    Actual start date of recruitment
    26 Jul 2010
    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
    Spain: 1
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Saudi Arabia: 1
    Worldwide total number of subjects
    69
    EEA total number of subjects
    25
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    4
    Infants and toddlers (28 days-23 months)
    35
    Children (2-11 years)
    30
    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
    The main criteria for inclusion in the study were male and female patients less than or equal to 5 years of age with a documented diagnosis of infantile onset hypophosphatasia (HPP) who were otherwise medically stable. Patients must have had onset of HPP signs/symptoms prior to 6 months of age.

    Pre-assignment
    Screening details
    After a Screening visit to assess their eligibility, patients were to receive 6 mg/kg per week of asfotase alfa, administered SC as either 1 mg/kg 6 times per week or 2 mg/kg 3 times per week.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    Asfotase Alfa
    Arm description
    A total of 6 mg/kg/week of asfotase alfa administered by SC injection (either 1 mg/kg asfotase alfa 6 times per week, or 2 mg/kg asfotase alfa 3 times per week)
    Arm type
    Experimental

    Investigational medicinal product name
    Asfotase Alfa
    Investigational medicinal product code
    Other name
    ENB-0040
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Patients received a total of 6 mg/kg/week of asfotase alfa administered by SC injection, either 1 mg/kg asfotase alfa 6 times per week or 2 mg/kg asfotase alfa 3 times per week.

    Number of subjects in period 1
    Asfotase Alfa
    Started
    69
    Completed
    60
    Not completed
    9
         Adverse event, serious fatal
    6
         Consent withdrawn by subject
    3

    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
    69 69
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    4 4
        Infants and toddlers (28 days-23 months)
    35 35
        Children (2-11 years)
    30 30
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Full Analysis Set (defined as all patients who received any asfotase alfa treatment)
    Units: weeks
        arithmetic mean (standard deviation)
    113.42 ± 108.912 -
    Gender categorical
    Units: Subjects
        Female
    36 36
        Male
    33 33
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 1
        Not Hispanic or Latino
    63 63
        Unknown or Not Reported
    5 5
    Race
    Units: Subjects
        Asian
    7 7
        White
    54 54
        Unknown or Not Reported
    8 8

    End points

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    End points reporting groups
    Reporting group title
    Asfotase Alfa
    Reporting group description
    A total of 6 mg/kg/week of asfotase alfa administered by SC injection (either 1 mg/kg asfotase alfa 6 times per week, or 2 mg/kg asfotase alfa 3 times per week)

    Primary: Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)

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    End point title
    Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP) [1]
    End point description
    The effect of asfotase alfa treatment on skeletal manifestations of HPP (i.e., change in rickets severity) was measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale. Skeletal radiographs obtained at Week 48 were compared with skeletal radiographs obtained before initiation of treatment. The RGI-C is a 7-point rating scale that ranges from -3 (indicative of severe worsening of HPP-associated rickets) to +3 (indicative of complete or near complete healing of HPP-associated rickets).
    End point type
    Primary
    End point timeframe
    From Baseline to Week 48
    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: The system EudraCT does not allow entering for statistical analysis for single arm studies. Thus, the analysis was removed in order to resolve the IT 'error'
    End point values
    Asfotase Alfa
    Number of subjects analysed
    69
    Units: Units on a scale
        median (full range (min-max))
    2.00 (-2.33 to 3.00)
    No statistical analyses for this end point

    Secondary: Safety and Tolerability of Repeated Subcutaneous (SC) Injections of Asfotase Alfa

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    End point title
    Safety and Tolerability of Repeated Subcutaneous (SC) Injections of Asfotase Alfa
    End point description
    Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients was assessed by the number of patients with 1 or more treatment-emergent adverse event.
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    69
    Units: Participants
    69
    No statistical analyses for this end point

    Secondary: Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)

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    End point title
    Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)
    End point description
    The effect of asfotase alfa treatment on skeletal manifestations of HPP was measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale from Baseline to the last assessment for each patient.
    End point type
    Secondary
    End point timeframe
    Up to 72 Months or regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    67
    Units: units on a scale
        median (full range (min-max))
    2.33 (-2.67 to 3.00)
    No statistical analyses for this end point

    Secondary: Effect of Asfotase Alfa Treatment on Ventilator-free Survival (Week 288)

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    End point title
    Effect of Asfotase Alfa Treatment on Ventilator-free Survival (Week 288)
    End point description
    For patients who were not on respiratory support at the time of enrollment, the Kaplan-Meier estimate of ventilator-free survival at the end of the study
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    45
    Units: Kaplan-Meier estimate of survival
        number (not applicable)
    0.84
    No statistical analyses for this end point

    Secondary: Effect of Asfotase Alfa Treatment on Respiratory Function

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    End point title
    Effect of Asfotase Alfa Treatment on Respiratory Function
    End point description
    Effect of asfotase alfa treatment on respiratory function as measured by the shift in proportion of patients requiring respiratory support at their last assessment compared with Baseline. Baseline: Baseline assessment before initiation of asfotase alfa Asfotase Alfa - Without Respiratory Support at Baseline: Results at End of Study for Those Without Respiratory Support at Baseline (Last Assessment for Each Patient) Asfotase Alfa - With Respiratory Support at Baseline: Results at End of Study for Those Without Respiratory Support at Baseline (Last Assessment for Each Patient)
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    69
    Units: Participants
        No respiratory support
    45
        Supplemental oxygen
    6
        Biphasic positive airway pressure
    0
        Continuous positive airway pressure
    4
        Mechanical ventilation
    13
        Other
    1
    Attachments
    Measured Values
    No statistical analyses for this end point

    Secondary: Effect of Asfotase Alfa Treatment on Physical Growth - Length/Height Z-scores Change From Baseline

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    End point title
    Effect of Asfotase Alfa Treatment on Physical Growth - Length/Height Z-scores Change From Baseline
    End point description
    Effect of asfotase alfa treatment on physical growth as measured by change from Baseline to last assessment for each patient in length/height Z-scores
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    66
    Units: Z-Scores
        median (full range (min-max))
    0.5 (-4 to 4)
    No statistical analyses for this end point

    Secondary: Effect of Asfotase Alfa Treatment on Physical Growth - Weight Z-scores Change From Baseline

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    End point title
    Effect of Asfotase Alfa Treatment on Physical Growth - Weight Z-scores Change From Baseline
    End point description
    Effect of asfotase alfa treatment on physical growth as measured by change from Baseline to last assessment for each patient in weight Z-scores
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    67
    Units: Z-Scores
        median (full range (min-max))
    1.0 (-5 to 6)
    No statistical analyses for this end point

    Secondary: Effect of Asfotase Alfa on Biomarkers - Plasma Inorganic Pyrophosphate (PPi) Change From Baseline

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    End point title
    Effect of Asfotase Alfa on Biomarkers - Plasma Inorganic Pyrophosphate (PPi) Change From Baseline
    End point description
    Effect of asfotase alfa on PPi as measured by change from Baseline to last assessment for each patient
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    63
    Units: uM
        median (full range (min-max))
    -2.460 (-12.18 to 22.47)
    No statistical analyses for this end point

    Secondary: Effect of Asfotase Alfa on Biomarkers - Plasma Pyridoxal-5’ Phosphate (PLP) Change From Baseline

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    End point title
    Effect of Asfotase Alfa on Biomarkers - Plasma Pyridoxal-5’ Phosphate (PLP) Change From Baseline
    End point description
    Effect of asfotase alfa on PLP as measured by change from Baseline to last assessment for each patient
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    56
    Units: ng/mL
        median (full range (min-max))
    -395.40 (-23836.0 to 2400.0)
    No statistical analyses for this end point

    Secondary: Effect of Asfotase Alfa on Serum Parathyroid Hormone (PTH) - Change From Baseline

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    End point title
    Effect of Asfotase Alfa on Serum Parathyroid Hormone (PTH) - Change From Baseline
    End point description
    Effect of asfotase alfa on serum PTH as measured by change from Baseline to last assessment for each patient
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    47
    Units: pmol/L
        median (full range (min-max))
    0.70 (-4.7 to 5.7)
    No statistical analyses for this end point

    Secondary: Effect of Asfotase Alfa Treatment on Tooth Loss

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    End point title
    Effect of Asfotase Alfa Treatment on Tooth Loss
    End point description
    Effect of asfotase alfa treatment on tooth loss assessed by the proportion of patients who experienced tooth loss during the study
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    69
    Units: Participants
    42
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Properties of Asfotase Alfa

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    End point title
    Pharmacokinetic (PK) Properties of Asfotase Alfa
    End point description
    The PK properties of asfotase alfa
    End point type
    Secondary
    End point timeframe
    Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
    End point values
    Asfotase Alfa
    Number of subjects analysed
    0 [2]
    Units: Participants
    Notes
    [2] - No Data was reported for this end point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time the parents/legal guardians signed the informed consent form through completion of the patients participation in the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Asfotase Alfa
    Reporting group description
    -

    Serious adverse events
    Asfotase Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    50 / 69 (72.46%)
         number of deaths (all causes)
    9
         number of deaths resulting from adverse events
    9
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Cranial operation
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Medical device removal
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheal operation
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheostomy
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wean from ventilator
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactoid reaction
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injection site erythema
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Irritability
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences causally related to treatment / all
    2 / 14
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Breath holding
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staring
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain herniation
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Eye injury
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Feeding tube complication
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incorrect dose administered
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Aspiration tracheal
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    CSF pressure
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterovirus test positive
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Human rhinovirus test positive
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurological examination abnormal
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nuclear magnetic resonance imaging
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    Respiratory rate increased
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory syncytial virus test positive
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cyanosis
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Wolff-Parkinson-White syndrome
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Arnold-Chiari malformation
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Craniosynostosis
         subjects affected / exposed
    13 / 69 (18.84%)
         occurrences causally related to treatment / all
    1 / 13
         deaths causally related to treatment / all
    0 / 0
    Hypophosphatasia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Apnoea
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atelectasis
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Collapse of lung
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Respiratory distress
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Upper respiratory tract inflammation
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Convulsion
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Intracranial hypotension
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Motor developmental delay
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurological symptom
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syringomyelia
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Optic neuropathy
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint contracture
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteopenia
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hyperparathyroidism tertiary
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dystrophic calcification
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Failure to thrive
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Feeding disorder
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Food intolerance
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Adenoviral upper respiratory infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Beta haemolytic streptococcal infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Enterobacter infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis staphylococcal
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 69 (11.59%)
         occurrences causally related to treatment / all
    1 / 9
         deaths causally related to treatment / all
    0 / 3
    Pneumonia viral
         subjects affected / exposed
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Serratia infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Serratia sepsis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stenotrophomonas infection
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Asfotase Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 69 (98.55%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    4
    General disorders and administration site conditions
    Catheter site erythema
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    16
    Catheter site inflammation
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    5
    Device occlusion
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    8
    Injection site atrophy
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    15
    Injection site discolouration
         subjects affected / exposed
    12 / 69 (17.39%)
         occurrences all number
    43
    Injection site erythema
         subjects affected / exposed
    33 / 69 (47.83%)
         occurrences all number
    223
    Injection site haematoma
         subjects affected / exposed
    10 / 69 (14.49%)
         occurrences all number
    22
    Injection site induration
         subjects affected / exposed
    11 / 69 (15.94%)
         occurrences all number
    44
    Injection site pain
         subjects affected / exposed
    8 / 69 (11.59%)
         occurrences all number
    22
    Injection site papule
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    91
    Injection site pruritus
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    14
    Injection site rash
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Injection site reaction
         subjects affected / exposed
    8 / 69 (11.59%)
         occurrences all number
    13
    Injection site swelling
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    21
    Irritability
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    6
    Pyrexia
         subjects affected / exposed
    47 / 69 (68.12%)
         occurrences all number
    131
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    11
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Contusion
         subjects affected / exposed
    10 / 69 (14.49%)
         occurrences all number
    21
    Fall
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    9
    Procedural pain
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    6
    Rib fracture
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Tooth fracture
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    6
    Oxygen saturation decreased
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    54
    Vitamin D decreased
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    6
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    7
    Tachycardia
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    16
    Congenital, familial and genetic disorders
    Congenital bowing of long bones
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    6
    Craniosynostosis
         subjects affected / exposed
    10 / 69 (14.49%)
         occurrences all number
    11
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    12
    Cough
         subjects affected / exposed
    17 / 69 (24.64%)
         occurrences all number
    34
    Dyspnoea
         subjects affected / exposed
    8 / 69 (11.59%)
         occurrences all number
    30
    Oropharyngeal pain
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    6
    Respiratory distress
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    7
    Rhinorrhoea
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    4
    Tachypnoea
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    7
    Tracheomalacia
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    5
    Use of accessory respiratory muscles
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    16
    Wheezing
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 69 (13.04%)
         occurrences all number
    13
    Lymphadenopathy
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    7
    Neutropenia
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    4
    Nervous system disorders
    Cerebral ventricle dilatation
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    6
    Headache
         subjects affected / exposed
    10 / 69 (14.49%)
         occurrences all number
    22
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    8 / 69 (11.59%)
         occurrences all number
    16
    Papilloedema
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    8
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    11
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    7
    Constipation
         subjects affected / exposed
    16 / 69 (23.19%)
         occurrences all number
    37
    Dental caries
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    11
    Diarrhoea
         subjects affected / exposed
    20 / 69 (28.99%)
         occurrences all number
    35
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 69 (13.04%)
         occurrences all number
    10
    Teething
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    10
    Tooth loss
         subjects affected / exposed
    41 / 69 (59.42%)
         occurrences all number
    109
    Toothache
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    8
    Vomiting
         subjects affected / exposed
    30 / 69 (43.48%)
         occurrences all number
    92
    Renal and urinary disorders
    Nephrocalcinosis
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    10 / 69 (14.49%)
         occurrences all number
    18
    Dry skin
         subjects affected / exposed
    8 / 69 (11.59%)
         occurrences all number
    10
    Eczema
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    14
    Erythema
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    8
    Excessive granulation tissue
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    6
    Granuloma skin
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    7
    Heat rash
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    5
    Rash
         subjects affected / exposed
    11 / 69 (15.94%)
         occurrences all number
    23
    Musculoskeletal and connective tissue disorders
    Bone disorder
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    23
    Knee deformity
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Kyphosis
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    10
    Pain in extremity
         subjects affected / exposed
    11 / 69 (15.94%)
         occurrences all number
    13
    Metabolism and nutrition disorders
    Food intolerance
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    5
    Hypocalcaemia
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    8
    Hypoglycaemia
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    6
    Hypokalaemia
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 69 (13.04%)
         occurrences all number
    16
    Device related infection
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Ear infection
         subjects affected / exposed
    13 / 69 (18.84%)
         occurrences all number
    18
    Gastroenteritis
         subjects affected / exposed
    16 / 69 (23.19%)
         occurrences all number
    20
    Gastroenteritis viral
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    5
    Gastrointestinal infection
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    9
    Hand-foot-and-mouth disease
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Influenza
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    8
    Nasopharyngitis
         subjects affected / exposed
    18 / 69 (26.09%)
         occurrences all number
    52
    Otitis media
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Pneumonia
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    9
    Respiratory tract infection
         subjects affected / exposed
    16 / 69 (23.19%)
         occurrences all number
    62
    Rhinitis
         subjects affected / exposed
    10 / 69 (14.49%)
         occurrences all number
    17
    Tonsillitis
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 69 (24.64%)
         occurrences all number
    31
    Urinary tract infection
         subjects affected / exposed
    8 / 69 (11.59%)
         occurrences all number
    8
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2011
    Amendment 1: The major changes to the protocol made with this amendment included the following: • The duration of the study was extended to 24 months or until regulatory approval for asfotase alfa was obtained. • The BOT-2 was added to the list of clinical assessments and all functional assessments were added to the Month 9 study visit • Change from Baseline in the Gross Motor Milestone Checklist was added as a secondary endpoint
    27 Oct 2011
    EU Amendment 1 to German sites. The major changes to the protocol made with this amendment were identical to those made to the USA, Canadian, Taiwanese and Turkish versions under Protocol ENB-010-10 Amendment 1 (13 October 2011), except the duration of the study was extended to 48 months (not 24). Amendment 1 was not submitted for approval.
    15 Dec 2011
    EU Amendment 2: There were no new major changes to the protocol with this amendment and it was not submitted or implemented.
    06 Jun 2012
    EU Amendment 3: There were no new major changes to the protocol with this amendment and it was not implemented.
    10 Oct 2012
    EU Amendment 4: The following major changes were made to the protocol with this amendment: • Vital signs collection was added following study drug administration. • The schedule originally indicated that skeletal radiographs should be obtained at Month 15, which was incorrect. This mistake was corrected.
    25 Oct 2012
    Japan Amendment 1.3: The version of the protocol first implemented at sites in Japan was Version 1.2 dated 09 October 2012. Per the Japanese protocol, patients enrolled were to be hospitalized for the first week of the study, regardless of disease severity. The major changes in the conduct of the study which were made with subsequent versions of the protocol for the sites in Japan are summarized below: Version 1.3 (25 October 2012): • Enrollment was changed from 3 to 4 patients from Japan • Skeletal radiographs to be obtained at the Month 15 visit were added to the schedule of assessments.
    24 Jan 2013
    Amendment 5: The major change to the protocol made with this amendment was to allow for expansion of the study into territories outside of the EU not currently covered under the protocol including Australia, Germany, Italy, Saudi Arabia, Spain, and UK) • The protocol number was changed from ENB-010-10 (EU-specific) to ENB-010-10 • The total number of patients to be enrolled was increased from 30 to 60 patients • The asfotase alfa treatment period was changed to continue until the product becomes registered and available to treat patients diagnosed with HPP (in accordance with country specific regulations), or for a maximum of approximately 48 months, whichever occurred first. In the UK, patient participation may have continued for a maximum of 48 months.
    04 Mar 2013
    Japan Amendment 1.4: • Total enrollment was changed to up to 5 patients from Japan. • Historical values for vitamin D obtained within 3 months before the Screening visit were allowed to be used to determine patient eligibility. • In Version 1.3 of the protocol, skeletal radiographs obtained at Month 15 were added, which was incorrect. This mistake was corrected.
    07 Mar 2013
    Amendment 6 (French-specific) • The primary reason for Amendment 6 was to clarify the details of study drug administration for the maximum allowable dose of 9 mg/kg/week, such that study drug would be administered at a dosing regimen of either 1.5 mg/kg 6 times per week or 3 mg/kg 3 times per week.
    06 May 2013
    Amendment 7(French-specific) Significant changes made to the protocol in Amendment 7, for France, included the following: • Considering the age of patients being enrolled in this clinical study (≤ 5 years), the description of assent for study participation was removed as not applicable. • Actual timing for a planned interim statistical analysis was added (after
    06 Jun 2013
    Japan Amendment 1.5: • The total number of enrollment for the study was revised from 30 to 60 patients, based on the revision of the EU protocol.
    27 Sep 2013
    Japan Amendment 1.6: There were no new major changes with this version.
    12 Mar 2014
    Japan Amendment 1.7: • Procedures for home injection were added to reduce the burden on the patient for site visits as well as a plan to differentiate home versus site injections in the analysis at the onset of any AEs.
    02 Jun 2014
    Amendment 8: Global Protocols (Except for Japan) – Not Submitted Protocol Amendment 8 was written to update and harmonize protocol requirements across the aforementioned regions. Significant changes from the regional protocols to Protocol Amendment 8, included the following: • Incorporation of relevant changes from Amendment 1 (Canada, Taiwan, Turkey, US), Amendment 5 (Australia, Germany, Italy, Saudi Arabia, Spain, UK, and Amendment 7 (France) to create 1 global protocol (excluding Japan) for use. • Increase in enrollment from approximately 30 (Amendment 1) or 60 (Amendments 5 and 7) patients to approximately 80 patients and the number of sites from approximately 20 to approximately 25. • Extension of the study duration to regulatory approval and commercial availability of asfotase alfa or a maximum of 72 or (in the UK) 48 months.
    15 Sep 2014
    Amendment 9: Significant changes made to the protocol in Amendment 9, which was global except for Japan, included the following: • Change in wording on the study duration to clarify that the minimum treatment duration for patients will be 12 months, and that the overall study duration will be approximately 72 months, except in the UK where patient participation may continue for a maximum of 48 months. • Change in exclusion criteria regarding bisphosphonates to allow patients who received ≤ 2 cumulative doses of bisphosphonates to enroll in the study, upon approval of Alexion’s Medical Monitor.
    07 Nov 2014
    Japan Amendment 1.8: • The contact information for SAE reporting was revised. • The study period completion date was revised to add an extra 6 months of patient participation, from 31 December 2014 to 30 June 2015.
    09 Mar 2015
    Japan Amendment 1.9: Amendment 1.9 was aligned with global protocol ver8.0 Global protocol ver. 8.0 was the first integrated international protocol for 10-10 study.
    10 Apr 2015
    Amendment 10: Significant changes made to the protocol in Amendment 10, which was global except for Japan, included the following: • Clarified the treatment/study duration in anticipation of marketing approval. Protocol text was modified clarifying that patient participation in the study may continue until the product is registered and/or available to treat patients diagnosed with HPP (in accordance with country-specific regulations) or until approximately 72 months (regardless of duration of asfotase alfa treatment for individual patients) (whichever occurs first), except in the UK where patient participation may continue for a maximum of 48 months. Text indicating that patients will receive treatment with asfotase alfa for a minimum of 12 months was removed. • Approximate number of patients to be enrolled was updated from 80 to 100 patients.

    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
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