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    Clinical Trial Results:
    A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Historical Control Study of the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Children With Hypophosphatasia (HPP)

    Summary
    EudraCT number
    		 2015-001128-52
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    29 Jul 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Aug 2016
    First version publication date
    07 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENB-006-09
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00952484
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alexion Pharma GmbH
    Sponsor organisation address
    Giesshübelstrasse 30, Zurich, Switzerland, 8045
    Public contact
    European Clinical Trial Information, Alexion Europe SAS, +33 147100606, Clinicaltrials.eu@alxn.com
    Scientific contact
    European Clinical Trial Information, Alexion Europe SAS, +33 147100606, Clinicaltrials.eu@alxn.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Mar 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jul 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This clinical trial studied the safety and efficacy of asfotase alfa in children with HPP compared to a historical control group.
    Protection of trial subjects
    No specific measure
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    29
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    27
    Adolescents (12-17 years)
    2
    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
    		 Patients were recruited to participate in the study from September to December 2009 at investigational sites via posting in clinicaltrials.gov and contact with physicians experienced in the diagnosis and management of HPP. De-identified historical controls were also selected from a natural history database of patients with HPP.

    Pre-assignment
    Screening details
    		 Patients meeting eligibility criteria were randomly assigned to receive 2mg/kg or 3mg/kg of asfotase alfa SC 3 times weekly for 24 weeks.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Arm description
    		 2 mg/kg or 3 mg/kg subcutaneous (SC) injection three times per week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asfotase alfa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 mg/kg or 3 mg/kg subcutaneous (SC) injection three times per week

    Arm title
    		 Historical control
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		2 mg/kg or 3 mg/kg Asfotase Alfa Historical control
    Started
    13
    16
    Completed
    12
    16
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2 mg/kg or 3 mg/kg Asfotase Alfa
    Reporting group description
    		 2 mg/kg or 3 mg/kg subcutaneous (SC) injection three times per week.

    Reporting group title
    Historical control
    Reporting group description
    		 -

    Reporting group values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa Historical control Total
    Number of subjects
    		 13 16 29
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 11 16 27
        Adolescents (12-17 years)
    		 2 0 2
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.8 ( 2.21 ) 6 ( 1.78 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 5 7
        Male
    		 11 11 22
    Subject analysis sets

    Subject analysis set title
    2 mg/kg SC inj. three times per week
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial.

    Subject analysis set title
    3 mg/kg SC inj. three times per week
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population, which included all randomized patients that received any treatment with asfotase alfa (3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial.

    Subject analysis sets values
    		 2 mg/kg SC inj. three times per week 3 mg/kg SC inj. three times per week
    Number of subjects
    6
    7
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    5
    6
        Adolescents (12-17 years)
    1
    1
        Adults (18-64 years)
    0
    0
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.4 ( 2.2 )
    9.1 ( 2.3 )
    Gender categorical
    Units: Subjects
        Female
    1
    1
        Male
    5
    6

    End points

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    End points reporting groups
    Reporting group title
    2 mg/kg or 3 mg/kg Asfotase Alfa
    Reporting group description
    		 2 mg/kg or 3 mg/kg subcutaneous (SC) injection three times per week.

    Reporting group title
    Historical control
    Reporting group description
    		 -

    Subject analysis set title
    2 mg/kg SC inj. three times per week
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial.

    Subject analysis set title
    3 mg/kg SC inj. three times per week
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population, which included all randomized patients that received any treatment with asfotase alfa (3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial.

    Primary: Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale

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    End point title
    		 Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale
    End point description
    A 7-point RGI-C (radiographic global impression of change) score was used to rate change in rickets severity. Only those patients with a minimum score of +2 indicating substantial healing of rickets) were considered responders. Three pediatric radiologists not affiliated with the conduct of the study performed the ratings.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa Historical control
    Number of subjects analysed
    13
    16
    Units: unit(s)
        median (full range (min-max))
    2 (0 to 2.3)
    0 (-1.3 to 2)
    Statistical analysis title
    		 Statistical analysis 1 for Outcome measure 1
    Statistical analysis description
    ITT population, which included randomized patients that received treatment with asfotase alfa, even if discontinued or lost to follow-up. The last assessment prior to Week 24 is used for missing Week 24 data; patients with no post-baseline assessments imputed as having no change. A historical control group is used for comparison.
    Comparison groups
    2 mg/kg or 3 mg/kg Asfotase Alfa v Historical control
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0007 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - P-value based on Wilcoxon rank sum test comparing the median RGI-C score for the asfotase alfa combined reporting group to the historical control group.

    Secondary: Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy)

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    End point title
    		 Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy) [2]
    End point description
    Change from Baseline to Week 24 in osteoid thickness
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    12
    Units: um
        arithmetic mean (standard deviation)
    -3.858 ( 4.2784 )
    No statistical analyses for this end point

    Secondary: Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy)

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    End point title
    		 Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy) [3]
    End point description
    Change from Baseline to Week 24 in osteoid volume/bone volume (%), calculated as the absolute difference of the Baseline and Week 24 percentages.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    12 [4]
    Units: percent
        arithmetic mean (standard deviation)
    -4.225 ( 7.5582 )
    Notes
    [4] - Asfotase alfa combined
    No statistical analyses for this end point

    Secondary: Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy)

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    End point title
    		 Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy) [5]
    End point description
    Change from Baseline to Week 24 in mineralization lag time.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    12
    Units: days
        arithmetic mean (standard deviation)
    20.392 ( 208.9814 )
    No statistical analyses for this end point

    Secondary: Change in Height (Z-scores)

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    End point title
    		 Change in Height (Z-scores) [6]
    End point description
    Change from Baseline to Week 24 in Height Z-Score. Height Z-Scores assigned based on Centers for Disease Control (CDC) growth charts and methodology
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    12
    Units: Height Z score
        arithmetic mean (standard deviation)
    0.01 ( 0.141 )
    No statistical analyses for this end point

    Secondary: Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi)

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    End point title
    		 Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi) [7]
    End point description
    Change from Baseline to Week 24 in Plasma PPi
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    12
    Units: uM
        arithmetic mean (standard deviation)
    -1.883 ( 0.7285 )
    No statistical analyses for this end point

    Secondary: Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP)

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    End point title
    		 Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP) [8]
    End point description
    Change from Baseline to Week 24 in Plasma PLP
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    12
    Units: ng/mL
        arithmetic mean (standard deviation)
    -164.533 ( 121.484 )
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration of Asfotase Alfa (Cmax).

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    End point title
    		 Maximum Serum Concentration of Asfotase Alfa (Cmax). [9]
    End point description
    Maximum serum concentration observed following single dose of asfotase alfa.
    End point type
    Secondary
    End point timeframe
    Study Week 1 (0 to 48 hours post-dose)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    13 [10]
    Units: U/L
    arithmetic mean (standard deviation)
        2 mg/kg SC inj. three times per week
    566 ( 120 )
        3 mg/kg SC inj. three times per week
    1260 ( 439 )
    Notes
    [10] - 2 mg/kg SC inj. 3 times/week: 6 patients analysed 3 mg/kg SC inj. 3 times/week: 7 patients analysed
    No statistical analyses for this end point

    Secondary: Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)

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    End point title
    		 Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) [11]
    End point description
    Maximum serum concentration observed following single dose of asfotase alfa.
    End point type
    Secondary
    End point timeframe
    Study Week 1 (0 to 48 hours post-dose)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    13 [12]
    Units: hours
    arithmetic mean (standard deviation)
        2 mg/kg SC inj. three times per week
    37.2 ( 8.1 )
        3 mg/kg SC inj. three times per week
    34.3 ( 6 )
    Notes
    [12] - 2 mg/kg SC inj. 3 times/week: 6 patients analysed 3 mg/kg SC inj. 3 times/week: 7 patients analysed
    No statistical analyses for this end point

    Secondary: Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)

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    End point title
    		 Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) [13]
    End point description
    Area under serum concentration-time curve to last measurable concentration following single dose of asfotase alfa.
    End point type
    Secondary
    End point timeframe
    Study Week 1 (0 to 48 hours post-dose)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    13 [14]
    Units: h*U/L
    arithmetic mean (standard deviation)
        2 mg/kg SC inj. three times per week
    19700 ( 5720 )
        3 mg/kg SC inj. three times per week
    45200 ( 15100 )
    Notes
    [14] - 2 mg/kg SC inj. 3 times/week: 6 patients analysed 3 mg/kg SC inj. 3 times/week: 7 patients analysed
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration of Asfotase Alfa (Cmax).

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    End point title
    		 Maximum Serum Concentration of Asfotase Alfa (Cmax). [15]
    End point description
    Maximum serum concentration observed following multiple doses of asfotase alfa.
    End point type
    Secondary
    End point timeframe
    Study Week 6 (0 to 48 hours post-dose)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    13 [16]
    Units: U/L
    arithmetic mean (standard deviation)
        2 mg/kg SC inj. three times per week
    1780 ( 666 )
        3 mg/kg SC inj. three times per week
    2280 ( 875 )
    Notes
    [16] - 2 mg/kg SC inj. 3 times/week: 6 patients analysed 3 mg/kg SC inj. 3 times/week: 7 patients analysed
    No statistical analyses for this end point

    Secondary: Time at Maximum Serum Concentration of Asfotase Alfa (Tmax).

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    End point title
    		 Time at Maximum Serum Concentration of Asfotase Alfa (Tmax). [17]
    End point description
    Time at maximum serum concentration observed following multiple doses of asfotase alfa.
    End point type
    Secondary
    End point timeframe
    Study Week 6 (0 to 48 hours post-dose)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    13 [18]
    Units: hours
    arithmetic mean (standard deviation)
        2 mg/kg SC inj. three times per week
    20.8 ( 10 )
        3 mg/kg SC inj. three times per week
    17.3 ( 8.6 )
    Notes
    [18] - 2 mg/kg SC inj. 3 times/week: 6 patients analysed 3 mg/kg SC inj. 3 times/week: 7 patients analysed
    No statistical analyses for this end point

    Secondary: Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)

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    End point title
    		 Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) [19]
    End point description
    Area under serum concentration-time curve to last measurable concentration following multiple doses of asfotase alfa.
    End point type
    Secondary
    End point timeframe
    Study Week 6 (0 to 48 hours post-dose).
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis cannot be done for the historical control arm (non-interventional arm).
    End point values
    		 2 mg/kg or 3 mg/kg Asfotase Alfa
    Number of subjects analysed
    13 [20]
    Units: h*U/L
    arithmetic mean (standard deviation)
        2 mg/kg SC inj. three times per week
    76000 ( 28100 )
        3 mg/kg SC inj. three times per week
    94200 ( 44400 )
    Notes
    [20] - 2 mg/kg SC inj. 3 times/week: 6 patients analysed 3 mg/kg SC inj. 3 times/week: 7 patients analysed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    res6 months
    Adverse event reporting additional description
    Adverse event data for the historical control group were not collected.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13
    Reporting groups
    Reporting group title
    2 mg/kg Asfotase Alfa
    Reporting group description
    		 2 mg/kg subcutaneous (SC) injection three times per week.

    Reporting group title
    3 mg/kg Asfotase Alfa
    Reporting group description
    		 3 mg/kg subcutaneous (SC) injection three times per week.

    Serious adverse events
    		 2 mg/kg Asfotase Alfa 3 mg/kg Asfotase Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 2 mg/kg Asfotase Alfa 3 mg/kg Asfotase Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    5 / 6 (83.33%)
    7 / 7 (100.00%)
         occurrences all number
    13
    16
    Injection site discolouration
         subjects affected / exposed
    4 / 6 (66.67%)
    4 / 7 (57.14%)
         occurrences all number
    4
    4
    Injection site pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 6 (66.67%)
    3 / 7 (42.86%)
         occurrences all number
    8
    3
    Injection site swelling
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 7 (28.57%)
         occurrences all number
    3
    2
    Infusion site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Injection site pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 7 (42.86%)
         occurrences all number
    5
    5
    Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    infection site hemorrage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Infection site nodule
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Irritability
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Seasonal allergy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 7 (28.57%)
         occurrences all number
    1
    2
    Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    3
    1
    Nasal congestion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Rhinorrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Epistaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    6
    Rhinitis allergic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood 1,25-dihydroxycholecalciferol decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Blood 25-hydroxycholecalciferol decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Vitamin B6 decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    4 / 6 (66.67%)
    3 / 7 (42.86%)
         occurrences all number
    4
    3
    Excoriation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Animal bite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Tongue injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    Foreign body
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Laceration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Limb injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Procedural nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    5
    1
    Eye disorders
    Scleral haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Eye allergy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 6 (66.67%)
    1 / 7 (14.29%)
         occurrences all number
    8
    1
    Dental caries
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Sensitivity of teeth
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Teething
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Toothache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Anal fissure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Tooth loss
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Sinus congestion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Medial tibial stress syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Unequal limb length
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Myalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Neck pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 7 (42.86%)
         occurrences all number
    1
    3
    Otitis media
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Otitis externa
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/18086009
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