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

    Summary
    EudraCT number
    		 2017-001831-38
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    28 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Oct 2018
    First version publication date
    20 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENB-009-10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01163149
    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@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Europe SAS, +33 147100606, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This clinical trial was conducted to study hypophosphatasia (HPP), a bone disorder caused by gene mutations or changes. These gene mutations cause low levels of an enzyme needed to harden bone. The purpose of this study was to test the safety and efficacy of 2 doses of the study drug called asfotase alfa as compared to a control group to see effects on adolescents and adults with HPP.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 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
    Canada: 8
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    19
    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)
    0
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    13
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 19 patients, who had HPP, a bone disorder caused by gene mutations or changes, were enrolled in this study.

    Period 1
    Period 1 title
    Primary Treatment (First 24 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment)
    Arm description
    		 Asfotase alfa Cohort 1: Daily subcutaneous (SC) injections of 0.3 milligrams (mg)/kilograms (kg) asfotase alfa (2.1 mg/kg/week total) during Primary Treatment Period through Week 24. Following completion of the Week 24 visit, all patients were eligible to participate in an open-label extension treatment period. In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.
    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
    Cohort 1: 0.3 mg/kg (2.1 mg/kg/week total)

    Arm title
    		 0.5 mg/kg Asfotase Alfa (Primary Treatment)
    Arm description
    		 Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total) during Primary Treatment Period through Week 24. Following completion of the Week 24 visit, all patients were eligible to participate in an open-label extension treatment period. In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.
    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
    Cohort 2: 0.5 mg/kg (3.5 mg/kg/week total)

    Arm title
    		 Concurrent Control (Primary Treatment)
    Arm description
    		 No asfotase alfa during first 24 weeks (primary treatment period). Following completion of the Week 24 visit, all patients randomized to the concurrent control cohort were eligible to participate in an open-label extension treatment period. In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment)
    Started
    7
    6
    6
    Received at Least 1 Dose of Study Drug
    7
    6
    6
    Completed
    7
    6
    6
    Period 2
    Period 2 title
    Extension Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Asfotase Alfa Combined (Extension Treatment)
    Arm description
    		 In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug. Patients treated during the Extension Period were from Cohort 1 (Number [N]=7), Cohort 2 (N=6), and the Control group (N=6) combined; total N=19.
    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
    In the open label extension period, all patients were treated with 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.

    Number of subjects in period 2
    		Asfotase Alfa Combined (Extension Treatment)
    Started
    19
    Received at Least 1 Dose of Study Drug
    19
    Completed
    14
    Not completed
    5
         Adverse event, non-fatal
    1
         Consent withdrawn by patient
    3
         Noncompliance
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    0.3 mg/kg Asfotase Alfa (Primary Treatment)
    Reporting group description
    		 Asfotase alfa Cohort 1: Daily subcutaneous (SC) injections of 0.3 milligrams (mg)/kilograms (kg) asfotase alfa (2.1 mg/kg/week total) during Primary Treatment Period through Week 24. Following completion of the Week 24 visit, all patients were eligible to participate in an open-label extension treatment period. In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.

    Reporting group title
    0.5 mg/kg Asfotase Alfa (Primary Treatment)
    Reporting group description
    		 Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total) during Primary Treatment Period through Week 24. Following completion of the Week 24 visit, all patients were eligible to participate in an open-label extension treatment period. In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.

    Reporting group title
    Concurrent Control (Primary Treatment)
    Reporting group description
    		 No asfotase alfa during first 24 weeks (primary treatment period). Following completion of the Week 24 visit, all patients randomized to the concurrent control cohort were eligible to participate in an open-label extension treatment period. In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.

    Reporting group values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Total
    Number of subjects
    		 7 6 6 19
    Age categorical
    Units: Subjects
        Adolescent (12-17 years)
    		 2 1 3 6
        Adult (18 years or older)
    		 5 5 3 13
    Age continuous
    Units: years
        median (full range (min-max))
    		 45 (14 to 66) 55 (15 to 57) 21 (13 to 58) -
    Gender categorical
    Units: Subjects
        Female
    		 6 4 2 12
        Male
    		 1 2 4 7
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 7 6 5 18
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0
        Not Hispanic or Latino
    		 7 6 6 19
        Unknown or Not Reported
    		 0 0 0 0
    Hypophosphatasia (HPP) Phenotype
    Units: Subjects
        Infantile (<6 months)
    		 1 2 1 4
        Juvenile (≥6 months to <18 years)
    		 5 4 5 14
        Adult (≥ 18 years)
    		 1 0 0 1
    Age at Onset of Symptoms
    Units: years
        median (full range (min-max))
    		 2 (0.2 to 36) 2 (0 to 3) 0.88 (0.2 to 4) -

    End points

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    End points reporting groups
    Reporting group title
    0.3 mg/kg Asfotase Alfa (Primary Treatment)
    Reporting group description
    		 Asfotase alfa Cohort 1: Daily subcutaneous (SC) injections of 0.3 milligrams (mg)/kilograms (kg) asfotase alfa (2.1 mg/kg/week total) during Primary Treatment Period through Week 24. Following completion of the Week 24 visit, all patients were eligible to participate in an open-label extension treatment period. In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.

    Reporting group title
    0.5 mg/kg Asfotase Alfa (Primary Treatment)
    Reporting group description
    		 Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total) during Primary Treatment Period through Week 24. Following completion of the Week 24 visit, all patients were eligible to participate in an open-label extension treatment period. In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.

    Reporting group title
    Concurrent Control (Primary Treatment)
    Reporting group description
    		 No asfotase alfa during first 24 weeks (primary treatment period). Following completion of the Week 24 visit, all patients randomized to the concurrent control cohort were eligible to participate in an open-label extension treatment period. In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug.
    Reporting group title
    Asfotase Alfa Combined (Extension Treatment)
    Reporting group description
    		 In this extension period, all patients were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then patients received 1 mg/kg/day 6 days/week until regulatory approval of the drug. Patients treated during the Extension Period were from Cohort 1 (Number [N]=7), Cohort 2 (N=6), and the Control group (N=6) combined; total N=19.

    Subject analysis set title
    Asfotase Alfa Combined (Primary Treatment)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients treated during the Primary Treatment Period were from Cohort 1 (N=7) and Cohort 2 (N=6) combined; total N=13.

    Primary: Change From Baseline To Week 24 For Plasma Pyridoxal-5' Phosphate (PLP)

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    End point title
    		 Change From Baseline To Week 24 For Plasma Pyridoxal-5' Phosphate (PLP)
    End point description
    Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma pyridoxal-5' phosphate (PLP).
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Primary Treatment)
    Number of subjects analysed
    7
    6
    6
    13
    Units: ng/mL
        arithmetic mean (standard deviation)
    -254.96 ( 196.206 )
    -564.27 ( 624.009 )
    3.13 ( 242.721 )
    -397.72 ( 455.249 )
    Statistical analysis title
    		 Change From Baseline To Week 24 For PLP
    Statistical analysis description
    Change from Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP)
    Comparison groups
    Concurrent Control (Primary Treatment) v Asfotase Alfa Combined (Primary Treatment)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0285 [2]
    Method
    		 Wilcoxon rank-sum
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -626.4
         upper limit
    		 -59.2
    Notes
    [1] - If p-values were less than 0.05 and the Hodges-Lehman-Sen estimate (-302.05) favored asfotase alfa (that is, it had a negative sign indicating the between-group differences in change from Baseline favored treated patients), then superiority over control was claimed.
    [2] - Two-sided with p-value threshold <0.05 for statistical significance

    Primary: Change From Baseline To Week 24 For Plasma Inorganic Pyrophosphate (PPi)

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    End point title
    		 Change From Baseline To Week 24 For Plasma Inorganic Pyrophosphate (PPi)
    End point description
    Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma inorganic pyrophosphate (PPi).
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Primary Treatment)
    Number of subjects analysed
    7
    6
    6
    13
    Units: uM
        arithmetic mean (standard deviation)
    -2.027 ( 1.4381 )
    -2.185 ( 1.3304 )
    -1.052 ( 2.9248 )
    -2.100 ( 1.3335 )
    Statistical analysis title
    		 Change From Baseline To Week 24 For PPi
    Statistical analysis description
    Change From Baseline to Week 24 for Plasma Inorganic Pyrophosphate (PPi)
    Comparison groups
    Concurrent Control (Primary Treatment) v Asfotase Alfa Combined (Primary Treatment)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0715 [4]
    Method
    		 Wilcoxon rank-sum
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.21
         upper limit
    		 0.23
    Notes
    [3] - If p-values were less than 0.05 and the Hodges-Lehman-Sen estimate (-1.825) favored asfotase alfa (that is, it had a negative sign indicating the between-group differences in change from Baseline favored treated patients), then superiority over control was claimed.
    [4] - Two-sided with p-value threshold <0.05 for statistical significance

    Primary: Safety And Tolerability Of Asfotase Alfa

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    End point title
    		 Safety And Tolerability Of Asfotase Alfa [5]
    End point description
    The safety and tolerability of daily subcutaneous (SC) injections of asfotase alfa was assessed by routine monitoring of patients for treatment-emergent adverse events (TEAEs) and injection associated reactions (IARs).
    End point type
    Primary
    End point timeframe
    Up to 288 weeks exposure to asfotase alfa
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses data were not calculated for adverse events per study protocol.
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Extension Treatment)
    Number of subjects analysed
    7
    6
    6
    19
    Units: Number of Treatment-Emergent Events
        Any TEAE
    243
    81
    45
    1145
        Not related TEAE
    110
    69
    45
    731
        Related TEAE
    133
    12
    0
    414
        Injection Site Reactions
    133
    12
    0
    385
        Serious TEAEs
    1
    1
    4
    29
        TEAEs leading to withdrawal
    0
    0
    0
    2
        Deaths
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline In Bone Mineral Content (BMC) As Measured By Dual-energy X-ray Absorptiometry (DXA) To Week 24

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    End point title
    		 Change From Baseline In Bone Mineral Content (BMC) As Measured By Dual-energy X-ray Absorptiometry (DXA) To Week 24
    End point description
    A DXA scan was performed to evaluate BMC of the spine, hip, and whole body during the primary (first 24 weeks) treatment period. The number (N) of patients evaluated for the various time points differ from the total number of patients in the group. The N of patients evaluated is reported in the Category Title.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Primary Treatment)
    Number of subjects analysed
    7
    6
    6
    13
    Units: grams (g)
    arithmetic mean (standard deviation)
        Hip Total BMC Week 24, N=4, 5, 4, 9
    -3.288 ( 7.7669 )
    1.214 ( 2.2154 )
    1.288 ( 0.9161 )
    -0.787 ( 5.5411 )
        Lumbar Spine BMC Week 24, N=7, 5, 5, 12
    2.477 ( 2.5616 )
    2.768 ( 2.0007 )
    1.432 ( 1.7824 )
    2.598 ( 2.2488 )
        Whole Body BMC Week 24, N=7, 5, 5, 12
    -21.871 ( 35.4370 )
    41.454 ( 20.0358 )
    237.248 ( 414.0877 )
    4.514 ( 43.5228 )
    Statistical analysis title
    		 Hip Total BMC Change From Baseline To Week 24
    Statistical analysis description
    Change From Baseline to Week 24 in Hip Total BMC as Measured by DXA
    Comparison groups
    Concurrent Control (Primary Treatment) v Asfotase Alfa Combined (Primary Treatment)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.3301 [7]
    Method
    		 Wilcoxon rank-sum
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.32
         upper limit
    		 1.78
    Notes
    [6] - The Hodges-Lehman-Sen estimate = -0.910.
    [7] - Two-sided with p-value threshold <0.05 for statistical significance
    Statistical analysis title
    		 Lumbar Spine BMC Change From Baseline To Week 24
    Statistical analysis description
    Change From Baseline to Week 24 in Lumbar Spine BMC as Measured by DXA
    Comparison groups
    Concurrent Control (Primary Treatment) v Asfotase Alfa Combined (Primary Treatment)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.3827 [9]
    Method
    		 Wilcoxon rank-sum
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.36
         upper limit
    		 3.12
    Notes
    [8] - The Hodges-Lehman-Sen estimate = 1.330.
    [9] - Two-sided with p-value threshold <0.05 for statistical significance
    Statistical analysis title
    		 Whole Body BMC Change From Baseline To Week 24
    Statistical analysis description
    Change From Baseline to Week 24 in Whole Body BMC as Measured by DXA
    Comparison groups
    Concurrent Control (Primary Treatment) v Asfotase Alfa Combined (Primary Treatment)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.0485 [11]
    Method
    		 Wilcoxon rank-sum
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -917.44
         upper limit
    		 -1.74
    Notes
    [10] - The Hodges-Lehman-Sen estimate = -77.100.
    [11] - Two-sided with p-value threshold <0.05 for statistical significance

    Secondary: Change From Baseline In BMC As Measured By DXA From Week 48 Until Week 288

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    End point title
    		 Change From Baseline In BMC As Measured By DXA From Week 48 Until Week 288
    End point description
    A DXA scan was performed to evaluate BMC of the spine, hip, and whole body during the extension treatment period (up to 288 weeks, including a last overall exposure [LOE]). The N of patients evaluated for the various time points differ from the total number of patients in the group. The N of patients evaluated is reported in the Category Title.
    End point type
    Secondary
    End point timeframe
    Baseline, every 24 weeks from Week 48 through Week 96, and from Week 144 every 48 weeks until Week 288
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Extension Treatment)
    Number of subjects analysed
    7 [12]
    6 [13]
    6 [14]
    19 [15]
    Units: grams
    arithmetic mean (standard deviation)
        Hip Total BMC Week 48, N=1, 1, 4, 6
    1.160 ( 0.0 )
    4.530 ( 0.0 )
    2.320 ( 1.3990 )
    2.495 ( 1.5438 )
        Hip Total BMC Week 96, N=4, 4, 3, 11
    0.082 ( 1.4046 )
    4.345 ( 4.0466 )
    2.907 ( 2.0087 )
    2.403 ( 3.1702 )
        Hip Total BMC Week 144, N=3, 4, 3, 10
    1.630 ( 1.8719 )
    5.043 ( 5.5955 )
    4.533 ( 1.4621 )
    3.866 ( 3.7577 )
        Hip Total BMC Week 192, N=2, 4, 3, 9
    1.080 ( 2.0082 )
    4.725 ( 6.4843 )
    2.910 ( 0.2910 )
    3.310 ( 4.3124 )
        Hip Total BMC Week 240, N=2, 3, 3, 8
    0.550 ( 2.4042 )
    6.807 ( 5.7557 )
    -0.673 ( 0.1644 )
    2.438 ( 4.8626 )
        Hip Total BMC Week 288, N=0, 1, 0, 1
    0.0 ( 0.0 )
    -2.780 ( 0.0 )
    0.0 ( 0.0 )
    -2.780 ( 0.0 )
        Hip Total BMC LOE, N=4, 5, 4, 13
    0.080 ( 1.8713 )
    3.604 ( 5.8284 )
    0.328 ( 2.0062 )
    1.512 ( 4.0224 )
        Lumbar Spine BMC Week 48, N=1, 1, 5, 7
    2.420 ( 0.0 )
    5.550 ( 0.0 )
    4.842 ( 5.7882 )
    4.597 ( 4.8298 )
        Lumbar Spine BMC Week 96, N=7, 5, 4, 16
    3.356 ( 4.4566 )
    4.174 ( 3.7068 )
    7.330 ( 5.6953 )
    4.605 ( 4.5680 )
        Lumbar Spine BMC Week 144, N=5, 5, 4, 14
    2.086 ( 5.2198 )
    5.828 ( 3.9791 )
    6.710 ( 4.0174 )
    4.744 ( 4.6193 )
        Lumbar Spine BMC Week 192, N=5, 5, 4, 14
    2.094 ( 16.4419 )
    6.162 ( 4.1628 )
    5.197 ( 5.7568 )
    4.434 ( 9.9797 )
        Lumbar Spine BMC Week 240, N=5, 4, 4, 13
    3.536 ( 17.0957 )
    3.298 ( 2.4931 )
    5.037 ( 4.7161 )
    3.925 ( 10.2539 )
        Lumbar Spine BMC Week 288, N=1, 1, 0, 2
    20.910 ( 0.0 )
    6.500 ( 0.0 )
    0.0 ( 0.0 )
    13.705 ( 10.1894 )
        Lumbar Spine BMC LOE, N=7, 5, 5, 17
    4.306 ( 14.5714 )
    5.130 ( 3.5930 )
    6.714 ( 5.1113 )
    5.256 ( 9.5103 )
        Whole Body BMC Week 48, N=1, 1, 5, 7
    49.820 ( 0.0 )
    72.530 ( 0.0 )
    30.228 ( 82.4369 )
    39.070 ( 69.2934 )
        Whole Body BMC Week 96, N=7, 5, 4, 16
    7.537 ( 74.2838 )
    59.604 ( 97.9214 )
    98.018 ( 111.9259 )
    46.428 ( 93.5046 )
        Whole Body BMC Week 144, N=5, 5, 4, 14
    -48.236 ( 111.6604 )
    17.446 ( 173.3574 )
    92.063 ( 107.9837 )
    15.307 ( 138.3534 )
        Whole Body BMC Week 192, N=5, 5, 4, 14
    -121.916 ( 92.0001 )
    23.938 ( 195.8402 )
    50.375 ( 99.6281 )
    -20.599 ( 151.5153 )
        Whole Body BMC Week 240, N=5, 4, 4, 13
    -97.706 ( 106.6581 )
    82.310 ( 223.0794 )
    40.572 ( 162.1575 )
    0.231 ( 172.0218 )
        Whole Body BMC Week 288, N=1, 1, 0, 2
    -243.080 ( 0.0 )
    -144.660 ( 0.0 )
    0.0 ( 0.0 )
    -193.870 ( 69.5934 )
        Whole Body BMC LOE, N=7, 5, 5, 17
    -113.296 ( 178.8050 )
    11.252 ( 217.5674 )
    82.548 ( 128.7017 )
    -19.063 ( 188.0498 )
    Notes
    [12] - "0.0" entered for arithmetic mean for no data and for standard deviation when number (N) = 1.
    [13] - "0.0" entered for arithmetic mean for no data and for standard deviation when number (N) = 1.
    [14] - "0.0" entered for arithmetic mean for no data and for standard deviation when number (N) = 1.
    [15] - "0.0" entered for arithmetic mean for no data and for standard deviation when number (N) = 1.
    No statistical analyses for this end point

    Secondary: Change From Baseline In Bone Mineral Density (BMD) As Measured By Dual-energy X-ray Absorptiometry (DXA) To Week 24

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    End point title
    		 Change From Baseline In Bone Mineral Density (BMD) As Measured By Dual-energy X-ray Absorptiometry (DXA) To Week 24
    End point description
    A DXA scan was performed to evaluate BMD of the spine, hip, and whole body during the primary (first 24 weeks) treatment period. The N of patients evaluated for the various time points differ from the total number of patients in the group. The N of patients evaluated is reported in the Category Title.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Primary Treatment)
    Number of subjects analysed
    7
    6
    6
    13
    Units: grams/centimeters squared (g/m2)
    arithmetic mean (standard deviation)
        Hip Total BMD Week 24, N=4, 5, 4, 9
    0.0447 ( 0.07710 )
    0.0094 ( 0.02441 )
    0.0195 ( 0.01642 )
    0.0251 ( 0.05361 )
        Lumbar Spine BMD Week 24, N=7, 5, 5, 12
    0.0269 ( 0.02113 )
    0.0272 ( 0.01492 )
    0.0098 ( 0.02475 )
    0.0270 ( 0.01802 )
        Whole Body BMD Week 24, N=7, 5, 5, 12
    -0.0003 ( 0.01788 )
    -0.0122 ( 0.01055 )
    0.0206 ( 0.03173 )
    -0.0052 ( 0.01589 )
    Statistical analysis title
    		 Hip Total BMD Change From Baseline To Week 24
    Statistical analysis description
    Change From Baseline to Week 24 in Hip Total BMD as Measured by DXA
    Comparison groups
    Concurrent Control (Primary Treatment) v Asfotase Alfa Combined (Primary Treatment)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.7357 [17]
    Method
    		 Wilcoxon rank-sum
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.039
    Notes
    [16] - The Hodges-Lehman-Sen estimate = -0.0125.
    [17] - Two-sided with p-value threshold <0.05 for statistical significance
    Statistical analysis title
    		 Lumbar Spine BMD Change From Baseline To Week 24
    Statistical analysis description
    Change From Baseline to Week 24 in Lumbar Spine BMD as Measured by DXA
    Comparison groups
    Concurrent Control (Primary Treatment) v Asfotase Alfa Combined (Primary Treatment)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.2439 [19]
    Method
    		 Wilcoxon rank-sum
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.009
         upper limit
    		 0.041
    Notes
    [18] - The Hodges-Lehman-Sen estimate = 0.0255.
    [19] - Two-sided with p-value threshold <0.05 for statistical significance
    Statistical analysis title
    		 Whole Body BMD Change From Baseline To Week 24
    Statistical analysis description
    Change From Baseline to Week 24 in Whole Body BMD as Measured by DXA
    Comparison groups
    Concurrent Control (Primary Treatment) v Asfotase Alfa Combined (Primary Treatment)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.1222 [21]
    Method
    		 Wilcoxon rank-sum
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.059
         upper limit
    		 0.012
    Notes
    [20] - The Hodges-Lehman-Sen estimate = -0.0315.
    [21] - Two-sided with p-value threshold <0.05 for statistical significance

    Secondary: Change From Baseline In BMD As Measured By DXA From Week 48 Until Week 288

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    End point title
    		 Change From Baseline In BMD As Measured By DXA From Week 48 Until Week 288
    End point description
    A DXA scan was performed to evaluate BMD of the spine, hip, and whole body during the extension treatment period (up to 288 weeks, including an LOE). The N of patients evaluated for the various time points differ from the total number of patients in the group. The N of patients evaluated is reported in the Category Title.
    End point type
    Secondary
    End point timeframe
    Baseline, every 24 weeks from Week 48 through Week 96,and from Week 144 every 48 weeks until Week 288
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Extension Treatment)
    Number of subjects analysed
    7 [22]
    6 [23]
    6 [24]
    19 [25]
    Units: g/cm2
    arithmetic mean (standard deviation)
        Hip Total BMD Week 48, N=1, 1, 4, 6
    0.0190 ( 0.0 )
    0.0240 ( 0.0 )
    0.0590 ( 0.04109 )
    0.0465 ( 0.03729 )
        Hip Total BMD Week 96, N=4, 4, 3, 11
    0.0003 ( 0.00532 )
    0.0780 ( 0.06703 )
    0.0480 ( 0.04943 )
    0.0415 ( 0.05542 )
        Hip Total BMD Week 144, N=3, 4, 3, 10
    0.0340 ( 0.02524 )
    0.0923 ( 0.07682 )
    0.0933 ( 0.04150 )
    0.0751 ( 0.05741 )
        Hip Total BMD Week 192, N=2, 4, 3, 9
    0.0135 ( 0.00919 )
    0.0983 ( 0.10856 )
    0.0563 ( 0.07100 )
    0.0654 ( 0.08327 )
        Hip Total BMD Week 240, N-2, 3, 3, 8
    0.0115 ( 0.02192 )
    0.1137 ( 0.05701 )
    -0.0073 ( 0.06178 )
    0.0428 ( 0.07481 )
        Hip Total BMD Week 288, N=0, 1, 0, 1
    0.0 ( 0.0 )
    -0.0200 ( 0.0 )
    0.0 ( 0.0 )
    -0.0200 ( 0.0 )
        Hip Total BMD LOE, N=4, 5, 4, 13
    -0.0115 ( 0.03899 )
    0.0658 ( 0.07776 )
    0.0207 ( 0.07549 )
    0.0282 ( 0.07038 )
        Lumbar Spine BMD Week 48, N=1, 1, 5, 7
    0.0480 ( 0.0 )
    0.0590 ( 0.0 )
    0.0914 ( 0.05647 )
    0.0806 ( 0.04978 )
        Lumbar Spine BMD Week 96, N=7, 5, 4, 16
    0.0414 ( 0.05230 )
    0.0554 ( 0.04271 )
    0.1158 ( 0.08060 )
    0.0644 ( 0.06210 )
        Lumbar Spine BMD Week 144, N=5, 5, 4, 14
    0.0200 ( 0.06257 )
    0.0850 ( 0.05323 )
    0.1138 ( 0.05734 )
    0.0700 ( 0.06688 )
        Lumbar Spine BMD Week 192, N=5, 5, 4, 14
    0.0554 ( 0.13220 )
    0.0766 ( 0.04180 )
    0.1123 ( 0.05197 )
    0.0792 ( 0.08423 )
        Lumbar Spine BMD Week 240, N=5, 4, 4, 13
    0.0750 ( 0.14168 )
    0.0455 ( 0.04107 )
    0.1027 ( 0.04786 )
    0.0745 ( 0.09073 )
        Lumbar Spine BMD Week 288, N=1, 1, 0, 2
    0.1860 ( 0.0 )
    0.0700 ( 0.0 )
    0.0 ( 0.0 )
    0.1280 ( 0.08202 )
        Lumbar Spine BMD LOE, N=7, 5, 5, 17
    0.0737 ( 0.11346 )
    0.0492 ( 0.04649 )
    0.1194 ( 0.04999 )
    0.0799 ( 0.08241 )
        Whole Body BMD Week 48, N=1, 1, 5, 7
    0.0050 ( 0.0 )
    0.0090 ( 0.0 )
    0.0178 ( 0.05277 )
    0.0147 ( 0.04342 )
        Whole Body BMD Week 96, N=7, 5, 4, 16
    -0.0103 ( 0.03523 )
    -0.0100 ( 0.04136 )
    0.0230 ( 0.04872 )
    -0.0019 ( 0.04059 )
        Whole Body BMD Week 144, N=5, 5, 4, 14
    -0.0250 ( 0.03662 )
    -0.0278 ( 0.05823 )
    -0.0060 ( 0.04721 )
    -0.0206 ( 0.04542 )
        Whole Body BMD Week 192, N=5, 5, 4, 14
    -0.0532 ( 0.02477 )
    -0.0220 ( 0.07088 )
    -0.0212 ( 0.06209 )
    -0.0329 ( 0.05358 )
        Whole Body BMD Week 240, N=5, 4, 4, 13
    -0.0426 ( 0.05601 )
    -0.0122 ( 0.08610 )
    -0.0493 ( 0.06965 )
    -0.0353 ( 0.06615 )
        Whole Body BMD Week 288, N=1, 1, 0, 2
    -0.1140 ( 0.0 )
    -0.0710 ( 0.0 )
    0.0 ( 0.0 )
    -0.0925 ( 0.03041 )
        Whole Body BMD LOE, N=7, 5, 5, 17
    -0.0501 ( 0.07360 )
    -0.0298 ( 0.08785 )
    -0.0224 ( 0.05773 )
    -0.0360 ( 0.07036 )
    Notes
    [22] - "0.0" entered for arithmetic mean for no data and for standard deviation when number (N) = 1.
    [23] - "0.0" entered for arithmetic mean for no data and for standard deviation when number (N) = 1.
    [24] - "0.0" entered for arithmetic mean for no data and for standard deviation when number (N) = 1.
    [25] - "0.0" entered for arithmetic mean for no data and for standard deviation when number (N) = 1.
    No statistical analyses for this end point

    Secondary: Change In Walking Ability As Measured By The Six-Minute Walk Test (6MWT) To Week 24

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    End point title
    		 Change In Walking Ability As Measured By The Six-Minute Walk Test (6MWT) To Week 24
    End point description
    The patient was instructed to walk the length of a pre-measured hallway for 6 minutes. The primary measurement was distance walked (in meters). The N of patients evaluated for the various time points differ from the total number of patients in the group. The N of patients evaluated is reported in the Category Title.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 (primary treatment period)
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Primary Treatment)
    Number of subjects analysed
    7
    6
    6
    13
    Units: meters
    arithmetic mean (standard deviation)
        Change from Baseline to Week 24, N=7, 6, 4, 13
    64.7 ( 73.04 )
    43.5 ( 43.18 )
    13.5 ( 69.77 )
    54.9 ( 59.71 )
    Statistical analysis title
    		 Walking Ability Change From Baseline To Week 24
    Statistical analysis description
    Change From Baseline to Week 24 in Walking Ability as Measured by the 6MWT
    Comparison groups
    Concurrent Control (Primary Treatment) v Asfotase Alfa Combined (Primary Treatment)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.1303 [27]
    Method
    		 Wilcoxon rank-sum
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -73
         upper limit
    		 114
    Notes
    [26] - The Hodges-Lehman-Sen estimate = 44.0.
    [27] - Two-sided with p-value threshold <0.05 for statistical significance

    Secondary: Change In Walking Ability As Measured By The 6MWT To Last Overall Exposure (LOE)

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    End point title
    		 Change In Walking Ability As Measured By The 6MWT To Last Overall Exposure (LOE)
    End point description
    The patient was instructed to walk the length of a pre-measured hallway for 6 minutes. The primary measurement was distance walked (in meters). The N of patients evaluated for the various time points differ from the total number of patients in the group. The N of patients evaluated is reported in the Category Title.
    End point type
    Secondary
    End point timeframe
    Baseline, up to 288 weeks of asfotase alfa exposure, including LOE
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Primary Treatment)
    Number of subjects analysed
    7
    6
    6
    19
    Units: meters
    arithmetic mean (standard deviation)
        Change from Baseline LOE, N=7, 6, 5, 18
    89.4 ( 81.32 )
    2.2 ( 121.79 )
    74.4 ( 107.40 )
    56.2 ( 104.85 )
    No statistical analyses for this end point

    Secondary: Change From Baseline In HPP-related Osteomalacia As Measured By Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume

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    End point title
    		 Change From Baseline In HPP-related Osteomalacia As Measured By Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume
    End point description
    A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Volume/Bone Volume (%). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design. Control patients did not receive active treatment for the first 24 weeks, and were not on active treatment when bone biopsy assessments were performed. The N of patients evaluated differs from the total number of patients in the group. The N of patients evaluated is reported in the Category Title.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups)
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Primary Treatment)
    Number of subjects analysed
    7
    6
    6
    13
    Units: percentage of volume
    arithmetic mean (standard deviation)
        Change from Baseline, N=6, 6, 6, 12
    1.213 ( 3.2488 )
    -2.845 ( 2.3769 )
    0.200 ( 4.7679 )
    -0.816 ( 3.4434 )
    No statistical analyses for this end point

    Secondary: Change From Baseline In HPP-related Osteomalacia As Measured By Trans-iliac Crest Bone Biopsy: Osteoid Thickness

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    End point title
    		 Change From Baseline In HPP-related Osteomalacia As Measured By Trans-iliac Crest Bone Biopsy: Osteoid Thickness
    End point description
    A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Thickness (micrometers [um]). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design. Control patients did not receive active treatment for the first 24 weeks, and were not on active treatment when bone biopsy assessments were performed. The N of patients evaluated differs from the total number of patients in the group. The N of patients evaluated is reported in the Category Title.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups)
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Primary Treatment)
    Number of subjects analysed
    7
    6
    6
    13
    Units: um
    arithmetic mean (standard deviation)
        Change from Baseline, N=6, 6, 6, 12
    -0.013 ( 3.6333 )
    -1.516 ( 2.3556 )
    -1.132 ( 6.0884 )
    -0.764 ( 3.0229 )
    No statistical analyses for this end point

    Secondary: Change From Baseline In HPP-related Osteomalacia As Measured By Trans-iliac Crest Bone Biopsy: Mineralization Lag Time

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    End point title
    		 Change From Baseline In HPP-related Osteomalacia As Measured By Trans-iliac Crest Bone Biopsy: Mineralization Lag Time
    End point description
    A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Mineralization Lag Time (days). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design. Control patients did not receive active treatment for the first 24 weeks, and were not on active treatment when bone biopsy assessments were performed. The N of patients evaluated differs from the total number of patients in the group. The N of patients evaluated is reported in the Category Title.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups)
    End point values
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Primary Treatment)
    Number of subjects analysed
    7
    6
    6
    13
    Units: days
    arithmetic mean (standard deviation)
        Change from Baseline, N=4, 5, 5, 9
    -908.255 ( 1313.6158 )
    -126.946 ( 142.2929 )
    78.296 ( 167.0895 )
    -474.195 ( 909.2779 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 288 weeks
    Adverse event reporting additional description
    Only adverse events with an onset date are included in the cumulative exposure category.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    0.3 mg/kg Asfotase Alfa (Primary Treatment)
    Reporting group description
    		 Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)

    Reporting group title
    0.5 mg/kg Asfotase Alfa (Primary Treatment)
    Reporting group description
    		 Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)

    Reporting group title
    Concurrent Control (Primary Treatment)
    Reporting group description
    		 No asfotase alfa treatment during primary treatment period: first 24 weeks. After 24 weeks, Control Group patients were eligible to begin asfotase alfa treatment in the open-label extension treatment period.

    Reporting group title
    Asfotase Alfa Combined (Extension Treatment)
    Reporting group description
    		 Adverse events occurring in patients from Cohort 1, Cohort 2, and original Control group during exposure to asfotase alfa.

    Serious adverse events
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Extension Treatment)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    9 / 19 (47.37%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arnold-Chiari malformation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection site hypersensitivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactoid reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 0.3 mg/kg Asfotase Alfa (Primary Treatment) 0.5 mg/kg Asfotase Alfa (Primary Treatment) Concurrent Control (Primary Treatment) Asfotase Alfa Combined (Extension Treatment)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    19 / 19 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign renal neoplasm
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Lipoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Lung neoplasm
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Melanocytic naevus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Surgical and medical procedures
    Colon polypectomy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Axillary pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Catheter site inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    17
    Catheter site erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Cyst
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Device failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Facial pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    5
    0
    7
    Feeling abnormal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Fibrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Gait disturbance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Injection site atrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 19 (26.32%)
         occurrences all number
    0
    0
    0
    8
    Injection site discolouration
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    9 / 19 (47.37%)
         occurrences all number
    9
    0
    0
    66
    Injection site erythema
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    13 / 19 (68.42%)
         occurrences all number
    61
    5
    0
    121
    Injection site exfoliation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Injection site haematoma
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    10 / 19 (52.63%)
         occurrences all number
    14
    6
    0
    33
    Injection site haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Injection site hypertrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    0
    0
    12
    Injection site induration
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    0
    0
    4
    Injection site inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Injection site macule
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    10
    Injection site mass
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    5
    Injection site nodule
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Injection site pain
         subjects affected / exposed
    4 / 7 (57.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    6 / 19 (31.58%)
         occurrences all number
    20
    0
    0
    26
    Injection site papule
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Injection site pruritus
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 19 (26.32%)
         occurrences all number
    16
    0
    0
    20
    Injection site reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    7 / 19 (36.84%)
         occurrences all number
    0
    0
    0
    56
    Injection site scar
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Injection site swelling
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    10
    0
    0
    12
    Injection site vesicles
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Injection site warmth
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    3
    Local swelling
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Malaise
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Medical device pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    0
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    8 / 19 (42.11%)
         occurrences all number
    7
    1
    0
    16
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    1
    0
    4
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Immune system disorders
    Food allergy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    0
    2
    Immunisation reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Seasonal allergy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Reproductive system and breast disorders
    Breast calcifications
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Breast mass
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Dysmenorrhea
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    0
    0
    8
    Ovarian cyst
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Pelvic pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Spermatocele
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 19 (26.32%)
         occurrences all number
    3
    0
    0
    6
    Dry throat
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Emphysema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Hypoxia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    1
    2
    Oropharyngeal pain
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    2
    2
    0
    5
    Respiratory disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    1
    Respiratory tract congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Sinus congestion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Initial insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Intentional self-injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Nightmare
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    3
    Blood 25-hydroxycholecalciferol increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Blood parathyroid hormone increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    0
    3
    Blood pressure increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    0
    2
    Blood human chorionic gonadotropin abnormal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Heart rate decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Heart rate increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Physical examination abnormal
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Red blood cells urine
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Ultrasound kidney abnormal
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    3
    White blood cell count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Arthropod bite
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    4
    Contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 19 (15.79%)
         occurrences all number
    0
    1
    1
    4
    Excoriation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    5 / 19 (26.32%)
         occurrences all number
    1
    1
    0
    8
    Femur fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Fibula fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Foot fracture
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    7 / 19 (36.84%)
         occurrences all number
    1
    0
    0
    10
    Hand fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Ilium fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Joint dislocation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    1
    Joint injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    3
    Joint sprain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    1
    0
    3
    Limb injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Meniscus lesion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Post procedural swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    0
    2
    Post-traumatic pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    1
    0
    0
    4
    Procedural nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    5 / 19 (26.32%)
         occurrences all number
    0
    2
    3
    11
    Procedural vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Radius fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Tibia fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    3
    Tooth fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Ulna fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    7 / 19 (36.84%)
         occurrences all number
    1
    1
    0
    7
    Dizziness exertional
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Headache
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    5 / 19 (26.32%)
         occurrences all number
    4
    1
    1
    28
    Hypoaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    2
    0
    5
    Intracranial pressure increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Loss of consciousness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    5
    Neuralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    1
    0
    0
    9
    Post-traumatic headache
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Sinus headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Burning sensation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Ear discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    0
    2
    Ear pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Ear pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Tympanic membrane disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Vertigo
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cataract
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Conjunctival deposit
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    1
    2
    Conjunctival discolouration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Conjunctival disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Corneal deposits
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Deposit eye
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    7 / 19 (36.84%)
         occurrences all number
    0
    0
    0
    8
    Dry eye
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Eyelid disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Keratopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    0
    2
    Optic atrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Photopsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Punctate keratitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Vitreous detachment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    0
    3
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Abdominal hernia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Abdominal mass
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    6
    Colitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Colonic polyp
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    0
    0
    4
    Dental caries
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    0
    3
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    0
    3
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Gingival hypertrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Gingival swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Gingivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Hyperchlorhydria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Loose tooth
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    4 / 19 (21.05%)
         occurrences all number
    2
    1
    2
    7
    Tooth disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Tooth loss
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    1
    3
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    0
    2
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Actinic keratosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Blister
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Dermal cyst
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    0
    2
    Dermatitis contact
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Dry skin
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Erythema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    8
    0
    0
    8
    Excessive skin
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    3
    0
    3
    Ingrown hair
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Onychalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Onychomadesis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Photodermatosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Rash macular
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    0
    0
    4
    Rash papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Scar
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    1
    Skin discolouration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Renal and urinary disorders
    Bladder pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    3
    Nephrocalcinosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Nephrolithiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    3
    Renal cyst
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Renal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    13 / 19 (68.42%)
         occurrences all number
    6
    3
    2
    41
    Arthritis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    0
    2
    Arthropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Back pain
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    10 / 19 (52.63%)
         occurrences all number
    3
    3
    3
    14
    Bone pain
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    9 / 19 (47.37%)
         occurrences all number
    3
    2
    0
    14
    Bursitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    0
    3
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Deformity thorax
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Jaw disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    3
    Joint stiffness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Joint swelling
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    7 / 19 (36.84%)
         occurrences all number
    7
    3
    0
    16
    Joint warmth
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Lower extremity mass
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Metatarsalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    0
    7
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    1
    4
    Muscular weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    4
    2
    Musculoskeletal disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    8 / 19 (42.11%)
         occurrences all number
    1
    0
    1
    11
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    3
    3
    Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    1
    0
    4
    Neck pain
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    2
    0
    0
    5
    Nodule on extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    4
    0
    5
    Osteoarthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    0
    0
    4
    Pain in extremity
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    12 / 19 (63.16%)
         occurrences all number
    13
    7
    1
    46
    Sacroiliitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Spinal disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Tendon disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Tendon pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tendonitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    1
    3
    Trigger finger
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Wrist deformity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Acute sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Adenovirus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Bronchiolitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Diarrhoea infectious
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Diverticulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Endocarditis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    1
    3
    Gastroenteritis viral
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    2
    Gastrointestinal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    6 / 19 (31.58%)
         occurrences all number
    0
    2
    2
    8
    Oral candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Post procedural infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Sinusitis
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 19 (26.32%)
         occurrences all number
    2
    0
    0
    20
    Staphylococcal abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Staphylococcal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Tinea cruris
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Tinea pedis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    0
    5
    Tinea infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Upper Respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    7 / 19 (36.84%)
         occurrences all number
    1
    1
    0
    22
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Vaginitis bacterial
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Viral infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    1
    Viral pharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    0
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2010
    • Reference to pharmacodynamics was removed from the protocol title and overall study objectives. This change aligned with the primary objectives to assess the safety, efficacy, and pharmacokinetic (PK) of asfotase alfa. • Inclusion criteria for osteomalacia were changed from an osteoid surface z-score of at least + 2 on bone biopsy to an osteoid thickness (O.Th) and mineralization lag time (MLT) z score of + 2 or more, as these were determined to be the best parameters for assessing osteomalacia on bone biopsy (that is, mineralization defects). Additional nutritional assessments were added, including caloric and calcium intake.
    01 Sep 2010
    • Reference to the absence of asfotase alfa antibodies in the patient population was removed due to detection of antibodies in some patients. • Language was changed to indicate that screening would continue until 18 adolescent and adult patients eligible for study participation and randomization were identified. • Language was changed to clarify the use of birth control by female patients of childbearing potential and sexually mature males, and the definition of “nonchildbearing female” was provided. • Pregnancy testing methods were modified to include urine sample testing at any time serum sample testing was performed. • Exclusion criterion on bisphosphonate use was changed to allow patients to enter the study who had not used bisphosphonates within the past 2 years, under the stipulation that their bone resorption marker assessments were within the normal range or elevated. • Language was added to clarify the flexibility of assessment scheduling, as long as the specified order of assessments and/or availability of results pertaining to assessments were maintained. • Language was added to clarify that the required radiographic images that needed to be collected at the Screening and Week 24 study visits, and to indicate that only those patients randomized to asfotase alfa treatment needed to undergo PK testing. • Required radiographic images to be collected at the Screening and Week 24 study visits were provided as follows: Screening: Lateral skull, lateral thoracic spine, lateral lumbar spine, posterior anterior (PA) hand/wrist (unilateral non-dominant), anteroposterior (AP) pelvis, AP bilateral femurs (femora), AP bilateral tibia/fibula, and bilateral AP feet. • Urinary calcium: creatinine ratio was changed from a safety evaluation to a disease biomarker evaluation. In addition, text was added to specify that a spot urine sample must be collected for this evaluation.
    01 Sep 2010
    • The definition of injection-associated reactions (IARs) was clarified to reflect that an IAR must represent a systemic sign/symptom/finding, be assessed as related to the study drug, and occur within 3 hours of drug administration. Notification of serious IARs was changed to be within 24 hours rather than 48 hours of the investigational site’s first knowledge. Language was also added to more fully define ISRs and assist investigational sites in identifying them. Information was also added that explicitly detailed injection site reaction (ISR) data recording and reporting procedures. • A 12-lead electrocardiogram (ECG) assessment was added at Baseline and Week 24 as a routine safety measure to assess potential changes in cardiac function. • Language was added to reflect that both prior and concomitant medications and therapies taken by the patient were recorded if administered within 2 weeks prior to study entry. • Language was added to allow for the collection of fasting blood and urine samples for testing of the bone resorption markers serum C-telopeptide and urine N-telopeptide or urine deoxypyridinoline. This testing was added to the Screening visit to assess patients with a history of prior bisphosphonate use. • Tanner staging was added as an assessment for patients <18 years at time of study entry for the Baseline and Week 24 visits to assist in the analysis of functional endpoints. • The assessment of serum 25-hydroxy (25[OH]) vitamin D was changed from a safety evaluation to an “other” study evaluation. This evaluation was used to exclude patients with nutritional rickets and to assist in the evaluation of radiographic endpoints for the study, and it was not intended to be a routine safety measure. • Nutritional assessment was changed from a safety evaluation to an “other” study evaluation. This was primarily intended for purposes of evaluating caloric and calcium intake in relation to growth parameters.
    01 Sep 2010
    • A newly created section was added to reflect that medical monitoring responsibilities for the study were delegated to Premier Research. The scope of these responsibilities and relevant contact information were added. • Language describing the assessment of the safety and tolerability of SC injections of asfotase alfa was altered to demonstrate that the totality of safety information collected was examined when assessments were performed. • Language was added to distinguish enrolled patients from those who were confirmed as eligible for the study. • Language was added to clarify the required study assessments for patients randomized to receive asfotase alfa versus those receiving no treatment. • Language was added to reflect that IARs and ISRs were subsets of AEs.
    10 Dec 2010
    • The study methodology section was updated to reflect that the study was extended from 6 months to a total of 18 months. • Reference to osteoid thickness as an inclusion criterion was removed after examining data from ongoing studies that indicated MLT is a more relevant parameter. • Language was added to reflect that all patients who enrolled in the extension period would receive 0.5 mg/kg/day asfotase alfa (3.5 mg/kg/week) and to reflect the change in study duration. • Language was added to reflect the transition of no treatment group patients to active treatment. Patients from this group received training in the injection of asfotase alfa at the beginning of the extension period. • An additional transiliac crest bone biopsy was added at Week 72. Additional assessments, including skeletal radiographs, tooth loss, panorex radiographs, Dual-energy X-ray absorptiometry (DEXA) assessments, 6MWT, Lower Extremity Functional Scale (LEFS), Brief Pain Inventory-Short Form (BPI-SF), Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2), muscle strength assessment by handheld dynamometry (HHD), forced vital capacity (FVC) assessed by pulmonary function testing (PFT), and growth measurements (in adolescent patients only), were also added as described in the schedule of assessments. • Language was added to permit the continual assessment of dose/dosing schedule during the extension period and to reflect that the maximum allowable dose for all patients was 40 mg/day. • The number of eligible patients for the study was changed from 18 to 22 to account for screening failures. • Language was added to clarify the schedule/responsibilities of the home care nurse during the initial 4 weeks of home injections.
    10 Dec 2010
    • The statistical methods were modified and additional study visits were added to reflect the extension period timeline. • Language was updated to reflect the status of other asfotase alfa studies and listing the entire population of patients that have been exposed to this drug. • The term “ALPL” was replaced throughout the document with tissue-nonspecific alkaline phosphatase (“TNSALP”) for consistency. • A new medical monitor was added to the study. Contact information was updated accordingly.
    28 Mar 2011
    • Language was clarified that the extension period of the study could extend out to regulatory approval of the drug. • The primary objective, in which a bone biopsy was analyzed for signs of osteomalacia, was moved to a secondary endpoint. Further research on osteomalacia indicated that bone changes in adults would be slower than in younger patients; therefore, a biopsy before 12 months was thought unlikely to show any effects of treatment. While a biopsy at 12 months was still performed in asfotase alfa patients, control patients had signed a consent allowing them to receive treatment after only 6 months. Lack of a 12-month control for osteomalacia prevented it from being a primary endpoint. • Reductions in inorganic pyrophosphate (PPi) and pyridoxal-5’-phosphate (PLP) were shifted from the secondary objectives to the primary objectives. • The efficacy, PK, pharmacodynamic (PD), safety, and other evaluations were updated to align with the revised objectives in the current protocol amendment. • Dose adjustment language was updated to increase flexibility and safety, allowing dose adjustments at any time during the study with input from the medical monitor. • Vital signs language was updated to align with other asfotase alfa protocols. • Knee flexors and extensors were added to the list of parameters assessed using handheld dynamometry (HHD) to bring the protocol in alignment with other asfotase alfa protocols. • Discontinuation of patient diaries, which collected data on treatment compliance.
    20 Oct 2011
    • Dosing of asfotase alfa was increased to 1 mg/kg/day, 6 days/week, after the first 6 months of the extension period. Rationale was also added for this adjustment: The highest dose given to adults was comparable to the lowest dose given to juveniles that had shown effectiveness. As a consequence of this change, the maximum daily dose was adjusted to 80 mg/day. • The End of Study visit language was modified to include all assessments scheduled every 6 months after Week 48. • Language in the introduction of the protocol was modified for consistency with the latest version of the Investigator’s Brochure (IB). • The study medication description was updated to reflect the actual vial contents. • Safety officer information was updated.
    14 Oct 2014
    • Removed pulmonary function testing from the exploratory objectives. • Updated wording regarding dose adjustments for efficacy or safety reasons. • Added sampling for PK analysis to the extension period of the study, at all visits at which anti-asfotase alfa antibodies are being assessed. Antibody testing and PK analysis were performed at the same time to allow for evaluation of the impact of the antibodies on PK. • Full ophthalmology examinations (including funduscopy) were added to better characterize potential ectopic calcifications. • Changes to Data Monitoring Committee (DMC) operations (endorsed by the DMC) were made based on a new DMC charter (dated 10 January 2013) and Sponsor discussions on DMC stopping rules; ad hoc review and stopping rules are no longer required; however, the DMC must be notified immediately. • Changed testing requirements for IARs. • Medical monitor and drug safety physician information for study was updated 26 October 2015 • Updating of title page to current protocol cover page format. • Updating of site information for Alexion European office • Updating Medical Monitor information
    26 Oct 2015
    • Updating of title page to current protocol cover page format. • Updating of site information for Alexion European office • Updating Medical Monitor information

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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