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    Clinical Trial Results:
    A 1-year, multicenter, open-label, extension to CZOL446H2337 to evaluate safety and efficacy of zoledronic acid twice yearly in osteoporotic children treated with glucocorticoids

    Summary
    EudraCT number
    		 2010-020399-41
    Trial protocol
    		 GB   HU  
    Global end of trial date
    27 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Sep 2019
    First version publication date
    04 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CZOL446H2337E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01197300
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate that zoledronic acid given long-term, over an additional 12 months from the Core study (CZOL446H2337), was safe for the treatment of osteoporotic children treated with glucocorticoids (GCs).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Oct 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
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    South Africa: 3
    Worldwide total number of subjects
    25
    EEA total number of subjects
    3
    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)
    8
    Adolescents (12-17 years)
    17
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 10 centers in 6 countries: Australia (1), Canada (4), Hungary (1), United Kingdom (1), Russian Federation (2), and South Africa (1).

    Pre-assignment
    Screening details
    		 This was an open label extension to the Core study CZOL446H2337 (NCT00799266), where all patients received zoledronic acid. However, the study groups from the Core study were used to compare the patient populations within this extension phase, who received the same treatment under each particular group during the duration of core study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Core treatment Zoledronic acid
    Arm description
    		 Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid

    Arm title
    		 Core treatment: Placebo
    Arm description
    		 Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
    Arm type
    		 Placebo

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid

    Number of subjects in period 1
    		Core treatment Zoledronic acid Core treatment: Placebo
    Started
    10
    15
    Completed
    10
    13
    Not completed
    0
    2
         Protocol deviation
    -
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Core treatment Zoledronic acid
    Reporting group description
    		 Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid

    Reporting group title
    Core treatment: Placebo
    Reporting group description
    		 Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid

    Reporting group values
    		 Core treatment Zoledronic acid Core treatment: Placebo Total
    Number of subjects
    		 10 15 25
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 1 7 8
        Adolescents (12-17 years)
    		 9 8 17
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Age at extension informed consent
    Units: Years
        arithmetic mean (standard deviation)
    		 15.3 ± 2.58 13.2 ± 3.38 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 3 5 8
        Male
    		 7 10 17
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 8 13 21
        Black
    		 2 1 3
        Native American
    		 0 1 1
    Lumbar Spine Bone Mineral Density (BMD) Z-score
    Lumbar Spine Bone Mineral Density (BMD) Z-score in the Full Analysis (FAS) population. Extension baseline was defined as the last non-missing measurement on or prior to the date of first study drug infusion in the extension study. Bone mass, as measured by DXA, is reported as BMC (g) or areal BMD (g/cm2). These values are compared with reference values from healthy youth of similar age, sex, and race/ ethnicity to calculate a z score, the number of SDs from the expected mean. A BMC or BMD z score that is >2 SDs below expected (< –2.0) is referred to as “low for age”.
    Units: Z-score
        arithmetic mean (standard deviation)
    		 -1.568 ± 1.0196 -2.291 ± 1.0712 -
    Lumbar Spine Bone Mineral Content (BMC)
    Lumbar Spine Bone Mineral Content (BMC) in the Full Analysis (FAS) population. Extension baseline was defined as the last non-missing measurement on or prior to the date of first study drug infusion in the extension study.
    Units: gram (g)
        arithmetic mean (standard deviation)
    		 42.106 ± 15.6967 25.890 ± 7.3089 -
    Total body Bone Mineral Content (BMC)
    Total body Bone Mineral Content (BMC) in the Full Analysis (FAS) population. Extension baseline was defined as the last non-missing measurement on or prior to the date of first study drug infusion in the extension study.
    Units: gram (g)
        arithmetic mean (standard deviation)
    		 1976.698 ± 636.2144 1144.613 ± 253.5405 -
    Serum Procollagen type 1 amino-terminal propeptide (P1NP)
    Serum Procollagen type 1 amino-terminal propeptide (P1NP) in the Full Analysis (FAS) population. Extension baseline was defined as the last non-missing measurement on or prior to the date of first study drug infusion in the extension study.
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    		 141.300 ± 100.8111 523.933 ± 475.5547 -
    Bone specific alkaline phosphatase (BSAP)
    Serum Bone specific alkaline phosphatase (BSAP) in the Full Analysis (FAS) population. Extension baseline was defined as the last non-missing measurement on or prior to the date of first study drug infusion in the extension study.
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    		 25.841 ± 14.8595 49.737 ± 36.6580 -
    Serum Cross linked N-telopeptide (NTX)
    Serum Cross linked N-telopeptide (NTX) in the Full Analysis (FAS) population. Extension baseline was defined as the last non-missing measurement on or prior to the date of first study drug infusion in the extension study.
    Units: nmol BCE/L
        arithmetic mean (standard deviation)
    		 19.092 ± 8.3760 42.217 ± 25.2275 -
    Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP-5b)
    Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP-5b) in the Full Analysis (FAS) population. Extension baseline was defined as the last non-missing measurement on or prior to the date of first study drug infusion in the extension study.
    Units: U/L
        arithmetic mean (standard deviation)
    		 5.338 ± 2.5097 8.636 ± 5.2925 -
    Second metacarpal cortical width
    Second metacarpal cortical width in the Full Analysis (FAS) population. Metacarpal cortical width of "0" was not included. An analysis of covariance model used with treatment, pooled centers, underlying condition treated with glucocorticoids at baseline value as explanatory variables and pooled centers as random effect.
    Units: millimeter (mm)
        arithmetic mean (standard deviation)
    		 0.45 ± 0.207 0.38 ± 0.163 -

    End points

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    End points reporting groups
    Reporting group title
    Core treatment Zoledronic acid
    Reporting group description
    		 Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid

    Reporting group title
    Core treatment: Placebo
    Reporting group description
    		 Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid

    Primary: Long-term Safety of zoledronic acid for the treatment of osteoporotic children treated with glucocorticoids.

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    End point title
    		 Long-term Safety of zoledronic acid for the treatment of osteoporotic children treated with glucocorticoids. [1]
    End point description
    Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) to demonstrate that zoledronic acid given long-term, over an additional 12 months from the Core study (CZOL446H2337), is safe for the treatment of osteoporotic children treated with glucocorticoids through the monitoring of relevant clinical and laboratory safety parameters.
    End point type
    Primary
    End point timeframe
    Baseline 1 (Visit 1 of the Core Study) through Month 24 (Visit 15/Final Extension Visit)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis performed.
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: Participants
    number (not applicable)
        On-treatment Adverse Events (AEs)
    7
    12
        On-treatment Serious Adverse Events (SAEs)
    3
    0
        On-treatment Deaths
    0
    0
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline 1 (Visit 1 of the Core study) in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 18 and 24 by Core treatment group.

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    End point title
    		 Mean Change from Baseline 1 (Visit 1 of the Core study) in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 18 and 24 by Core treatment group.
    End point description
    Lumbar Spine Bone Mineral Density (BMD) Z-score was determined by the central imaging vendor at the final visit of Core study (Visit 8) or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension Study visit/EOS) of Extension study. The methods to be used to measure Lumbar Spine BMD Z-score were described in the respective DXA Manuals provided by central imaging vendor. Positive changes from Core baseline indicated an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: Z-score
    least squares mean (standard error)
        Lumbar Spine BMD Z-score Change at Month 18
    -40.648 ± 14.1205
    -44.348 ± 14.0348
        Lumbar Spine BMD Z-score Change at Month 24
    -46.161 ± 12.4486
    -67.913 ± 12.1722
    Statistical analysis title
    		 Lumbar Spine BMD Z-score Change at Month 18
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.8505 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.242
         upper limit
    		 44.642
    Notes
    [2] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [3] - An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.
    Statistical analysis title
    		 Lumbar Spine BMD Z-score Change at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.218 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    21.752
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.126
         upper limit
    		 57.63
    Notes
    [4] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [5] - An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.

    Secondary: Mean Change from Baseline 1 (Visit 1 of the Core study) in Lumbar Spine Bone Mineral Content (BMC) at Month 18 and 24 by Core treatment group.

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    End point title
    		 Mean Change from Baseline 1 (Visit 1 of the Core study) in Lumbar Spine Bone Mineral Content (BMC) at Month 18 and 24 by Core treatment group.
    End point description
    Lumbar Spine Bone Mineral Content (BMC) was determined by the central imaging vendor at the final visit of Core study (Visit 8) or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension Study visit/EOS) of Extension study. The methods to be used to measure BMC were described in the respective DXA Manuals. Positive changes from Core baseline indicated an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: gram
    least squares mean (standard error)
        Lumbar Spine BMC Change at Month 18
    12.293 ± 1.7749
    9.933 ± 1.6717
        Lumbar Spine BMC Change at Month 24
    15.845 ± 2.2217
    14.666 ± 2.0500
    Statistical analysis title
    		 Lumbar Spine BMC Change at Month 18
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.3544 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    2.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.886
         upper limit
    		 7.606
    Notes
    [6] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [7] - An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.
    Statistical analysis title
    		 Lumbar Spine BMC Change at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.705 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    1.179
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.281
         upper limit
    		 7.639
    Notes
    [8] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [9] - An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.

    Secondary: Mean Change from Baseline 1 (Visit 1 of the Core study) in total body BMC at Month 18 and 24 by Core treatment group.

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    End point title
    		 Mean Change from Baseline 1 (Visit 1 of the Core study) in total body BMC at Month 18 and 24 by Core treatment group.
    End point description
    Total body BMC were determined by the central imaging vendor at the final visit of Core study (Visit 8) or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension Study visit/EOS) of Extension study. The methods to be used to measure BMC were described in the respective DXA Manuals. Positive changes from Core baseline indicated an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: gram
    least squares mean (standard error)
        Total body BMC Change at Month 18
    387.721 ± 87396.2756
    266.592 ± 87396.2698
        Total body BMC Change at Month 24
    496.997 ± 120.9281
    431.323 ± 123.5462
    Statistical analysis title
    		 Total body BMC Change at Month 18
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.531 [11]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    121.129
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -291
         upper limit
    		 533.258
    Notes
    [10] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [11] - An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.
    Statistical analysis title
    		 Total body BMC Change at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.7347 [13]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    65.674
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -344.067
         upper limit
    		 475.415
    Notes
    [12] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [13] - An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.

    Secondary: Mean Change from Baseline 1 (Visit 1 of the Core study) in Serum P1NP at Month 18 and 24 by Core treatment group.

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    End point title
    		 Mean Change from Baseline 1 (Visit 1 of the Core study) in Serum P1NP at Month 18 and 24 by Core treatment group.
    End point description
    Serum Procollagen type 1 amino-terminal propeptide (P1NP) was collected at the final visit Core study at Visit 8, or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension study Visit/EOS) of Extension study according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory. Decrease or negative changes from Core baseline indicated a pharmacological response to therapy.
    End point type
    Secondary
    End point timeframe
    Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: nanogram per milliliter (ng/mL)
    least squares mean (standard error)
        Serum P1NP Change at Month 18
    -169.837 ± 86.8640
    -22.157 ± 82.6761
        Serum P1NP Change at Month 24
    -228.068 ± 54.1402
    -95.631 ± 53.0765
    Statistical analysis title
    		 Serum P1NP Change at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 = 0.1266 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -132.437
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -286.452
         upper limit
    		 21.579
    Notes
    [14] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [15] - An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.
    Statistical analysis title
    		 Serum P1NP Change at Month 18
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [16]
    P-value
    		 = 0.4143 [17]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -147.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -394.41
         upper limit
    		 99.049
    Notes
    [16] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [17] - An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.

    Secondary: Mean Change from Baseline 1 (Visit 1 of the Core study) in BSAP at Month 18 and 24 by Core treatment group.

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    End point title
    		 Mean Change from Baseline 1 (Visit 1 of the Core study) in BSAP at Month 18 and 24 by Core treatment group.
    End point description
    Bone specific alkaline phosphatase (BSAP) was collected at the final visit Core study at Visit 8, or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension study Visit/EOS) of Extension study according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory. Decrease or negative changes from Core baseline indicated a pharmacological response to therapy.
    End point type
    Secondary
    End point timeframe
    Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: nanogram per milliliter (ng/mL)
    least squares mean (standard error)
        BSAP Change at Month 18
    -13.716 ± 8.5909
    3.975 ± 8.0523
        BSAP Change at Month 24
    -9.675 ± 6.4159
    -6.013 ± 5.9316
    Statistical analysis title
    		 BSAP Change at Month 18
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [18]
    P-value
    		 = 0.2123 [19]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -17.691
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.925
         upper limit
    		 6.543
    Notes
    [18] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [19] - An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.
    Statistical analysis title
    		 BSAP Change at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [20]
    P-value
    		 = 0.4852 [21]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -3.662
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.479
         upper limit
    		 14.155
    Notes
    [20] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [21] - An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.

    Secondary: Mean Change from Baseline 1 (Visit 1 of the Core study) in Serum NTX at Month 18 and 24 by Core treatment group.

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    End point title
    		 Mean Change from Baseline 1 (Visit 1 of the Core study) in Serum NTX at Month 18 and 24 by Core treatment group.
    End point description
    Serum Cross linked N-telopeptide (NTX) was collected at the final visit Core study at Visit 8, or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension study Visit/EOS) of Extension study according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory. Decrease or negative changes from Core baseline indicated a pharmacological response to therapy.
    End point type
    Secondary
    End point timeframe
    Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: nmol BCE/L
    least squares mean (standard error)
        Serum NTX Change at Month 18
    -17.577 ± 168.8975
    -12.916 ± 168.8965
        Serum NTX Change at Month 24
    -17.450 ± 2.3585
    -14.891 ± 2.0590
    Statistical analysis title
    		 Serum NTX Change at Month 18
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [22]
    P-value
    		 = 0.9009 [23]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -4.661
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.647
         upper limit
    		 7.325
    Notes
    [22] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [23] - An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.
    Statistical analysis title
    		 Serum NTX Change at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [24]
    P-value
    		 = 0.9472 [25]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -2.558
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.864
         upper limit
    		 3.747
    Notes
    [24] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [25] - An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.

    Secondary: Mean Change from Baseline 1 (Visit 1 of the Core study) in Serum TRAP-5b at Month 18 and 24 by Core treatment group.

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    End point title
    		 Mean Change from Baseline 1 (Visit 1 of the Core study) in Serum TRAP-5b at Month 18 and 24 by Core treatment group.
    End point description
    Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP 5b) were collected at the final visit Core study at Visit 8, or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension study Visit/EOS) of Extension study according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory. Decrease or negative changes from Core baseline indicated a pharmacological response to therapy.
    End point type
    Secondary
    End point timeframe
    Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: U/L
    least squares mean (standard error)
        Serum TRAP-5b Change at Month 18
    -2.661 ± 0.8126
    -1.179 ± 0.7725
        Serum TRAP-5b Change at Month 24
    -2.670 ± 0.7158
    -2.260 ± 0.6701
    Statistical analysis title
    		 Serum TRAP-5b Change at Month 18
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [26]
    P-value
    		 = 0.46 [27]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -1.482
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.805
         upper limit
    		 0.841
    Notes
    [26] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [27] - An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.
    Statistical analysis title
    		 Serum TRAP-5b Change at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [28]
    P-value
    		 = 0.9236 [29]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.423
         upper limit
    		 1.603
    Notes
    [28] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group — LS mean for the Core treatment Placebo group.
    [29] - An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.

    Secondary: Number of participants with new vertebral fractures during the 12 month Extension period by Core treatment group.

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    End point title
    		 Number of participants with new vertebral fractures during the 12 month Extension period by Core treatment group.
    End point description
    New vertebral fractures are defined as fractures of Genant grade 1 or higher that occur at lumbar or thoracic spine from first extension dose infusion to the end of the study in a previously normal vertebra.
    End point type
    Secondary
    End point timeframe
    Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: Participants
        number (not applicable)
    1
    1
    Statistical analysis title
    		 New vertebral fractures at Month 12 Extension
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [30]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [30] - The number and percentage of patients with new vertebral fractures during the 12 month Extension period was presented by Core treatment group. Between-treatment differences were evaluated using Fisher’s exact test.

    Secondary: Number of participants with new morphometric vertebral fractures during the 12 month Extension period by Core treatment group.

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    End point title
    		 Number of participants with new morphometric vertebral fractures during the 12 month Extension period by Core treatment group.
    End point description
    Vertebral morphometry (or concave index) was calculated using the average ratio between mid-height and posterior height from L1 to L4 and performed by a central reader. A new morphometric vertebral fractures during the 12 month Extension Period was defined as a morphometric vertebral fracture present at Month 24 X-ray which was not present at the Extension Baseline (Baseline 2).
    End point type
    Secondary
    End point timeframe
    Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: Participants
        number (not applicable)
    1
    1
    Statistical analysis title
    		 New morphometric vertebral fractures
    Statistical analysis description
    New morphometric vertebral fractures at Month 12 Extension
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [31]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [31] - The number and percentage of patients with new morphometric vertebral fractures during the 12 month extension period was presented by core treatment group. Between-treatment differences will be evaluated using Fisher’s exact test.

    Secondary: Percentage of Patients with reduction in Pain from Baseline 1 (Visit 1 of the Core study) at Month 15, 18, 21 and 24 by Core treatment group.

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    End point title
    		 Percentage of Patients with reduction in Pain from Baseline 1 (Visit 1 of the Core study) at Month 15, 18, 21 and 24 by Core treatment group.
    End point description
    Pain was evaluated at each visit (at office and telephone visit) at the final visit of the Core study and first visit of the Extension study (Visit 9), Visits 11 (Month 15), 12 (Month 18), 14 (Month 21) and 15 (Month 24) using the Faces Pain Scale-Revised (FPS-R). Children were selecting the face that best fits their pain. The pain score ranged from 0 (No Pain) to 10 (Very Much Pain). The reduction in pain from Core baseline by visit was evaluated based on whether or not patients had a decrease in their FPS-R from baseline. If pain remained the same or worsened from baseline a patient was classified as ‘0’ and if the pain scale decreased then the patient was classified as ‘1’.
    End point type
    Secondary
    End point timeframe
    Month 15, Month 18, Month 21, Month 24
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: Percentage of Patients
    number (not applicable)
        Reduction in Pain at Month 15
    55.6
    46.2
        Reduction in Pain at Month 18
    30.0
    50.0
        Reduction in Pain at Month 21
    30.0
    50.0
        Reduction in Pain at Month 24
    30.0
    38.5
    Statistical analysis title
    		 Reduction in Pain at Month 15
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3971 [32]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 173.07
    Notes
    [32] - Presented by treatment group and evaluated using a logistic regression model with Core treatment, pooled centers, underlying condition treated with glucocorticoids and Core baseline pain score as explanatory variables.
    Statistical analysis title
    		 Reduction in Pain at Month 18
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6046 [33]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 999.99
    Notes
    [33] - Presented by treatment group and evaluated using a logistic regression model with Core treatment, pooled centers, underlying condition treated with glucocorticoids and Core baseline pain score as explanatory variables.
    Statistical analysis title
    		 Reduction in Pain at Month 21
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6046 [34]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 999.99
    Notes
    [34] - Presented by treatment group and evaluated using a logistic regression model with Core treatment, pooled centers, underlying condition treated with glucocorticoids and Core baseline pain score as explanatory variables.
    Statistical analysis title
    		 Reduction in Pain at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.875 [35]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 38.04
    Notes
    [35] - Presented by treatment group and evaluated using a logistic regression model with Core treatment, pooled centers, underlying condition treated with glucocorticoids and Core baseline pain score as explanatory variables.

    Secondary: Mean Change from Baseline (Core and Extension) in 2nd metacarpal cortical width at month 24 by Core treatment group.

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    End point title
    		 Mean Change from Baseline (Core and Extension) in 2nd metacarpal cortical width at month 24 by Core treatment group.
    End point description
    Left postero-anterior (PA) hand/wrist X-ray were taken at the final visit of Core study and at Visit 15/EOS (Month 24) to assess bone age. The change in 2nd metacarpal cortical width at Month 24 relative to the respective Baseline was calculated. If a fracture of the left upper extremity precluded radiographic imaging, (or precluded this X-ray in the Core study) then the right hand was evaluated for this purpose. In this case, an image of the right hand was carried out at both Visit 8 and at Visit 15/EOS (Month 24). The information was used in the assessment of bone density.
    End point type
    Secondary
    End point timeframe
    Baseline 1 (Visit 1 of the Core Study) and Baseline 2 (Visit 9 of the Extension Study) through Month 24 (Visit 15/Final Extension Visit)
    End point values
    		 Core treatment Zoledronic acid Core treatment: Placebo
    Number of subjects analysed
    10
    15
    Units: millimeter (mm)
    least squares mean (standard error)
        2nd metacarpal cortical width change from BL1
    -0.04 ± 0.068
    -0.03 ± 0.054
        2nd metacarpal cortical width change from BL2
    -0.09 ± 0.089
    0.02 ± 0.063
    Statistical analysis title
    		 2nd metacarpal cortical width chge from BL1
    Statistical analysis description
    2nd metacarpal cortical width chge from BL1 at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [36]
    P-value
    		 = 0.9231 [37]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.17
    Notes
    [36] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group - LS mean for the Core treatment Placebo group.
    [37] - An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline bone age as explanatory variables and pooled centers as random effect.
    Statistical analysis title
    		 2nd metacarpal cortical width chge from BL2
    Statistical analysis description
    2nd metacarpal cortical width chge from BL2 at Month 24
    Comparison groups
    Core treatment Zoledronic acid v Core treatment: Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 [38]
    P-value
    		 = 0.2694 [39]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.1
    Notes
    [38] - Difference in least squares mean = LS mean for the Core treatment Zoledronic acid group - LS mean for the Core treatment Placebo group.
    [39] - An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Extension baseline bone age as explanatory variables and pooled centers as random effect.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 13 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Core Treatment Placebo
    Reporting group description
    		 Core Treatment Placebo

    Reporting group title
    Core Treatment Zoledronic acid
    Reporting group description
    		 Core Treatment Zoledronic acid

    Serious adverse events
    		 Core Treatment Placebo Core Treatment Zoledronic acid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 10 (30.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Postictal state
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Core Treatment Placebo Core Treatment Zoledronic acid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 15 (80.00%)
    7 / 10 (70.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Secondary hypertension
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Infusion site pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 10 (20.00%)
         occurrences all number
    3
    2
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Hypoxia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Suicide attempt
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Investigations
    Liver function test increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Therapeutic agent urine positive
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Vitamin B12 decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Joint dislocation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    Nervous system disorders
    Epileptic aura
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    2 / 15 (13.33%)
    3 / 10 (30.00%)
         occurrences all number
    2
    3
    Postictal state
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    4
    Sciatica
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    Abdominal pain lower
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 10 (20.00%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Butterfly rash
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Ingrowing nail
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Skin discolouration
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 15 (33.33%)
    0 / 10 (0.00%)
         occurrences all number
    8
    0
    Arthritis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    5
    1
    Bone pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Neck pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Scoliosis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Spinal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Trismus
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Candida infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Herpes virus infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Insulin resistance
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Nov 2012
    Amendment 1 applied to UK sites only, regarding contraception and pregnancy in female patients of child bearing potential
    15 Jan 2014
    The rationale for Amendment 2 was to reflect the changes in the Core (CZOL446H2337) protocol v04 which extended the study population to include patients with underlying conditions other than chronic inflammatory disorders e.g. Duchenne muscular dystrophy (DMD).
    18 May 2016
    The rationale for Amendment 3 was to reflect the changes in the Core protocol (CZOL446H2337) v05 which has been amended to address Health Authority requests to provide a Risk Benefit statement, and allow more countries to apply the contraceptive wording originally provided for United Kingdom (UK) sites only.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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