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    Clinical Trial Results:
    An international, multicenter, randomized, open-label, safety and efficacy trial of intravenous zoledronic acid administered either once or twice yearly in children with severe osteogenesis imperfecta, a 1-year extension to CZOL446H2202

    Summary
    EudraCT number
    		 2004-001666-40
    Trial protocol
    		 HU   GB   BE  
    Global end of trial date
    01 May 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CZOL446H2202E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00131118
    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,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 May 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2007
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to examine the long-term general and renal safety of once yearly or twice yearly zoledronic acid (ZOL) over a 12 month extension treatment period in children aged 1 to 17 years with severe osteogenesis imperfecta (OI) who had completed one year of treatment with either ZOL or pamidronate (PAM) in the core CZOL446H2202 study.
    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
    06 Aug 2004
    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
    Belgium: 11
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Finland: 11
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    103
    EEA total number of subjects
    46
    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)
    61
    Adolescents (12-17 years)
    42
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 16 centres in 8 countries.

    Pre-assignment
    Screening details
    		 The study enrolled a total of 103 subjects who completed the core study (CZOL446H2202).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study. However, the Novartis clinical trial team, data analysts and vendor personnel were blinded to the subject treatment groups until the study database was locked.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ZOL-ZOL once yearly
    Arm description
    		 Subjects who received ZOL in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 milligram/kilogram (mg/kg) of ZOL up to a maximum of 4 mg once yearly. Subjects aged 1 to less than (<) 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg once yearly, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    ZOL 0.025 mg/kg or 0.05mg/kg intravenous (i.v.) infusion was administered once a year.

    Arm title
    		 ZOL-ZOL twice yearly
    Arm description
    		 Subjects who received ZOL in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 mg/kg of ZOL up to a maximum of 4 mg twice yearly at 6 month intervals. Subjects aged 1 to < 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg twice yearly at 6 month intervals, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    ZOL 0.025 mg/kg or 0.05mg/kg i.v. infusion was administered twice yearly at 6 months intervals.

    Arm title
    		 PAM-ZOL once yearly
    Arm description
    		 Subjects who received pamidronate (PAM) in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 mg/kg of ZOL up to a maximum of 4 mg once yearly. Subjects aged 1 to less than < 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg once yearly, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    ZOL 0.025 mg/kg or 0.05mg/kg intravenous (i.v.) infusion was administered once a year.

    Arm title
    		 PAM-ZOL twice yearly
    Arm description
    		 Subjects who received PAM in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 mg/kg of ZOL up to a maximum of 4 mg twice yearly at 6 month intervals. Subjects aged 1 to < 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg twice yearly at 6 month intervals, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    ZOL 0.025 mg/kg or 0.05mg/kg i.v. infusion was administered twice yearly at 6 months intervals.

    Number of subjects in period 1
    		ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Started
    25
    27
    24
    27
    Completed
    23
    24
    21
    24
    Not completed
    2
    3
    3
    3
         Consent withdrawn by subject
    2
    1
    -
    -
         Administrative problems
    -
    2
    3
    2
         Lost to follow-up
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ZOL-ZOL once yearly
    Reporting group description
    		 Subjects who received ZOL in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 milligram/kilogram (mg/kg) of ZOL up to a maximum of 4 mg once yearly. Subjects aged 1 to less than (<) 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg once yearly, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.

    Reporting group title
    ZOL-ZOL twice yearly
    Reporting group description
    		 Subjects who received ZOL in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 mg/kg of ZOL up to a maximum of 4 mg twice yearly at 6 month intervals. Subjects aged 1 to < 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg twice yearly at 6 month intervals, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.

    Reporting group title
    PAM-ZOL once yearly
    Reporting group description
    		 Subjects who received pamidronate (PAM) in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 mg/kg of ZOL up to a maximum of 4 mg once yearly. Subjects aged 1 to less than < 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg once yearly, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.

    Reporting group title
    PAM-ZOL twice yearly
    Reporting group description
    		 Subjects who received PAM in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 mg/kg of ZOL up to a maximum of 4 mg twice yearly at 6 month intervals. Subjects aged 1 to < 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg twice yearly at 6 month intervals, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.

    Reporting group values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly Total
    Number of subjects
    		 25 27 24 27 103
    Age categorical
    Units: Subjects
        2- <3 years
    		 1 0 0 1 2
        3- <9 years
    		 13 12 9 8 42
        9 years or older
    		 11 15 15 18 59
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.9 ± 4.98 9.9 ± 4.29 10 ± 4.81 10 ± 3.97 -
    Gender categorical
    Units: Subjects
        Female
    		 11 14 11 9 45
        Male
    		 14 13 13 18 58

    End points

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    End points reporting groups
    Reporting group title
    ZOL-ZOL once yearly
    Reporting group description
    		 Subjects who received ZOL in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 milligram/kilogram (mg/kg) of ZOL up to a maximum of 4 mg once yearly. Subjects aged 1 to less than (<) 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg once yearly, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.

    Reporting group title
    ZOL-ZOL twice yearly
    Reporting group description
    		 Subjects who received ZOL in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 mg/kg of ZOL up to a maximum of 4 mg twice yearly at 6 month intervals. Subjects aged 1 to < 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg twice yearly at 6 month intervals, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.

    Reporting group title
    PAM-ZOL once yearly
    Reporting group description
    		 Subjects who received pamidronate (PAM) in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 mg/kg of ZOL up to a maximum of 4 mg once yearly. Subjects aged 1 to less than < 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg once yearly, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.

    Reporting group title
    PAM-ZOL twice yearly
    Reporting group description
    		 Subjects who received PAM in core study received ZOL based on age and body weight in extension study. Subjects aged 3 to 17 years received 0.05 mg/kg of ZOL up to a maximum of 4 mg twice yearly at 6 month intervals. Subjects aged 1 to < 3 years received a lower ZOL dose of 0.025 mg/kg up to a maximum of 2 mg twice yearly at 6 month intervals, until they reached their third birthday when the dose was increased to 0.05 mg/kg at the next scheduled dose administration visit.

    Primary: Number of subjects with adverse events (AEs) and serious adverse events (SAEs)

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    End point title
    		 Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [1]
    End point description
    An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the subject or require medical or surgical intervention to prevent one of the aforementioned outcomes. Analysis was performed in safety population (SAF), defined as the subjects who received at least one dose of study medication in the extension study and had at least one post-baseline safety assessment.
    End point type
    Primary
    End point timeframe
    From start of study treatment (extension phase) to end of study (extension phase)
    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 was planned for this outcome measure.
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    25
    27
    24
    27
    Units: Number of subjects
        AEs
    24
    24
    17
    20
        SAEs
    5
    6
    3
    5
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in lumbar spine bone mineral density (BMD) at months 18 and 24

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    End point title
    		 Percentage change from baseline in lumbar spine bone mineral density (BMD) at months 18 and 24
    End point description
    Bone-mineral density (BMD) was estimated dual energy X-ray absorptiometry (DEXA) method. Percent change from core baseline in lumbar spine BMD was calculated by using the formula: 100 (endpoint -core baseline)/core baseline. The analysis was performed in Intent-to-treat (ITT) population, defined as all randomized subjects who received at least one dose of study drug and had at least one post baseline efficacy assessment on the efficacy variable. The 'n' signifies those subjects with lumbar spine BMD measurements at both baseline and the respective specified time points, as determined by the visit window after last observation carried forward (LOCF) imputation for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (core study), Month 18, Month 24 (core+extension study)
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    25
    27
    24
    27
    Units: grams/ square centimetres
    arithmetic mean (standard deviation)
        Change from baseline to Month 18(n=22,21, 22,22)
    58.61 ± 28.871
    49.043 ± 19.43
    43.659 ± 27.492
    50.721 ± 33.172
        Change from baseline to Month 24(n=22,21, 22,22)
    64.569 ± 30.373
    59.1 ± 21.338
    52.538 ± 31.341
    62.202 ± 44.71
    No statistical analyses for this end point

    Secondary: Change from baseline in lumbar spine bone mineral density (BMD) Z-scores at months 18 and 24

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    End point title
    		 Change from baseline in lumbar spine bone mineral density (BMD) Z-scores at months 18 and 24
    End point description
    The BMD Z-score was used to diagnose low bone mass in young adults and children. Z-score was determined as: (Measured BMD - Age-matched mean BMD)/ Age matched population standard deviation. Lumbar spine Z-scores were available only for subjects aged 3 years or older using a Hologic imaging equipment, and subjects aged 5 years or older were imaged using the Lunar equipment. The analysis was performed in ITT population. The 'n' signifies those subjects with lumbar spine BMD Z-score measurements at both baseline and the respective specified time points, as determined by the visit window after LOCF imputation for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (core study), Month 18, Month 24 (core+extension study)
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    25
    27
    24
    27
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change from baseline to Month 18(n=13,12, 12,18)
    2.459 ± 1.017
    2.073 ± 0.963
    1.198 ± 0.576
    2.017 ± 1.333
        Change from baseline to Month 24(n=13,12, 12,18)
    2.633 ± 0.991
    2.253 ± 1.211
    1.411 ± 0.685
    2.238 ± 1.465
    No statistical analyses for this end point

    Secondary: Change from baseline in bone mineral content (BMC) of the total body at months 18 and 24

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    End point title
    		 Change from baseline in bone mineral content (BMC) of the total body at months 18 and 24
    End point description
    Bone mineral content (BMC) was used to diagnose the bone loss in the study subjects. Percent change from core baseline in BMC was calculated by using the formula: 100*(endpoint - core baseline)/core baseline. The analysis was performed in ITT population. The 'n' signifies those subjects with total BMC measurements at both baseline and the respective specified time points, as determined by the visit window after LOCF imputation for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (core study), Month 18, Month 24 (core+extension study)
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    25
    27
    24
    27
    Units: grams
    arithmetic mean (standard deviation)
        Change from baseline to Month 18(n=24, 27, 23, 24)
    299.379 ± 205.819
    329.843 ± 236.744
    366.794 ± 192.875
    346.233 ± 161.58
        Change from baseline to Month 24(n=24, 27, 23, 24)
    365.499 ± 239.374
    422.261 ± 278.864
    431.069 ± 234.943
    435.566 ± 240.497
    No statistical analyses for this end point

    Secondary: Number of clinical fractures per subject

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    End point title
    		 Number of clinical fractures per subject
    End point description
    The total number of clinical fractures per subject was determined from the sum of all anatomic sites captured in the radiographic interpretation report. Analysis was performed in ITT population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Extension Period (12 months) and Core+Extension period (24 months)
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    25
    27
    24
    27
    Units: fractures/subject
    arithmetic mean (standard deviation)
        Extension Period (12 months)(n=8, 8, 9, 12)
    1.6 ± 0.74
    2.5 ± 2.07
    1.4 ± 0.88
    1.9 ± 1.31
        Core+Extension period (24 months)(n=14,15,17,17)
    4.1 ± 6.02
    2.6 ± 2.77
    1.5 ± 0.94
    2.7 ± 2.87
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in serum biomarkers of bone turnover at months 15, 18, 21 and 24

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    End point title
    		 Percentage change from baseline in serum biomarkers of bone turnover at months 15, 18, 21 and 24
    End point description
    Serum biomarkers i.e bone resorption marker C-telopeptide (beta-CTx), bone formation markers N-terminal propeptide of type I collagen (P1NP) and bone-specific alkaline phosphatase (BSAP) were measured in children aged 3 years or older. Percent change from core baseline in serum biomarkers was calculated by using the formula: 100*(endpoint - core baseline)/core baseline. Analysis was performed in ITT population. The 'n' signifies those subjects with total Serum biomarkers measurements at both baseline and the respective specified time points, as determined by available data..
    End point type
    Secondary
    End point timeframe
    Baseline (core study), Month 15, 18, 21, 24 (core+extension study)
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    25
    27
    24
    26
    Units: nanogram/milliilitre(ng/mL)
    arithmetic mean (standard deviation)
        Month 15, Serum beta–CTx(n=14,13,16,13)
    -24.951 ± 39.382
    -20.94 ± 27.039
    -14.459 ± 68.783
    48.943 ± 182.127
        Month 18, Serum beta–CTx (n=19,17,16,18)
    -18.889 ± 37.431
    -28.666 ± 23.101
    -17.07 ± 69.033
    62.38 ± 213.296
        Month 21, Serum beta–CTx (n=16,16,15,18)
    -14.523 ± 34.039
    -21.682 ± 31.279
    -2.691 ± 73.35
    8.255 ± 105.953
        Month 24, Serum beta–CTx (n=16,17,16,17)
    -24.787 ± 29.412
    -15.167 ± 37.279
    -9.097 ± 61.236
    15.116 ± 119.355
        Month 15, Serum P1NP (n=14,13,16,14)
    -47.028 ± 41.699
    -35.236 ± 18.03
    -57.439 ± 17.025
    -25.991 ± 54.741
        Month 18, Serum P1NP (n=18,17,16,18)
    -42.705 ± 38.071
    -40.015 ± 21.195
    -52.307 ± 25.034
    -15.926 ± 65.164
        Month 21, Serum P1NP (n=15,16,15,18)
    -41.123 ± 36.322
    -40.727 ± 35.033
    -44.831 ± 36.28
    -34.64 ± 47.944
        Month 24, Serum P1NP (n=15,17,16,17)
    -53.948 ± 18.645
    -39.928 ± 29.892
    -44.852 ± 35.594
    -25.532 ± 53.942
        Month 15, Serum BSAP (n=14,13,16,14)
    -43.016 ± 25.058
    -24.88 ± 21.182
    -42.306 ± 21.196
    -30.919 ± 28.386
        Month 18, Serum BSAP (n=19,17,16,18)
    -32.095 ± 25.962
    -27.017 ± 22.682
    -43.864 ± 24.084
    -15.189 ± 38.864
        Month 21, Serum BSAP (n=16,16,15,18)
    -27.6 ± 32.165
    -31.117 ± 18.021
    -35.627 ± 31.915
    -32.154 ± 30.217
        Month 24, Serum BSAP (n=16,17,16,17)
    -30.81 ± 28.518
    -33.915 ± 19.387
    -34.481 ± 32.976
    -26.107 ± 38.807
    No statistical analyses for this end point

    Secondary: Change from baseline in supine length at months 15, 18, 21 and 24

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    End point title
    		 Change from baseline in supine length at months 15, 18, 21 and 24
    End point description
    Supine length was measured by using stadiometer. Two to four measurements were taken and the average length measurements were used if the two measurements differed by >4 millimetre (mm), two additional measurements were recorded. Change from core baseline in supine length was calculated by using the formula: (endpoint - core baseline). Analysis was performed in ITT population. The 'n' signifies those subjects with vertebral spine length measurements at both baseline and the respective specified time points, as determined by the visit window after LOCF imputation for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (core study), Month 15, Month 18, Month 21, Month 24 (core+extension study)
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    25
    27
    24
    27
    Units: centimetres (cm)
    arithmetic mean (standard deviation)
        Change from baseline to Month 15(n=24, 27,24,27)
    8.292 ± 7.16
    6.63 ± 3.488
    7.5 ± 5.158
    7.815 ± 3.962
        Change from baseline to Month 18(n=24, 27,24,27)
    9.417 ± 7.199
    8.296 ± 4.017
    9.167 ± 5.475
    9.407 ± 6.253
        Change from baseline to Month 21(n=24, 27,24,27)
    10.5 ± 6.846
    8.704 ± 4.103
    9.625 ± 5.64
    11.926 ± 7.849
        Change from baseline to Month 24(n=24, 27, 24, 27)
    9.125 ± 15.358
    9.963 ± 4.238
    10.583 ± 5.778
    12.926 ± 7.706
    No statistical analyses for this end point

    Secondary: Percentage of subjects with bone pain

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    End point title
    		 Percentage of subjects with bone pain
    End point description
    The Wong-Baker FACES pain rating scale was used to assess bone pain in all subjects. For very young children, their parent or guardian was rated the bone pain scale and the older subjects were self-rated the bone pain scale. There were 6 categories of pain intensity described from “no hurt” to “hurts worst”, Face 0: no hurt, face 1: hurts little bit, face 2: hurts little more, face 3: hurts even more, face 4: hurts whole lot and face 5: hurts worst. Analysis was performed in ITT population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (core study), Month 12, Month 24 (core+extension study)
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    25
    27
    24
    27
    Units: Percentage of subjects
    number (not applicable)
        Month 12 No hurt
    92
    74.1
    75
    74.1
        Month 12 Hurts little bit
    8
    22.2
    12.5
    11.1
        Month 12 Hurts little more
    0
    0
    8.3
    7.4
        Month 12 Hurts even more
    0
    3.7
    4.2
    3.7
        Month 12 Hurts whole lot
    0
    0
    0
    3.7
        Month 12 Hurts worst
    0
    0
    0
    0
        Month 24 No Hurt
    72
    63
    75
    63
        Month 24 Hurts little bit
    4
    18.5
    8.3
    18.5
        Month 24 Hurts little more
    0
    3.7
    0
    0
        Month 24 Hurts even more
    4
    0
    4.2
    0
        Month 24 Hurts whole lot
    4
    0
    0
    0
        Month 24 Hurts worst
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change from baseline in cortical bone thickness at month 24

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    End point title
    		 Change from baseline in cortical bone thickness at month 24
    End point description
    Cortical bone thickness was used to diagnose the bone loss in the study subjects. X-rays of the vertebral spine were used to determine cortical bone thickness. Change from core baseline in cortical bone thickness was calculated by using the formula: (endpoint - core baseline). Analysis was performed in ITT population. The number of subjects analysed (N) signifies those subjects with cortical bone thickness measurements at both baseline and the respective specified time points, as determined by the visit window after LOCF imputation for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (core study), Month 24 (core+extension study)
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    16
    18
    12
    18
    Units: millimetre (mm)
        arithmetic mean (standard deviation)
    -0.05 ± 0.126
    -0.017 ± 0.079
    0.008 ± 0.051
    0.011 ± 0.076
    No statistical analyses for this end point

    Secondary: Change from baseline in vertebral spine length at month 24

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    End point title
    		 Change from baseline in vertebral spine length at month 24
    End point description
    The X-rays of the spine and hand were used to determine the changes in vertebral spine length. Change from core baseline vertebral spine length was calculated by using the formula: (endpoint - core baseline). Analysis was performed in ITT population. The number of subjects analysed (N) signifies those subjects with vertebral spine length measurements at both baseline and the respective specified time points, as determined by the visit window after LOCF imputation for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (core study), Month 24 (core+extension study
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    12
    13
    13
    14
    Units: centimetre (cm)
        arithmetic mean (standard deviation)
    4.703 ± 2.037
    4.075 ± 6.939
    4.774 ± 6.959
    2.642 ± 5.006
    No statistical analyses for this end point

    Secondary: Change from baseline in grip strength at month 15, 18, 21 and 24

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    End point title
    		 Change from baseline in grip strength at month 15, 18, 21 and 24
    End point description
    Grip strength assessed by hand dynamometry in subjects aged 3 years or older. The assessment was made from the best of three measurements attained with the dominant hand. The Change from core baseline in grip strength was calculated by using the formula: (endpoint - core baseline). Analysis was performed in ITT population. The 'n' signifies those subjects with grip strength measurements at both baseline and the respective specified time points, as determined by the visit window after LOCF imputation for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (core study), Month 15, Month 18, Month 21, Month 24 (core+extension study)
    End point values
    		 ZOL-ZOL once yearly ZOL-ZOL twice yearly PAM-ZOL once yearly PAM-ZOL twice yearly
    Number of subjects analysed
    24
    27
    24
    26
    Units: Grams(g)
    arithmetic mean (standard deviation)
        Change from baseline to Month 15 (n=17,20,18,23)
    2.418 ± 2.848
    2.675 ± 3.512
    2.611 ± 5.217
    2.37 ± 6.572
        Change from baseline to Month 18 (n=17,20,18,23)
    3.371 ± 2.026
    3.425 ± 4.836
    3.778 ± 5.236
    2.739 ± 6.473
        Change from baseline to Month 21 (n=17,20,18,23)
    4.988 ± 3.904
    4.475 ± 5.333
    4.25 ± 5.899
    3.717 ± 6.694
        Change from baseline to Month 24 (n=17,20,18,23)
    5.365 ± 4.04
    5.825 ± 7.276
    4.667 ± 5.773
    6.717 ± 12.902
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    Zoledronic acid: Zol 1x/yr
    Reporting group description
    		 Zoledronic acid: Zol 1x/yr

    Reporting group title
    Zoledronic acid: Zol 2x/yr
    Reporting group description
    		 Zoledronic acid: Zol 2x/yr

    Reporting group title
    Pamidronate: Zol 1x/yr
    Reporting group description
    		 Pamidronate: Zol 1x/yr

    Reporting group title
    Pamidronate: Zol 2x/yr
    Reporting group description
    		 Pamidronate: Zol 2x/yr

    Serious adverse events
    		 Zoledronic acid: Zol 1x/yr Zoledronic acid: Zol 2x/yr Pamidronate: Zol 1x/yr Pamidronate: Zol 2x/yr
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 25 (20.00%)
    6 / 27 (22.22%)
    3 / 24 (12.50%)
    5 / 27 (18.52%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 27 (3.70%)
         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
    Medical device discomfort
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 27 (3.70%)
         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
    Tibia fracture
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 27 (3.70%)
         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
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 27 (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
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 27 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture malunion
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scoliosis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         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
    		 Zoledronic acid: Zol 1x/yr Zoledronic acid: Zol 2x/yr Pamidronate: Zol 1x/yr Pamidronate: Zol 2x/yr
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 25 (88.00%)
    19 / 27 (70.37%)
    15 / 24 (62.50%)
    19 / 27 (70.37%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    1
    2
    Femur fracture
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 27 (11.11%)
    1 / 24 (4.17%)
    1 / 27 (3.70%)
         occurrences all number
    3
    3
    1
    1
    Forearm fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    3
    Hand fracture
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    3
    1
    Humerus fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 27 (11.11%)
    1 / 24 (4.17%)
    0 / 27 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Sunburn
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Tibia fracture
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 27 (14.81%)
    1 / 24 (4.17%)
    4 / 27 (14.81%)
         occurrences all number
    8
    5
    1
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
    3 / 27 (11.11%)
         occurrences all number
    6
    1
    2
    5
    Migraine
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 27 (7.41%)
    3 / 24 (12.50%)
    2 / 27 (7.41%)
         occurrences all number
    1
    3
    4
    2
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Nausea
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 27 (0.00%)
         occurrences all number
    5
    0
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
    1 / 27 (3.70%)
         occurrences all number
    2
    1
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
    1 / 27 (3.70%)
         occurrences all number
    0
    3
    2
    1
    Epistaxis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
    4 / 27 (14.81%)
         occurrences all number
    2
    2
    2
    5
    Back pain
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 27 (14.81%)
    3 / 24 (12.50%)
    1 / 27 (3.70%)
         occurrences all number
    4
    4
    3
    2
    Bone pain
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
    4 / 27 (14.81%)
         occurrences all number
    1
    2
    2
    4
    Muscle spasms
         subjects affected / exposed
    5 / 25 (20.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 27 (14.81%)
    0 / 24 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    4
    0
    1
    Pain in extremity
         subjects affected / exposed
    4 / 25 (16.00%)
    5 / 27 (18.52%)
    0 / 24 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    6
    9
    0
    3
    Scoliosis
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    2
    0
    1
    Infections and infestations
    Ear infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Influenza
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 27 (14.81%)
    2 / 24 (8.33%)
    1 / 27 (3.70%)
         occurrences all number
    2
    5
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    5 / 25 (20.00%)
    5 / 27 (18.52%)
    0 / 24 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    9
    5
    0
    2
    Pharyngitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sinusitis
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
    3 / 27 (11.11%)
         occurrences all number
    4
    5
    1
    6
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    0
    2

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Study was terminated prematurely at the recommendation of the independent Data Safety Monitoring Board, who after review of interim unblinded safety and efficacy data observed an excess of fracture risk that had not changed from the core study.
    For support, Contact us.
    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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