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    Clinical Trial Results:
    An international, multicenter, randomized, open-label, parallel efficacy, and safety trial of intravenous zoledronic acid compared to intravenous pamidronate in children with severe osteogenesis imperfect Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2015-003539-37
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    09 May 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2018
    First version publication date
    07 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CZOL446H2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00063479
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000024-PIP01-07
    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
    09 May 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy objective was to assess the percentage (%) change in lumbar spine (LS) bone mineral density (BMD) at month 12 relative to baseline in zoledronic acid-treated pediatric patients with severe OI compared to pamidronate-treated pediatric patients who were 1 to 17 years of age.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 Pamidronate was established as an off-label therapy for treating children with OI as there was no approved therapy for this indication. Based on severity of disease in this pediatric population, it was ethically difficult for parents/guardians to give consent for participation in the study if their child had the possibility of being randomized to placebo.
    Actual start date of recruitment
    26 Jun 2003
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 51
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Finland: 14
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    South Africa: 8
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Poland: 17
    Worldwide total number of subjects
    150
    EEA total number of subjects
    76
    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)
    2
    Children (2-11 years)
    104
    Adolescents (12-17 years)
    44
    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 at 20 centers in 9 countries.

    Pre-assignment
    Screening details
    		 A total of 155 subjects were randomized in the study. 150 patients were in the ITT group. The trial analysis was performed on intent to treat (ITT) population defined as all randomized subjects who had a least one post-baseline efficacy assessment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronic acid
    Arm description
    		 Subjects were peripherally intravenously (i.v.) infused with doses of zoledronic acid based on age and body weight. Subjects aged from 1 to <3 years received 0.025 milligram (mg)/kilogram (kg) diluted in 50 milliliter (mL) of normal saline up to a maximum dose of at a frequency of 30 to 45 minute infusion every 3 months. Subjects aged from 3 to 17 years received 0.05 mg/kg diluted in 100 mL of normal saline up to a maximum of 4 mg at a frequency of 30 minute infusion every 3 months. All subjects were hospitalized for 48 hours at the first infusion of zoledronic acid and post-dose symptoms were assessed. A total of 4 infusions were received during the study treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects aged 1 to <3 years received a dose of 0.025 mg/kg up to a maximum of 2 mg every 3 months. Subjects aged 3 to 17 years received 0.05 mg/kg of zoledronic acid up to a maximum of 4 mg every 3 months. Zoledronic acid was provided in 5 mg/100 mL vials; for older children 5mg/5mL vials were used. The calculated dose of zoledronic acid was diluted to 50 mL with normal saline and infused over 30 to 45 minutes for children <3 years old; and diluted to 100 mL with normal saline for infusion over 30 minutes in subjects aged 3 to 17 years. All Subjects were hospitalised for 48 hours at the first infusion of zoledronic acid and post-dose symptoms were assessed. A total of 4 infusions were received during the study treatment period.

    Arm title
    		 Pamidronate
    Arm description
    		 Subjects were peripherally i.v. infused with doses of pamidronate based on age and body weight. Subjects aged from 1 to <2 years received 0.5 mg/kg/day at frequency of 4 hour infusion on each of 3 successive days, every 2 months. Subjects aged 2 years received 0.75 mg/kg/day at a frequency of 4 hour infusion on each of 3 successive days, every 3 months. Subjects aged from 3 to 17 years received 1 mg/kg/day at a frequency of 4 hour infusion on each of 3 successive days, every 3 months. Subjects received a maximum daily dose of up to 60 mg.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pamidronate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects aged 1 to <2 years received a daily dose of 0.5 mg/kg up to a maximum of 60 on each of 3 successive days, every 2 months. Subjects aged 2 and 3 to 17 years received a daily dose of 0.75 mg/kg and 1 mg/kg of pamidronate, respectively up to a maximum of 60 mg on each of 3 successive days, every 3 months. Each 90 mg vial of lyophilized pamidronate was reconstituted with 10.0 mL of sterile water for injection.

    Number of subjects in period 1
    		Zoledronic acid Pamidronate
    Started
    74
    76
    Completed
    68
    69
    Not completed
    6
    7
         Consent withdrawn by subject
    3
    3
         Adverse event, non-fatal
    2
    2
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Subjects were peripherally intravenously (i.v.) infused with doses of zoledronic acid based on age and body weight. Subjects aged from 1 to <3 years received 0.025 milligram (mg)/kilogram (kg) diluted in 50 milliliter (mL) of normal saline up to a maximum dose of at a frequency of 30 to 45 minute infusion every 3 months. Subjects aged from 3 to 17 years received 0.05 mg/kg diluted in 100 mL of normal saline up to a maximum of 4 mg at a frequency of 30 minute infusion every 3 months. All subjects were hospitalized for 48 hours at the first infusion of zoledronic acid and post-dose symptoms were assessed. A total of 4 infusions were received during the study treatment period.

    Reporting group title
    Pamidronate
    Reporting group description
    		 Subjects were peripherally i.v. infused with doses of pamidronate based on age and body weight. Subjects aged from 1 to <2 years received 0.5 mg/kg/day at frequency of 4 hour infusion on each of 3 successive days, every 2 months. Subjects aged 2 years received 0.75 mg/kg/day at a frequency of 4 hour infusion on each of 3 successive days, every 3 months. Subjects aged from 3 to 17 years received 1 mg/kg/day at a frequency of 4 hour infusion on each of 3 successive days, every 3 months. Subjects received a maximum daily dose of up to 60 mg.

    Reporting group values
    		 Zoledronic acid Pamidronate Total
    Number of subjects
    		 74 76 150
    Age categorical
    150 patients were in the ITT group. The trial analysis was performed on intent to treat (ITT) population defined as all randomized subjects who had a least one post-baseline efficacy assessment.
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 1 1 2
        Children (2-11 years)
    		 49 55 104
        Adolescents (12-17 years)
    		 24 20 44
    Age continuous
    150 patients were in the ITT group. The trial analysis was performed on intent to treat (ITT) population defined as all randomized subjects who had a least one post-baseline efficacy assessment.
    Units: years
        arithmetic mean (standard deviation)
    		 8.6 ± 4.25 8.5 ± 4.2 -
    Gender categorical
    150 patients were in the ITT group. The trial analysis was performed on intent to treat (ITT) population defined as all randomized subjects who had a least one post-baseline efficacy assessment.
    Units: Subjects
        Female
    		 36 31 67
        Male
    		 38 45 83

    End points

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    End points reporting groups
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Subjects were peripherally intravenously (i.v.) infused with doses of zoledronic acid based on age and body weight. Subjects aged from 1 to <3 years received 0.025 milligram (mg)/kilogram (kg) diluted in 50 milliliter (mL) of normal saline up to a maximum dose of at a frequency of 30 to 45 minute infusion every 3 months. Subjects aged from 3 to 17 years received 0.05 mg/kg diluted in 100 mL of normal saline up to a maximum of 4 mg at a frequency of 30 minute infusion every 3 months. All subjects were hospitalized for 48 hours at the first infusion of zoledronic acid and post-dose symptoms were assessed. A total of 4 infusions were received during the study treatment period.

    Reporting group title
    Pamidronate
    Reporting group description
    		 Subjects were peripherally i.v. infused with doses of pamidronate based on age and body weight. Subjects aged from 1 to <2 years received 0.5 mg/kg/day at frequency of 4 hour infusion on each of 3 successive days, every 2 months. Subjects aged 2 years received 0.75 mg/kg/day at a frequency of 4 hour infusion on each of 3 successive days, every 3 months. Subjects aged from 3 to 17 years received 1 mg/kg/day at a frequency of 4 hour infusion on each of 3 successive days, every 3 months. Subjects received a maximum daily dose of up to 60 mg.

    Primary: Percent change from baseline in lumbar spine bone mineral density (BMD) at Month 12

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    End point title
    		 Percent change from baseline in lumbar spine bone mineral density (BMD) at Month 12
    End point description
    BMD was measured by dual energy x-ray absorptiometry (DEXA) at specified visits. The skeletal scanning sites was anteroposterior (AP) lumbar spine (L1-L4) in infant to ≤ 17 years of age. The analysis was performed on intent to treat (ITT) population defined as all randomized subjects who had a least one post-baseline efficacy assessment. The missing values were imputed using the last post-baseline observation carried forward (LOCF) approach.
    End point type
    Primary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    63
    68
    Units: Percentage change
        number (not applicable)
    42.71
    34.65
    Statistical analysis title
    		 Change in lumbar spine BMD at month 12
    Comparison groups
    Zoledronic acid v Pamidronate
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 15.71
    Variability estimate
    Standard error of the mean

    Secondary: Change from baseline in lumbar spine Z-score at Month 12

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    End point title
    		 Change from baseline in lumbar spine Z-score at Month 12
    End point description
    Z-score was defined as the comparison of BMD in subjects with osteoporosis to a healthy subject of similar age and body size. It is the number of standard deviations of the BMD measurement above or below that of healthy subject. A Z-score above 2.0 was considered normal according to the International Society for Clinical Densitometry (ISCD). Positive values shows improvement. Subjects aged greater than or equal to 3 years were imaged on the Hologic equipment and subjects aged greater than or equal to 5 years were imaged on the Lunar equipment with validated normalized ranges. The analysis was performed on ITT population. The missing values were imputed using the LOCF approach.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    43
    49
    Units: Gram (g)/Centimeter (cm)^2
        least squares mean (standard error)
    1.57 ± 0.13
    1.31 ± 0.13
    No statistical analyses for this end point

    Secondary: Change from baseline in femoral neck bone mineral content (BMC) at Month 6 and 12

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    End point title
    		 Change from baseline in femoral neck bone mineral content (BMC) at Month 6 and 12
    End point description
    Femoral neck BMD was measured by DEXA, using skeletal scanning in infant to subjects aged ≤17 years. The analysis was performed on ITT population. The missing values were imputed using the last post-baseline observation carried forward (LOCF).
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    42
    45
    Units: Gram (g)
    least squares mean (standard error)
        Month 6
    0.31 ± 0.04
    0.26 ± 0.04
        Month 12
    0.47 ± 0.04
    0.4 ± 0.04
    No statistical analyses for this end point

    Secondary: Number of clinical fractures during 12 Months

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    End point title
    		 Number of clinical fractures during 12 Months
    End point description
    Subjects were evaluated for any new fractures over an year using X-ray technique. The analysis was performed on ITT population. The missing values were imputed using the LOCF approach.
    End point type
    Secondary
    End point timeframe
    Day 1 to Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    68
    67
    Units: Number of clinical fractures
        arithmetic mean (standard deviation)
    1.04 ± 3
    0.67 ± 1.21
    No statistical analyses for this end point

    Secondary: Percent change from baseline in serum C-terminal telopeptide of type I collagen (CTx) at Month 6 and Month 12

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    End point title
    		 Percent change from baseline in serum C-terminal telopeptide of type I collagen (CTx) at Month 6 and Month 12
    End point description
    C-terminal telopeptide of type I collagen (CTx) was bone resorption biomarker measured in subjects aged ≥3 years. Percent change from baseline was measured as 100*(endpoint ­ baseline)/baseline. Negative change indicated improvement in bone resorption. The analysis was performed on ITT population. Here 'n' signifies number of subjects evaluated for C-telopeptide at the specified time-points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    74
    76
    Units: Nanogram (ng)/ milliliter (mL)
    arithmetic mean (standard deviation)
        Month 6 (n=44,49)
    -34.288 ± 19.199
    3.07 ± 79.661
        Month 12 (n=40,49)
    -34.228 ± 20.775
    9.377 ± 99.581
    No statistical analyses for this end point

    Secondary: Percent change from baseline in N-terminal propeptide of type I collagen (P1NP) at Month 6 and Month 12

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    End point title
    		 Percent change from baseline in N-terminal propeptide of type I collagen (P1NP) at Month 6 and Month 12
    End point description
    P1NP was the bone formation biomarker in serum measured in subjects aged ≥3 years. Percent change from baseline was measured as 100*(Month 6 or 12 - baseline)/baseline values. Negative change indicated improvement in bone formation. The analysis was performed on ITT population. Here, 'n' signifies number of subjects evaluated for P1NP at Month 6 and 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    74
    76
    Units: ng/mL
    arithmetic mean (standard deviation)
        Month 6 (n=44,48)
    -36.809 ± 26.137
    -21.958 ± 26.693
        Month 12 (n= 40, 50)
    -45.59 ± 21.302
    -27.703 ± 34.907
    No statistical analyses for this end point

    Secondary: Percent change from baseline in bone specific alkaline phosphatase (BALP) at Month 6 and Month 12

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    End point title
    		 Percent change from baseline in bone specific alkaline phosphatase (BALP) at Month 6 and Month 12
    End point description
    BALP was the bone formation biomarker in serum measured in subjects aged ≥3 years. Percent change from baseline was measured as 100*(Month 6 or 12 - baseline)/baseline values. Negative change indicated improvement in bone formation. The analysis was performed on ITT population. Here, 'n' signifies number of subjects evaluated for BALP at Month 6 and 12.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    74
    76
    Units: ng/mL
    arithmetic mean (standard deviation)
        Month 6 (n=44,49)
    -25.387 ± 27.118
    -19.687 ± 22.468
        Month 12 (n= 40, 50)
    -34.77 ± 20.821
    -26.849 ± 25
    No statistical analyses for this end point

    Secondary: Change from baseline in supine height at Month 6 and Month 12

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    End point title
    		 Change from baseline in supine height at Month 6 and Month 12
    End point description
    Supine height was measured using a stadiometer. Average of two height measurements were taken in millimeters (mm). If the two measurements differed by greater than 4 mm than two additional measurements were recorded and the average of the four height measurements was used for the analysis. The effect of zoledronic acid on the change in supine length was compared to pamidronate in children aged ≥ 1 year to ≤ 17 years. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    73
    74
    Units: Centimeter
    arithmetic mean (standard deviation)
        Month 6
    3.26 ± 3.06
    4.108 ± 7.18
        Month 12
    6.041 ± 5.264
    6.527 ± 7.009
    No statistical analyses for this end point

    Secondary: Number of subjects with bone pain scores at Month 6 and Month 12

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    End point title
    		 Number of subjects with bone pain scores at Month 6 and Month 12
    End point description
    Bone pain in pediatric was assessed by using Wong-Baker FACES Pain Rating questionnaires. The questionnaires included a face scale of six categories (faces) based on pain intensity rating from “No Hurt” to “Hurts Worst”. Face scale was rated as: Face 0 - very happy because no pain at all; Face 1 - hurts just a little bit; Face 2 - hurts a little more; Face 3 - hurts even more; Face 4 - hurts a whole lot; Face 5 - hurts as much as can be imagined, although you don’t have to be crying to feel this bad. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    74
    76
    Units: Subjects
        Month 6 (No hurt)
    52
    55
        Month 6 (Hurts little bit)
    13
    12
        Month 6 (Hurts little more)
    5
    1
        Month 6 (Hurts even more)
    0
    0
        Month 6 (Hurts whole lot)
    0
    1
        Month 6 (Hurts worst)
    0
    1
        Month 6 (Missing)
    4
    6
        Month 12 (No hurt)
    54
    49
        Month 12 (Hurts little bit)
    7
    7
        Month 12 (Hurts little more)
    0
    5
        Month 12 (Hurts even more)
    2
    2
        Month 12 (Hurts whole lot)
    0
    1
        Month 12 (Hurts worst)
    0
    0
        Month 12 (Missing)
    11
    12
    No statistical analyses for this end point

    Secondary: Time to first fracture during 12 Months

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    End point title
    		 Time to first fracture during 12 Months
    End point description
    Subjects were evaluated for time to first fracture after infusion of the treatment drug. Subjects with no fractures were reported and censored at day 365 or the last visit, whichever was earlier and the fractures occurred after 365 days were truncated at Day 365. The analysis was performed on ITT population. Here, '99999' in median and confidence interval represents the non-estimable data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Month 12
    End point values
    		 Zoledronic acid Pamidronate
    Number of subjects analysed
    74
    76
    Units: Days
        median (confidence interval 95%)
    99999 (334 to 99999)
    99999 (326 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All other adverse events are monitored from First Subject First Treatment until LSLV.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Zoledronic Acid
    Reporting group description
    		 Subjects were peripherally i.v. infused with doses of zoledronic acid based on age and body weight. Subjects aged from 1 to <3 years received 0.025 mg/kg diluted in 50 mL of normal saline up to a maximum dose of at a frequency of 30 to 45 minute infusion every 3 months. Subjects aged from 3 to 17 years received 0.05 mg/kg diluted in 100 mL of normal saline up to a maximum of 4 mg at a frequency of 30 minute infusion every 3 months.

    Reporting group title
    Pamidronate
    Reporting group description
    		 Subjects were peripherally i.v. infused with doses of pamidronate based on age and body weight. Subjects aged from 1 to <2 years received 0.5 mg/kg/day at frequency of 4 hour infusion on each of 3 successive days, every 2 months. Subjects aged 2 years received 0.75 mg/kg/day at a frequency of 4 hour infusion on each of 3 successive days, every 3 months. Subjects aged from 3 to 17 years received 1 mg/kg/day at a frequency of 4 hour infusion on each of 3 successive days, every 3 months. Subjects received a maximum daily dose of up to 60 mg.

    Serious adverse events
    		 Zoledronic Acid Pamidronate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 74 (32.43%)
    15 / 78 (19.23%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood calcium decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    10 / 74 (13.51%)
    5 / 78 (6.41%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site haematoma
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vasculitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral disorder
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint instability
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb deformity
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb deformity
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    6 / 74 (8.11%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Zoledronic Acid Pamidronate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 74 (91.89%)
    72 / 78 (92.31%)
    Investigations
    Blood calcium decreased
         subjects affected / exposed
    2 / 74 (2.70%)
    5 / 78 (6.41%)
         occurrences all number
    3
    8
    Body temperature increased
         subjects affected / exposed
    5 / 74 (6.76%)
    1 / 78 (1.28%)
         occurrences all number
    5
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 78 (5.13%)
         occurrences all number
    3
    4
    Fall
         subjects affected / exposed
    2 / 74 (2.70%)
    5 / 78 (6.41%)
         occurrences all number
    4
    8
    Femur fracture
         subjects affected / exposed
    9 / 74 (12.16%)
    4 / 78 (5.13%)
         occurrences all number
    14
    6
    Fibula fracture
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 78 (1.28%)
         occurrences all number
    4
    1
    Foot fracture
         subjects affected / exposed
    2 / 74 (2.70%)
    5 / 78 (6.41%)
         occurrences all number
    2
    5
    Hand fracture
         subjects affected / exposed
    6 / 74 (8.11%)
    2 / 78 (2.56%)
         occurrences all number
    6
    3
    Humerus fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    6 / 78 (7.69%)
         occurrences all number
    1
    7
    Limb injury
         subjects affected / exposed
    0 / 74 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    0
    4
    Tibia fracture
         subjects affected / exposed
    9 / 74 (12.16%)
    3 / 78 (3.85%)
         occurrences all number
    9
    5
    Upper limb fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    5 / 78 (6.41%)
         occurrences all number
    1
    5
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    6 / 74 (8.11%)
    4 / 78 (5.13%)
         occurrences all number
    6
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 78 (3.85%)
         occurrences all number
    4
    3
    Headache
         subjects affected / exposed
    16 / 74 (21.62%)
    15 / 78 (19.23%)
         occurrences all number
    24
    20
    General disorders and administration site conditions
    Acute phase reaction
         subjects affected / exposed
    4 / 74 (5.41%)
    5 / 78 (6.41%)
         occurrences all number
    4
    5
    Chills
         subjects affected / exposed
    1 / 74 (1.35%)
    4 / 78 (5.13%)
         occurrences all number
    1
    4
    Fatigue
         subjects affected / exposed
    11 / 74 (14.86%)
    6 / 78 (7.69%)
         occurrences all number
    12
    6
    Influenza like illness
         subjects affected / exposed
    2 / 74 (2.70%)
    5 / 78 (6.41%)
         occurrences all number
    2
    5
    Infusion site pain
         subjects affected / exposed
    0 / 74 (0.00%)
    7 / 78 (8.97%)
         occurrences all number
    0
    10
    Pain
         subjects affected / exposed
    5 / 74 (6.76%)
    8 / 78 (10.26%)
         occurrences all number
    5
    10
    Pyrexia
         subjects affected / exposed
    43 / 74 (58.11%)
    42 / 78 (53.85%)
         occurrences all number
    52
    56
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    8 / 74 (10.81%)
    4 / 78 (5.13%)
         occurrences all number
    10
    4
    Diarrhoea
         subjects affected / exposed
    5 / 74 (6.76%)
    5 / 78 (6.41%)
         occurrences all number
    6
    5
    Nausea
         subjects affected / exposed
    9 / 74 (12.16%)
    10 / 78 (12.82%)
         occurrences all number
    11
    15
    Vomiting
         subjects affected / exposed
    21 / 74 (28.38%)
    12 / 78 (15.38%)
         occurrences all number
    22
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 74 (6.76%)
    4 / 78 (5.13%)
         occurrences all number
    7
    5
    Epistaxis
         subjects affected / exposed
    3 / 74 (4.05%)
    5 / 78 (6.41%)
         occurrences all number
    4
    5
    Nasal congestion
         subjects affected / exposed
    3 / 74 (4.05%)
    4 / 78 (5.13%)
         occurrences all number
    3
    5
    Pharyngolaryngeal pain
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 78 (5.13%)
         occurrences all number
    2
    5
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 74 (5.41%)
    4 / 78 (5.13%)
         occurrences all number
    5
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 74 (25.68%)
    17 / 78 (21.79%)
         occurrences all number
    28
    23
    Back pain
         subjects affected / exposed
    14 / 74 (18.92%)
    14 / 78 (17.95%)
         occurrences all number
    15
    15
    Bone pain
         subjects affected / exposed
    12 / 74 (16.22%)
    4 / 78 (5.13%)
         occurrences all number
    20
    6
    Muscle spasms
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 78 (1.28%)
         occurrences all number
    4
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    6 / 74 (8.11%)
    2 / 78 (2.56%)
         occurrences all number
    10
    2
    Musculoskeletal pain
         subjects affected / exposed
    9 / 74 (12.16%)
    3 / 78 (3.85%)
         occurrences all number
    15
    4
    Neck pain
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 78 (5.13%)
         occurrences all number
    2
    4
    Pain in extremity
         subjects affected / exposed
    21 / 74 (28.38%)
    19 / 78 (24.36%)
         occurrences all number
    35
    30
    Scoliosis
         subjects affected / exposed
    2 / 74 (2.70%)
    5 / 78 (6.41%)
         occurrences all number
    2
    5
    Infections and infestations
    Ear infection
         subjects affected / exposed
    4 / 74 (5.41%)
    4 / 78 (5.13%)
         occurrences all number
    5
    5
    Influenza
         subjects affected / exposed
    8 / 74 (10.81%)
    2 / 78 (2.56%)
         occurrences all number
    10
    2
    Nasopharyngitis
         subjects affected / exposed
    12 / 74 (16.22%)
    9 / 78 (11.54%)
         occurrences all number
    16
    13
    Otitis media
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 78 (1.28%)
         occurrences all number
    5
    1
    Pharyngitis
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 78 (5.13%)
         occurrences all number
    3
    5
    Pharyngitis streptococcal
         subjects affected / exposed
    4 / 74 (5.41%)
    4 / 78 (5.13%)
         occurrences all number
    5
    4
    Sinusitis
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 78 (0.00%)
         occurrences all number
    6
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 74 (8.11%)
    7 / 78 (8.97%)
         occurrences all number
    8
    11
    Urinary tract infection
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 78 (1.28%)
         occurrences all number
    5
    1
    Viral infection
         subjects affected / exposed
    3 / 74 (4.05%)
    4 / 78 (5.13%)
         occurrences all number
    4
    4
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    5 / 74 (6.76%)
    8 / 78 (10.26%)
         occurrences all number
    7
    8
    Hypocalcaemia
         subjects affected / exposed
    11 / 74 (14.86%)
    7 / 78 (8.97%)
         occurrences all number
    11
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2003
    The amendment was issued 4 months before the first subject first visit. The amendment complied with an Food and Drug Administration (FDA) written request requiring the inclusion of children in the 1-3 year age group. Safety related changes were also added as per the suggestion of the Data Safety Monitoring Board (DSMB) concerning definitions and tests for renal abnormalities. The amendment also added six infants, 3 to 11 months of age, to be treated with zoledronic acid at (a) pre-designated site(s). Nine infants were screened, but none met the inclusion/exclusion criteria.
    02 Feb 2004
    The amendment was issued after data were reviewed for the first 36 subjects enrolled in the study. The amendment included change in the conduct of the study based on the recommendations of the DSMB. The amendment included: • The ionized calcium assessments and required hospitalisations for subjects were amended to reflect the standard of treatment. • A re-test for the pathologic proteinuria exclusion criterion was allowed. • Approval was granted for enrollment of subjects aged 1 to 3 years at all study sites. Subjects aged 3 to 11 months were to be enrolled at a pre-designated site. • For subjects less than 3 years old randomized to zoledronic acid treatment, 5 mg/100 mL plastic vials (rather than 5 mg/5 mL vials) were used to ensure greater accuracy for these subjects who were to receive smaller doses of zoledronic acid.
    19 Jan 2006
    The amendment included: • The lower age entry criterion for infants was removed and upper limit increased to 12 months (from 11 months). • An exclusion criterion for urine protein/creatinine ratio of >0.4 for infants was added. • The urine sample collected for urine protein/creatinine ratio assessment was to be a first morning void. • The number of subjects randomized was increased to approximately 154 subjects to evaluate all primary endpoints.
    31 Jan 2007
    The amendment was to clarify and implement the DSMB recommendations, when they reviewed un-blinded efficacy and safety data. Subjects with type I OI, regardless of study drug assignment received no further study drug due to an observed increased incidence of femur fracture, while all other subjects (type III or IV OI) continued to receive their assigned study drug.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    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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