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    Clinical Trial Results:
    A prospective, bicentric, randomised, primarily double blind, placebo-controlled study to evaluate the efficacy of zoledronic acid for the treatment of bone marrow syndrome

    Summary
    EudraCT number
    		 2010-019415-38
    Trial protocol
    		 DE  
    Global end of trial date
    26 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jul 2021
    First version publication date
    22 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CZOL446HDE38T
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01348269
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Wuerzburg
    Sponsor organisation address
    Josef-Schneider-Str. 2, Wuerzburg, Germany, 97080
    Public contact
    Dr. Lothar Seefried, University Hospital Wuerzburg Clinical Study Unit Department of Orthopaedics Koenig-Ludwig-Haus, 0049 9318033590, l-seefried.klh@uni-wuerzburg.de
    Scientific contact
    Dr. Lothar Seefried, University Hospital Wuerzburg Clinical Study Unit Department of Orthopaedics Koenig-Ludwig-Haus, 0049 9318033590, l-seefried.klh@uni-wuerzburg.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim is to test the reduction of bone marrow edema syndrome after a singular intravenous treatment with Zoledronic Acid within 6 weeks compared to placebo. The volume of the edema is defined as biometric data measured by the use of MRT before and six weeks after treatment. The hypothesis has to be checked whether Zoledronic Acid is efficient in the treatment of painfull bone marrow edema. A statistically significant reduction of the edema in the MRT is considered as evidence for efficacy.
    Protection of trial subjects
    Safety monitoring (adverse Events, serious adverse Events, adverse drug reactions) and continous assessment of laboratory values (clinical chemistry, hematology)
    Background therapy
    		 All patients received Vitamin D background therapy.
    Evidence for comparator
    		 Placebo-controlled study. No active comparator was used.
    Actual start date of recruitment
    01 Jun 2011
    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
    Germany: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    42
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient (FPFV) was enrolled on 13-Jul-2011 and last patient (LPFV) was enrolled on 26-May-2015. All patients were recruited by a single center in Germany.

    Pre-assignment
    Screening details
    		 Suitable patients were selected by the investigator. A total of 63 patients were screened. 15 patients were deemed screening failure and eight of these patients were randomized but did not receive intervention.

    Pre-assignment period milestones
    Number of subjects started
    		 63 [1]
    Number of subjects completed
    		 48

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failure: 7
    Reason: Number of subjects
    		 Screening failure - randomized w/o intervention: 8
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: As not all randomized patients received study medication, more patients were enrolled than specified in worldwide number of enrolled in the trial. Randomized patients not receiving study medication were replaced. In total, 56 patients were enrolled. Of these 56 patients, 48 patients received study medication and were considered for analysis.
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronic acid
    Arm description
    		 Patients in this arm received zoledronic acid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    5 mg zoledronic acid (0.05 mg/ml solution; 100 ml)

    Arm title
    		 Placebo
    Arm description
    		 Patients in this arm received placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    0.9 % NaCl solution (100 ml)

    Number of subjects in period 1
    		Zoledronic acid Placebo
    Started
    34
    14
    Completed
    34
    14
    Period 2
    Period 2 title
    Treatment | Core Study (until week 6)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronic acid
    Arm description
    		 Patients in this arm received zoledronic acid.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    5 mg zoledronic acid (0.05 mg/ml solution; 100 ml)

    Arm title
    		 Placebo
    Arm description
    		 Patients in this arm received placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    0.9 % NaCl solution (100 ml)

    Number of subjects in period 2
    		Zoledronic acid Placebo
    Started
    34
    14
    Completed
    34
    14
    Period 3
    Period 3 title
    Follow-up (until week 12)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronic acid
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    5 mg zoledronic acid (0.05 mg/ml solution; 100 ml)

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    0.9 % NaCl solution (100 ml)

    Number of subjects in period 3
    		Zoledronic acid Placebo
    Started
    34
    14
    Completed
    32
    13
    Not completed
    2
    1
         Surgical intervention - Not study related
    1
    -
         Subsequent follow-up treatment required
    -
    1
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Patients in this arm received zoledronic acid

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received placebo.

    Reporting group values
    		 Zoledronic acid Placebo Total
    Number of subjects
    		 34 14 48
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 29 13 42
        From 65-84 years
    		 5 1 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.1 ( 12.9 ) 53.6 ( 6.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 4 16
        Male
    		 22 10 32
    Severity of disease
    Units: Subjects
        mild
    		 4 2 6
        moderate
    		 22 10 32
        severe
    		 8 2 10
    Pain (VAS)
    Assessment of pain as measured by a visual analog scale (VAS)
    Units: arbitrary units
        arithmetic mean (standard deviation)
    		 36.9 ( 27.4 ) 34.1 ( 21.1 ) -
    Qualeffo-41
    Assessment of quality of life by Qualeffo-41 questionnaire - Quality of life questionnaire of the European Foundation for Osteoporosis
    Units: arbitrary units
        arithmetic mean (standard deviation)
    		 2.1 ( 0.5 ) 2.2 ( 0.6 ) -
    Subjective estimation of medical condition (PDI)
    Subjective estimation of medical condition (Pain Disability Index)
    Units: arbitrary units
        arithmetic mean (standard deviation)
    		 20.8 ( 6.8 ) 21.3 ( 6.4 ) -
    Subject analysis sets

    Subject analysis set title
    Modified ITT | Zoledronic acid
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified ITT for analysis of primary endpoint (omititng outlier value of one patient with in placebo group [>500% increase in edema volumen]).

    Subject analysis set title
    Modified ITT | Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified ITT for analysis of primary endpoint (omititng outlier value of one patient with in placebo group [>500% increase in edema volumen]).

    Subject analysis sets values
    		 Modified ITT | Zoledronic acid Modified ITT | Placebo
    Number of subjects
    34
    13
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    29
    12
        From 65-84 years
    5
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Severity of disease
    Units: Subjects
        mild
        moderate
        severe
    Pain (VAS)
    Assessment of pain as measured by a visual analog scale (VAS)
    Units: arbitrary units
        arithmetic mean (standard deviation)
    ( )
    ( )
    Qualeffo-41
    Assessment of quality of life by Qualeffo-41 questionnaire - Quality of life questionnaire of the European Foundation for Osteoporosis
    Units: arbitrary units
        arithmetic mean (standard deviation)
    ( )
    ( )
    Subjective estimation of medical condition (PDI)
    Subjective estimation of medical condition (Pain Disability Index)
    Units: arbitrary units
        arithmetic mean (standard deviation)
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Patients in this arm received zoledronic acid

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received placebo.
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Patients in this arm received zoledronic acid.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received placebo.
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Modified ITT | Zoledronic acid
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified ITT for analysis of primary endpoint (omititng outlier value of one patient with in placebo group [>500% increase in edema volumen]).

    Subject analysis set title
    Modified ITT | Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified ITT for analysis of primary endpoint (omititng outlier value of one patient with in placebo group [>500% increase in edema volumen]).

    Primary: Primary endpoint | Bone marrow edeme volume

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    End point title
    		 Primary endpoint | Bone marrow edeme volume
    End point description
    The volume of the edema in cm³ is defined as biometric data measured by the use of MRI before and six weeks after treatment. Edema volume at screening was set to 100% . Edema volume six weeks after study drug administration was provided as percentage reduction compared to the value at screening.
    End point type
    Primary
    End point timeframe
    Bone marrow edema volume six weeks after administration of a single intravenous dose of zoledronic acid (5mg).
    End point values
    		 Zoledronic acid Placebo Modified ITT | Zoledronic acid Modified ITT | Placebo
    Number of subjects analysed
    34
    14
    34
    13
    Units: Percent change in volume
        arithmetic mean (standard deviation)
    64.53 ( 41.92 )
    -14.43 ( 150.46 )
    64.53 ( 41.92 )
    23.97 ( 46.52 )
    Statistical analysis title
    		 Primary endpoint | T-test
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.074 [2]
    Method
    		 t-test, 2-sided
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [1] - T-test | Satterthwaite method
    [2] - Results biased by outlier value of one patient in placebo group.
    Statistical analysis title
    		 Primary endpoint | Change in edema volumen (mITT)
    Comparison groups
    Modified ITT | Zoledronic acid v Modified ITT | Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 other [3]
    P-value
    		 = 0.006
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [3] - T-test (with mITT, omitting outlier value of one patient in placebo group)
    Statistical analysis title
    		 Primary endpoint | Mann-Whitney-Test
    Comparison groups
    Zoledronic acid v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 other [4]
    P-value
    		 = 0.007
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - Mann-Whitney-Test
    Statistical analysis title
    		 Primary endpoint | Mann-Whitney-Test (mITT)
    Comparison groups
    Modified ITT | Zoledronic acid v Modified ITT | Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 other [5]
    P-value
    		 = 0.015
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Mann-Whitney-Test

    Secondary: Secondary endpoint | Reduction of pain (VAS) - Week 3

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    End point title
    		 Secondary endpoint | Reduction of pain (VAS) - Week 3
    End point description
    Reduction of pain as measured by a visual analog scale (VAS).
    End point type
    Secondary
    End point timeframe
    Assessment at week 3.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: arbitrary units
        arithmetic mean (standard deviation)
    25.5 ( 22.7 )
    25.6 ( 24.4 )
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Reduction of pain (VAS) - Week 6

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    End point title
    		 Secondary endpoint | Reduction of pain (VAS) - Week 6
    End point description
    Reduction of pain as measured by a visual analog scale (VAS).
    End point type
    Secondary
    End point timeframe
    Assessment at week 6.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: arbitrary units
        arithmetic mean (standard deviation)
    25.0 ( 28.7 )
    38.5 ( 30.2 )
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Qualeffo-41 - Week 3

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    End point title
    		 Secondary endpoint | Qualeffo-41 - Week 3
    End point description
    Quality of life as measured by the Qualeffo-41 questionnaire - Quality of life questionnaire of the European Foundation for Osteoporosis
    End point type
    Secondary
    End point timeframe
    Assessment at week 3.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: arbitrary units
        arithmetic mean (standard deviation)
    2.1 ( 0.4 )
    2.1 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Qualeffo-41 - Week 6

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    End point title
    		 Secondary endpoint | Qualeffo-41 - Week 6
    End point description
    Quality of life as measured by the Qualeffo-41 questionnaire - Quality of life questionnaire of the European Foundation for Osteoporosis
    End point type
    Secondary
    End point timeframe
    Assessment at week 6.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: arbitrary units
        arithmetic mean (standard deviation)
    2.0 ( 0.5 )
    2.1 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Subjective estimation of medical condition (PDI) - Week 3

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    End point title
    		 Secondary endpoint | Subjective estimation of medical condition (PDI) - Week 3
    End point description
    Subjective estimation of medical condition as assessed by PDI (Pain Disability Index).
    End point type
    Secondary
    End point timeframe
    Assessment at week 3.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: arbitrary units
        arithmetic mean (standard deviation)
    14.8 ( 5.8 )
    20.5 ( 7.3 )
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Subjective estimation of medical condition (PDI) - Week 6

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    End point title
    		 Secondary endpoint | Subjective estimation of medical condition (PDI) - Week 6
    End point description
    Subjective estimation of medical condition as assessed by PDI.
    End point type
    Secondary
    End point timeframe
    Assessment at week 6.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: arbitrary units
        arithmetic mean (standard deviation)
    13.1 ( 6.0 )
    18.8 ( 7.7 )
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Number of additional medicinal visits - Week 3

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    End point title
    		 Secondary endpoint | Number of additional medicinal visits - Week 3
    End point description
    Number of additional medicinal visits until week 6.
    End point type
    Secondary
    End point timeframe
    Assessment at week 3.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: Patients with additional visits
    1
    0
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Number of additional medicinal visits - Week 6

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    End point title
    		 Secondary endpoint | Number of additional medicinal visits - Week 6
    End point description
    Number of additional medicinal visits until week 6.
    End point type
    Secondary
    End point timeframe
    Assessment at week 6.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: Patients with additional visits
    0
    0
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Number of days of illness - Week 3

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    End point title
    		 Secondary endpoint | Number of days of illness - Week 3
    End point description
    Number of days of illness assessed until week 6.
    End point type
    Secondary
    End point timeframe
    Assessment at week 3.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: Days
        arithmetic mean (standard deviation)
    1.24 ( 5.02 )
    3.00 ( 7.63 )
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Number of days of illness - Week 6

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    End point title
    		 Secondary endpoint | Number of days of illness - Week 6
    End point description
    Number of days of illness assessed until week 6.
    End point type
    Secondary
    End point timeframe
    Assessment at week 6.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: Days
        arithmetic mean (standard deviation)
    0.94 ( 4.10 )
    3.14 ( 4.10 )
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Number of aseptic bone necrosis and fatigue fractures

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    End point title
    		 Secondary endpoint | Number of aseptic bone necrosis and fatigue fractures
    End point description
    Assessemnt of number of patients with aseptic bone necrosis and/or fatigue fractures.
    End point type
    Secondary
    End point timeframe
    Baseline until end of study (week 12).
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: Number of patients
    0
    0
    No statistical analyses for this end point

    Secondary: Secondary endpoint | Changes of parameters concerning osteological values

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    End point title
    		 Secondary endpoint | Changes of parameters concerning osteological values
    End point description
    Assessment of laboratory values related to osteological values (including serum calcium, serum phosphate, serum alkaline phosphatase, gamma-GT, serum creatinine, C-reactive protein, Thyroid stimulating hormone at week 3 and week 6.
    End point type
    Secondary
    End point timeframe
    Week 3 and week 6.
    End point values
    		 Zoledronic acid Placebo
    Number of subjects analysed
    34
    14
    Units: Pts with clinical significant values (%)
    number (not applicable)
        Serum Calcium
    0
    0
        Serum Phosphate
    0
    0
        Serum Alkaline Phosphatase
    0
    0
        Gamma-GT
    0
    0
        Serum Creatinine
    0
    1
        C-reactive protein
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from time of enrollment until study completion (end of study).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Patients in this arm received zoledronic acid

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received placebo.

    Serious adverse events
    		 Zoledronic acid Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 14 (7.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Post-traumatic neck syndrome
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Zoledronic acid Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 34 (100.00%)
    11 / 14 (78.57%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Chills
         subjects affected / exposed
    8 / 34 (23.53%)
    2 / 14 (14.29%)
         occurrences all number
    8
    2
    Fatigue
         subjects affected / exposed
    10 / 34 (29.41%)
    3 / 14 (21.43%)
         occurrences all number
    11
    3
    Influenza like illness
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 14 (14.29%)
         occurrences all number
    3
    3
    Malaise
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    Pyrexia
         subjects affected / exposed
    7 / 34 (20.59%)
    1 / 14 (7.14%)
         occurrences all number
    7
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 34 (38.24%)
    5 / 14 (35.71%)
         occurrences all number
    14
    6
    Sciatica
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    2
    1
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 34 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    4
    0
    Dry mouth
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 14 (14.29%)
         occurrences all number
    2
    2
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Skin discolouration
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    11 / 34 (32.35%)
    3 / 14 (21.43%)
         occurrences all number
    11
    4
    Arthralgia
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 14 (14.29%)
         occurrences all number
    3
    2
    Back pain
         subjects affected / exposed
    4 / 34 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    4
    0
    Bone pain
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    2
    1
    Myalgia
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    0
    3
    Osteoarthritis
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    2
    2
    Rheumatic disorder
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Spinal pain
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 14 (21.43%)
         occurrences all number
    2
    3
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 14 (21.43%)
         occurrences all number
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 34 (11.76%)
    2 / 14 (14.29%)
         occurrences all number
    4
    2
    Tonsillitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1

    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.
    The originally intended primary analysis did not include outlier analysis. An outlier value in the placebo group (<500% increase in edema size) biased statistical results. Analysis was modified respecting outlier analysis.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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