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    Clinical Trial Results:
    Zoledronate against fractures in children with cerebral palsy

    Summary
    EudraCT number
    		 2014-002118-21
    Trial protocol
    		 DK  
    Global end of trial date
    01 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Feb 2025
    First version publication date
    11 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CPZOL
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Regional health research ethics application number: 1-10-72-204-14
    Sponsors
    Sponsor organisation name
    Randers Regional Hospital
    Sponsor organisation address
    Oestervangsvej 70, Randers NE, Denmark, 8930
    Public contact
    Research Unit, Randers Regional Hospital, 45 7842 0172, zol.mod.brud@gmail.com
    Scientific contact
    Research Unit, Randers Regional Hospital, 45 7842 0172, zol.mod.brud@gmail.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of 12 months treatment with i.v. zoledronic acid on bone mineralization in children with non-ambulatory cerebral palsy.
    Protection of trial subjects
    Local analgesia as needed for intravenous access. Comfortable position in bed during exams and treatments. Paracetamol and dietary supplements of vitamin D and calcium to avoid post-infusion side effects.
    Background therapy
    		 Vitamin D and calcium supplements recommended.
    Evidence for comparator
    		 The comparator was infusion of physiological saline solution which has no effect and is safe to infuse.
    Actual start date of recruitment
    01 Aug 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    14
    Adolescents (12-17 years)
    10
    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
    		 Participants were included from September 2017 to March 2020 (both inclusive). Subjects were recruited from 5 pediatric departments in Denmark (Aalborg, Viborg, Randers, Aarhus, and Herning)

    Pre-assignment
    Screening details
    		 Exclusion criteria were having osteotomy planned between 48 hours before and 4 months after each dose of ZOL, p-25-dihydroxy-vitamin D3 below 50 nmol/L, diagnosis of a bone metabolic disease, alanine transaminase above 90 U/L, INR above 1.3, creatinine above 90 µmol/L, or any contraindication to zoledronate treatment

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Numbered, sealed packages of active drug (5 mL of ZOL and 100 mL of 0.9% saline) or placebo (5 mL of 0.9% saline and 100 mL of 0.9% saline) were pre- pared by the AUH Pharmacy and used during the first study visit in the numbered order for each consecutive, included participant. All statistical analyses were performed before the study was unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronate
    Arm description
    		 Subjects receiving active drug (Zoledronate)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronate
    Investigational medicinal product code
    SUB00176MIG
    Other name
    zol, CAS number 118072-93-8
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Less than 60 minutes prior to each infusion, the study drug or placebo was mixed with saline by an unblinded nurse or doctor (not otherwise involved in the study) and the appropriate dose per kilogram body weight was infused by a blinded nurse or doctor over 30 minutes. Doses of active medication were 0.025 mg/kg and 0.05 mg/kg ZOL (maximum 2.5 mg) for first and second doses, respectively.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    natriumchlorid in sterile water, NaCl
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Less than 60 minutes prior to each infusion, the study drug or placebo was mixed with saline by an unblinded nurse or doctor (not otherwise involved in the study) and the appropriate dose per kilogram body weight was infused by a blinded nurse or doctor over 30 minutes.

    Number of subjects in period 1
    		Zoledronate Placebo
    Started
    14
    10
    Completed
    14
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zoledronate
    Reporting group description
    		 Subjects receiving active drug (Zoledronate)

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Zoledronate Placebo Total
    Number of subjects
    		 14 10 24
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Median age, years (range)
    Units: years
        median (full range (min-max))
    		 10.9 (6.0 to 17.1) 10.7 (8.3 to 16.5) -
    Gender categorical
    Female (%)
    Units: Subjects
        Female
    		 7 5 12
        Male
    		 7 5 12
    GMFCS level
    GMFCS level IV/V
    Units: Subjects
        GMFCS level IV
    		 8 5 13
        GMFCS level V
    		 6 5 11
    Prior fracture
    Subject with a prior fracture before inclusion
    Units: Subjects
        Yes
    		 2 4 6
        No
    		 12 6 18
    Vitamin D
    Vitamin D at entry
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 89 ( 20.4 ) 87 ( 18.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Zoledronate
    Reporting group description
    		 Subjects receiving active drug (Zoledronate)

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Lumbar Spine and Lateral Distal Femur BMD Z-score change

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    End point title
    		 Lumbar Spine and Lateral Distal Femur BMD Z-score change
    End point description
    The primary end points of the trial were the LS and LDF BMD Z-score changes from the 0- to 12-month visits. DXA scans were performed at AUH Osteoporosis Clinic at visits 1 and 3 using the same Hologic DXA machine (Hologic Horizon A [S/N 100100, fan beam], software version 13.6.0.5:3) for all scans.
    End point type
    Primary
    End point timeframe
    from the 0- to 12-month visits
    End point values
    		 Zoledronate Placebo
    Number of subjects analysed
    14
    10
    Units: Z-score change
    arithmetic mean (standard deviation)
        Lumbar Spine change
    0.83 ( 0.59 )
    0.02 ( 0.26 )
        R1 of the Lateral Distal Femur change
    1.55 ( 1.44 )
    0.85 ( 1.15 )
        R2 of the Lateral Distal Femur change
    0.83 ( 1.28 )
    -0.82 ( 1.77 )
        R3 of the Lateral Distal Femur change
    0.34 ( 0.46 )
    -0.11 ( 0.55 )
    Attachments
    		 Untitled (Filename: barzscores.pdf)
    Statistical analysis title
    		 Student t test (unpaired)
    Statistical analysis description
    Student t test (unpaired) after checking for Gaussian distributions
    Comparison groups
    Zoledronate v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.012 [2]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - An intention-to-treat approach was adopted for all analyses and statistical analyses were performed using STATA statistical software (Stata/SE 17.0 for Mac (Intel 64-bit), revision 23 Aug 2022, StataCorp LLC) whereas GraphPad Prism (Prism 9 for macOS, version 9.4.1 (458), July 18, 2022) was used for graphs of bloodwork results.
    [2] - R1 change 0..213 R2 change 0.014 R3 change 0.045 LS change 0.012

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion to last visit. All subjects were included and had last visits within the period September 2017 to February 2022, both included
    Adverse event reporting additional description
    Self-reporting by subjects families and care-takers.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Zoledronate
    Reporting group description
    		 Subjects receiving active drug (Zoledronate)

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Zoledronate Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Endocrine disorders
    Hypocalcaemia
    Additional description: 1 patient was admitted due to hypocalcemia with drowsiness and shivering, no further symptoms were observed and the patient was discharged.
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (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
    		 Zoledronate Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 10 (0.00%)
    Endocrine disorders
    Hypocalcaemia
    Additional description: asymptomatic hypocalcemia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Acidosis
    Additional description: Asymptomatic acidosis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0

    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.
    Not all primary end points were measurable in all subjects. The planned sample size of 52 subjects total was not reached.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37235798
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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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