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    Clinical Trial Results:
    Chronic non bacterial osteomyelitis treated with pamidronat in a randomised placebo controlled trial

    Summary
    EudraCT number
    		 2015-002038-36
    Trial protocol
    		 DK  
    Global end of trial date
    30 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 May 2020
    First version publication date
    29 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    48438
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02594878
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital, Denmark
    Sponsor organisation address
    Palle Juul-Jensens Boukevard 99, Aarhus, Denmark, 8200
    Public contact
    Caroline Marie Andreasen, Aarhus University Hospital, Department of Rheumatology, +45 7846 4252, carand@rm.dk
    Scientific contact
    Caroline Marie Andreasen, Aarhus University Hospital, Department of Rheumatology, +45 7846 4252, carand@rm.dk
    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
    30 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In a randomized double blind placebo controlled design in patients with chronic non bacterial osteomyelitis to investigate whether it is possible by treating with pamidronat to achieve a 1. Reduction of the inflammatory activity in the osteomyelytic boneproces measured by whole body MRIafter 9 months 2. Healing of the inflammatory activity in the osteomyelytic boneproces measured by whole body MRI after 9 months Full length article has been accepted for publication Scandinavian Journal of Rheumatology, Accepted January 2020.
    Protection of trial subjects
    Clinical evaluation and blood samples included laboratory screening for inflammation, renal and liver functional parameters
    Background therapy
    		 Placebo (NaCl)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    1
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    13
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Fifty-six patients were approached of whom 23 adults and one child/family provided written consent and were assessed for eligibility. Randomisation was performed in 13 of 23 adults. One child completed the study but was excluded from the analyses for methodological reasons.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 14
    Number of subjects completed
    		 14

    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
    Blinding implementation details
    The hospital pharmacy performed the randomization. Pamidronate or placebo were identically packed at the hospital pharmacy.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pamidronate
    Arm description
    		 Pamifos 3mg/ml, Medac, Hamburg, Germany
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pamifos 3mg/ml, Medac, Hamburg, Germany
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    pamidronate 1 mg pamidronate kg/day, max 60 mg, first dose first series 0.5 mg/kg, administered for three consecutive days at baseline, week 12 and week 24.

    Arm title
    		 Sodium chloride
    Arm description
    		 sodium chloride 9g/l
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride 9g/l
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    intravenous sodium chloride 9g/l

    Number of subjects in period 1
    		Pamidronate Sodium chloride
    Started
    7
    7
    Completed
    6
    7
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 14 14
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 1 1
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 13 13
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 32 (23 to 57) -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 3 3
    Subject analysis sets

    Subject analysis set title
    Data analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Randomisation was performed in 14. One patient in the pamidronate group dropped out of the study for personal reasons after the first pamidronate cycle. One child completed the study but was excluded from the analyses for methodological reasons. Analysis were performed in placebo (n=6) and IMP (pamidronatedinatrium) (n=6)

    Subject analysis sets values
    		 Data analysis
    Number of subjects
    12
    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)
    12
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    32 (23 to 57)
    Gender categorical
    Units: Subjects
        Female
    9
        Male
    3

    End points

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    End points reporting groups
    Reporting group title
    Pamidronate
    Reporting group description
    		 Pamifos 3mg/ml, Medac, Hamburg, Germany

    Reporting group title
    Sodium chloride
    Reporting group description
    		 sodium chloride 9g/l

    Subject analysis set title
    Data analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Randomisation was performed in 14. One patient in the pamidronate group dropped out of the study for personal reasons after the first pamidronate cycle. One child completed the study but was excluded from the analyses for methodological reasons. Analysis were performed in placebo (n=6) and IMP (pamidronatedinatrium) (n=6)

    Primary: Endpoints listed in table attached

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    End point title
    		 Endpoints listed in table attached
    End point description
    Primary endpoint: Changes in disease activity score of the anterior chest wall assessed by whole body magnetic resonance imaging Secondary endpoint: Changes in disease chronicity score of the anterior chest wall assessed by whole body magnetic resonance imaging Changes in disease chronicity score of the anterior chest wall assessed by computered tomography Changes in diseaseactivity score of the spine assessed by whole body magnetic resonance imaging Changes in disease chronicity score of the spine assessed by whole body magnetic resonance imaging Changes in VAS pain Changes in VAS global Changes in biomarkers of boneresorption, boneformation and inflammation
    End point type
    Primary
    End point timeframe
    Baseline and week 36
    End point values
    		 Pamidronate Sodium chloride Data analysis
    Number of subjects analysed
    6
    6
    12 [1]
    Units: variable
        arithmetic mean (standard deviation)
    2.3 ± 1.5
    0 ± 2.3
    1 ± 1
    Attachments
    		 Results CNOPAM
    Notes
    [1] - See reuslts attached
    Statistical analysis title
    		 See results attached
    Comparison groups
    Pamidronate v Sodium chloride v Data analysis
    Number of subjects included in analysis
    24
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Assessment of AE was performed at week 1,4,12,24 and week 36 and if an extra visit was acquired.
    Adverse event reporting additional description
    Reporting of all adverse event follows The European Commission and Danish law: ”Guidelines on medical devices. Clinical investigations: Serious adverse event reporting” MEDDEV 2.7/3.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MEDDEV 2.7
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Adverse events
    Reporting group description
    		 Non- serious adverse events were reported in the pamidronate group/placebo group were: gastrointestinal symptoms (n=1/2), aching joints (n=2/1), flu-like symptoms (n=3/1), headache (n=5/1), mild hypophosphatemia (n=1/0), mild hypocalcaemia (n=1/0) and phlebitis in cubitalis vein (n=1/1). Adverse events were mainly seen following the first treatment cycle.

    Serious adverse events
    		 Adverse events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Adverse events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    General disorders and administration site conditions
    Specified below
    Additional description: Non- serious adverse events were reported in the pamidronate group/placebo group: gastrointestinal symptoms (n=1/2), tender joints (n=2/1), flu-like symptoms (n=3/1), headache (n=5/1), mild hypophosph (n=1/0), mild hypocalcaemi (n=1/0)
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    6

    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.
    Due to recruitment challenges, only 12 adults and one child completed the study and because of inadequate sample size the study was a posteriori converted to a pilot study. The child was excluded from analyses for methodological reasons.
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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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