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    Clinical Trial Results:
    Translational therapy in patients with Osteogenesis imperfecta - a pilot trial on treatment with the RANKL-antibody Denosumab

    Summary
    EudraCT number
    2012-002887-29
    Trial protocol
    DE  
    Global end of trial date
    26 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jan 2021
    First version publication date
    06 Jan 2021
    Other versions
    Summary report(s)
    OI-AK_summary

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-1574
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Cologne, Germany, 50923
    Public contact
    Klinisches Studienzentrum Pädiatrie, Children's Hospital of the University of Cologne, +49 2214784361, joerg.semler@uk-koeln.de
    Scientific contact
    Klinisches Studienzentrum Pädiatrie, Children's Hospital of the University of Cologne, +49 2214784361, joerg.semler@uk-koeln.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
    26 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Pilot study to assess the safety and efficacy of a therapy with the RANKL-antibody Denosumab in children 5-10 years of age with mutation in COL1A1 or COL1A2 leading to a defect in collagen production (Osteogenesis imperfecta). Efficacy will be assessed by DXA measurements at the lumbar spine (BMD).
    Protection of trial subjects
    The trial was conducted according to Good Clinical Practice guidelines, the applicable local laws, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The competent authorities approved the trial as required by national regulations. Regulatory authorities were notified of the trial and amendments as required by national regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jan 2013
    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: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    10
    Adolescents (12-17 years)
    0
    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
    -

    Pre-assignment
    Screening details
    11 patients were screened into the trial (The screening period was defined as week -12 until week 0 (baseline). Patients who met all in- and exclusion criteria were enrolle (n=10) and received the investigational medicinal product

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

    Arms
    Arm title
    Denosumab
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    Other name
    Prolia
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1mg/kg body weight in 3-monthly intervals

    Number of subjects in period 1
    Denosumab
    Started
    10
    Completed
    10

    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
    10 10
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    7 (5.02 to 10.96) -
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    7 7

    End points

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    End points reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    -

    Subject analysis set title
    baseline-BMD (g/cm2)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    xxx

    Subject analysis set title
    48h-BMD (g/cm2)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    xxx

    Primary: Changes in bone mineral density (BMD)

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    End point title
    Changes in bone mineral density (BMD)
    End point description
    Changes of bone mineral density (BMD [g/cm2]) in study week 48 of the lumbar vertebrae L2-L4 after 36 weeks of treatment with denosumab compared to baseline
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    Denosumab baseline-BMD (g/cm2) 48h-BMD (g/cm2)
    Number of subjects analysed
    10
    10
    10
    Units: g/cm²
        arithmetic mean (confidence interval 95%)
    0.1 (0.06 to 0.15)
    0.5070 (0.3912 to 0.6228)
    0.6118 (0.4696 to 0.7540)
    Statistical analysis title
    xx
    Statistical analysis description
    Add text from CSR
    Comparison groups
    48h-BMD (g/cm2) v baseline-BMD (g/cm2)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.05 [2]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    90
         upper limit
    99
    Variability estimate
    Standard deviation
    Dispersion value
    1
    Notes
    [1] - not mandatory
    [2] - xx

    Primary: Changes in bone mineral density (BMD): Z-score

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    End point title
    Changes in bone mineral density (BMD): Z-score [3]
    End point description
    BMD lumbar vertebrae L2-L4 Z-score. Z-score: Age-dependent standard deviation
    End point type
    Primary
    End point timeframe
    48 weeks after baseline
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: For the statistical analysis of the primary endpoint, please refer to the attached summary report.
    End point values
    Denosumab
    Number of subjects analysed
    10
    Units: standard deviation score
        arithmetic mean (confidence interval 95%)
    0.96 (0.597 to 1.323)
    No statistical analyses for this end point

    Secondary: Osteoclastic activity-DPD

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    End point title
    Osteoclastic activity-DPD
    End point description
    DPD: Deoxypyridinolin
    End point type
    Secondary
    End point timeframe
    Week 0 (baseline) and week 48 weeks
    End point values
    Denosumab
    Number of subjects analysed
    10
    Units: µg/g
    arithmetic mean (standard deviation)
        baseline
    189.700 ± 71.294
        week 48
    237.600 ± 95.539
    No statistical analyses for this end point

    Secondary: Mobility of patients-Walking

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    End point title
    Mobility of patients-Walking
    End point description
    Mobility of patients: Walking 1 and 6 minute walking test
    End point type
    Secondary
    End point timeframe
    change from baseline to 48h
    End point values
    Denosumab
    Number of subjects analysed
    7 [4]
    Units: meters
    arithmetic mean (confidence interval 95%)
        1 minute walking
    11 (-3.633 to 25.63)
        6 minutes walking
    48.7 (18.561 to 78.773)
    Notes
    [4] - 7 for 1 minute and 6 for 6 minutes
    No statistical analyses for this end point

    Secondary: Morphometry of spine-anterior-posterior index

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    End point title
    Morphometry of spine-anterior-posterior index
    End point description
    Morphometry of spine anterior-posterior index
    End point type
    Secondary
    End point timeframe
    baseline and 48 weeks
    End point values
    Denosumab
    Number of subjects analysed
    8
    Units: (1-ah/ph)*100
    arithmetic mean (standard deviation)
        Baseline
    -16.18 ± 41.46
        Week 48
    -4.475 ± 14.67
    No statistical analyses for this end point

    Secondary: Morphometry of spine-concavity index

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    End point title
    Morphometry of spine-concavity index
    End point description
    Morphometry of spine-concavity index
    End point type
    Secondary
    End point timeframe
    baseline and week 48
    End point values
    Denosumab
    Number of subjects analysed
    8
    Units: (1-mh/ah)*100
    arithmetic mean (standard deviation)
        Baseline
    5.436 ± 25.7
        Week 48
    7.332 ± 23.96
    No statistical analyses for this end point

    Secondary: Mobility of patients-GMFM88

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    End point title
    Mobility of patients-GMFM88
    End point description
    GMFM= Gross Motor Function Measure
    End point type
    Secondary
    End point timeframe
    changes from baseline to 48 hours
    End point values
    Denosumab
    Number of subjects analysed
    9
    Units: percent
        arithmetic mean (confidence interval 95%)
    2.722 (0.8253 to 6.27)
    No statistical analyses for this end point

    Secondary: Changes of bone mineral density (BMD)-total without head

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    End point title
    Changes of bone mineral density (BMD)-total without head
    End point description
    End point type
    Secondary
    End point timeframe
    change in value between week 48 and baseline
    End point values
    Denosumab
    Number of subjects analysed
    9
    Units: g/cm²
        arithmetic mean (confidence interval 95%)
    0.049 (-0.0005 to 0.099)
    No statistical analyses for this end point

    Secondary: Changes of bone mineral density (BMD)-total without head

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    End point title
    Changes of bone mineral density (BMD)-total without head
    End point description
    End point type
    Secondary
    End point timeframe
    change in value 48 weeks after baseline
    End point values
    Denosumab
    Number of subjects analysed
    9
    Units: Z-score
        arithmetic mean (confidence interval 95%)
    0.566 (0.30738 to 0.8259)
    No statistical analyses for this end point

    Secondary: BMC total body withour head

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    End point title
    BMC total body withour head
    End point description
    BMC: bone mineral content
    End point type
    Secondary
    End point timeframe
    change in value 48 weeks after baseline
    End point values
    Denosumab
    Number of subjects analysed
    10
    Units: gram(s)
        arithmetic mean (confidence interval 95%)
    85 (36 to 134)
    No statistical analyses for this end point

    Secondary: Osteoclastic activity-Calcium

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    End point title
    Osteoclastic activity-Calcium
    End point description
    End point type
    Secondary
    End point timeframe
    baseline (week 0) and 48 weeks
    End point values
    Denosumab
    Number of subjects analysed
    10
    Units: mmol/l
    arithmetic mean (standard deviation)
        baseline
    2.440 ± 0.080
        week 48
    2.568 ± 0.124
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were reported from inclusion of patients into the study (signature of informed consent).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    -

    Serious adverse events
    Denosumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Surgical and medical procedures
    Interne Fixatur einer Fraktur
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Denosumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    Injury, poisoning and procedural complications
    Fraktur des Schluesselbeins
    Additional description: Clavicle fracture
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    2
    Obeschenkelfraktur
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    4
    Sturz
    Additional description: fall
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Tibiafraktur
    Additional description: Tibia fracture
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Investigations
    Kalzium im Blut erniedrigt
    Additional description: Calcium ionised decreased
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    2
    Surgical and medical procedures
    Operation am Penis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Husten
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Lymphadenopathie
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Nasenverstopfung
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Schmerzen im Oropharynx
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Symptom einer allergischen Erkrankung
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Nervous system disorders
    Erniedrigter Muskeltonus
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fieber
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    4
    Gastrointestinal disorders
    Abdominalschmerz
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Diarrhoe
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Erbrechen
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    5
    Funktionsstoerung des Gastrointestinaltrakts
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gaumenerkrankung
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Ausschlag mit Juckreiz
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgie
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    7
    Brustschmerzen die Skelettmuskulatur betreffend
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gelenkschwellung
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gliederbeschwerden
    Additional description: Limb discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Muskelspasmen
    Additional description: Muscle spasms
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Rückenschmerzen
    Additional description: Back pain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Schmerz in einer Extremitaet
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    4
    Wachstumsschmerzen
    Additional description: Growing pains
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Appetit vermindert
    Additional description: Decreased appetite
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Hand-Fuß-Mund Krankheit
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Infektion
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Infektion der oberen Atemwege
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    5
    Nasopharyngitis
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    3
    Streptokokken-Infektion
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    2
    Virusinfektion
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    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.
    None reported
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