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    Clinical Trial Results:
    A pilot Phase I/IIa, multicentre, open proof-of-concept study on the efficacy and safety of allogeneic osteoblastic cells (ALLOB®) implantation in non-infected delayed-union fractures

    Summary
    EudraCT number
    		 2012-005333-36
    Trial protocol
    		 BE   GB   DE  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2020
    First version publication date
    15 Mar 2020
    Other versions
    Summary report(s)
    		 ALLOB-DU1 synopsis study report

    Trial information

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    Trial identification
    Sponsor protocol code
    ALLOB-DU1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02020590
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bone Therapeutics S.A.
    Sponsor organisation address
    Auguste Piccard 37, Gosselies, Belgium, 6041
    Public contact
    Clinical Trial Information, Bone Therapeutics S.A., allob.du1@bonetherapeutics.com
    Scientific contact
    Clinical Trial Information, Bone Therapeutics S.A., allob.du1@bonetherapeutics.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
    Interim
    Date of interim/final analysis
    11 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jan 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the main study is to assess the safety and efficacy of ALLOB® single percutaneous implantation in healing delayed-union fractures at the end of the study period (Month 6). Safety: Subjects will be systematically assessed for the potential occurrence of any AE or SAE, related to the product or related to the procedure, using patient open questionnaires, physical examination, (including vital signs), and laboratory measurements. Efficacy: The success will be based on the percentage of treated patients (ALLOB®) not failing under treatment. A patient will be considered as failed under a treatment if, at the end of the study period (Month 6), the patient had required a rescue surgery or the Global Disease Evaluation score (VAS) as perceived by the patient has not improved by at least 25% and the TUS as assessed by CT scan has not increased by at least two points (versus baseline).
    Protection of trial subjects
    For the first 16 patients, the patient recruitment was proceeded stepwise by blocks of 4. Full first 2 weeks safety data of the first block of 4 patients was analysed before the first patient of the second block of 4 patients was treated. First 48 hours safety data of the second block of 4 patients was analysed before treating the first patient of the next block. This latter scheme was repeated until the first 16 patients was treated. A Data Safety Monitoring Board (DSMB) was established to assess the safety and efficacy when 6-month post treatment results for the first 16 assessable patients was available (i.e., interim analysis). This Board recommended to the Sponsor whether to stop the trial for efficacy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Feb 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Germany: 10
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    21
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 recruitment period: 17 February 2014 - 30 January 2018 countries: Belgium and Germany

    Pre-assignment
    Screening details
    		 Patient diagnosed with a non-infected delayed-union fracture of a long bone of minimum 3 months and maximum 7 months (± 2 weeks)without signs of healing over the last 4 weeks at the time of screening Modified Radiographic Union Score (mRUS) < 10 Global Disease Evaluation Score as assessed by the patients.

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

    Arms
    Arm title
    		 active treatment
    Arm description
    		 active treatment with ALLOB single injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALLOB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Percutaneous use
    Dosage and administration details
    25X10^6 cell/ml (2-4 ml) administered percoutaneously into the delayed union site

    Number of subjects in period 1
    		active treatment
    Started
    25
    Completed
    22
    Not completed
    3
         Consent withdrawn by subject
    1
         Protocol deviation
    2
    Period 2
    Period 2 title
    final efficacy analysis
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 active treatment
    Arm description
    		 active treatment with ALLOB
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALLOB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Percutaneous use
    Dosage and administration details
    25X10^6 cell/ml (2-4 ml) administered percoutaneously into the delayed union site

    Number of subjects in period 2
    		active treatment
    Started
    22
    Completed
    21
    Not completed
    1
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    active treatment
    Reporting group description
    		 active treatment with ALLOB single injection

    Reporting group values
    		 active treatment Total
    Number of subjects
    		 25 25
    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)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 22 22
        From 65-84 years
    		 3 3
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 16 16
    Subject analysis sets

    Subject analysis set title
    per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    21 subjects were included in the per protocol population

    Subject analysis set title
    safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    22 subjects were included in the safety analysis

    Subject analysis sets values
    		 per protocol safety population
    Number of subjects
    21
    22
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    19
    19
        From 65-84 years
    2
    3
        85 years and over
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    8
    9
        Male
    13
    13

    End points

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    End points reporting groups
    Reporting group title
    active treatment
    Reporting group description
    		 active treatment with ALLOB single injection
    Reporting group title
    active treatment
    Reporting group description
    		 active treatment with ALLOB

    Subject analysis set title
    per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    21 subjects were included in the per protocol population

    Subject analysis set title
    safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    22 subjects were included in the safety analysis

    Primary: Percentage of responders at 6 months (efficacy of ALLOB)

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    End point title
    		 Percentage of responders at 6 months (efficacy of ALLOB)
    End point description
    The efficacy of ALLOB® will be evaluated at Month 6. The success of the study will be based on the percentage of treated patients (ALLOB®) not failing under treatment. A patient will be considered as failed under treatment if, at Month 6: - He/she had a rescue surgery Or - The Global Disease Evaluation score (VAS) as perceived by the patient has not improved by at least 25% and the TUS as assessed by CT scan has not increased by at least two points (versus baseline).
    End point type
    Primary
    End point timeframe
    At 6-months after treatment
    End point values
    		 active treatment per protocol
    Number of subjects analysed
    21
    21
    Units: percentage
    21
    21
    Statistical analysis title
    		 2-stage fleming method design
    Statistical analysis description
    According to the Schoenfeld approach (Schoenfeld et al., 1980), for the efficacy analysis, the type I error rate will be increased from the usual 5% to the 10% rate. Indeed, in this pilot single arm “proof of concept” study, it is appropriate to maintain the power and increase the type I error rate. This increases the risk of erroneously concluding that the treatment is worthy of further investigation, but does not increase the risk of missing an efficacious treatment. So in this phase II study,
    Comparison groups
    active treatment v per protocol
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 5
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 One single treatment arm
    Confidence interval
         level
    		 90%

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From ICF signature till end of long-term safety follow-up (24 months after the end of the study)
    Adverse event reporting additional description
    questionnaire submitted to subjects during on site visits and phone calls
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    active treatment
    Reporting group description
    		 active treatment with ALLOB single injection

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Display of non-serious AEs will be encoded at a later stage
    Serious adverse events
    		 active treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 22 (9.09%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Skin and subcutaneous tissue disorders
    angioedema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    urticaria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    implant site infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 active treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)

    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? Yes
    Date
    Interruption
    Restart date
    20 Sep 2017
    trial prematurely stoped for efficacy reason, based on the positive results of the planned Interim Analysis.
    -

    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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    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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