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    Clinical Trial Results:
    Phase III, pivotal, multicentre, randomised, double-blind controlled Study to evaluate the Efficacy and Safety of Autologous Osteoblastic Cells (PREOB®) Implantation in Early Stage Non Traumatic Osteonecrosis of the Femoral Head

    Summary
    EudraCT number
    		 2009-012929-11
    Trial protocol
    		 BE   DE   GB  
    Global end of trial date
    04 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jul 2020
    First version publication date
    19 Jul 2020
    Other versions
    Summary report(s)
    		 summary clinical study report

    Trial information

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    Trial identification
    Sponsor protocol code
    PREOB-ON3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01529008
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bone Therapeutics S.A.
    Sponsor organisation address
    rue Auguste Piccard, Gosselies, Belgium,
    Public contact
    Clinical Trial Information, Bone Therapeutics S.A., clinicaltrials@bonetherapeutics.com
    Scientific contact
    Clinical Trial Information, Bone Therapeutics S.A., clinicaltrials@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
    Final
    Date of interim/final analysis
    26 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study objectives are to demonstrate that Core decompression/PREOB® implantation is superior to Core decompression/Placebo implantation in relieving clinical hip symptoms and halting (or reverting) radiological progression (to fractural stages III or higher) at 24 months. Patients will be assessed using the Western Ontario and McMaster Universities (WOMAC®) Index. Central radiological evaluation will include conventional bilateral X-ray and MRI of the hips to assess ARCO Staging and to measure the sum of the coronal and sagittal necrotic angles.
    Protection of trial subjects
    no specific trial subjects protection was in place
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2011
    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
    Netherlands: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Belgium: 25
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    France: 23
    Worldwide total number of subjects
    68
    EEA total number of subjects
    68
    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)
    67
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 recruitment between 2011 and 2018 in Belgium, Germany, France, The Netherlands andUnited Kingdom

    Pre-assignment
    Screening details
    		 Men and women, aged 18 to 70 years old, diagnosed with non-fractural (ARCO stages I or II) non traumatic osteonecrosis of the femoral head, confirmed by conventional X-ray and magnetic resonance imaging (MRI). All patients had to be symptomatic, except ARCO stage II patients.

    Period 1
    Period 1 title
    screening
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PREOB
    Arm description
    		 PREOB injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    PREOB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    20 X 10^6 cells in 5 ml

    Arm title
    		 Placebo
    Arm description
    		 placebo injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    phosphate buffer saline and human serum albumine in a total volume of 5 ml

    Number of subjects in period 1
    		PREOB Placebo
    Started
    35
    33
    Completed
    35
    33
    Period 2
    Period 2 title
    bone marrow harvesting
    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
    		 PREOB
    Arm description
    		 PREOB injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    PREOB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    20 X 10^6 cells in 5 ml

    Arm title
    		 Placebo
    Arm description
    		 placebo injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    phosphate buffer saline and human serum albumine in a total volume of 5 ml

    Number of subjects in period 2
    		PREOB Placebo
    Started
    35
    33
    Completed
    34
    30
    Not completed
    1
    3
         Physician decision
    1
    1
         Consent withdrawn by subject
    -
    2
    Period 3
    Period 3 title
    treatment
    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
    		 PREOB
    Arm description
    		 PREOB injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    PREOB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    20 X 10^6 cells in 5 ml

    Arm title
    		 Placebo
    Arm description
    		 placebo injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    phosphate buffer saline and human serum albumine in a total volume of 5 ml

    Number of subjects in period 3
    		PREOB Placebo
    Started
    34
    30
    Completed
    25
    29
    Not completed
    9
    1
         Adverse event, non-fatal
    6
    -
         not specified
    3
    1
    Period 4
    Period 4 title
    efficacy analysis
    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
    		 PREOB
    Arm description
    		 PREOB injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    PREOB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    20 X 10^6 cells in 5 ml

    Arm title
    		 Placebo
    Arm description
    		 placebo injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraosseous use
    Dosage and administration details
    phosphate buffer saline and human serum albumine in a total volume of 5 ml

    Number of subjects in period 4
    		PREOB Placebo
    Started
    25
    29
    Completed
    23
    26
    Not completed
    2
    3
         Consent withdrawn by subject
    -
    2
         Physician decision
    -
    1
         major protocol deviations
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PREOB
    Reporting group description
    		 PREOB injection

    Reporting group title
    Placebo
    Reporting group description
    		 placebo injection

    Reporting group values
    		 PREOB Placebo Total
    Number of subjects
    		 35 33 68
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 35 32 67
        From 65-84 years
    		 0 1 1
    Gender categorical
    Units: Subjects
        Female
    		 8 7 15
        Male
    		 27 26 53
    Subject analysis sets

    Subject analysis set title
    per protocol
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    included all randomised and treated patients (i.e., patients with both (i) core decompression and (ii) PREOB® or Placebo implantation), with a baseline value available for both the ARCO stage and the WOMAC® pain subscale score, and at least one post-baseline value available for both the ARCO stage and the WOMAC® pain subscale score for the study treated hip and whose eligibility was confirmed after adjudication. These analyses on randomized and treated patients were performed according to the randomisation group regardless of the IMP actually received.

    Subject analysis sets values
    		 per protocol
    Number of subjects
    49
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    48
        From 65-84 years
    1
    Age continuous
    Units: years
        
    ±
    Gender categorical
    Units: Subjects
        Female
    8
        Male
    41

    End points

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    End points reporting groups
    Reporting group title
    PREOB
    Reporting group description
    		 PREOB injection

    Reporting group title
    Placebo
    Reporting group description
    		 placebo injection
    Reporting group title
    PREOB
    Reporting group description
    		 PREOB injection

    Reporting group title
    Placebo
    Reporting group description
    		 placebo injection
    Reporting group title
    PREOB
    Reporting group description
    		 PREOB injection

    Reporting group title
    Placebo
    Reporting group description
    		 placebo injection
    Reporting group title
    PREOB
    Reporting group description
    		 PREOB injection

    Reporting group title
    Placebo
    Reporting group description
    		 placebo injection

    Subject analysis set title
    per protocol
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    included all randomised and treated patients (i.e., patients with both (i) core decompression and (ii) PREOB® or Placebo implantation), with a baseline value available for both the ARCO stage and the WOMAC® pain subscale score, and at least one post-baseline value available for both the ARCO stage and the WOMAC® pain subscale score for the study treated hip and whose eligibility was confirmed after adjudication. These analyses on randomized and treated patients were performed according to the randomisation group regardless of the IMP actually received.

    Primary: primary endpoint

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    End point title
    		 primary endpoint
    End point description
    Treatment Responders for the Study Treated Hip at Month 24
    End point type
    Primary
    End point timeframe
    Month 24
    End point values
    		 PREOB Placebo
    Number of subjects analysed
    23
    26
    Units: patients
    number (not applicable)
        treatment responder
    14
    18
    Statistical analysis title
    		 primary efficacy analysis
    Statistical analysis description
    Pearson’s Chi-Square test / Fisher’s exact test
    Comparison groups
    PREOB v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Pearson’s Chi-Square test / Fisher’s exa
    Parameter type
    		 absolute difference
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were defined as treatment-emergent (TEAEs) only when they occurred following core decompression/IMP implantation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    PREOB
    Reporting group description
    		 PREOB injection

    Reporting group title
    Placebo
    Reporting group description
    		 placebo injection

    Serious adverse events
    		 PREOB Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 25 (64.00%)
    18 / 29 (62.07%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    7 / 25 (28.00%)
    14 / 29 (48.28%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 PREOB Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 25 (76.00%)
    19 / 29 (65.52%)
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 25 (76.00%)
    19 / 29 (65.52%)
         occurrences all number
    19
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2017
    change of the statistical method

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    05 Jun 2018
    manufacturing technical issuses
    -

    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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