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    Summary
    EudraCT Number:2009-012929-11
    Sponsor's Protocol Code Number:PREOB-ON3
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-11-19
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2009-012929-11
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.3.2Name or abbreviated title of the trial where available
    PREOB-ON3
    A.4.1Sponsor's protocol code numberPREOB-ON3
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBone Therapeutics S.A.
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBone Therapeutics S.A.
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBone Therapeutics S.A.
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street AddressRue Auguste Piccard, 37
    B.5.3.2Town/ cityGosselies
    B.5.3.3Post code6041
    B.5.3.4CountryBelgium
    B.5.6E-mailpreob.on3@bonetherapeutics.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/07/490
    D.3 Description of the IMP
    D.3.1Product namePREOB®
    D.3.2Product code PREOB®
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraosseous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPREOB® cells
    D.3.9.2Current sponsor codePREOB® cells
    D.3.10 Strength
    D.3.10.1Concentration unit ml millilitre(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.10E6 cells
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Yes
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberit has been classified as somatic cell therapy product by EMA on May 24, 2007 (before the release of Regulation 1394/2007 that defines Tissue-Engineered product).
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSuspension for injection
    D.8.4Route of administration of the placeboIntraosseous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Osteonecrosis of the Femoral Head
    E.1.1.1Medical condition in easily understood language
    Osteonecrosis of the Femoral Head
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10031264
    E.1.2Term Osteonecrosis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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 (ARCO III or higher) in patients with non-traumatic early stage osteonecrosis of the femoral head, 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 bilateral MRI of the hips to assess the ARCO staging and to measure the sum of the coronal and sagittal necrotic angles.
    E.2.2Secondary objectives of the trial
    Exploratory Endpoints include
    • Change from baseline of the size of the necrotic lesion of the study treated hip, as assessed by MRI at Month 6, 12 and 24
    • Absolute change from baseline in WOMAC® VA3.1 total score and composite pain, stiffness, and function subscale scores of contralateral hip (i.e., the hip contralateral to the study treated hip) at Month 1, 3, 6, 12, 18 and 24, and over the 24-month follow-up period
    • Radiological evolution of contralateral hip (i.e., the hip contralateral to the study treated hip) as assessed by conventional X-ray at Month 6, 12, 18 and 24 and by MRI at Month 6, 12 and 24
    • Percentage of patients requiring hip arthroplasty on contralateral hip (i.e., the hip contralateral to the study treated hip) at Month 1, 3, 6, 12, 18 and 24
    • Assessment of serum biomarkers at Day +1 after IMP implantation, Month 1 and 6 (as applicable)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men or women between 18 and 70 years (inclusive)
    2. Ability to provide a written, dated, and signed informed consent prior to any study related procedure and to understand and comply with study requirements
    3.Diagnosis of Osteonecrosis:
    a.ARCO stage I associated with WOMAC® VA3.1 pain score ≥20 mm and necrotic angle sum ≥190° based on sagittal and coronal MRI views
    or
    b.ARCO stage II associated with WOMAC® VA3.1 pain score ≥20 mm if necrotic angle sum <190°
    based on sagittal and coronal MRI views
    or
    c.ARCO stage II associated or not with pain if necrotic angle sum is ≥190° based on sagittal and coronal MRI views
    d.Associated with corticosteroid and/or with alcohol abuse and/or idiopathic.
    4.Normal haematology function, defined as: leukocytes ≥3000/mm3, absolute neutrophils count ≥1500/mm3, platelets ≥140,000/mm3, and haemoglobin concentration ≥10g/dl (peripheral blood test)
    E.4Principal exclusion criteria
    1.Exclusively diaphyseal or metaphyseal osteonecrotic lesion
    2.Traumatic or hyperbaric osteonecrosis, or osteonecrosis associated with hemoglobinopathy or coagulopathy (e.g., thalassemia, sickle cell disease,…), or Gaucher’s disease
    3.Osteoarthritis at the hip under evaluation defined as Kellgrens stage ≥2, as assessed by the Central Radiologist
    4.Patients suffering from any medical conditions interfering with patient’s pain evaluation of the hip under evaluation, such as knee arthritis.
    5.Bone fracture or bone infection at hip under evaluation.
    6.Patients who are candidates for any predictable joint replacement on the hip that is evaluated
    7.Blood not qualifying for PREOB® production, including active hepatitis B (defined as positive HBs Ag and/or positive PCR), or active hepatitis C (defined as positive PCR), positive serology for HIV, or Syphilis, or HTLV-1, and any other tests that may be required by the authorities in case of a new disease outbreak that can affect the safety of the physicians and operators at the time of patient screening.
    8.Presence, or previous history, of risks factors for diseases caused by prions, and recipients of grafts of cornea, sclera, and dura mater
    9.History of blood loss exceeding 450 ml (incl. donations) within 1 month of screening
    10.Renal impairment defined by an estimated creatinine clearance value < 30 ml per min, calculated with the Cockcroft-Gault formula
    11.Hepatic impairment, defined as alanine aminotransferase or aspartate aminotransferase ≥ 3 times the upper limit of normal
    12.Poorly controlled diabetes mellitus, defined as HbA1C > 9%
    13.Global sepsis
    14.Allergy to gentamicin or any substance or device the patient might be exposed to in the context of the study related interventions (i.e., bone marrow harvesting and implantation), as judged by the Investigator
    15. History of hypersensitivity to human biological material, including blood and blood derived products, documented clinically or by laboratory tests
    16.Current or past history of solid or haematological neoplasia (except for basal cell carcinoma of the skin and for carcinoma in situ of the cervix that has been treated with no evidence of recurrence)
    17.History of bone marrow transplantation
    18.Patients with a life expectancy less than 2 years, as judged by the Investigator
    19.Patients treated by core decompression of the hip under evaluation within 6 months of screening
    20.Treatment with doses of prednisolone ≥15 mg per day (or equivalent) within 1 month from screening, and patients with anticipated needs of daily corticoid doses ≥15 mg prednisone (or equivalent) in the 6-month period following PREOB®/Placebo implantation
    21.Illicit drug or alcohol abuse interfering with patient’s ability to understand and comply with study requirements, as judged by the Investigator
    22.Pregnancy
    23.Breast-feeding
    24.Patients unable to undergo MRI, e.g. patients with pace-maker, intra-ocular or intra-cerebral metallic foreign bodies, and mechanical artificial heart valves




    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint
    • Percentage of treatment responders at Month 24,
    a treatment responder at the studied timepoint being defined as a patient who responded both:
    - Clinically, i.e., if at the studied timepoint, the WOMAC® VA3.1 pain subscale score of the study treated hip improved from baseline by at least the minimal clinically important difference (MCID)*,
    and
    - Radiologically, i.e., if at the studied timepoint, the study treated hip did not progress to fractural stages (ARCO III or higher), as assessed by conventional X-ray.

    * The MCID value is set at 10 mm.
    Patients with a baseline WOMAC® VA3.1 pain subscale score ≥10 mm will be considered, at the studied timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip decreased from baseline by at least the MCID.
    Patients with a baseline WOMAC® VA3.1 pain subscale score <10 mm will be considered, at the studied timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip is found in the range [0;4] (VAS pain range labelled as “no pain”).

    Safety Endpoints
    From the beginning to the end of the main study period at Month 24, patients will be systematically assessed for the potential occurrence of any AE or SAE, related to the product or related to the procedure by patient interview, physical examination (including body mass index and vital signs), and laboratory measurements.
    During the long term follow-up up to Month 48, hip symptoms (pain, stiffness, and function) using WOMAC® LK3.1 (Likert Scale) and the potential occurrence of any AEs and SAEs (patient open questionnaire, including notably any changes in health status and need for total hip arthroplasty) will be assessed.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary Efficacy Endpoint: at month 24

    Safety endpoints: at every visit, up to month 48
    E.5.2Secondary end point(s)
    • Percentage of treatment responders at Month 6, 12 and 18, and over the 24-month follow-up period
    • Percentage of clinical responders at Month 1, 3, 6, 12, 18 and 24, and over the 24–month follow-up period; a clinical responder being defined as a patient whom the WOMAC® VA3.1 pain subscale score of the study treated hip improved from baseline by at least the MCID* at the studied timepoint
    • Percentage of radiological responders at Month 6, 12, 18 and 24, and over the 24–month follow-up period; a radiological responder being defined as a patient whom the study treated hip did not progress to fractural stages (ARCO III or higher), as assessed by conventional X-ray, at the studied timepoint
    • Absolute change from baseline in WOMAC® VA3.1 total score and composite pain, stiffness, and function subscale scores of the study treated hip at Month 1, 3, 6, 12, 18 and 24, and over the 24-month follow-up period
    • Time to progression to fractural stages (ARCO III or higher) of the study treated hip
    • Percentage of patients requiring hip arthroplasty for the study treated hip at Month 1, 3, 6, 12, 18 and 24, and over the 24-month follow-up period
    • Time to hip arthroplasty for the study treated hip

    * The MCID value is set at 10 mm.
    Patients with a baseline WOMAC® VA3.1 pain subscale score ≥10 mm will be considered, at the studied timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip decreased from baseline by at least the MCID.
    Patients with a baseline WOMAC® VA3.1 pain subscale score <10 mm will be considered, at the studied timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip is found in the range [0;4] (VAS pain range labelled as “no pain”).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary Efficacy Endpoints: up to month 24
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA37
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 18
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 118
    F.4.2.2In the whole clinical trial 118
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    as described in the protocol
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-03-04
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-11-08
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