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    Summary
    EudraCT Number:2018-001054-96
    Sponsor's Protocol Code Number:000013/BT
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-01-06
    Trial 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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2018-001054-96
    A.3Full title of the trial
    Phase IIb, Placebo-Controlled, Randomized, Double-blind, Multicenter Study to Assess the Efficacy and Safety of Allogeneic Osteoblastic Cells (ALLOB) Single Implantation in Tibial Fracture
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Assess the Efficacy and Safety of ALLOB in Tibial Fracture
    A.3.2Name or abbreviated title of the trial where available
    ALLOB-TF2
    A.4.1Sponsor's protocol code number000013/BT
    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 Team
    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-mailallob.tf2@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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameALLOB
    D.3.2Product code ALLOB
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPPercutaneous use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNALLOB cells
    D.3.9.2Current sponsor codeALLOB cells
    D.3.9.3Other descriptive nameAllogeneic bone-marrow-derived osteoblasts
    D.3.10 Strength
    D.3.10.1Concentration unit U/ml unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25000000
    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) No
    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 a tissue engineering product (non-combined) (reference : EMA/647468/2011) by the EMA on July 19, 2011 (as defined in Article 2(1)(a-d) of Regulation (EC) No 1394/2007)
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboPercutaneous use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Tibial fracture considered at risk of DU/NU (based on the combination of risk factors documented to be associated with increased proportion of DU/NU).
    E.1.1.1Medical condition in easily understood language
    Tibial fracture considered at risk of Delay union/non union
    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 10043827
    E.1.2Term Tibia fracture
    E.1.2System Organ Class 10022117 - Injury, poisoning and procedural complications
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that treatment with ALLOB leads to a significant improvement in radiological success with respect to placebo in subjects with a tibial fracture.
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    - To assess the impact of ALLOB on the speed of fracture healing, radiological fracture healing and clinical fracture healing
    - To assess the impact of ALLOB on the rate of fracture healing, radiological fracture healing, clinical fracture healing, DU and NU
    - To assess the impact of ALLOB on the rate of rescue intervention due to tibial DU and NU
    - To assess the impact of ALLOB on functional status and return to normal activities
    - To assess the impact of ALLOB on RUST score
    - To assess the accuracy of RUST threshold value predictive of bone healing
    - To demonstrate the overall safety of ALLOB particularly based on key safety outcomes (product failure, infection related to implantation, hypersensitivity reaction, ectopic bone formation)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All subjects must satisfy ALL of the following criteria to be included in the study:
    1. Men and women at least 18 years of age
    2. Subject diagnosed with a fresh proximal, midshaft or distal tibial fracture with definitive reduction performed with nail(s) and wound closure within 1 week of fracture occurrence
    3. Mechanism of injury at risk of DU/NU: fracture occurring because of a high energy impact
    4. At increased risk of DU/NU defined by: Severe open fracture (Gustilo-Anderson grade IIIa and IIIb) OR Open (Gustilo-Anderson grade I-II) or closed (Tscherne grade II-III) fracture with at least one additional risk factor among smoking, comminuted fracture or cortical continuity (0-50%)
    5. Ability to obtain a written, dated, and signed informed consent prior to any study related procedures and ability to understand and comply with study requirements
    E.4Principal exclusion criteria
    Current symptoms and/or signs related to the disease under study:
    1. Definitive reduction at the fracture site under investigation performed with plate, screw or external fixator
    2. Subjects who did not receive a standard antibiotic prophylaxis before definitive reduction at the fracture site under investigation
    3. Intra-articular tibial pilon and/or plateau fracture at the site under investigation
    4. Known osteomyelitis at the fracture site under investigation
    5. Bone defect post-definitive reduction greater than 1cm at least on 2 cortices at the fracture site under investigation
    6. Fracture requiring vascular surgery at the site under investigation
    7. Pathological fractures as judged by the Investigator, such as tumor or metabolic bone disease
    8. Bifocal or multifocal fracture at the site under investigation

    Current or previous diagnoses, signs and/or symptoms:
    9. Presence of fever (defined as body temperature ≥ 38°C) or other signs/symptoms suggestive of active infection before randomization
    10. Severe brain trauma with a Glasgow Coma Scale (GCS) [3 – 8] or severe spinal cord injury with impossibility of weight-bearing
    11. Current or history (within 5 years) of any 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)
    12. Known metabolic diseases potentially interfering with bone healing as judged by the Investigator, such as thyroid dysfunction, Paget disease or severe osteoporosis
    13. Planned or history of solid organ transplantation or bone marrow transplantation
    14. Known disease, including genetic disease, that may possibly need solid organ transplantation
    15. Subject with renal impairment requiring dialysis or with clinically significant renal impairment defined as serum creatinine >2.0 x ULN
    16. Clinically significant hepatic function impairment defined as ALT/AST levels > 3x ULN or total bilirubin levels > 2 x ULN
    17. Known hematologic disease as evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet values < 100,000/ul without another explanation
    18. Subject with an history of long standing poorly controlled chronic hypertension or diabetes that could put him at risk of needing a kidney transplant later on according to the Investigator
    19. History of hypersensitivity to human biological material including blood and blood derived products
    20. Known allergy to DMSO, dextran, gentamicin and any other aminoglycosides

    Current or previous treatment:
    21. Participation in another interventional clinical study within 3 months prior to screening
    22. Any chronic intake of medication within one month that might affect bone metabolism or the quality of bone formation such as but not limited to bisphosphonates, teriparatide, systemic steroids, anticoagulant therapies, methotrexate and other immunosuppressant drugs or related immunotherapy
    23. Previous (within 10 years) treatment with bisphosphonates
    24. Current treatment with bone morphogenic protein or any other osteo-biologic intervention at the site of the tibial fracture

    Safety aspects concerning female subjects of childbearing potential
    25. Breast-feeding
    26. Pregnancy
    27. Woman with positive urine pregnancy test at screening
    28. Woman not willing or not able to use a reliable contraceptive method during the active study follow-up period. Reliable contraceptive methods exclusively highly effective birth control methods: a. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) b. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) c. Intrauterine device d. Intrauterine hormone-releasing system e. Bilateral tubal occlusion

    Other exclusion criteria:
    29. Life expectancy less than 12 months at screening
    30. Signs of an active drug or alcohol dependence, serious current illness, mental illness or any other factors which, in the opinion of the Investigator, may interfere with subject’s ability to understand and comply with study requirements, as judged by the Investigator
    31. Prisoner
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the proportion of subjects with a radiological success at Week 12 (Visit #4). A radiological success is defined as a subject with a RUST score above the threshold value predictive of a normal bone healing. The threshold value that would best predict bone healing is hypothesized to be between 6 and 8 (on a scale from 4 to 12). It will be selected at an interim analysis by an Independent Data Monitoring Committee (IDMC) based on predefined decision rules.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks
    E.5.2Secondary end point(s)
    Efficacy endpoints:

    Key efficacy secondary endpoints:
    - Proportion of subjects with radiological success at Week 16 (Visit #5), Week 20 (Visit #6) and Month 6 (Visit #7)
    - Change in RUST at Week 12 (Visit #4), Week 16 (Visit #5), Week 20 (Visit #6) and Month 6 (Visit #7) compared to baseline visit

    Other efficacy secondary endpoints:
    - Time to fracture healing: based on Investigator judgement, fracture healing is defined by a full weight bearing of the treated tibia, a lack of pain at palpation, and a radiological fracture union. Radiological fracture union is defined by a bone bridging on at least three of the four cortices and absence of fracture line
    - Time to clinical fracture healing: based on Investigator judgement with the condition of a full weight bearing of the treated tibia and a lack of pain at palpation
    - Time to radiological fracture healing: performed by Independent Radiologists with the condition of a radiological fracture union
    - Proportion of subjects with fracture healing at each follow-up visit
    - Proportion of subjects with clinical fracture healing at each follow-up visit
    - Proportion of subjects with radiological fracture healing at each follow-up visit
    - Proportion of subjects with full weight-bearing at each follow-up visit
    - Time to rescue intervention
    - Time to full weight-bearing
    - Proportion of subjects requiring rescue intervention within 12 months
    - Proportion of subjects diagnosed with NU at Month 9 (Visit #8)
    - Proportion of subjects diagnosed with DU at Week 20 (Visit #6)
    - Pain at palpation at each follow-up visit
    - Lower Extremity Functional Scale (LEFS) score at each follow-up visit
    - Short Form 12 (SF-12) score at each follow-up visit
    - Sensitivity and specificity of RUST threshold value at 6 months predictive of bone healing with regard to fracture outcome

    Safety endpoints:
    - Any Adverse Event (AE)/Serious Adverse Event (SAE)
    - Adverse Event of Special Interest (AESI):
    o Suspected or confirmed acute or chronic infection related to the medical condition under evaluation
    o AEs possibly related to product failure
    o AEs suggesting infection related to implantation procedure
    o AEs suggesting hypersensitivity reaction
    o AEs suggesting ectopic bone formation
    E.5.2.1Timepoint(s) of evaluation of this end point
    6-12-16-20 weeks
    6-9-12 months
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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 last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 160
    F.1.3Elderly (>=65 years) Yes
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 178
    F.4.2.2In the whole clinical trial 178
    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)
    Study treatment will be administered once only. If the patient is in further need of treatment past study, the patient will receive treatment per local standard of care. Subjects treated with ALLOB® (discontinued or not) will also be followed up in an additional 5 years post-study safety follow-up (Separate Study 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 Decision2020-03-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-19
    P. End of Trial
    P.End of Trial StatusOngoing
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