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    Summary
    EudraCT Number:2015-000431-32
    Sponsor's Protocol Code Number:ORTHOUNION
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-05-29
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2015-000431-32
    A.3Full title of the trial
    A MULTI-CENTRE, OPEN-LABEL, RANDOMIZED, COMPARATIVE CLINICAL TRIAL OF TWO DIFFERENT DOSES OF BONE MARROW AUTOLOGOUS HUMAN MESENCHYMAL STEM CELLS PLUS BIOMATERIAL VERSUS ILIAC CREST AUTOLOGOUS GRAFT, FOR BONE HEALING IN NON-UNION AFTER LONG BONE FRACTURES.
    Ensayo clínico multicéntrico, abierto, randomizado que compara dos dosis diferentes de células madre mesenquimales autólogas, de médula ósea, expandidas y combinadas con biocerámica frente al autoinjerto de cresta ilíaca, en la curación de fracturas de huesos largos sin consolidación.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A COMPARATIVE STUDY OF TWO DIFFERENT DOSES OF BONE MARROW AUTOLOGOUS HUMAN MESENCHYMAL STEM CELLS PLUS BIOMATERIAL VERSUS ILIAC CREST AUTOLOGOUS GRAFT, FOR BONE HEALING IN NON-UNION AFTER LONG BONE FRACTURES
    Comparación de dos dosis diferentes de células mesenquimales autólogas de médula osea, combinadas con biomateriales, versus autoinjerto de creta ilíaca osea, en la curación de fracturas de huesos largos sin consolidación hasta el momento.
    A.3.2Name or abbreviated title of the trial where available
    ORTHOUNION
    ORTHOUNION
    A.4.1Sponsor's protocol code numberORTHOUNION
    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 SponsorUniversidad Autónoma de Madrid (U.A.M.)
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Comission (Horizon 2020)
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDepartamento de Farmacología Clínica-Universitary Hospital Puerta de Hierro Majadahonda
    B.5.2Functional name of contact pointCristina Avendaño-Sola
    B.5.3 Address:
    B.5.3.1Street Addressc/Manuel de Falla 1. Hospital Puerta de Hierro Majadahonda. Servicio de Farmacología Clínica
    B.5.3.2Town/ cityMajadahonda-Madrid
    B.5.3.3Post code28220
    B.5.3.4CountrySpain
    B.5.4Telephone number34911916479
    B.5.5Fax number34911917650
    B.5.6E-mailcristina.avendano@uam.es
    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 nameCultured Mesenchymal Cells from bone marrow isolation
    D.3.2Product code Low Dose BM-MSCs
    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 INNAutologous Mesenchymal Stem Cells
    D.3.9.2Current sponsor codeLow dose BM-MSCs
    D.3.9.3Other descriptive nameHUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS
    D.3.9.4EV Substance CodeSUB180295
    D.3.10 Strength
    D.3.10.1Concentration unit CFU/ml colony forming unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10000000
    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 No
    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.IMP: 2
    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 nameCultured Mesenchymal Cells from bone marrow isolation
    D.3.2Product code High Dose BM-MSCs
    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 INNAutologous Mesenchymal Stem Cells
    D.3.9.2Current sponsor codeHigh dose BM-MSCs
    D.3.9.3Other descriptive nameHUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS
    D.3.9.4EV Substance CodeSUB180295
    D.3.10 Strength
    D.3.10.1Concentration unit CFU/ml colony forming unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20000000
    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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Diaphyseal and/or metaphysodiaphyseal fractures (femur, tibia, humerus) with status of non-union
    Fracturas diafisarias y/o metafiso-diafisarias (fémur, tibia y húmero) sin consolidación
    E.1.1.1Medical condition in easily understood language
    Long bones (femur, tibia, humerus) fractures with non-union
    Fracturas de huesos largos (fémur, tibia y húmero) sin consolidación
    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 SOC
    E.1.2Classification code 10028395
    E.1.2Term Musculoskeletal and connective tissue disorders
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10017085
    E.1.2Term Fracture malunion
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if the combined treatment of hBM-MSC+Biomaterial(G2) is superior to Iliac Crest Autologous Graft(G1) to obtain bone consolidation at 12 months after surgery of diaphyseal and/or metaphysodiaphyseal fractures (femur, tibia, humerus) with status of non-union (more than 9 months after the acute fracture)
    Determinar si el tratamiento combinado con hBM-MSC + Biomaterial (G2) es superior al injerto autólogo de cresta ilíaca (G1) para obtener consolidación ósea, 12 meses después de la cirugía de fracturas diafisarias y /o metafisio-diafisarias (fémur, tibia, húmero) con estatus de no consolidación (más de 9 meses después de la fractura aguda)
    E.2.2Secondary objectives of the trial
    * Compare % bone consolidation between G1 and G2 arms at 6 and 24 months after surgery (m. aft. surg.)
    * Compare, G1 and G2 arms, at 6, 12 and 24 m. aft. surg., the following:
    - Radiological consolidation with REBORNE-scale
    - Pain w/ and w/o weight bearing
    - Rate of re-intervention in the callus
    - Complication rate
    - Assess safety of autologous hBM-MSCs
    - Physical & metal health status
    * Identify associated factors to bone consolidation (time from the acute fracture, type of prior-surgery, severity, and country)
    and
    * Determine if G2b is non-inferior to G2a to obtain radiological consolidation at 12 months after surgery.
    * Compare radiological consolidation, w/ REBORNE-Scale, between G2a and G2b arms at basal, 24 and 96 w. aft. surg.
    * Compare, between G2a and G2b arms, at 6, 12 and 24 m. aft. surg., the following:
    - % bone consolidation
    - Pain w/ and w/o weight bearing
    - Rate of re-intervention in the callus
    - Complication rate
    - Physical & metal health status
    * Comparar % consolidación ósea entre los brazos G1 y G2 a las 6 y 24 meses después de la cirugía (m.d.c.)
    * Comparar, los brazos G1 y G2, a 6, 12 y 24 m.d.c., lo siguiente:
    - Consolidación radiológica con la escala REBORNE
    - El grado de dolor con/sin peso
    - Tasa reintervención en el callo
    - Tasa de complicación
    - Evaluar la seguridad de las hBM-MSC autólogos
    - Salud mental y psicológica
    * Identificar factores asociados a la consolidación ósea (tiempo de la fractura aguda, tipo de cirugía previa, gravedad y país)
    y
    *Determinar si G2b no es inferior a G2a para obtener consolidación radiológica a lo 12 meses de la cirugía.
    *Comparar el % de consolidación ósea, con escala REBORNE, entre los brazos G2a y G2b a los 6 y 24 m.d.c.
    * Comparar, entre los brazos G2a y G2b, a 6, 12 y 24 m.d.c., lo siguiente:
    - Consolidación radiológica
    - El grado de dolor con/sin peso
    - Tasa reintervención en el callo
    - Tasa de complicación
    - Salud mental y psicológica
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible to enter the study candidates must satisfy all of the following criteria:
    1. Age 18 to 65, both sexes
    2. Traumatic isolated closed or open Gustilo I and II, IIIA and IIIB humerus, tibial or femur diaphyseal or metaphysodiaphyseal fracture with a status of atrophic, oligotrophic or normotrophic non-union. A non-union is defined as a fracture not healed at least 9 months after the originating trauma, that meets the following criteria (Weber 1986):
    ‐ Insufficient bone bridging to stabilize the fracture
    ‐ Insufficient bone biological activity in the fracture
    ‐ Failure of previous treatments

    3. Able to understand, accept and sign informed consent
    4. Medical health coverage
    5. Able to understand and accept the study constraints
    Para poder ser candidato a entrar en el estudio se deben de cumplir los siguientes criterios:
    1. Edad entre 18 to 65, de ambos sexos
    2. Fractura diafisaria o metafisodiafisaria de tibia, femur o húmero, con traumatismo cerrado o abierto Gustilo I y II, IIIA y IIIB, con estatus de no consolidación. Se define como no consolidación a aquella fractura con más de 9 meses sin curación, desde que se originó el traumatismo, que cumple los siguientes criterios (Weber 1986):
    ‐ Insuficientes puentes óseos para estabilizar la fractura
    ‐ Actividad biológica insuficiente en la fractura
    ‐ Fracaso de los tratamientos previos

    3. Con capacidad para entender, aceptar y firmar el consentimiento informado
    4. Con cobertura sanitaria
    5. Con capacidad de entender y aceptar las restricciones del estudio
    E.4Principal exclusion criteria
    1. Hypertrophic non-unions
    2. Segmental bone loss requiring specific therapy (bone transport, vascularized graft, large structural allograft, megaprosthesis, etc)
    3. Unrecovered vascular or neural injury
    4. Other fractures causing interference with weight bearing
    5. Visceral injuries or diseases interfering with callus formation (severe cranioencephalic trauma, etc.)
    6. Active infection of any location and aetiology
    7. Surgical contraindication of any cause
    8. Pregnancy, breast feeding women and women who are of childbearing age and not practicing adequate birth control. The following methods are considered adequate:
    ‐ Combined hormonal contraception
    ‐ Injected hormonal contraception
    ‐ Implanted hormonal contraception
    ‐ Progesterone-only hormonal contraception associated with inhibition of ovulation
    ‐ Placement of an intrauterine device (IUD)
    ‐ Placement of intrauterine hormone-realising system (IUS)

    9. Malignant tumor (past history or concurrent disease)(except carcinoma in situ or basalioma in remission)
    10. History of bone harvesting on iliac crest contraindicating new iliac crest bone graft harvesting or bone marrow collection
    11. Insulin dependent diabetes
    12. Any evidence (confirmed by PCR) of active infection with HIV, Hepatitis B or Hepatitis C infection
    13. Any evidence of Syphilis
    14. Known allergies to products involved in the production process of MSC
    15. Corticoid or immunosuppressive therapy more than one week in the three months prior to study inclusion
    16. Autoimmune inflammatory disease
    17. Current treatment by biphosphonates not stopped three months prior to study inclusion
    18. Impossibility to meet at the appointments for the follow up
    19. Participation in another therapeutic trial in the previous 3 months
    20. Second non-union in case of bilateral or multiple non-unions (only one non-union per patient will be included in the trial)
    1. Fractura no consolidada hipertrófica
    2. Perdida segmentaria de hueso que requiera tratamiento específico (transporte óseo, injerto vascularizado, aloinjerto estructural de gran tamaño, megaprótesis, etc.).
    3. Lesión vascular o nerviosa no recuperada.
    4. Presencia de otras fracturas que puedan interferir con la capacidad de soportar peso
    5. Existencia de lesiones viscerales o enfermedades que puedan interferir con la formación del callo óseo (traumatismo craneoencefálico grave, etc.)
    6. Infección activa en cualquier localización y de cualquier causa.
    7. Presencia de contraindicaciones para la cirugía
    8. Embarazo, mujeres en periodo de lactancia y mujeres en edad fértil que no realicen un método anticonceptivo adecuado. Los siguientes métodos anticonceptivos se consideran adecuados:
    - Anticoncepción hormonal combinada
    - Anticoncepción hormonal inyectable
    - Anticoncepción hormonal solo con progesterona, asociada a inhibición de la ovulación
    - Colocación de un dispositivo intrauterino (DIU)
    - Colocación de un sistema intrauterino con liberación hormonal (SIU)
    9. Neoplasia (historia previa o actual) (excepto carcinoma in situ o basalioma en remisión).
    10. Historia de extracción de injerto de cresta iliaca previo que contraindique una nueva extracción de cresta iliaca o de médula ósea
    11. Diabetes insulinodependiente
    12. Evidencia de infección activa (confirmada con PCR) por VIH, VHB o VHC
    13. Sífilis
    14. Alergia conocida a productos involucrados en el procesamiento de las células mesenquimales
    15. Tratamiento con corticoides o inmunosuprsores de duración superior a una semana en los 3 meses previos a la inclusión en el estudio.
    16. Enfermedad inflamatoria autoinmune
    17. Tratamiento (actual) con bifosfonatos, no suspendidos con al menos 3 meses antes de la inclusión en el estudio.
    18. Imposibilidad de asistir a las consultas de seguimiento
    19. Participación en otro ensayo clínico en los 3 meses previos
    20. Segunda fractura no consolidada, en el caso de fracturas bilaterales o múltiples no consolidadas (solo se incluirá una fractura no consolidad por paciente).
    E.5 End points
    E.5.1Primary end point(s)
    The percentage of patients with bone consolidation (Yes/No) in the G1 (comparator) and G2 (experimental) treatment arms at 12 months after the surgery. A superiority test will compare this endpoint in both treatment arms. Each endpoint will be estimated as the number of bone consolidations in each arm, over the total number of treated patients in each arm.
    For this first primary endpoint, bone consolidation will be considered achieved when all three of the following criteria are met:
    a) Radiographic bone bridging: New bone formation across the fracture site visible in 3/4 cortices, on at least 3/4 views (Front views: Internal and external cortical; Lateral views: Anterior and Posterior cortical).
    b) Clinical healing: Pain less than 3 in a Numeric Rating Scale (NRS, 0 to 10) for pain during full weight-bearing and without weight bearing.
    c) No further surgical intervention in the callus site: mayor surgery will be considered either as nail replacement, plate replacement, or replacement of all components of the previous surgery.
    Porcentaje de pacientes con consolidación del hueso (SI/NO), de los brazos de tratamiento G1 y G2 respecto al brazo control, 12 meses después de la cirugía. Se llevará a cabo una comparación de superioridad
    entre ambos tratamientos. El objetivo principal se estimará como el número de huesos consolidados en cada brazo sobre el total de pacientes tratados en cada brazo.
    Para este primer objetivo principal, se considerará que existe consolidación cuando se cumplan los siguientes criterios:
    a) Consolidación ósea radiográfica: Formación de hueso nuevo en la fractura, visible en 3/4 cortezas o almenos en 3/4 de las vistas(Vistas frontales: cortical interna y externa; vistas laterales: cortical anterior y posterior)
    b) Recuperación clínica. Dolor por debajo de 3 en la escala NRS (NRS, 0 a 10) con peso completo y sin carga de peso
    c) No más intervenciones en el callo óseo: será considerado como cirugía mayor un cambio de clavo, un cambio de placa o cualquier cambio de algún componente de la cirugía anterior.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months after surgery
    E.5.2Secondary end point(s)
    EFFICACY ENDPOINTS:
    ** G1/G2 arms
    - Percentage of patients with bone consolidation (Yes/No) in the G1 and G2 treatment arms at 6 and 24 months after surgery. Estimated as the number of bone consolidations in each arm, over the total number of treated patients in each arm. For this endpoint, bone consolidation was defined as previously established for the primary endpoint.
    - Radiological punctuation score using the REBORNE-Scale in the G1 and G2 treatment arms of treatment at 6, 12 and 24 months after surgery calculated in xR images (and/or CT for ratify purpose).
    - Pain scale value in the G1 and G2 treatment arms at basal baseline, 6, 12 and 24 months after surgery, using the Numeric Rating Scale (NRS) for pain (from 0 to 10).
    - Rate of reoperation in the callus site in G1 and G2 arms of treatment arms at 6, 12 and 24 months after surgery.
    - Average percentage of the Short Form-36 Health Survey at baseline, 6, 12 and 24 months after surgery.

    ** G2b/G2a arms:
    - Radiological score in the G2a (High dose of hBM-MSC+Biomaterial) and G2b (Low dose of hBM-MSC+Biomaterial) treatment arms at 12 months after surgery. This endpoint will be calculated using the REBORNE-Scale, which can obtain a score ranging from 0 to 1. The score will be calculated in xR images (and/or CT for ratify ratification purposes) using a specific formula.
    - Radiological score using the REBORNE-Scale in the G2a and G2b treatment arms at 6 and 24 months after surgery calculated in XR images (and/or CT for ratify purpose).
    - Percentage of bone consolidation (Yes/No) in the G2a and G2b treatment arms at 6, 12 and 24 months after surgery. Estimated as the number of bone consolidations in each arm, over the total number of treated patients in each arm . For this endpoint, bone consolidation was defined as previously established for the primary endpoint.
    - Pain scale value in the G2a and G2b treatment arms at baseline, 6, 12 and 24 months after surgery, using Numeric Rating Scale (NRS) for pain (from 0 to 10).
    - Rate of reoperation in the callus site in the G2a and G2b treatment arms of treatment at 6, 12 and 24 months after surgery.
    - Average percentage of the Short Form-36 Health Survey at baseline, 6, 12 and 24 months after surgery.


    SAFETY ENDPOINTS:
    ** G1/G2 arms:
    Safety endpoints will be estimated in the G1 and G2 treatment arms and includes:
    a) Early local complication rate, as percentage of patients with local complications within three months after surgery.
    b) Global complication rate, as percentage of patients with local or general complications regarding potential effects of the treatment at 6, 12 and 24 months after surgery.
    For early and global complications we will specifically investigate:
    - Adverse event related to the product application process (surgical or other, including the bone marrow harvesting process or the iliac crest graft)
    - Local heterotopic ossification
    - Local bone resorption
    - Local osteolysis
    - Local and general infection
    - Vascular complication (ischemia, phlebitis)
    - Neurological problems
    - Unexpected events (e.g. hypersensitivity, immunological, toxic or other)
    - Adverse events related to mandatory concomitant medication (e.g. anaesthetics)


    ** G2b/G2a arms:
    Safety endpoints (early complication rate and global complication rate) will be compared in the G2a and G2b of treatments arm as described above (for the G1-G2 arm comparison).
    VARIABLES DE EFICACIA:
    ** Brazo G1/G2:
    - Porcentaje de consolidación del hueso (SI/NO) en los brazos G1 y G2, a los 6 y 24 meses después de la cirugía. Se estimará como el número de huesos consolidados en cada brazo sobre el total de pacientes tratados en cada brazo.
    - Puntuación radiológica, utilizando la escala REBORNE, en los brazos G1 y G2, a los 6, 12 y 24 meses después de la cirugía, calculado sobre las imágenes de Rayos-X (y/o CT para confirmación).
    - Escala de dolor en los brazos G1 y G2 al inicio y a los 6, 12 y 24 meses después de la operación, utilizando la escala para el dolor NRS.
    - Proporción de reoperaciones del callo en los brazos G1 y G2 a los 6, 12 y 24 meses después de la cirugía.
    - Cambios en la valoración de la calidad de vida, utilizando la escala SF-36 Health Survey, entre el inicio y a los 6, 12 y 24 meses después de la cirugía.

    ** Brazos G2b/G2a:
    - Valoración radiológica entre el tratamiento G2a ( dosis alta de hBM-MSC + Biomaterial) y el tratamiento G2b ( dosis baja de hBM-MSC + Biomaterial) 12 meses después de la cirugía. Esta valoración se realizará utilizando la escala REBORNE, que permite obtener una puntuación de 0 a 1. La puntuación se calculará a partir de imágenes de rayos X (y/o TACs para confirmar) y utilizando una fórmula específica para ello.
    - Puntuación radiológica, utilizando la escala REBORNE, en los brazos G2a y G2b, a los 6 y 24 meses después de la cirugía, calculado sobre las imágenes de Rayos-X (y/o CT para confirmación).
    - Porcentaje de consolidación del hueso (SI/NO) en los brazos G2a y G2b, a los 6, 12 y 24 meses después de la cirugía. Se estimará como el número de huesos consolidados en cada brazo sobre el total de pacientes tratados en cada brazo.
    - Escala de dolor en los brazos G2a y G2b al inicio y a los 6, 12 y 24 meses después de la operación, utilizando la escala para el dolor NRS.
    - Proporción de reoperaciones del callo en los brazos G2a y G2b a los 6, 12 y 24 meses después de la cirugía.
    - Cambios en la valoración de la calidad de vida, utilizando la escala SF-36 Health Survey, entre el inicio y a los 6, 12 y 24 meses después de la cirugía.

    VARIABLES DE SEGURIDAD:
    ** Brazos G1/G2:
    - Proporción de complicaciones locales, indicado como porcentaje de pacientes con complicaciones a los 3 meses de la cirugía.
    - Proporción de complicaciones globales, indicado como el porcentaje de pacientes con complicaciones locales y/o generales, a los 6, 12 y 24 meses de la cirugía, potencialmente relacionadas con el tratamiento recibido.

    ** Brazos G2b/G2a:
    Se comparará la variable de seguridad (proporción de complicaciones locales y proporción de complicaciones globales) en los brazo G2a y G2b, según se ha descrito para los brazos G1/G2.
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 and 24 months after surgery, in some items, and 6, 12 and 24 months, in other.
    6 y 24 meses después de la cirugía, en algunos casos, y 6, 12 y 24 meses después de la cirugía, en otros casos.
    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 Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Autologous graft harvested from the iliac crest
    E.8.2.4Number of treatment arms in the trial3
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    LVLS
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    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: 108
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state33
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 108
    F.4.2.2In the whole clinical trial 108
    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)
    If bone healing has not occurred, the patient may require additional treatment and an additional follow-up, under the care of the Hospital, the treating physician or service, or the provider in charge of his process, even if unrelated to the study.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation ECRIN
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-05-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-17
    P. End of Trial
    P.End of Trial StatusOngoing
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