Clinical Trials Register

Summary
EudraCT Number:	2015-000431-32
Sponsor's Protocol Code Number:	ORTHOUNION
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-04-11
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.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-000431-32

A.3

Full 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.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

ORTHOUNION

A.4.1

Sponsor's protocol code number

ORTHOUNION

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Universidad Autónoma de Madrid (U.A.M.)
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	European Comission (Horizon 2020)
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Departamento de Farmacología Clínica-Universitary Hospital Puerta de Hierro Majadahonda
B.5.2	Functional name of contact point	Cristina Avendaño-Sola
B.5.3	Address:
B.5.3.1	Street Address	c/Manuel de Falla 1. Hospital Puerta de Hierro Majadahonda. Servicio de Farmacología Clínica
B.5.3.2	Town/ city	Majadahonda-Madrid
B.5.3.3	Post code	28220
B.5.3.4	Country	Spain
B.5.4	Telephone number	34911916479
B.5.5	Fax number	34911917650
B.5.6	E-mail	cristina.avendano@uam.es

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cultured Mesenchymal Cells from bone marrow isolation
D.3.2	Product code	Low Dose BM-MSCs
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraosseous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Autologous Mesenchymal Stem Cells
D.3.9.2	Current sponsor code	Low dose BM-MSCs
D.3.9.3	Other descriptive name	HUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS
D.3.9.4	EV Substance Code	SUB180295
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/ml colony forming unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Yes
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cultured Mesenchymal Cells from bone marrow isolation
D.3.2	Product code	High Dose BM-MSCs
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraosseous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Autologous Mesenchymal Stem Cells
D.3.9.2	Current sponsor code	High dose BM-MSCs
D.3.9.3	Other descriptive name	HUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS
D.3.9.4	EV Substance Code	SUB180295
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/ml colony forming unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Yes
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical 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.1.1.1

Medical 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.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10028395
E.1.2	Term	Musculoskeletal and connective tissue disorders
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10017085
E.1.2	Term	Fracture malunion
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary 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.2.3

Trial contains a sub-study

E.3

Principal 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.4

Principal 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.5.1

Primary 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.5.1.1

Timepoint(s) of evaluation of this end point

12 months after surgery

E.5.2

Secondary 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.5.2.1

Timepoint(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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Autologous graft harvested from the iliac crest

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial 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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

108

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

108

F.4.2.2

In 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.4.1	Name of Organisation	ECRIN

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-10-16

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials