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Note: This record shows only 22 elements of the WHO Trial Registration Data Set. To view changes that have been made to the source record, or for additional information about this trial, click on the URL below to go to the source record in the primary register.
Register: EUCTR
Last refreshed on: 3 July 2017
Main ID:  EUCTR2015-000431-32-ES
Date of registration: 29/05/2017
Prospective Registration: Yes
Primary sponsor: Universidad Autónoma de Madrid (U.A.M.)
Public title: 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
Scientific title: 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. - ORTHOUNION
Date of first enrolment: 25/05/2017
Target sample size: 108
Recruitment status: Authorised-recruitment may be ongoing or finished
URL:  https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-000431-32
Study type:  Interventional clinical trial of medicinal product
Study design:  Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Autologous graft harvested from the iliac crest Number of treatment arms in the trial: 3  
Phase:  Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no
Countries of recruitment
Spain
Contacts
Name: Cristina Avendaño-Sola   
Address:  c/Manuel de Falla 1. Hospital Puerta de Hierro Majadahonda. Servicio de Farmacología Clínica 28220 Majadahonda-Madrid Spain
Telephone: 34911916479
Email: cristina.avendano@uam.es
Affiliation:  Departamento de Farmacología Clínica-Universitary Hospital Puerta de Hierro Majadahonda
Name: Cristina Avendaño-Sola   
Address:  c/Manuel de Falla 1. Hospital Puerta de Hierro Majadahonda. Servicio de Farmacología Clínica 28220 Majadahonda-Madrid Spain
Telephone: 34911916479
Email: cristina.avendano@uam.es
Affiliation:  Departamento de Farmacología Clínica-Universitary Hospital Puerta de Hierro Majadahonda
Key inclusion & exclusion criteria
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
Are the trial subjects under 18? no
Number of subjects for this age range:
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) no
F.1.3.1 Number of subjects for this age range

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)


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes
Health Condition(s) or Problem(s) studied
Diaphyseal and/or metaphysodiaphyseal fractures (femur, tibia, humerus) with status of non-union
MedDRA version: 20.0 Level: SOC Classification code 10028395 Term: Musculoskeletal and connective tissue disorders System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders
MedDRA version: 20.0 Level: PT Classification code 10017085 Term: Fracture malunion System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders
Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]
Intervention(s)

Product Name: Cultured Mesenchymal Cells from bone marrow isolation
Product Code: Low Dose BM-MSCs
Pharmaceutical Form: Suspension for injection
INN or Proposed INN: Autologous Mesenchymal Stem Cells
Current Sponsor code: Low dose BM-MSCs
Other descriptive name: HUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS
Concentration unit: CFU/ml colony forming unit(s)/millilitre
Concentration type: equal
Concentration number: 10000000-

Product Name: Cultured Mesenchymal Cells from bone marrow isolation
Product Code: High Dose BM-MSCs
Pharmaceutical Form: Suspension for injection
INN or Proposed INN: Autologous Mesenchymal Stem Cells
Current Sponsor code: High dose BM-MSCs
Other descriptive name: HUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS
Concentration unit: CFU/ml colony forming unit(s)/millilitre
Concentration type: equal
Concentration number: 20000000-

Primary Outcome(s)
Main Objective: 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)
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.
Secondary Objective: * 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
Timepoint(s) of evaluation of this end point: 12 months after surgery
Secondary Outcome(s)
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).
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.
Secondary ID(s)
ORTHOUNION
Source(s) of Monetary Support
European Comission (Horizon 2020)
Secondary Sponsor(s)
Ethics review
Results
Results available:
Date Posted:
Date Completed:
URL:
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