A Comparative Study of 2 Doses of BM Autologous H-MSC+Biomaterial vs Iliac Crest AutoGraft for Bone Healing in Non-Union

Study Overview
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Brief Summary
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ORTHOUNION is a multi-centre, open, comparative, randomized, clinical trial with three parallel arms that aims to compare the efficacy of three treatments to enhance bone healing in patients with long bone non-union.

Detailed Description
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Bone injuries represent an important world medical problem producing significant healthcare and societal expenditure. While most bone injuries are not severe and are capable of healing through bone regeneration by natural callus formation with standard treatments, severe bone injuries may not heal, becoming an important unmet clinical need. Non-unions, or pseudarthrosis, may occur in 5% to 20% of long-bone fractures that fail to heal properly after more than 6 months, with morbidity, prolonged hospitalization, and increased expenses. The most commonly accepted standard augmentation to procure fracture and non-union healing consists of autologous bone grafting, obtained from the same patient in a different surgical site and transplanted to the reconstruction site. However, autologous bone grafting has some drawbacks (such as persistent pain, scar, late recovery, limited amount of bone, etc) and a limited regeneration efficacy (success rate of about 74%) and high societal cost. Culture-expanded autologous MSCs combined with biphasic calcium phosphate (BCP) biomaterial granules have been claimed as a solid regenerative medicine alternative to autologous bone grafting in non-unions, although current data are limited. In this context, the ORTHOUNION initiative focuses on the opportunity to test the hypothesis of superiority of MSC, the investigational ATMP, versus the currently accepted standard therapy, iliac crest bone autograft to biologically augment surgical treatment of long-bone non-unions.

Official Title
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A Multi-centre, Open-label, Randomized, Comparative Clinical Trial of Two Doses of Bone Marrow Autologous MSC+ Biomaterial vs Iliac Crest Autologous Graft, for Bone Healing in Non-union After Long Bone Fractures

Conditions
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Non Union Fracture

Intervention / Treatment
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* Biological: Cultured Mesenchymal Stem Cells
* Procedure: Autologous iliac crest graft


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years and older, both sexes 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. Able to understand, accept and sign informed consent Medical health coverage Able to understand and accept the study constraints Exclusion Criteria: Hypertrophic non-unions Segmental bone loss requiring specific therapy (bone transport, vascularized graft, large structural allograft, megaprosthesis, etc) Unrecovered vascular or neural injury Other fractures causing interference with weight bearing Visceral injuries or diseases interfering with callus formation (severe cranioencephalic trauma, etc.) Active infection of any location and aetiology Surgical contraindication of any cause Pregnancy, breast feeding women and women who are of childbearing age and not practicing adequate birth control. Malignant tumour (past history or concurrent disease)(except carcinoma in situ or basalioma in remission) History of bone harvesting on iliac crest contraindicating new iliac crest bone graft harvesting or bone marrow collection Insulin dependent diabetes Any evidence (confirmed by PCR) of active infection with HIV, Hepatitis B or Hepatitis C infection Any evidence of Syphilis Known allergies to products involved in the production process of MSC Corticoid or immunosuppressive therapy more than one week in the three months prior to study inclusion Autoimmune inflammatory disease Current treatment by biphosphonates not stopped three months prior to study inclusion Impossibility to meet at the appointments for the follow up Participation in another therapeutic trial in the previous 3 months Second non-union in case of bilateral or multiple non-unions (only one non-union per patient will be included in the trial)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hBM-MSCs-Low Dose<br>Autologous Cultured Mesenchymal Stem Cells +Biomaterial (Low Dose): 100x106 cells | Biological: Cultured Mesenchymal Stem Cells<br>* Cultured Mesenchymal Stem Cells obtained from expanded bone marrow<br>|
| Experimental: hBM-MSCs-High Dose<br>Autologous Cultured Mesenchymal Stem Cells+Biomaterial (High Dose): 200x106 cells | Biological: Cultured Mesenchymal Stem Cells<br>* Cultured Mesenchymal Stem Cells obtained from expanded bone marrow<br>|
| Active Comparator: Autologous iliac crest graft<br>Autologous Iliac Crest Grafting | Procedure: Autologous iliac crest graft<br>* Autologous iliac crest grafting<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone consolidation | The percentage of bone consolidation in the comparator treatment arm ( iliac crest autograft) and experimental treatment arm (mesenchymal cells). | 12 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone consolidation | To compare bone consolidation between the experimental arms and the comparator | 6 and 24 months | 
| Radiological Bone consolidation | To compare bone consolidation, using the REBORNE scale, between the experimental arms and the comparator. The REBORNE scale is an ad-hoc and validated scale, developed by Gomez-Barrena et al. (article currently under preparation) as a modification of the RUST score (Whelan, 2010; Journal of Trauma). In the REBORNE scale, the presence/absence of radiological consolidation is evaluated on a total of 4 cortices. Score range from 0 (no bone callus visible) to 4 (callus present with same density as cortical). The total score will be recorded. | 6, 12 and 24 months | 
| Level of Pain | To compare level of pain (by Numeric Rating Scale [NRS]) between the experimental arms and the comparator. The NRS is a scale that rates the patient´s pain from 0-10 (0= no pain, 10= worst pain), at the time of the visit. | 6, 12 and 24 months | 
| Complications | To compare the rate of complications between the experimental arms and the comparator | 6, 12 and 24 months | 
| Health status | To compare the health status (by using the Short Form-36 Health Questionnaire) between treatment arms. The SF-36 questionnaire is a validated, widely used patient-reported health survey which measures their physical and mental health status. It consists of 36 questions organized in 8 dimensions. The total score will be recorded. | 6, 12 and 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-union, Advanced therapies, Mesenchymal stem cells, Long bone