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

Phase 3

Completed

• Conditions: Non Union Fracture
• Interventions: Biological: Cultured Mesenchymal Stem Cells; Procedure: Autologous iliac crest graft

• Registration Number: NCT03325504
• Lead Sponsor: Universidad Autonoma de Madrid

Brief Summary

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

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.

Study Timeline

• Study Start: 2017-09-05
• Study First Submitted: 2017-10-25
• Study First Submitted QC: 2017-10-25
• Study First Posted: 2017-10-30
• Primary Completion: 2022-10-17
• Study Completion: 2023-12-15
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-02
• Last Update Posted: 2024-12-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

1. Age 18 years and older, 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.
3. Able to understand, accept and sign informed consent
4. Medical health coverage
5. Able to understand and accept the study constraints

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.
9. Malignant tumour (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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
hBM-MSCs-High Dose	Cultured Mesenchymal Stem Cells	Autologous Cultured Mesenchymal Stem Cells+Biomaterial (High Dose): 200x106 cells
Autologous iliac crest graft	Autologous iliac crest graft	Autologous Iliac Crest Grafting
hBM-MSCs-Low Dose	Cultured Mesenchymal Stem Cells	Autologous Cultured Mesenchymal Stem Cells +Biomaterial (Low Dose): 100x106 cells

Primary Outcome Measures

Name	Time	Method
Bone consolidation	12 months after treatment	The percentage of bone consolidation in the comparator treatment arm ( iliac crest autograft) and experimental treatment arm (mesenchymal cells).

Secondary Outcome Measures

Name	Time	Method
Level of Pain	6, 12 and 24 months	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.
Radiological Bone consolidation	6, 12 and 24 months	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.
Complications	6, 12 and 24 months	To compare the rate of complications between the experimental arms and the comparator
Bone consolidation	6 and 24 months	To compare bone consolidation between the experimental arms and the comparator
Health status	6, 12 and 24 months	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.

Trial Locations

Locations (19)

Universitätsklinikum Frankfurt, Department of Trauma, Hand and Reconstructive Surgery; 🇩🇪 Frankfurt, Germany

Istituto Ortopedico Rizzoli, SSD Fisiopatologia Ortopedica e Medicina Rigenerativa; 🇮🇹 Bologna, Italy

Hospital U. 12 de Octubre, Servicio de Cirugía Ortopédica y Traumatología; 🇪🇸 Madrid, Spain

Department of Orthopaedic Surgery Toulouse University Hospital; 🇫🇷 Toulouse, France

Department of Orthopaedic Surgery, CHU Nantes; 🇫🇷 Nantes, France

Department of Orthopaedic Surgery, CHU Tours; 🇫🇷 Tours, France

Department of Orthopaedic Surgery, Hospital Henri Mondor; 🇫🇷 Créteil, France

CHU Clermont-Ferrand; 🇫🇷 Clermont-Ferrand, France

Universitätsklinikum Freiburg, Klinik für Orthopädie und Unfallchirurgie; 🇩🇪 Freiburg, Germany

Universitätsklinikum München; 🇩🇪 Munich, Germany

Arienda Spedali Civili di Brescia II Ortopedia e Traumatologia; 🇮🇹 Brescia, Italy

Department of Orthopaedic Trauma, University of Ulm; 🇩🇪 Ulm, Germany

Istituto Ortopedico Galeazzi, Chirugia dell´Anca l; 🇮🇹 Milano, Italy

Hospital U. Puerta de Hierro-Majadahonda, Servicio de Cirugía Ortopédica y Traumatología; 🇪🇸 Majadahonda, Madrid, Spain

Hospital U. La Princesa, Servicio de CirugíaOrtopédica y Traumatología; 🇪🇸 Madrid, Spain

Hospital Clínica San Carlos, Servicio de Cirugía Ortopédica y Traumatología; 🇪🇸 Madrid, Spain

Hospital U. Gregorio Marañon, Servicio de Cirugía Ortopédica y Traumatología; 🇪🇸 Madrid, Spain

Hospital Universitario Ramón y Cajal; 🇪🇸 Madrid, Spain

Servicio de Cirugía Ortopédica y Traumatología "A", Hospital La Paz; 🇪🇸 Madrid, Spain