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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ORTHOUNION (ORTHOpedic randomized clinical trial with expanded bone marrow MSC and bioceramics versus autograft in long bone nonUNIONs)

Teaser

Bone injuries represent an important world medical problem producing significant healthcare and societal expenditure. While most bone injuries are not severe and capable of healing through bone regeneration by natural callus formation with standard treatments, severe bone...

Summary

Bone injuries represent an important world medical problem producing significant healthcare and societal expenditure. While most bone injuries are not severe and 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. In Europe, complex fractures are increasing in frequency due severe traumatic injuries such as traffic accidents (with higher survivorship in polytrauma patients). High prevalence of specific limitations has been confirmed after severe traumatic injury, ranging from 40 to 70% of patients. Female gender and comorbidities are associated factors to predict long-term disability. Functional capacity and quality of life in survivors of severe injuries often do not return to normal one year after trauma. Severe bone injuries may associate soft tissue injuries and impaired biological scenario (poor vascularity, damaged skin coverage, devitalized bone endings or fragments, soft tissue compromise, bone fragments with limited muscle insertion, etc.), frequently leading to consolidation problems after a fracture, and eventually to recalcitrant non-unions. Therefore, this proposal is oriented to prove the added value of bone regenerative medicine to heal bone with consolidation problems.
Non-unions, also known as 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. With more than one million bone grafts each year in Europe, bone is the most transplanted tissue in humans. Autologous bone graft, frequently obtained from the iliac crest, is the best available biological option. Its major advantage is to provide extracellular matrix (for osteoconduction), growth factors (modulating bone healing as per osteoinduction), and patient’s cells (leading to local osteogenesis). These factors are considered to guide bone regeneration and thus to heal the bone injury. However, autologous bone graft has drawbacks due to the persistent pain, patient refusal, scar, late recovery, limping and gait abnormality associated with pain, and limited amount of bone , and all these with 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.

The primary aim of ORTHOUNION is to prove the efficacy of an advanced therapy medicinal product (ATMP) in long bone non-unions, developed after bone fracture, in a comparative, multicentre, multinational, well-powered randomized clinical trial (RCT). This advanced RCT may confirm previous encouraging results and provide high level evidence. The importance of an evidence-based positive confirmation would be the translation of this ATMP towards clinical application as an efficacious therapeutic strategy for unmet clinical needs of significant complexity such as unhealed severe traumatic injuries, while decreasing disability and improving quality of life in patients.
The secondary aim of the project is to pave the way to the future clinical translation by defining exploitation strategies based on real economic evaluations. This is reinforced by associated innovation to facilitate personalized medicine approaches with safe and efficacious but variable autologous cells.
Therefore, the overall objective of ORTHOUNION is to obtain evidence on the efficacy of an ATMP for bone regeneration. In case of positive results, these would support the progress of bone regenerative

Work performed

During this first periodic report, we set up the bases to conduct the comparative clinical trial by producing the 100% of the study documents and to get the corresponding national competent authorities (NCA) and ethic committees (EC) authorizations. All the needed standard operating procedures (SOP) to produce and to transport the Investigational Medicinal Product (IMP, expanded bone marrow derived mesenchymal stromal cells) has been established as well as the SOPs for storage of the samples that will be used for innovation purposes.
We achieved the 22% of the project actions, with 50% of the clinical centres available for recruiting and treating cases. The methodology for cost studies was established and the instruments to collect cost were included in the clinical trial case report form (CRF) for future cost utility/cost effectiveness studies.
Eight patients were included in the clinical trial (six treated) and not safety issues were seen in the reporting period.
Regarding the innovation actions, the delay in starting the recruitment in some of the participating countries delayed the availability of cell samples for the innovation working package. Some actions have been started but without conclusive results.

Final results

Although the clinical trial is still ongoing, and therefore the results will not be available until the end of the trial, the project has obtained results beyond the state-of-the-art in some aspects. First, the validation of the non-union radiological bone healing scale (REBORNE scale) has been completed. The REBORNE bone healing scale was defined to approach a more detailed evaluation of long bone consolidation from radiographs and CTs. Measures with CT or radiographic were found reliable among 3 raters at a follow-up time above 6 months for long bones non-union fractures, based on the clinical cases from the ORTHO1 pivotal trial before the ORTHOUNION project. The REBORNE scale measured with radiographs proved to be valid to assess consolidation against CT measurements. These results increased the robustness of the ORTHOUNION clinical trial efficacy endpoint assessment.
Secondly, the international multicentric approval of the clinical trial was completed in all the participating countries. This is a beyond the state-of-the-art achievement because many new hurdles appeared, even in the case of previously approved investigational medicinal product, associated to continuous changes in the regulatory approach of the participating member states.

Website & more info

More info: https://orthounion.eu/.