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ORTHOpedic randomized clinical trial with expanded bone marrow MSC and bioceramics versus autograft in long bone nonUNIONs

Periodic Reporting for period 3 - ORTHOUNION (ORTHOpedic randomized clinical trial with expanded bone marrow MSC and bioceramics versus autograft in long bone nonUNIONs)

Reporting period: 2020-01-01 to 2021-06-30

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 a critical unmet clinical need. Functional capacity and quality of life in survivors of severe injuries often do not return to normal, even one year after trauma. Severe bone injuries may associate soft tissue injuries and impaired biological scenarios (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% of long-bone fractures that cannot heal properly after more than six months, with morbidity, prolonged hospitalization, and increased expenses. The most accepted standard augmentation to procure fracture and non-union healing consists of autologous bone grafting frequently obtained from the iliac crest (ICAG). ICAG is the best available biological option. Its significant 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 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 a 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 a bone fracture, in a comparative, multicentre, multinational, 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 translating 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 objective 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 medicine towards clinical application. In case of negative outcomes, these would inform the limitations of obtaining clinical benefits from this technology. Either positive or negative results may be highly valuable to define the future of the field.
Progress results indicate that 56% of the project has been executed, submitting 46% of the deliverables and achieving the 45% of Milestones. The consortium has participated in 93 communication and dissemination actions (3% Media, 59% Scientific community, 33% General Public) and publishing 16 peer-reviewed communications.
About the Orthounion clinical trial, 53 patients fulfilled the selection criteria (signed the informed consent form) and were screened by the clinical trial committee. Of the screened patients, 39 were treated, one is surgically scheduled, and two are pending randomization (total, 42 patients). Eighteen patients completed the safety follow-up and ended their participation in the trial. Twenty-three more patients are under follow-up. No relevant safety issues have been observed during screening, surgery or follow-up period.
Regarding cost studies, WP4 has developed the methodology and tools for collecting cost and utility variables and established the Decision Analytic model for the economic evaluation.
Five groups are conducting experimental studies in the innovation WP, whereas results are available but not conclusive. Groups 1 and 2 are running three experimental studies to in-vitro identity molecules released by hMSCs that could activate osteoclastogenesis; to in-vivo assess the efficiency of hCD14+ monocytes in bone formation; to in-vivo compare bone formation between allogeneic and autologous cells. Group 3 developed smart scaffold MBCP®+ granules with freeze-dried polysaccharide hydrogel. Results show the high potential of FDBS to be used as a platform for bone tissue engineering strategy. The technical file for the submission of an EC registration and FDA approval is in process. Group 4 is collecting blood samples from all the ORTHOUNION patients. Samples will be tested in order to detect the circulating biomarkers of bone regeneration. Preliminary results of group 5 show that the automation of manufacturing using bioreactor systems results in expansions above 90%, which is the release criterium for MSC in the clinical trial ORTHOUNION.
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 beyond the state-of-the-art achievement because many new hurdles appeared, even in the case of the previously approved investigational medicinal product, associated with continuous changes in the regulatory approach of the participating member states.
Studies to optimize the cell expansion cost shows the viability of cells obtained from any bioreactor system tested above 90%, which is the release criterium for MSC in the clinical trial ORTHOUNION.