Percutaneous administration of allogeneic bone-forming cells for the treatment of delayed unions of fractures: a pilot study

Abstract

Background: Overall, 5-10% of fractures result in delayed unions or non-unions, causing major disabilities and a huge socioeconomic burden. Since rescue surgery with autologous bone grafts can cause additional challenges, alternative treatment options have been developed to stimulate a deficient healing process. This study assessed the technical feasibility, safety and preliminary efficacy of local percutaneous implantation of allogeneic bone-forming cells in delayed unions of long bone fractures.

Methods: In this phase I/IIA open-label pilot trial, 22 adult patients with non-infected delayed unions of long bone fractures, which failed to consolidate after 3 to 7 months, received a percutaneous implantation of allogeneic bone-forming cells derived from bone marrow mesenchymal stem cells (ALLOB; Bone Therapeutics) into the fracture site (50 × 106 to 100 × 106 cells). Patients were monitored for adverse events and need for rescue surgery for 30 months. Fracture healing was monitored by Tomographic Union Score (TUS) and modified Radiographic Union Score. The health status was evaluated using the Global Disease Evaluation (GDE) score and pain at palpation using a visual analogue scale. The presence of reactive anti-human leukocyte antigen (HLA) antibodies was evaluated.

Results: During the 6-month follow-up, three serious treatment-emergent adverse events were reported in two patients, of which two were considered as possibly treatment-related. None of the 21 patients in the per-protocol efficacy population needed rescue surgery within 6 months, but 2/21 (9.5%) patients had rescue surgery within 30 months post-treatment. At 6 months post-treatment, an improvement of at least 2 points in TUS was reached in 76.2% of patients, the GDE score improved by a mean of 48%, and pain at palpation at the fracture site was reduced by an average of 61% compared to baseline. The proportion of blood samples containing donor-specific anti-HLA antibodies increased from 8/22 (36.4%) before treatment to 13/22 (59.1%) at 6 months post-treatment, but no treatment-mediated allogeneic immune reactions were observed.

Conclusion: This pilot study showed that the percutaneous implantation of allogeneic bone-forming cells was technically feasible and well tolerated in patients with delayed unions of long bone fractures. Preliminary efficacy evidence is supporting the further development of this treatment.

Trial registration: NCT02020590 . Registered on 25 December 2013. ALLOB-DU1, A pilot Phase I/IIa, multicentre, open proof-of-concept study on the efficacy and safetyof allogeneic osteoblastic cells (ALLOB®) implantation in non-infected delayed-union fractures.

Keywords: Allogeneic; Bone marrow Mesenchymal stem cells; Cell therapy; Delayed union; Fracture; Long bone; Treatment.

Conflict of interest statement

MJ, APS, OD, RW and LS declare having received fees for the study conduct from Bone Therapeutics to cover their principal investigator activities.

BVB declares having received fees for consultancy and radiological reading from Bone Therapeutics.

GH is an employee of Bone Therapeutics and owns shares in the company.

WS is an employee of Bone Therapeutics.

Figures

Fig. 1

Study design. 1A second set of X-ray images could have been performed 1 month later during screening if pre-study images were not available; 2if CT scan and/or X-ray of less than 2 weeks at the time of screening were available and of sufficient quality, they could have been used as baseline images; 3GDE by both patient and physician; 4GDE by the patient only; 5GDE by the investigator; 6visual analogue scale; 7Likert scale; 8weight-bearing score (Likert scale); 9blood sampling for the biomarkers and auto-immunity using the blood sampling kits (in the initiation kit); 10evaluated before implantation and 24 and 48 h post-implantation. W, weeks; M, months; EoS, end of the study; D, days; CT, computed tomography; GDE; Global Disease Evaluation; AE, adverse event; SAE, serious adverse event. The dashed line represents the long-term safety follow-up period

Fig. 2

Flow of participants through the study. N, number of participants

Fig. 3

Evolution of mean A total TUS (CT scan) and B mRUS (X-ray) (per-protocol efficacy population). TUS, Tomographic Union Score; CT, computed tomography; mRUS, modified Radiographic Union Score. Error bars represent the standard deviation. **Significantly higher mean total TUS/mRUS than the mean total TUS/mRUS at baseline (least square means analysis with time and baseline as fixed effects provided p-values ≤ 0.01)

Fig. 4

Change from baseline in mean GDE score evaluated by the patient (per-protocol efficacy population). GDE, Global Disease Evaluation. Error bars represent the standard deviation. **Significantly lower mean GDE score than the mean GDE score at baseline (least square means analysis with time and baseline as fixed effects provided p-values ≤ 0.01)

Fig. 5

Change from baseline in mean pain at palpation score (per-protocol efficacy population). Error bars represent the standard deviation. *Significantly lower mean pain at palpation score than the mean pain at palpation score at baseline (least square means analysis with time and baseline as fixed effects provided p-values ≤ 0.05)

Fig. 6

Mean weight-bearing score for long bones of the lower extremities (per-protocol efficacy population). Error bars represent the standard deviation