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Recombinant Human Platelet-Derived Growth Factor BB in Combination With a Beta-Tricalcium Phosphate (rhPDGF-BB/β-TCP)-Collagen Matrix as an Alternative to Autograft.
Daniels, TR, Anderson, J, Swords, MP, Maislin, G, Donahue, R, Pinsker, E, Quiton, JD
Foot & ankle international. 2019;(9):1068-1078
Abstract
BACKGROUND Joint arthrodesis often employs autograft to promote union; graft harvesting can lead to perioperative morbidity. A Canadian randomized controlled trial (RCT) demonstrated that recombinant human platelet-derived growth factor BB homodimer (rhPDGF-BB) combined with beta-tricalcium phosphate (β-TCP)-collagen was a safe, effective alternative to autograft. This multicenter North American RCT compared the safety and efficacy of rhPDGF-BB/β-TCP-collagen with autograft for ankle and hindfoot fusion. Subclassification using propensity scores (PS) incorporated patients from previous trials for enhanced statistical power for noninferiority testing and broader review of treatments. METHODS Patients requiring ankle or hindfoot arthrodesis and supplemental bone graft were treated with rhPDGF-BB/β-TCP-collagen (n = 69) or autograft (n = 35). Outcomes included joint fusion on computed tomography (24 weeks), clinical healing status, visual analog scale (VAS) pain, Short-Form 12 (SF-12), American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Scale, and Foot Function Index (FFI) scores over 52 weeks. PS methodology addressed potential selection bias arising from pooling data among these patients and 2 previous RCTs with similar inclusion criteria, surgical techniques, graft harvest techniques, and outcomes. All 132 rhPDGF-BB/β-TCP-collagen-treated patients and 167 of 189 candidate autograft-treated controls were selected for comparison by an independent statistician blinded to outcomes. RESULTS In the PS subclassification, 68.1% treatment patients and 68.4% controls achieved >50% osseous bridging at fusion sites. Clinical healing status was achieved in 84.8% of treated patients and 90.7% of controls at 52 weeks. Clinical, functional, and quality of life results demonstrated noninferiority of rhPDGF-BB/β-TCP-collagen to autograft. Safety-related outcomes were equivalent. CONCLUSION PS subclassification analysis of 3 RCTs demonstrated that rhPDGF-BB/β-TCP-collagen was as effective as autograft for ankle and hindfoot fusions, with less pain and morbidity than treatment with autograft. LEVEL OF EVIDENCE Level I, prospective randomized study.
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Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial.
Gómez-Barrena, E, Rosset, P, Gebhard, F, Hernigou, P, Baldini, N, Rouard, H, Sensebé, L, Gonzalo-Daganzo, RM, Giordano, R, Padilla-Eguiluz, N, et al
Biomaterials. 2019;:100-108
Abstract
BACKGROUND ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. METHODS Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. FINDINGS With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). INTERPRETATION Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. FUNDING EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).
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A Prospective, Randomized, Multicenter Study Comparing Silicated Calcium Phosphate versus BMP-2 Synthetic Bone Graft in Posterolateral Instrumented Lumbar Fusion for Degenerative Spinal Disorders.
Coughlan, M, Davies, M, Mostert, AK, Nanda, D, Willems, PC, Rosenberg, G, Ferch, R
Spine. 2018;(15):E860-E868
Abstract
STUDY DESIGN A prospective, Phase IV, multicenter, randomized study. OBJECTIVE The aim of this study was to compare vertebral fusion success rates following posterolateral fusion [(PLF)/posterolateral intertransverse fusion (PITF)] surgery. The surgical procedure combined posterior lumbar interbody fusion (PLIF) and PLF with internal fixation over one or two levels using silicated calcium phosphate (SiCaP) or bone morphogenetic protein (BMP)-2 as graft material in patients with a degenerative disorder of the lumbar spine. SUMMARY OF BACKGROUND DATA Few controlled trials have evaluated the bone graft materials available to surgeons treating patients with spinal disorders, including degenerative disc disease, spondylolisthesis, and disc herniation. METHODS Following randomization, the surgical procedure consisting of PLIF and PLF with internal fixation over one or two levels was performed using SiCaP or BMP-2. No other osteoconductive/osteoinductive graft materials were permitted. Spinal fusion was assessed radiographically at ≤24 months. Clinical outcomes (pain on visual analog scale, Oswestry Disability Index, SF-36) and adverse events (AEs) were monitored. RESULTS One hundred three patients were enrolled. At 12 months, fusion was achieved in 25 of 35 (71.4%) of the SiCaP and 20 of 27 (74.1%) of the BMP-2 group, respectively (P = 1.000). At 24 months, the fusion rate was 78.6% and 84.8% for SiCaP and BMP-2, respectively (P = 0.5613). Clinical outcomes improved similarly in both groups over time. AEs were consistent with this surgical population. CONCLUSION SiCaP was safe and well tolerated in patients with degenerative spinal disorders requiring PLF and provided fusion rates similar to BMP-2. LEVEL OF EVIDENCE 2.
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Evaluating augmentation with calcium phosphate cement (chronOS Inject) for bone defects after internal fixation of proximal tibial fractures: A prospective, multicenter, observational study.
Oh, CW, Park, KC, Jo, YH
Orthopaedics & traumatology, surgery & research : OTSR. 2017;(1):105-109
Abstract
INTRODUCTION Managing subchondral bone defects in proximal tibia fractures after plateau reduction is an important consideration. ChronOS Inject is a recently developed calcium phosphate bone substitute that shows relatively fast osteointegration. HYPOTHESIS Using chronOS Inject during internal fixation of proximal tibial fractures provides a satisfactory treatment option that is both clinically and radiologically safe. PATIENTS AND METHODS Patients enrolled in this study were treated with chronOS Inject bone void filler, during internal fixation of proximal tibial fractures. Patients were evaluated preoperatively and at 6 weeks, 6 and 12 months postoperative. Radiographic union was assessed using plain films supplemented by CT scans. Pain, function and adverse events were collected at all visits. A total of 36 patients were enrolled in the study and treated according to a predetermined protocol. Seven of the 36 patients (19.4%) were lost to follow-up. RESULTS Successful radiographic union was achieved in 27/29 (93.1%) of patients at final follow-up. Articular subsidence of>2mm only occurred in one patient. Statistical analysis showed significant improvements both in leg pain and knee function. Progress in knee function was observed in 93.1% (27/29) of patients from 6 weeks to 12 months. No product-related complications were reported. CONCLUSIONS Successful union was achieved based on radiographic criteria as well as clinical outcomes. When managing bone defects after internal fixation of proximal tibial fractures, the use of chronOS Inject resulted in significant improvement of knee function and reduction of leg pain. LEVEL OF EVIDENCE Level IV, prospective observational study.
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Caphosol for prevention of oral mucositis in pediatric myeloablative haematopoietic cell transplantation.
Treister, N, Nieder, M, Baggott, C, Olson, E, Chen, L, Dang, H, Krailo, M, August, A, Sung, L
British journal of cancer. 2017;(1):21-27
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Abstract
BACKGROUND The primary objective was to determine whether topically administered Caphosol, rinsed orally four times daily at the initiation of conditioning, reduces the duration of severe oral mucositis (OM) compared with placebo among children and adolescents undergoing haematopoietic cell transplantation (HCT). METHODS This was a Children's Oncology Group multicentre randomised double-blinded placebo-controlled clinical trial. Patients between the ages of 4 and 21 years who were scheduled to undergo myeloablative HCT for any indication were randomised to Caphosol or placebo saline rinses four times daily from initiation of conditioning through day +20. Subjects were assessed daily for OM using the World Health Organisation (WHO) Oral Toxicity Scale, Mouth Pain Categorical Scale (0-10) and the Oral Mucositis Daily Questionnaire (OMDQ). The primary end point was duration of severe OM (WHO ⩾3). RESULTS The study enrolled 220 participants with a median age of 13.7 years (range 4.0-21.9); 163 (74%) received allogeneic HCT. The mean (±s.d.) duration of severe OM was not reduced among Caphosol (4.5±5.0 days) vs placebo (4.5±4.8; P=0.99) recipients. The incidence of severe OM in the Caphosol and placebo arms was 63% (57 out of 91) and 68% (62 out of 91), respectively (P=0.44). There were no significant differences in any of the secondary end points between the groups. CONCLUSIONS Caphosol did not reduce severe OM when compared with placebo among children and adolescents undergoing myeloablative HCT. Studies to identify effective interventions for OM are needed in this population.
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Efficacy and safety of porous hydroxyapatite/type 1 collagen composite implantation for bone regeneration: A randomized controlled study.
Sotome, S, Ae, K, Okawa, A, Ishizuki, M, Morioka, H, Matsumoto, S, Nakamura, T, Abe, S, Beppu, Y, Shinomiya, K
Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 2016;(3):373-80
Abstract
BACKGROUND Porous hydroxyapatite/collagen composite (HAp/Col) is a bioresorbable bone substitute composed of nano-scale HAp and porcine type 1 collagen. In this study, the efficacy and safety were assessed in comparison to commercially available porous β-tricalcium phosphate (β-TCP). METHODS Patients with bone defects caused by benign bone tumors, fractures, or harvesting of autografts were randomly allocated for implantation of porous HAp/Col (n = 63) or porous β-TCP (n = 63). X-ray images were scored and used to evaluate the efficacy of the implantation until 24 weeks after surgery. Blood tests and observation of the surgical site were also performed to evaluate the safety of the implants. In total, 59 and 60 cases were analyzed in the porous HAp/Col and β-TCP groups, respectively. RESULTS At 18 and 24 weeks after surgery, the highest grade of bone regeneration was more frequent in the porous HAp/Col group than in the porous β-TCP group (p = 0.0004 and 0.0254 respectively). Wilcoxon's rank sum test confirmed the superiority of porous HAp/Col from early time points onward (p = 0.0084, 4 w; p = 0.0037, 8 w; p = 0.0030, 12 w; p < 0.0001, 18 w; and p = 0.0316, 24 w). The incidence of adverse effects was higher in the porous HAp/Col group than in the β-TCP group. However, no serious adverse events were reported and no cases needed to drop out of the clinical trial. CONCLUSIONS The superiority of porous HAp/Col for bone regeneration in comparison to an established porous β-TCP was confirmed. Although the incidence of side effects associated with the porous HAp/Col implant was higher than that in the β-TCP group, no serious adverse events occurred that resulted in rejection of the implants.
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Prospective Randomized Controlled Trial of Hindfoot and Ankle Fusions Treated With rhPDGF-BB in Combination With a β-TCP-Collagen Matrix.
Daniels, TR, Younger, AS, Penner, MJ, Wing, KJ, Le, IL, Russell, IS, Lalonde, KA, Evangelista, PT, Quiton, JD, Glazebrook, M, et al
Foot & ankle international. 2015;(7):739-48
Abstract
BACKGROUND Ankle and hindfoot arthrodesis is often supplemented with autograft to promote bony union. Autograft harvest can lead to increased perioperative morbidity. Purified recombinant human platelet-derived growth factor BB homodimer (rhPDGF-BB) has stimulated bone formation in mandibular defects and hindfoot fusion. This randomized controlled trial evaluated the efficacy and safety of rhPDGF-BB combined with an injectable, osteoconductive beta-tricalcium phosphate (β-TCP)-collagen matrix versus autograft in ankle and hindfoot fusions. METHODS Seventy-five patients requiring ankle or hindfoot fusion were randomized 5:1 for rhPDGF-BB/β-TCP-collagen (treatment, n = 63) or autograft (control, n = 12). Prospective analysis included 142 autograft control subjects from another clinical trial with identical study protocols. Standardized operative and postoperative protocols were used. Patients underwent standard internal fixation augmented with autograft or 0.3 mg/mL rhPDGF-BB/β-TCP-collagen. Radiologic, clinical, and quality-of-life outcomes were assessed over 52 weeks. Primary outcome was joint fusion (50% or more osseous bridging on computed tomography) at 24 weeks. Secondary outcomes included radiographs, clinical healing status, visual analog scale pain score, American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Scale score, Foot Function Index score, and Short Form-12 score. Noninferiority P values were calculated. RESULTS Complete fusion of all involved joints at 24 weeks as indicated by computed tomography was achieved in 53 of 63 (84%) rhPDGF-BB/β-TCP-collagen-treated patients and 100 of 154 (65%) autograft-treated patients (P < .001). Mean time to fusion was 14.3 ± 8.9 weeks for rhPDGF-BB/β-TCP-collagen patients versus 19.7 ± 11.5 weeks for autograft patients (P < .01). Clinical success at 52 weeks was achieved in 57 of 63 (91%) rhPDGF-BB/β-TCP-collagen patients and 120 of 154 (78%) autograft patients (P < .001). Safety-related outcomes were equivalent. Autograft controls had 2 bone graft harvest infections. CONCLUSIONS Application of rhPDGF-BB/β-TCP-collagen was a safe, effective alternative to autograft for ankle and hindfoot fusions, eliminating the pain and morbidity associated with autograft harvesting. LEVEL OF EVIDENCE Level I, prospective randomized study.
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Caphosol, a therapeutic option in case of cancer therapy-induced oral mucositis in children? : Results from a prospective multicenter double blind randomized controlled trial.
Raphael, MF, den Boer, AM, Kollen, WJ, Mekelenkamp, H, Abbink, FC, Kaspers, GJ, Zomer-Kooijker, K, Molmans, BH, Tissing, WJ
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2014;(1):3-6
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Phase II multicenter trial of Caphosol for the reduction of mucositis in patients receiving radiation therapy for head and neck cancer.
Rao, NG, Trotti, A, Kim, J, Schell, MJ, Zhao, X, Amdur, RJ, Brizel, DM, Chambers, MS, Caudell, JJ, Miyamoto, C, et al
Oral oncology. 2014;(8):765-9
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Abstract
PURPOSE We conducted a phase II multicenter study evaluating Caphosol in patients receiving head and neck radiation (H/N RT) +/- chemotherapy or biologic sensitizer. MATERIALS/METHODS The primary endpoint of the study tested the rate of functional mucositis (WHO grade > or equal to 2) with the hypothesis that <75% of patients would develop > or equal to 2 mucositis with Caphosol compared with a historical rate of >90%. New methods were applied with higher than historic rigor. 5 Institutions were included in this study: Moffitt Cancer Center (MCC), MD Anderson Cancer Center (MDACC), Duke University Cancer Center (DUCC), University of Florida (UF) and Temple University Cancer Center (TUCC). Caphosol was taken by patients at least 4 times a day and up to 10 times per day commencing with day 1 of RT and for a total duration of 8 weeks after completion of RT. Detailed questionnaires were completed weekly by patients and a unique algorithm was used to generate the WHO grade of mucositis. RESULTS 98 Patients were enrolled in the study. 59/98 (60%) patients were evaluable for the primary endpoint giving us 80% power. All evaluable patients experienced WHO grade > or equal to 2 mucositis and the trial failed to reject the null hypothesis. > or equal to 2 mucositis rates at weeks 2, 4, 6, 11 and 15 were as follows: 45%, 90%, 98%, 71%, 50%. CONCLUSION We were unable to demonstrate that Caphosol significantly reduced WHO grade 2 or higher mucositis below a 90% historic rate. We are not surprised with this finding given our rigorous methodology in grading.
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Recombinant human platelet-derived growth factor-BB and beta-tricalcium phosphate (rhPDGF-BB/β-TCP): an alternative to autogenous bone graft.
DiGiovanni, CW, Lin, SS, Baumhauer, JF, Daniels, T, Younger, A, Glazebrook, M, Anderson, J, Anderson, R, Evangelista, P, Lynch, SE, et al
The Journal of bone and joint surgery. American volume. 2013;(13):1184-92
Abstract
BACKGROUND Joint arthrodesis employing autogenous bone graft (autograft) remains a mainstay in the treatment of many foot and ankle problems. However, graft harvest can lead to perioperative morbidity and increased cost. We tested the hypothesis that purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) homodimer combined with an osteoconductive matrix (beta-tricalcium phosphate [β-TCP]) would be a safe and effective alternative to autograft. METHODS A total of 434 patients were enrolled in thirty-seven clinical sites across North America in a prospective, randomized (2:1), controlled, non-inferiority clinical trial to compare the safety and efficacy of the combination rhPDGF-BB and β-TCP with those of autograft in patients requiring hindfoot or ankle arthrodesis. Radiographic, clinical, functional, and quality-of-life end points were assessed through fifty-two weeks postoperatively. RESULTS Two hundred and sixty patients (394 joints) underwent arthrodesis with use of rhPDGF-BB/β-TCP. One hundred and thirty-seven patients (203 joints) underwent arthrodesis with use of autograft. With regard to the primary end point, 159 patients (61.2% [262 joints (66.5%)]) in the rhPDGF-BB/β-TCP group and eighty-five patients (62.0% [127 joints (62.6%)]) in the autograft group were fused as determined by computed tomography at six months (p < 0.05). Clinically, 224 patients (86.2%) [348 joints (88.3%)]) in the rhPDGF-BB/β-TCP group were considered healed at fifty-two weeks, compared with 120 patients (87.6% [177 joints (87.2%)] in the autograft group (p = 0.008). Overall, fourteen of sixteen secondary end points at twenty-four weeks and fifteen of sixteen secondary end points at fifty-two weeks demonstrated statistical non-inferiority between the groups, and patients in the rhPDGF-BB/β-TCP group were found to have less pain and an improved safety profile. CONCLUSIONS In patients requiring hindfoot or ankle arthrodesis, treatment with rhPDGF-BB/β-TCP resulted in comparable fusion rates, less pain, and fewer side effects as compared with treatment with autograft.