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Efficacy of one-stage cartilage repair using allogeneic mesenchymal stromal cells and autologous chondron transplantation (IMPACT) compared to nonsurgical treatment for focal articular cartilage lesions of the knee: study protocol for a crossover randomized controlled trial.

ABSTRACT: BACKGROUND:Articular cartilage defects in the knee have poor intrinsic healing capacity and may lead to functional disability and osteoarthritis (OA). "Instant MSC Product accompanying Autologous Chondron Transplantation" (IMPACT) combines rapidly isolated recycled autologous chondrons with allogeneic MSCs in a one-stage surgery. IMPACT was successfully executed in a first-in-man investigator-driven phase I/II clinical trial in 35 patients. The purpose of this study is to compare the efficacy of IMPACT to nonsurgical treatment for the treatment of large (2-8?cm2) articular cartilage defects in the knee. METHODS:Sixty patients will be randomized to receive nonsurgical care or IMPACT. After 9 months of nonsurgical care, patients in the control group are allowed to receive IMPACT surgery. The Knee Injury and Osteoarthritis Outcome Score (KOOS), pain (numeric rating scale, NRS), and EuroQol five dimensions five levels (EQ5D-5?L) will be used to compare outcomes at baseline and 3, 6, 9, 12, and 18?months after inclusion. Cartilage formation will be assessed at baseline, and 6 and 18?months after inclusion using MRI. An independent rheumatologist will monitor the onset of a potential inflammatory response. (Severe) adverse events will be recorded. Lastly, the difference between IMPACT and nonsurgical care in terms of societal costs will be assessed by monitoring healthcare resource use and productivity losses during the study period. A health economic model will be developed to estimate the incremental cost-effectiveness ratio of IMPACT vs. nonsurgical treatment in terms of costs per quality adjusted life year over a 5-year time horizon. DISCUSSION:This study is designed to evaluate the efficacy of IMPACT compared to nonsurgical care. Additionally, safety of IMPACT will be assessed in 30 to 60 patients. Lastly, this study will evaluate the cost-effectiveness of IMPACT compared to nonsurgical care. TRIAL REGISTRATION:NL67161.000.18 [Registry ID: CCMO] 2018#003470#27 [EU-CTR; registered on 26 March 2019] NCT04236739 [ ClinicalTrials.gov ] [registered after start of inclusion; 22 January 2020].

SUBMITTER: Korpershoek JV

PROVIDER: S-EPMC7547426 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Efficacy of one-stage cartilage repair using allogeneic mesenchymal stromal cells and autologous chondron transplantation (IMPACT) compared to nonsurgical treatment for focal articular cartilage lesions of the knee: study protocol for a crossover randomized controlled trial.

Korpershoek J V JV Vonk L A LA Kester E C EC Creemers L B LB de Windt T S TS Kip M M A MMA Saris D B F DBF Custers R J H RJH

Trials 20201009 1

<h4>Background</h4>Articular cartilage defects in the knee have poor intrinsic healing capacity and may lead to functional disability and osteoarthritis (OA). "Instant MSC Product accompanying Autologous Chondron Transplantation" (IMPACT) combines rapidly isolated recycled autologous chondrons with allogeneic MSCs in a one-stage surgery. IMPACT was successfully executed in a first-in-man investigator-driven phase I/II clinical trial in 35 patients. The purpose of this study is to compare the eff ...[more]

PMID: 33036661

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Project description:BackgroundSpontaneous recovery from articular cartilage injury is difficult, and the ongoing progression of disease can eventually lead to osteoarthritis. Currently, there is no effective non-surgical treatment for articular cartilage injury. Arthroscopic debridement and microfracture surgery are performed for fibrocartilage repair. But fibrocartilage is different from normal articular cartilage, and functional recovery is not satisfactory. Therefore, it is necessary to develop more effective techniques for articular cartilage repair. Progress in material science, cell biology, biomechanics, and bioreactor technology has allowed the development of biomimetic, tissue-engineered osteochondral composites that have shown potential for the repair of damaged cartilage. We prepared biomimetic, tissue-engineered cartilage scaffolds optimized for biochemical composition and structural characteristics. Based on the experience of our pre-clinical studies on animals, a human articular cartilage acellular matrix scaffold was prepared and is in clinical use. The combination of autologous chondrocytes and scaffolds has shown satisfactory results in repairing cartilage defects in preliminary experiments.MethodsThis is a prospective randomized controlled trial. One hundred patients with full-thickness cartilage injury of the knee will be randomly divided into two groups to receive treatment with either tissue-engineered cartilage constructed using biomimetic cartilage extracellular-matrix-oriented scaffolds combined with autologous chondrocytes, or arthroscopic debridement and microfracture surgery. There will be five visiting time points: at baseline, then at 3, 6, 12, and 18 months postoperatively. The primary outcome will be therapeutic efficacy as assessed by the Lysholm score at 12 months postoperatively. The secondary outcomes will be the International Knee Documentation Committee score, Visual Analog Scale score, and cartilage injury and repair as assessed by magnetic resonance imaging as well as the incidence of postoperative adverse events.DiscussionThis trial will attempt to verify the use of tissue-engineered cartilage constructed using autologous chondrocytes combined with allogeneic, acellular cartilage matrix for the repair of cartilage defects, thereby providing favorable evidence for its use in clinical practice.Trial registrationClinicalTrials.gov, identifier: NCT02770209 . Registered on 11 May 2016.

Project description:Focal cartilage injuries in the knee might have devastating effect due to the predisposition of early onset osteoarthritis. Various surgical treatment options are available, however no statistically significant differences have been found between the different surgical treatments. This supports the suggestion that the improvement might be a result of the post-operative rehabilitation rather than the surgery itself. Autologous chondrocyte implantation (ACI) has become a recognized treatment option for larger cartilage lesions in the knee. Although ACI has been compared to other surgical treatment such as microfracture and mosaicplasty, it has never been directly compared to simple arthroscopic debridement and rehabilitation alone. In this study we want to increase clinical and economic knowledge about autologous chondrocyte implantation compared to arthroscopic debridement and physical rehabilitation in the short and long run.We will conduct a randomized controlled trial to compare ACI with simple arthroscopic debridement (AD) and physiotherapy for the treatment of cartilage lesions in the knee. The study will include a total of 82 patients, both men and non-pregnant women, with a full thickness cartilage defect in the weight bearing area of the femoral condyles or trochlea larger than 2 cm2. The lesion must be symptomatic, with a Lysholm score less than 75. The two treatment groups will receive identical rehabilitation protocol according to a modification of Wondrasch et al., which is an active rehabilitation and education program divided into 3 phases: accommodation, rehabilitation and return to activity. The patients will be followed for 24 months, with additional late follow-ups at 5 and 10 years to monitor the potential onset of osteoarthtitis. The primary outcome measure will be the difference in the KOOS knee-related quality of life (QoL) subscore in the ACI group compared to the AD group at 2 years. A combination of self-explanatory questionnaires, clinical parameters, clinical hop tests and radiographs and Magnetic Resonance Imaging (MRI) will be used as secondary endpoints.This is the first study with a high level of evidence to compare ACI with simple debridement and physiotherapy for the treatment of isolated symptomatic full thickness lesions of the knee.ClinicalTrial NCT02636881 (21 December 2015).

Project description:Background: Knee Osteoarthritis (kOA), the most common joint degenerative disorder, lacks effective therapeutics. Placenta-derived mesenchymal stromal cells (PMSCs) are effective in tissue repairing and generation, which have potential in treating kOA. This study aimed to determine the anti-kOA efficacy of PMSCs and to explore its action mode. Methods: Flow cytometry and three-line differentiation were performed for identification of PMSCs. In vivo, a rat kOA model established by anterior cruciate ligament transection (ACLT) surgery was used to evaluate the efficacy of PMSCs. Histopathological HE and SO staining with Osteoarthritis Research Society International scoring were conducted, and cartilage expressions of MMP13 and Col2 were measured by immunohistochemistry. Pain behavior parameters by mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL), were measured. In vitro, wound healing and cell immunofluorescence assays were conducted to detect the proliferation and migration ability of chondrocytes treated with PMSCs conditioned medium (PMSCs-CM). Quantitative real-time PCR (qRT-PCR) and Western blot (WB) assays were applied to explore the molecular action of PMSCs on chondrocytes. Results: The results of flow cytometry indicated that the surface markers of PMSCs (CD73 > 95%, CD90 > 95%, and CD34 < 2%) were consistent with the typical mesenchymal stromal cells. The in vivo data showed that PMSCs significantly reversed the kOA progression by protection of cartilage, regulation of anabolic (Col2) and catabolic (MMP13) expressions, and relief of pain symptoms. The in vitro data showed that PMSCs promoted chondrocyte proliferation and migration and significantly restored the IL-1β-induced abnormal gene expressions of Col2, Mmp13, Adamts4, Adamts5 and Sox9 and also restored the abnormal protein expressions of Col2, Mmp13 and Sox9 of chondrocytes. The molecular actions of PMSCs on chondrocytes in nested co-culture way or in conditioned medium way were similar, confirming a paracrine-based mode of action. Conclusion: This study demonstrated PMSCs' anti-kOA efficacy and its paracrine-based action mode, providing novel knowledge of PMSCs and suggesting it as a promising cell therapy for treatment of kOA.

Dataset Information

Efficacy of one-stage cartilage repair using allogeneic mesenchymal stromal cells and autologous chondron transplantation (IMPACT) compared to nonsurgical treatment for focal articular cartilage lesions of the knee: study protocol for a crossover randomized controlled trial.

Publications

Efficacy of one-stage cartilage repair using allogeneic mesenchymal stromal cells and autologous chondron transplantation (IMPACT) compared to nonsurgical treatment for focal articular cartilage lesions of the knee: study protocol for a crossover randomized controlled trial.

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