Treatment of Knee Osteoarthritis With Autologous Mesenchymal Stem Cells

Study Overview
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Brief Summary
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In this prospective study we aim to evaluate the feasibility and safety of the implantation of 40 millions MSV in knees with osteoarthritis of grade II-IV (Kellgren and Lawrence). The working hypothesis proposes that MSV antiinflammatory effect will help healing of articular cartilage degeneration to a grade enough to be objectivized by questionnaires and imaging procedures. The study of quantitative changes in structure and composition of cartilage determined by MRI T2-mapping (Cartigram ) will be performed at 6, 12 and 24 months. Pain and disability will be assessed by visual analogue scale (VAS), WOMAC, Lequesne Index and evaluation of the quality of life by Short Form 36 questionnaire (SF-36) completed at 3, 6,12 and 24 months.

Detailed Description
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Knee osteoarthritis is the most common form of arthritis. Treatments involve high costs in terms of social and economic, are palliative and do not contemplate healing by regenerative therapy. It has been shown recently, that mesenchymal stem cells (MSC) can be expanded in vitro and may regenerate several damaged or injured tissues. In addition its has demonstrated that MSC are able to modulate immune responses and to control inflammation through its action on T lymphocytes. Preliminary studies in animal models, including one carried out in an equine by our research group, confirms feasibility, safety and efficacy evidence proposed treatment protocol. Our research group has also experience in preparing clinical-grade MSC from bone marrow for other clinical trials and has all the necessary facilities and permissions to comply with GMPs imposed by recent EU legislation. Finally, our clinical team has a wide experience in regenerative therapies in several previous clinical trials for bone and cartilage. We present here an alternative proposal, aiming to anti-inflammation and regeneration by injection of single dose of mesenchymal stem cells expanded from autologous bone marrow by the GMP-complying IBGM-Valladolid procedure (MSV). Treatment involves two non-invasive surgical procedures with low morbidity: obtaining bone marrow under local anesthesia and sedation, and 4 weeks later, articular injection of the cell product (20 millions MSVs). The injection of cells does not even require anesthesia and obtaining bone marrow requires an outpatient admission two hours following safety criteria. Patients will be evaluated clinically, including pain score (VSA), pain and disability indexes (WOMAC and Lequesne) and life quality (SF-36), and by radiologic and MRI procedures no contrast and allowing quantification of morphological and structural changes of the cartilage region studied (MRI T2-mapping). The design of the study is an open-label prospective, multicenter study. It will recruit 12 patients with osteoarthritis of II-IV Kellgren and Lawrence grades, Patients will be evaluated clinically by previous studies imaging (X-rays and MRI). If they are eligible for the study we shall provide them information about the clinical trial with the Patient Information Sheet, quoting them for the Inclusion Visit. In the Inclusion Visit if the patient decides to participate in the test should sign the Informed Consent Document and a schedule for MRI and X-rays will be scheduled. The results of this exploration will be considered the standard to which compare any given change in the controls at 6 and 12 months. On this visit, routine preoperative examinations are performed (EKG, chest X-ray AP, basic analytic coagulation tests and identification of HIV, Lues and hepatitis B and C and the valuation by the Internal Medicine Service). During the visit V0 we shall verify that all inclusion criteria persist and not exclusion criteria have appeared, and we shall program V1 (to obtain bone marrow) and provide a preliminary date for MSV injection 4 week later (V2). After application, the patients will have follow-up schedule at 8 days (V3), 3 (V4), 6 (V5), 12 (V6) and eventually 24 months (V7) as detailed below. V0: Eligibility. Clinical History. Analysis, Imaging test. Programming of the following visits V1 (day 0): Bone marrow aspiration under local anesthesia and sedation V2 (day 23). MSV Implantation. V3 (+8 days from Implantation): Security evaluation. V4 (+3 months from Implantation): Security evaluation. VAS, WOMAC, Lequesne Index, SF-36 questionnaires. V5 (+6 months from Implantation): Security evaluation. VAS, WOMAC, Lequesne Index, SF-36 questionnaires, RX, RNM. V6 (+12 months from Implantation): Security evaluation. VAS, WOMAC, Lequesne Index, SF-36 questionnaires, RX, RNM. V7 (+24 months from Implantation): Security evaluation. VAS, WOMAC, Lequesne Index, SF-36 questionnaires, RX, RNM.

Official Title
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Regeneration of Articular Cartilage in Grade II, III and IV Knee Osteoarthritis by Intraarticular Injection of Autologous Bone Marrow Stem Cells Expanded ex Vivo With a GMP Procedure Developed by IBGM-Valladolid (MSV)

Conditions
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Osteoarthritis, Knee, Knee Degenerative Disease, Knee Osteoarthritis

Intervention / Treatment
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* Other: Autologous bone marrow mesenchymal stem cells (MSV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Knee osteoarthritis grade II, III and IV of Kellgren and Lawrence assessed by two observers. Chronic knee pain with mechanical characteristics. No local or systemic septic process. Haematological and biochemical analysis without significant alterations that contraindicate treatment. Informed written consent of the patient. The patient is able to understand the nature of the study Exclusion Criteria: Age over 75 or under 18 years or legally dependent Any sign of infection Positive serology for HIV-1 or HIV-2, Hepatitis B (HBsAg, Anti-HCV-Ab), Hepatitis C (Anti-HCV-Ab) and syphilis. Congenital or acquired malformation resulting in significant deformity of the knee and leading to problems in application or evaluation of results. Overweight expressed as body mass index (BMI) greater than 30.5 (obesity grade II). BMI estimated as mass (kg) / corporal surface (m2). Women who are pregnant or intend to become pregnant or breast-feeding Neoplasia Immunosuppressive states Participation in another clinical trial or treatment with a different investigational product within 30 days prior to inclusion in the study. Other pathologic conditions or circumstances that difficult participation in the study according to medical criteria

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 76 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSV autologous transplantation<br>Bone marrow collected from patient will be used for mesenchymal stem cells isolation and expansion under GMP conditions at IBGM-Valladolid (MSV). Autologous MSV implanted in knee by articular injection | Other: Autologous bone marrow mesenchymal stem cells (MSV)<br>* Bone marrow collection from patient, mesenchymal cells isolation and expansion under GMP conditions following the IBGM-Valladolid protocol (MSV). Autologous MSV implantation by articular injection.<br>* Other names: MSV, mesenchymal stem cells by IBGM-Valladolid protocol.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility and Safety of the Implementation of MSV in the Treatment of Osteoarthritis of the Knee. | Clinical review, questionaires (VAS - Visual Analogue Scale (a psychometric response scale which can be used for subjective measurements of knee pain), WOMAC - Western Ontario and McMaster Universities Osteoarthritis Index (questionnaire to quantify the pain, stiffness and physical function in patients with osteoarthritis of the knee or hip), Lequesne Index (is a composite measure of pain and disability, with specific self-report questionnaires for knee (osteoarthritis)), SF36 life quality - Short Form 36 (is a questionnaire for the detection of changes in quality of life)). In all cases, the scale was from 0 to 100%. Measurements were performed before cell transplantation (0) and 3, 6, 12 and 24 months afterwards depending on the questionnaire. For VAS, WOMAC and Lequesne, lower values represent a better outcome. For SF-36, higher values represent a better outcome. VAS-DA, VAS for pain associated to daily activities. VAS-SP, VAS for pain associated to sports activities. | 0, 3, 6, 12 and 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Indication of Efficacy | Clinical exploration, questionaires (VAS, WOMAC, Lequesne Index, SF-36 life quality) at all the periods. To evaluate effectiveness through development of criteria for quantitative MRI (Cartigram) denoting regeneration of articular cartilage at 6, 12 and 24 months after the implantation of MSV. Magnetic Resonance imaging measurements of T2 relaxation (Cartigram) performed at 0, 6 and 12 months to quantify articular cartilage degeneration. The values (in milliseconds) are T1/2 for decay of the T2 MRI signals. Normal values are below 50 ms; values above 50 ms correspond to inflamed cartilage. Mean (SD) are expressed as the percent of values (of a total of 88 measurements) that are between 50 and 90 ms. A value =5 is considered normal (can be attained by chance). Values above 5 are considered pathological. The worst possible is 100. | 0, 6, 12, 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Knee degenerative disease, osteoarthritis, gonarthrosis, stem cell, cellular therapy, regenerative therapy, Mesenchymal stem cells, Bone marrow, musculoskeletal Diseases