"Ready-to-use" Intra-articular Formulation of Mesenchymal Stromal Cells (PANLAR-II)

Enabling Advanced Medical Therapy in the Americas: A Pilot Study to Validate a "Ready-to-use" Intra-articular Formulation of Mesenchymal Stromal Cells, Aiming Toward an Effective and Scalable Treatment for Symptomatic Knee Osteoarthritis

The goal of this clinical trial is to compare a newly developed off-the-shelf cryopreserved "ready to inject" Mesenchymal Stem Cell (MSC) product with the usual MSC preparation the investigators have used in knee osteoarthritis (OA) patients. Since usual MSC therapy requires cell manipulation in GMP (Good Manufacturing Practices)-type facilities, this new formulation would enable wider access to Cell therapy and Multicentric clinical trials in areas devoid of expensive facilities and equipment.

This is a double blind randomized controlled trial testing a modified formulation of an allogenic Umbilical cord (UC) derived MSC therapy that the investigators have used in a prior published clinical trial. It has been modified and characterized according to the standards of quality control that are required for the development an off-the-shelf cryopreserved MSCs product. This so called "ready to inject" MSC preparation will be compared with the usual MSC formulation that requires centrifugation and resuspension in different media, thus requiring access to advanced (GMP-type) facilities. A total of 60 symptomatic knee OA patients will be randomized (1.1 ratio) to receive one or the other MSC product at baseline and month 6, to be followed blindly for 12 months with baseline and end of study knee MRI imaging. The primary endpoint of the trial will be the safety according to the occurrence of adverse events (AEs) as coded by the Common Terminology Criteria for Adverse Event classification. The secondary endpoint will be efficacy, as assessed by the following validated clinical outcome measures: Western Ontario and Mc Master Universities Arthritis Index (WOMAC) Spanish validated version, Pain Visual Analog scale (VAS), Quality of life by the Short-form 36 (SF-36) questionnaire, Patient Global Assessment, and the Outcome Measures in Rheumatology Committee (OMERACT)-Osteoarthritis Research Society International (OARSI) Responder Index Criteria. Baseline MRI will be performed mainly to exclude meniscal lesions associated with accelerated knee OA. Final (12 month) MRI will be performed to assess structural change in response to treatment The completion of this project represents a main technological advance, eventually leading to the scalability and enhanced quality control of a much needed treatment, within reasonable costs and logistics, and in particular, with no need of a GMP facility at the point of care or of clinical testing

Osteoarthritis, Degenerative joint disease, Cell therapy, Advanced Medicinal Therapy Product, Mesenchymal Stromal Cell, Mesenchymal Stem Cell, Cryopreserved cell therapy

Participants, providers, investigators and outcome assessments will be blind to randomization except in need to open code for security reasons

Adverse events (AEs) reported for each study group as coded by the Common Terminology Criteria for Adverse Event classification.

Western Ontario and Mc Master Universities Arthritis Index (WOMAC) Spanish validated version. Scale ranges from 0-240 with higher scores indicating worsened state

Short-form 36 (SF-36) questionnaire, ranging from 0-100 with higher scores indicating better health status

Assessed by the Outcome Measures in Rheumatology Committee (OMERACT)-Osteoarthritis Research Society International (OARSI) Responder Index Criteria. Responder status requires fulfilling at least 50% improvement in pain or function with absolute change of at least 20; or at least 20% improvemente in pain, function or patient´s global assessment, with absolute change of at least 20.

Baseline and 12 month MRI will be performed to assess structural change in response to treatment as computed by the Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. This score ranges 14 imaging features from 0-332 with higher scores indicating worsened state

Inclusion Criteria: Symptomatic knee OA defined by grade 1-3 Kellgren-Lawrence radiographic changes in the targeted knee. Daily pain at the affected joint for at least 3 months before inclusion Exclusion Criteria: Bilateral symptomatic knee OA (only if the contralateral knee has more severe disease) Meniscal rupture. Condylar or tibial plateau generalized bone marrow edema on MRI Major axial deviation defined by valgus (>10°) or varus (5°) deformity of the involved leg Use of oral or intra-articular steroids or hyaluronic acid in the past 6 months Ipsilateral hip or ankle pain, local or systemic infection Any form of secondary arthritis, previous malignancy, or body mass index ≥30.

Data will be shared with researchers or scholars with no conflict of interest and once we have confirmed the data are not subject to confidentiality due to intellectual property or other issues.

Matas J, Orrego M, Amenabar D, Infante C, Tapia-Limonchi R, Cadiz MI, Alcayaga-Miranda F, Gonzalez PL, Muse E, Khoury M, Figueroa FE, Espinoza F. Umbilical Cord-Derived Mesenchymal Stromal Cells (MSCs) for Knee Osteoarthritis: Repeated MSC Dosing Is Superior to a Single MSC Dose and to Hyaluronic Acid in a Controlled Randomized Phase I/II Trial. Stem Cells Transl Med. 2019 Mar;8(3):215-224. doi: 10.1002/sctm.18-0053. Epub 2018 Dec 28.