Bone Marrow Versus Adipose Tissue as a Cell Source for Infiltrative Treatment of Knee Osteoarthritis

Study Overview
=================
Brief Summary
-----------------
The MAST-GR study is a randomized controlled interventional trial with parallel treatment arms and 1:1 allocation The primary objective of the study is to compare the safety and efficacy of a single intra-articular infiltration of Bone marrow aspirate concentrate (BMAC) with one of minimally manipulated adipose tissue (MM-AT) so as to determine the most effective cellular product in treating patients with knee osteoarthritis (OA). The secondary objective is to demonstrate whether intra-articular infiltration of BMAC or MM-AT can induce disease-modifying effects in knee OA by imaging and biological assessments on peripheral blood. The tertiary objective of the study is to identify factors that influence the clinical response to treatment (baseline characteristics of patients, biological characteristics of the treated knee, characteristics of cellular products, BMAC and MM-AT).

Detailed Description
-----------------
Patients with symptomatic unilateral knee OA will be included in a randomized controlled Trial (RCT), in which one group of patients will be treated with 1 intra-articular infiltration of BMAC, and one group will be treated with 1 intra-articular infiltration of MM-AT. A total of 204 patients will be included and will undergo infiltrative treatment after collecting informed consent for study participation and master data. Patients will be clinically evaluated at 0-2-6-12 months follow-up. Possible disease-modifying effects of the two cell products will be investigated by analysis on peripheral blood at 0-2-6-12 months follow-up and by evaluation of radiographic and magnetic resonance imaging (MRI) at 0 and 12 months follow-up. In addition, characterization of the portion of BMAC and MM-AT remaining from treatment will be carried out, as well as baseline assessment of peripheral blood on all patients, and synovial fluid and synovial membrane, where possible, to analyze their influence on clinical outcome.

Official Title
-----------------
Bone Marrow vs Adipose Tissue as a Cell Source for Infiltrative Treatment of Knee Osteoarthritis: Randomized Clinical Trial

Conditions
-----------------
Knee Osteoarthritis

Intervention / Treatment
-----------------
* Biological: Bone marrow aspirate concentrate injection
* Biological: intra-articular injection of Minimally manipulated adipose tissue


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with symptomatic unilateral knee OA with: Men or women aged 40 to 75 years; Signs and symptoms of OA with a clinical history of gonalgia or swelling for at least 6 months; Radiographic signs of OA (Kellgren-Lawrence grade 1-4); No benefit after at least 4 months of conservative treatment; Ability and consent of patients to actively participate in clinical and radiological (rx and MRI) follow-up; Signing of informed consent. Exclusion Criteria: Patients unable to express consent; Patients aged < to 40 and > to 75 years; Patients with axial deviations > 5°; Patients who have suffered trauma or undergone intra-articular infiltration of other substance in the previous 6 months; Patients who have undergone knee surgery in the previous 12 months; Patients with concomitant knee injuries causing joint pain or swelling (-focal full-thickness osteochondral defects, acute meniscal injuries); Patients with malignant neoplasms; Patients with uncompensated systemic diseases (rheumatic diseases, metabolic disorders such as diabetes and thyroid diseases); Patients with infectious diseases; Patients with histories of alcohol or drug abuse; Patients who are pregnant; Patients with allergies to anesthetics used in the procedure.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized trial with 1:1 allocation.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single intra-articular injection of BMAC<br>Patients randomized in this group will undergo single knee intra-articular injection of bone marrow aspirate concentrate (BMAC) | Biological: Bone marrow aspirate concentrate injection<br>* single intra-articular injection of Bone Marrow aspirate concentrate derived from the patient's iliac crest<br>|
| Experimental: single intra-articular injection of MM-AT<br>Patients randomized in this group will undergo single knee intra-articular injection of minimally manipulated adipose tissue (MM-AT) | Biological: intra-articular injection of Minimally manipulated adipose tissue<br>* single intra-articular injection of Minimally manipulated adipose tissue derived from the patient's abdominal adipose tissue<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Western Ontario and McMaster University Osteoarthritis index (WOMAC) - Pain subscale | It is a pathology-specific questionnaire used for the assessment of referred pain at the knee joint level in patients with OA | 6 months follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) | It's a standardized and widely used questionnaire to assess the condition of patients with osteoarthritis of the knee and includes assessment of pain, stiffness, and physical function of the joints. It can be administered to the patient. It measures 5 items for pain (range 0-20), two for stiffness (range 0-8), and 17 for functional limitation (range 0-68) that mainly relate to activities of daily living (e.g., getting up from a sitting position, bending over, going up and down stairs etc.); The score is then normalized on a 0-100 scale. Higher values indicate a worse outcome | baseline, 2 months, 6 months, 12 months follow-up | 
| Knee Injury and Osteoarthritis Outcome Score (KOOS) | This is a subjective, knee-specific rating scale that is considered one of the most reliable assessment tools in the evaluation of knee pathology. The questionnaire examines the following categories: symptoms, stiffness, pain, daily activities, sports and quality of life | baseline, 2 months, 6 months, 12 months follow-up | 
| Visual Analogue Scale (VAS) | Visual analog scale consisting of a straight line segment (10 cm length), the ends of which correspond to no pain (0) and the strongest pain imaginable (10). | baseline, 2 months, 6 months, 12 months follow-up | 
| EuroQol Visual Analogue Scale (EQ-VAS) | EQ-VAS is a visual analog scale that has a range of scores from 0 (worst imaginable health condition) to 100 (best imaginable health condition). | baseline, 2 months, 6 months, 12 months follow-up | 
| Tegner Activity Level Scale | Tegner Activity Level Scale is a questionnaire to find out the patient's level of physical activity.All patients will indicate the type of sporting activity performed and its frequency. | baseline, 2 months, 6 months, 12 months follow-up | 
| Objective parameters- Range of Motion | Evaluation of the Range of Motion for comparative analysis. | baseline, 2 months, 6 months, 12 months follow-up | 
| Objective parameters - Circumferences | Bilateral trans- and supra- patellar circumferences measurement for comparative analysis | baseline, 2 months, 6 months, 12 months follow-up | 
| Patient Acceptable Symptom State (PASS) | A tool to assess patient satisfaction in consideration of their current degree of pain, function, and daily activity. Patients can express if their state of health will be satisfying, answering yes or no. | baseline, 2 months, 6 months, 12 months follow-up | 
| Minimally Clinical Important Difference (MCID) | The patient should indicate the degree of perceived improvement after the infiltrative procedure. | baseline, 2 months, 6 months, 12 months follow-up | 
| Expectations about the effectiveness of the treatment | The patient should indicate at baseline what clinical benefits he or she expects from the treatment according to the question, What benefits do you expect to get as a result of the treatment you will undergo? the patient can choose from one of the following items:Full recovery, Definitely better, Much better, Slightly better,No change | baseline | 
| Kellgren-Lawrence score | The Kellgren Lawrence scale classifies knee OA into 4 grades of subsequent greater severity, the parameters used being reduced joint space and the presence of osteophytes | baseline, 12 months follow-up | 
| 3 Tesla Nuclear Magnetic Resonance Imaging (3T MRI) | Sequences such as T2-weighted FSE, FS-3D SPGR, and T2 Mapping will be used to assess cartilage thickness and signal, the presence of cysts and subchondral edema, joint profile, the presence of osteophytes and their size, the status of the menisci, both medial and lateral, and the status of the synovium. | baseline, 12 months follow-up | 
| Analysis of circulating micro RNAs | miRNAs, involved in OA progression, will be identified and quantified, including miR675-5p, miR-31-5p and miR-33a-5p | baseline, 2 months, 6 months, 12 months follow-up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MM-AT, mesenchymal stromal cells, Randomized controlled trial, cellular orthobiological products, bone marrow aspirate concentrate, minimally manipulated adipose tissue, BMAC, intra-articular injection, knee injection