Cell Therapy for IBM by Muscle Injection of ADSVF

Study Overview
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Brief Summary
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Inclusion Body Myositis is a slowly but disabling myopathy, the most frequent in patients over 50 years old. No treatments (in particular immunosuppressive) are known to be efficient. Autologous uncultured adipose-derived stromal vascular fraction (ADSVF) is recognized as an easily accessible (by a standard liposuction to obtain adipose tissue, from which ADSVF are isolated by centrifugation), safe and well tolerated source of cells with angiogenic, anti-inflammatory, immunomodulatory and regenerative properties. The purpose of our ADSVF in IBM phase I trial is to evaluate, for the first time in human diseased muscle, first the tolerance of autologous ADSVF cells locally injected in affected forearm muscles and second their capability to repair those muscles. With always the goals of tolerance first and second muscle repair, we will recruit in parallel two groups of IBM patients: the first treated by sirolimus since at least 6 months (but still disabled) and the second currently (for at least 3 months) without specific treatment for inclusion myositis.

Detailed Description
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The main objective of this study is to evaluate the tolerance of escalating doses of ADSVF, one month after intramuscular injection in the finger flexors, in the non-dominant forearm. The second objective of this study is to evaluate the efficacy in term of muscle repair (regenerative properties of ADSVF) and in term of muscle inflammation control, during 6 months, by functional strength tests, quantitative MRI and PBMC monitoring. This research is a phase I trial evaluating first the tolerance and second the efficacy of 3 escalating doses of ADSVF intramuscularly injected in the non-dominant forearm. The volume of injection will be of 1 ml in each of the 5 sites of the finger flexoses, in line at 1 cm apart, for a total dose of 5 millions (low dose) or 10 millions (intermediate dose) or 20 millions (high dose) of viable nucleated cells.These doses are chosen because of the perfect tolerance of intra-muscle injection of (in average) one million ADSVF per millilitre, with a total dose of viable nucleated cells injected between 2.5 and 8.6 millions.The cell treatment will be prepared from autologous uncultured Adipose-Derived Stromal Vascular Fraction (ADSVF) isolated by centrifugation of adipose tissue obtain by liposuction. The study population will be adult patients suffering of an Inclusion Body Myositis (IBM) fulfilling the Lloyd criteria treated by sirolimus since at least 6 months (but still disabled) - who are part of group 1 or currently (for at least 3 months) without specific treatment for inclusion myositis - who are part of group 2. The main inclusion criteria are : Patients: with an age ≥ 45 and ≤ 80 years old, with IBM defined by the Lloyd criteria: muscle weakness of finger flexors or quadriceps, and endomysial inflammatory infiltrates on muscle biopsy, and presence of invaded fibers or rimmed vacuoles on muscle biopsy, who gave their written informed consent, affiliated to a social security regime (expected AME) ; and for: group 1: treated by sirolimus since at least 6 months (but still disabled ) - group 2: currently (for at least 3 months) without specific treatment for inclusion myositis - group 2. The duration of participation of the patients will be 7 months, included one month between maximum the inclusion visit and the injection visit, and 6 month of follow-up periof after ADSVF injection.

Official Title
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Cell Therapy for Inclusion Body Myositis (IBM) by Muscle Injection of Autologous Uncultured Adipose-Derived Stromal Vascular Fraction (ADSVF): a Phase I Trial

Conditions
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Inclusion Body Myositis

Intervention / Treatment
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* Biological: ADSVF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: With an age ≥ 45 and ≤ 80 yo. Man or menopausal woman. - With IBM defined by the Lloyd criteria (Lloyd et al., 2014): muscle weakness of finger flexors or quadriceps, and endomysial inflammatory infiltrates on muscle biopsy, and presence of invaded fibers or rimmed vacuoles on muscle biopsy. Who gave their written informed consent Affiliated to a social security regime (expected AME) And for: -group 1: treated by sirolimus since at least 6 months (but still disabled ) - group 2: currently (for at least 3 months) without specific treatment for inclusion myositis. Exclusion Criteria: Impossibility to walk 10 meters Grip evaluated by MRC5 MMT at 0 OR 1. Body mass index < 18 Not able to stop any anticoagulant, or antiaggregant drugs within the week before and the 48 hours before the liposuction Severe respiratory insufficiency (FVC < 50% and/or FEV1 < 50%) Severe chronic kidney disease (Estimated Glomerular Filtration Rate < 15 ml/min and/or proteinuria > 0.5 g/24h) Cancer non in remission (necessitating specific treatment) during the past 12 months Connective Tissue Disease non in remission (necessitating specific treatment) during the past 12 months - Bone marrow transplantation Connective Tissue disease non in remission (necessitating specific treatment) during the past 12months - Immunosuppressive drugs except sirolimus, ongoing or stopped in less than 3 months Polyvalent immunoglobulins (IV or sub-cut) ongoing or stopped in less than 3 months Any biotherapies (mAbs) such as ant-CD20, CTLA4Ig, anti-TNF, anti-IL6R, anti-IL1 etc… ongoing or stopped in less than 6 months. Seropositivity for HIV, HCV or HBV Contraindication to muscle MRI Contraindications to the liposuction: eg coagulation disorders, etc… - Contraindications to anaesthetics Documented conventional antibiotics severe allergy such as ß-lactam (cephalosporin), cyclins, macrolides (for example metronidazole), quinolones Participation in another trial (Jardé 1 or Jardé 2) Legal protection (curatorship or tutorship) or safety measure

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 80 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: Experimental<br>Group 1: Patients treated by sirolimus since at least 6 months (but still disabled) Group 2: Patients currently (for at least 3 months) without specific treatment for inclusion myositis | Biological: ADSVF<br>* Group 1 and 2 : Escalating dose of ADSVF injection (5 millions of cells, 10 millions of cells and 20 millions of cells).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In each group, tolerance of escalating doses (3+3) of ADSVF in the non-dominant forearm | By determining the dose-limiting toxicity (DLT) | Days 0 (day of the injection) to day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In each group, tolerance of escalating doses (3+3) of ADSVF in the non-dominant forearm | By research of adverse events | Days 0 (day of the injection) to 6 months (end of participation) | 
| In each group, efficacy in term of muscle repair (regenerative properties of ADSVF) | Functional muscle evaluations | At day 30, 3 month and 6 month | 
| In each group, efficacy in term of muscle repair (regenerative properties of ADSVF) | Muscle mass, fatty replacement and inflammation by quantitative NMRI | At 6 month | 
| In each group, evaluation of muscle inflammation control | Immunomonitoring of the peripheral blood mononuclear cells (PBMC) | At 6 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inclusion Body Myositis, Cell Therapy, ADSVF