MEsenchymal StEm Cells for Multiple Sclerosis

Study Overview
=================
Brief Summary
-----------------
A double-blind, randomized, cross-over phase I/II study to evaluate the safety and the efficacy of the intravenous administration of autologous Mesenchymal Stem Cells (MSC) to patients with active multiple sclerosis (MS) resistant to currently available therapies.

Detailed Description
-----------------
The mechanism of action of MSC relies on their ability to modulate pathogenic immune responses and provide neuroprotection through the release of anti-apoptotic, anti-oxidant and trophic factors as demonstrated by in vitro and in vivo preclinical studies. Patients will be randomized to receive immediate vs. delayed treatment with either a dose equal to 1-2 millions/kg of body weight of autologous MSC, or equivalent volume of suspension media at baseline. At 6 months treatments will be reversed. The primary outcome of this study is to evaluate treatment's safety within one year from MSC administration by measuring the the number, time-frame and severity of adverse event and treatment's activity in terms of reduction in the total number of contrast-gadolinium enhancing lesions (GEL) by magnetic resonance imaging (MRI) scans. Secondary outcomes are to gain preliminary information on the efficacy of the experimental treatment in terms of combined MRI activity and clinical efficacy (incidence of relapses and disability progression).

Official Title
-----------------
MEsenchymal StEm Cells for Multiple Sclerosis (MESEMS) Phase I-II Clinical Trial With Autologous Mesenchymal Stem Cells (MSCs) for the Therapy of Multiple Sclerosis

Conditions
-----------------
Multiple Sclerosis

Intervention / Treatment
-----------------
* Biological: Autologous Mesenchymal Stem Cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: - 1. Diagnosis of MS a. Relapsing remitting MS (RRMS) not responding to at least a year of attempted therapy with one or more of the approved therapies (beta-interferon, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) as evidenced by one or more of the following: i. ≥1 clinically documented relapse in past 12 months ii. ≥2 clinically documented relapses in last 24 months iii. ≥1 GEL at MRI performed within the last 12 months b. Secondary progressive MS (SPMS) not responding to at least a year of attempted therapy with one or more of the approved therapies (beta-interferon, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) as evidenced by both: i. an increase of ≥1 point of the expanded disability status scale (EDSS) (if at randomization EDSS ≤ 5.0) or 0.5 EDSS point (if at randomization EDSS ≥ 5.5) in the last 12 months ii. ≥1 clinically documented relapse or ≥ 1 GEL at MRI within the last twelve months. c. Primary progressive MS (PPMS) patients with all the following features: i. an increase of ≥1 EDSS point (if at randomization EDSS ≤ 5.0) or 0.5 EDSS point (if at randomization EDSS ≥5.5), in the last twelve months ii. ≥ 1 GEL at MRI performed within the last 12 months iii. positive cerebrospinal fluid (CSF) (oligoclonal banding 2. Age 18 to 50 years 3. Disease duration 2 to 10 years (included) 4. EDSS 3.0 to 6.5 Exclusion Criteria: 1. RRMS not fulfilling inclusion criteria 2. SPMS not fulfilling inclusion criteria 3. PPMS not fulfilling inclusion criteria 4. Any active or chronic infection including infection with HIV1-2 or chronic Hepatitis B or Hepatitis C 5. Treatment with any immunosuppressive therapy, including natalizumab and fingolimod, within the 3 months prior to randomization 6. Treatment with interferon-beta or glatiramer acetate within the 30 days prior to randomization 7. Treatment with corticosteroids within the 30 days prior to randomization 8. Relapse occurred during the 60 days prior to randomization 9. Previous history of a malignancy other than basal cell carcinoma of the skin or carcinoma in situ that has been in remission for more than one year 10. Severely limited life expectancy by another co-morbid illness 11. History of previous diagnosis of myelodysplasia or previous hematologic disease or current clinically relevant abnormalities of white blood cell counts 12. Pregnancy or risk or pregnancy (this includes patients that are unwilling to practice active contraception during the duration of the study) 13. eGFR < 60 mL/min/1.73m2 or known renal failure or inability to undergo MRI examination. 14. Inability to give written informed consent in accordance with research ethics board guidelines

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous Mesenchymal Stem Cells<br>At week 0 a single infusion of either ex-vivo expanded autologous MSC or suspension media will be administered intravenously at a dose of 1-2 x 1000000 MSC/Kg body weight. At week 24, another infusion will be performed for cross-over re-treatment: at week 24 treatments will be reversed compared to week 0 | Biological: Autologous Mesenchymal Stem Cells<br>* Single dose of 1-2 x 1000000 cells/Kg body weight<br>|
| Placebo Comparator: Suspension media<br>At week 0 a single infusion of either ex-vivo expanded autologous MSC or suspension media will be administered intravenously at a dose of 1-2 x 1000000 MSC/Kg body weight. At week 24, another infusion will be performed for cross-over re-treatment: at week 24 treatments will be reversed compared to week 0 | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | Incidence and severity of adverse events in MSC treatment group compared to placebo group. | 24 weeks from the first infusion | 
| efficacy | total number of contrast-enhancing lesions (GEL) at MRI scan | 24 weeks from the first infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy | Number of GEL counted over week 28, 36 and 48 compared with the number of GEL counted over 4, 12 and 24 weeks. | 48 weeks from the first infusion | 
| Efficacy | Combined unique MRI activity (number of new or enlarging T2, or enhancing or re-enhancing lesions), volume of GEL and volume of black holes (BH) over 4, 12, 24 weeks compared between treatment groups. | 24 weeks form the first infusion | 
| Efficacy | Combined unique MRI activity, volume of GEL and volume of BH over week 28, 36 and 48 compared with the same outcomes over 4, 12 and 24 weeks. | 48 weeks from the first infusion | 
| Efficacy | Number of relapses in MSC treatment group vs. placebo group in the first 24 weeks and after cross-over re-treatment in the two groups. | 48 weeks from the first infusion | 
| Efficacy | Time to sustained progression of disability and proportion of progression-free patients compared between treatment groups during the first 24 weeks and after cross-over | 48 weeks from the first infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multiple sclerosis, Mesenchymal stem cells