Effects of Repeated Mesenchymal Stem Cells (MSC) in Patients With Progressive Multiple Sclerosis

Study Overview
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Brief Summary
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An open prospective study with multiple (every 6-12 months) intrathecal or intravenous injections of autologous MSC in patients with progressive forms of MS (secondary progressive, primary progressive or relapsing-progressive), who failed to respond to first and second lines of immunomodulatory treatments and deteriorated (at least 0.5 degree in the EDSS scale) during the year preceding their inclusion to our study or had at least one major relapse without sufficient recovery.

Detailed Description
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An open prospective study with multiple intrathecal or intravenous injections of autologous MSC in 24 patients with progressive forms of MS (secondary progressive, primary progressive or relapsing-progressive), who failed to respond to first and second lines of immunomodulatory treatments and deteriorated (at least 0.5 degree in the EDSS scale) during the year preceding their inclusion to our study or had at least one major relapse without sufficient recovery. Patients will be treated with 1x10 million MSC per kg of body weight, intrathecally and intravenously and subsequently with up to 8 courses of IT- or IV-injections of MSC (at the same dose), at intervals of 6-12 months. The duration of the trial is 4 years. Patients will be followed up every 3 months for the whole duration of the trial, for safety assessment and changes in the disability scores (EDSS). Immunological analysis will be performed at 4 time points (day 1, month 1, month 3 and month 6) following the first MSC-treatment and will include a fluorescent cell sorter (FACS) analysis to evaluate the proportions of the lymphocytes expressing markers of immune activation or of regulatory cell phenotype.

Official Title
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Long Term Clinical and Immunological Effects of Repeated Mesenchymal Stem Cells (MSC) Injections in Patients With Progressive Forms of Multiple Sclerosis (MS)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Biological: Mesenchymal Stem Cells (MSC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consenting patients fulfilling the Poser's criteria for definite MS Age 18-70 Male and female EDSS rate 5.5-7.5 (moderate to high disability) Failure to two lines of the currently available registered immunomodulatory treatments for MS. The lack of response to these treatments was determined by either an increase in EDSS or the appearance of at least two relapses of MS during the year prior to inclusion. Exclusion Criteria: Patients who were treated with cytotoxic medications during the last three months prior to the infusion. Patients suffering from significant cardiac, renal or hepatic failure or any other disease that may risk the patient or interfere with the ability to interpret the results. Patients with active infections. Patients with cognitive decline or inability to understand and sign the informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Interventional Model Description: Single Center, Open phase study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Repeated MSCs treatment in MS patients<br>Treatment with intrathecal and intravenous injection of autologous MSC (1 million cells per Kg of body weight) | Biological: Mesenchymal Stem Cells (MSC)<br>* Repeated intrathecal and intravenous injection of autologous mesenchymal stem cells (1 million cells per Kg of body weight) at 6 months intervals.<br>* Other names: MSC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Appearance of adverse events | To evaluate the safety and tolerability of MSCs repeated treatment in progressive MS patients | 48 months following first treatment | 
| The changes in Expanded Disability Status Scale (EDSS) score 0-10 scale, higher scores show worsening of disability) | To evaluate the changes in Expanded Disability Status Scale (EDSS) score after repeated MSC treatments compared to run-in period. | 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the percentage of CD4/CD25/FoxP3 triple positive stained cells (T regulatory cells), following MSC-treatment | The percentage of CD4/CD25/FoxP3 triple positive stained cells, will be tested in the peripheral blood mononuclear cells obtained from MSC-treated patients using a fluorescent cell sorter (FACS) at 1 day, 1, 3 and 6 months post-MSC treatment and compared to baseline (before treatment) values for each patient. The mean post treatment values will be compared to the respective pre-treatmnent values at each time point. | up to 6 months | 
| Changes in the percentage of CD3+CD69+ cells (activated lymphocytes), following MSC-treatment | The percentage of CD3+CD69+ cells (activated lymphocytes), will be tested in the peripheral blood mononuclear cells obtained from MSC-treated patients using a fluorescent cell sorter (FACS) at 1 day, 1, 3 and 6 months post-MSC treatment and compared to baseline (before treatment) values for each patient. The mean post treatment values will be compared to the respective pre-treatmnent values at each time point. | up to 6 months | 
| Changes in the percentage of CD11c+/CD86+/Lin- cells (dendritic cells and antigen-presenting macrophages), following MSC-treatment | The percentage of CD11c+/CD86+/Lin- cells (dendritic cells and antigen-presenting macrophages), will be tested in the peripheral blood mononuclear cells obtained from MSC-treated patients using a fluorescent cell sorter (FACS) at 1 day, 1, 3 and 6 months post-MSC treatment and compared to baseline (before treatment) values for each patient. The mean post treatment values will be compared to the respective pre-treatmnent values at each time point. | up to 6 months | 
| Changes in the proliferation ability of mononuclear cells to PHA, following MSC-treatment | The proliferation ability of mononuclear cells to PHA will be tested in the peripheral blood mononuclear cells obtained from MSC-treated patients using a standard proliferative Thymidine-uptake assay at 1 day, 1, 3 and 6 months post-MSC treatment and compared to baseline (before treatment) values for each patient. The mean post treatment value (proliferation index) will be compared to the respective pre-treatmnent values at each time point. | up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Mesenchymal Stem Cells