Clinical Efficacy of Autologous Mesenchymal Bone Marrow Stem Cells in Active & Progressive Multiple Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the clinical efficacy and the optimal way of administration of autologous mesenchymal bone marrow stem cells (MSC) compering intravenous injection and intrathecal injection vs. placebo, in active-progressive Multiple Sclerosis patients.

Detailed Description
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Mesenchymal stem cells (MSC) induce immune-modulatory and neurotrophic effects and were shown to have an acceptable safety profile for clinical applications. We aimed to evaluate the safety and efficacy of MSC transplantation in active progressive MS and investigate possible neuroprotective effects. Methods: This single-center double-blind crossover trial enrolled 48 patients with progressive MS (expanded disability status scale (EDSS) range: 3.5-6.5, mean: 5.6+/-0.8). Patients were randomised into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1x106/Kg) or placebo. At 6-months, treatment groups were crossed over and patients re-treated with either MSC or placebo. During the 2-months run-in period and the 12-months after treatment, participants were followed using EDSS, 25-foot timed walking, 9-hole peg test, neurocognitive tests, quantitative magnetic resonance imaging (MRI), functional MRI, optic coherence tomography (OCT), visual evoked potentials (VEP), and dynamic visual tests.

Official Title
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Phase 2 Trial to Investigate the Clinical Efficacy & the Optimal Administration (Based on the Immunological, Clinical & Neuroradiological Effects) of Autologous Mesenchymal Bone Marrow Stem Cells in Active & Progressive Multiple Sclerosis

Conditions
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Multiple Sclerosis (MS)

Intervention / Treatment
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* Biological: Mesenchymal stem cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consenting patients fulfilling the Poser's clinical criteria for definite MS Age: 18-65, males and females Duration of disease: >3 years Progressive form of MS: PPMS, SPMS (with/without relapses) EDSS score of 3.5 - 6.5 Failure to currently available, registered - first and second line immunomodulatory treatments (at least one). Evidence for new activity of MS during the 3 months before the injection of MSC. Exclusion Criteria: Patients who were treated with cytotoxic medications during the last 3 months prior to the inclusion. 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 severe cognitive decline or inability to understand and sign the informed consent Patients who received any cellular treatment in the past

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
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Patients were randomised into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs or placebo. At 6-months, treatment groups were crossed over and patients re-treated with either MSC or placebo
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IT- Treated<br>Injection to IT (Group 1). After 6 months, 8 patients (group 1A) will be treated with MSC once again in IT, and 8 additional patients (group 1B) will receive a placebo. | Biological: Mesenchymal stem cells<br>* A culture of purified MSCs was prepared under aseptic conditions, and cultured for 4 weeks, until they reached confluency, and were then harvested. After sterility was confirmed, the cells resuspended in normal saline at a concentration of 10 × 106/mL to 15 × 106/mL.<br>* Other names: Autologous MSC;|
| Experimental: IV - Treated<br>Injection to IV (Group 2). After 6 months, 8 patients (group 2A) will be treated with MSC once again in IV, and 8 additional patients (group 2B) will receive a placebo. | Biological: Mesenchymal stem cells<br>* A culture of purified MSCs was prepared under aseptic conditions, and cultured for 4 weeks, until they reached confluency, and were then harvested. After sterility was confirmed, the cells resuspended in normal saline at a concentration of 10 × 106/mL to 15 × 106/mL.<br>* Other names: Autologous MSC;|
| Placebo Comparator: Placebo<br>Placebo at the first injection (group 3). After 6 months, 8 patients (group 3A) will be treated with MSC in IT, and 8 additional patients (group 3B) will be treated with MSC in IV. | Biological: Mesenchymal stem cells<br>* A culture of purified MSCs was prepared under aseptic conditions, and cultured for 4 weeks, until they reached confluency, and were then harvested. After sterility was confirmed, the cells resuspended in normal saline at a concentration of 10 × 106/mL to 15 × 106/mL.<br>* Other names: Autologous MSC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Assessment | The proportions of the patients in the three treatment-groups (MSC-IV, MSC-IT and placebo) who experienced any adverse event. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Neurological efficacy | The proportions of the patients with treatment failure (increase of the EDSS by 1 point for patients with baseline values of 5.0 or less and of 0.5 degree for baseline EDSS of more than 5.0), confirmed by two consecutive evaluations, in the three treatment-groups. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EDSS score | Change from baseline to 6 months visit post each treatment cycle in EDSS following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [A decrease in EDSS indicates clinical improvement]. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Ambulation score | Change from baseline to 6 months visit post each treatment cycle in ambulation score following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [A decrease in ambulation score indicates clinical improvement]. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Functional scores | Change from baseline to 6 months visit post each treatment cycle in the sum of all functional scores (from the EDSS scoring) following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [A decrease in the sum of functional scores indicates clinical improvement]. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Single injection vs. repeated MSCs injection | Change from baseline to final 12-month visit, in EDSS following treatment of a single injection of MSCs vs. repeated MSCs injections treatment. [A decrease in EDSS indicates clinical improvement]. *similar comparison will be performed for the ambulation score and the sum of all functional systems' scores | 12 months: ie the total duration of the trial | 
| Relapse rate | Annualized MS-Relapse rate during the 6 months of each treatment cycle, in the three treatment groups. | 12 months: ie the total duration of the trial | 
| T2-weighted flair lesions load in MRI | The annualized rate of change in the total lesions load of the T2-weighted MRI scans during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [An increase in the volume of lesions indicates progression of the disease]. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Total brain volume in MRI | The annualized rate of change in total brain volume in MRI scans during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [A decrease in the brain volume indicates progression of the disease]. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Gadolinium enhancing lesions in MRI | The mean annualized number of gadolinium-enhancing lesions during the 6 months of each treatment cycle, in the three treatment groups. [The appearance of gadolinium-enhancing lesions in MRI indicates activity of the disease]. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Functional MRI | The annualized rate of change in the z-scores of the motor networks in resting functional MRI during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [An increase in the z-score indicates functional improvement]. * similar measurements will apply for the pyramidal and visual networks | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| 25-feet timed walking | The mean time to walk 25-feet during the 6 months in each treatment cycle vs the mean time during the run-in pre-treatment period. [A decrease in the value of timed walking indicates clinical improvement]. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| 9-hole peg test | The mean time to perform the 9-hole peg test of hands dexterity during the 6 months in each treatment cycle vs the mean time during the run-in pre-treatment period. [A decrease in the value of timed walking indicates clinical improvement]. | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Paced Auditory Serial Addition Test (PASAT) | The score given in this neuropsychological test reflects the assess capacity and rate of information processing and sustained and divided attention. This perform during the 6 months in each treatment cycle vs the mean time during the run-in pre-treatment period. [An increase in z score indicates clinical improvement] | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Cognitive function: Controlled Oral Word Association Test (COWAT) | The annualized rate of change in the z-scores of the COWAT cognitive test during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [An increase in the z-score indicates functional improvement]. * similar measurements will apply for other cognitive tests (SDMT) | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Optical coherence tomography (OCT) | Change from baseline to 6 months visit, post each treatment cycle retinal nerve fiber layer (RNFL) thickness in OCT, following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [An increase in RNFL thickness indicates clinical improvement]. * similar measurements will apply for Macula thickness | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 
| Immunology | Change from baseline to 6 months visit post each treatment cycle in the proportion of the lymphocytes expressing the CD4+CD25+ markers (T-regulatory cells) following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment at 6 months post treatment. [An increase in the proportion may indicate beneficial effects]. * similar measurements (for evaluation of safety of the treatment) will be performed for additional white blood cell subpopulations | 6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group | 

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