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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
48
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.
Hadassah Medical Organization
Jerusalem, Israel
Safety Assessment
The proportions of the patients in the three treatment-groups (MSC-IV, MSC-IT and placebo) who experienced any adverse event.
Time frame: 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.
Time frame: 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
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. \[A decrease in EDSS indicates clinical improvement\].
Time frame: 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. \[A decrease in ambulation score indicates clinical improvement\].
Time frame: 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. \[A decrease in the sum of functional scores indicates clinical improvement\].
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Time frame: 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
Time frame: 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.
Time frame: 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). \[An increase in the volume of lesions indicates progression of the disease\].
Time frame: 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). \[A decrease in the brain volume indicates progression of the disease\].
Time frame: 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. \[The appearance of gadolinium-enhancing lesions in MRI indicates activity of the disease\].
Time frame: 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
Time frame: 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. \[A decrease in the value of timed walking indicates clinical improvement\].
Time frame: 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. \[A decrease in the value of timed walking indicates clinical improvement\].
Time frame: 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. \[An increase in z score indicates clinical improvement\]
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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