Immunomodulating and neuroprotective properties of autologous multipotent mesenchymal stem cells in patients with multiple sclerosis - A randomised placebo-controlled double-blinded phase II study

INTERVENTION: Trade Name: Mesenchymal stem/stromal cells Product Name: Mesenchymal stem cells (MSCs) Pharmaceutical Form: Concentrate for solution for infusion Pharmaceutical form of the placebo: Solution for injection/infusion Route of administration of the placebo: Intravenous use CONDITION: Multiple sclerosis ; MedDRA version: 18.1 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: To assess the effect of intra‐venously applied autologous MSCs on cerebral inflammation in multiple sclerosis patients Primary end point(s): Number of Gadolinium positive lesions and / or newly demonstrated or increased T2 lesions (combined unique activity) over a period of 24 weeks after administration of MSCs compared with the control period (24 weeks). Secondary Objective: To assess secondary endpoints as stated elsewhere Timepoint(s) of evaluation of this end point: 24 weeks after MSCs (or placebo) INCLUSION CRITERIA: 1. Inflammatory form of multiple sclerosis (MS) a. Relapsing‐remitting MS (RRMS) b. Secondary progressive MS (SPMS) with attacks within the last year 2. Age 18‐50 yr 3. Affected by MS 2 to 10 years 4. Expanded disability status scale (EDSS) 3.0‐6.5 5. Progression, attacks and/or progression on MRI after >= 1 yr on disease modifying treatment demonstrated by at least one of the following criteria: a. Increase >=1 EDSS point, if baseline EDSS >= 5.0 or 0.5 EDSS point, if baseline EDSS >=5.5, or quantifiable objective evidence for similar progression b. >=1 moderate‐severe attack within the last 18 months c. >=1 Gadolinium positive lesion (double or triple dose Gd) d. >=1 new T2 lesion 6. Evidence for actual inflammatory aktivity, demonstrated by one of the following: a. >=1 moderate‐severe attack within the last 18 months b. >=1 Gadolinium positive lesion (double or triple dose Gd) c. >=1 new T2 l SECONDARY OUTCOME: Secondary end point(s): 1. Comparison at 48 weeks between early versus late administration of MSCs by:; a. Change in CUA (combined unique MRI activity), ie. new or enlarged T2 lesions or Gd positive lesion over a period of 48 weeks after administration of mesenchymal stem cells in the MSC group versus the control group; b. Change in EDSS or functional systems; c. Number of relapses over a period of 24 weeks after administration of MSCs in the MSC group versus the control group; d. Disease‐free patients (no relapse, progression or MRI activity) over a period of 24 weeks after administration of MSCs in the MSC group versus the control group; ; 2. Time to first documented relapse over a period of 24 weeks after administration of MSCs versus a period of 24 weeks after administration of placebo (infusion).; A relapse is defined as development of new or worsening neurological symptoms and outcome in the absence of fever which lasts more than 48 hours. One documented relapse to be measured, corresponding to an increase of at least 1 point in either pyramidal, cerebellar, brain stem, sensory or visual function system or to an increase of at least ½ point on EDSS. A non‐documented attack is one that does not meet the criteria for a confirmed relapse.; ; 3. Total number of relapses (documented and undocumented) over a period of 24 weeks after administration of MSCs versus a period of 24 weeks after administration of placebo.; ; 4. The number of attack‐free patients over a period of 24 weeks after administration of MSCs versus a period of 24 weeks after administration of placebo.; ; 5. Change in brain volume (SIENA atrophy measurements) over a period of 24 weeks after administration of MSCs versus a period of 24 weeks after administration of placebo.; ; 6. The number of new and enlarged T2‐weighted lesions over a period of 24 weeks after administration of MSCs versus a period of 24 weeks after administration of placebo.; ; 7. Volume Change of T2‐weighted lesions over a period of 24 weeks after administration of MSCs versus a period of 24 weeks after administration of placebo.; ; 8. Volume Change of T1‐weighted lesions over a period of 24 weeks after administration of MSCs versus a period of 24 weeks after administration of placebo.; ; 9. Change in EDSS over a period of 24 weeks after administration of MSCs versus a period of 24 weeks after administration of placebo.; ; 10. The number of patients with a worsening in EDSS of 1 point maintained for 13 weeks over a period of 24 weeks after administration of MSCs versus a period of 24 weeks after administration of placebo. Timepoint(s) of evaluation of this end point: As described elsewhere (E.5.2)