Dataset Information

Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis.

ABSTRACT:

Objective

Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study.

Methods

Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2×10(6) bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects.

Results

At baseline 9 patients were randomized to receive MSCs (n?=?5) or placebo (n?=?4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI?=?1.1-8.8 vs 12.3, 95% CI?=?4.4-34.5, p?=?0.064), and at the end of study to reduced mean GEL (-2.8±5.9 vs 3±5.4, p?=?0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-?+) cells in blood of MSCs treated patients.

Conclusion

Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266.

SUBMITTER: Llufriu S

PROVIDER: S-EPMC4250058 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis.

Llufriu Sara S Sepúlveda María M Blanco Yolanda Y Marín Pedro P Moreno Beatriz B Berenguer Joan J Gabilondo Iñigo I Martínez-Heras Eloy E Sola-Valls Nuria N Arnaiz Joan-Albert JA Andreu Enrique J EJ Fernández Begoña B Bullich Santi S Sánchez-Dalmau Bernardo B Graus Francesc F Villoslada Pablo P Saiz Albert A

PloS one 20141201 12

<h4>Objective</h4>Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study.<h4>Methods</h4>Patients unrespo ...[more]

PMID: 25436769

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Project description:Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, up to 30% of MM patients are unable to collect optimal numbers of peripheral blood (PB) CD34+ hematopoietic stem and progenitor cells (HSPCs) with standard G-CSF mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended receptor occupancy and enhanced in-vivo activity. The GENESIS Trial is a prospective, phase III, double-blind, placebo-controlled, international, multicenter, superiority trial with 122 adult patients randomized (2:1) to motixafortide+G-CSF or placebo+G-CSF for HSPC mobilization for ASCT in MM (NCT03246529). The primary endpoint of the study was met, with motixafortide+G-CSF enabling 92.5% of patients to collect ≥6x106 CD34+ cells/kg within 2 apheresis procedures versus 26.2% with placebo+G-CSF (p<0.0001). A key, prespecified secondary endpoint was also met, with motixafortide+G-CSF enabling 88.8% of patients to collect ≥6x106 CD34+ cells/kg in 1 apheresis versus 9.5% with placebo+G-CSF (p<0.0001). Motixafortide+G-CSF was safe and well-tolerated, with the most common treatment-emergent adverse events observed being transient, Grade 1/2 injection site reactions (pain: 50%, erythema: 27.5%, pruritis: 21.3%). In addition, extended immunophenotyping and single-cell transcriptional profiling were performed on CD34+ HSPCs mobilized on the GENESIS Trial, as well as a contemporaneous MM cohort undergoing plerixafor+G-CSF mobilization for ASCT and 3 cohorts of allogeneic HSPC donors undergoing single-agent mobilization with motixafortide, plerixafor or G-CSF alone. Motixafortide+G-CSF resulted in a 10.5-fold increase in primitive HSPCs collected versus placebo+G-CSF (p<0.0001); and significantly greater numbers of early stem and progenitors versus both placebo+G-CSF (p<0.0001) and plerixafor+G-CSF (p=0.0327). Motixafortide also preferentially mobilized HSPC subsets with upregulated gene expression pathways associated with enhanced self-renewal, regeneration and quiescence (EGF, NFB/TNF and HBO1). In conclusion, motixafortide+G-CSF mobilized significantly greater CD34+ HSPC numbers within 2 apheresis procedures versus placebo+G-CSF. Motixafortide also preferentially mobilized primitive stem and early progenitor cells with unique transcriptional profiles versus plerixafor and G-CSF.

Dataset Information

Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis.

Objective

Methods

Results

Conclusion

Publications

Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis.

Similar Datasets

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