MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis

Abstract

Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS.

Methods/design: This is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses.

Discussion: Results will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials.

Trial registration: Andalusia: NCT01745783 , registered on Dec 10, 2012. Badalona: NCT02035514 EudraCT, 2010-024081-21. Registered on 2012. Canada: ClinicalTrials.gov, NCT02239393 . Registered on September 12, 2014. Copenhagen: EudraCT, 2012-000518-13 . Registered on June 21, 2012. Italy: EudraCT, 2011-001295-19, and ClinicalTrials.gov, NCT01854957 . Retrospectively registered on May 16, 2013. London: Eudra CT 2012-002357-35, and ClinicalTrials.gov, NCT01606215 . Registered on May 25, 2012. Salzburg: EudraCT, 2015-000137-78 . Registered on September 15, 2015. Stockholm: ClinicalTrials.gov, NCT01730547 . Registered on November 21, 2012. Toulouse: ClinicalTrials.gov, NCT02403947 . Registered on March 31, 2015.

Keywords: Clinical trial; Mesenchymal stem cells; Mesenchymal stromal cells; Multiple sclerosis.

Conflict of interest statement

Ethics approval and consent to participate

The MESEMS trial conducted in Italy was approved by the Ethics Committee of “Azienda Ospedaliera Universitaria S. Martino di Genova” on May 30, 2012.

All trials belonging to the MESEMS network have obtained approval by local Ethical Committees.

Written informed consent will be obtained from all study participants.

Competing interests

Antonio Uccelli has received personal compensation from Novartis, TEVA, Biogen, Merck, Roche and Genzyme for public speaking and advisory boards.

Alice Laroni has received personal compensation from Novartis, Sanofi Genzyme, Biogen, Merck, Roche, and TEVA for public speaking and advisory boards.

Lou Brundin has received travel grants and lecturing fees from Sanofi/ Genzyme, Biogen, and Amirall and has participated in advisory boards for Genzyme, Sanofi, Biogen, Amirall, and Merck. Brundin has grants from Swedish medical research foundation, the Brain foundation, Stockholm Council, and Karolinska Instituet.

Michel Clanet: no conflict of interest to declare.

Oscar Fernandez, has received honoraria from Actelion, Allergan, Almirall, Bayer Schering, Biogen, Merck Serono, Novartis, Roche, and Teva.

Seyed Massoud Nabavi has received honoraria from, Biogen, Bayer, Genzyme,, Merck Serono, Novartis, Sanofi, Abidi Co., Zist daru Co., Actoverco Co. as PI of trials grants or speaker bureau.

Paolo Muraro reports no conflict of interest. He discloses travel support and speaker honoraria from Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono, and Sanofi Aventis.

Roberto S. Oliveri is currently a full-time employee at Genmab.

Ernst Radue: no conflict of interest to declare.

Johann Sellner received support for attending scientific conferences, advisory boards, lectures and consultancy within the last 12 months from Bayer, Biogen, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme.

Per Soelberg Sorensen has received personal compensation for serving on scientific advisory boards, steering committees, or independent data monitoring boards for Biogen, Merck, Novartis, TEVA, GlaxoSmithKline, MedDay Pharmaceuticals, Genzyme, Celgene, and Forward Pharma and has received speaker honoraria from Biogen, Merck, Teva, Genzyme, and Novartis. His department has received research support from Biogen, Merck, TEVA, Novartis, Sanofi-Aventis/Genzyme, and Roche.

Maria Pia Sormani received compensation for serving on the Scientific Advisory Boards of Teva, Genzyme, Novartis, Roche, and Vertex; funding for travel or speaker honoraria from Merck Serono, Teva, Genzyme, Novartis, Biogen, and Roche; consultancy from Merck Serono, Biogen, Teva, Genzyme, Roche, GeNeuro, MedDay, and Novartis; Speakers’ Bureaus from Teva, Merck Serono, Biogen, Novartis, and Genzyme.

Jens Thomas Wuerfel is CEO of MIAC AG, Switzerland. He served on advisory boards for Actelion, Biogen, Genzyme-Sanofi, Novartis, and Roche. He received funds from EU (Horizon2020), the German Research Foundation (DFG), the German Ministeries of Science and Economy (BMBF, BMWi) unrelated to this study.

Mario Alberto Battaglia has nothing to disclose.

Mark S. Freedman has received honoraria from Actelion, Biogen, Bayer, Celgene, Chugai, EMD Inc., Genzyme, Hoffman La Roche, Merck Serono, Novartis, Pendopharm, Sanofi, and Teva; grants from Genzyme and is on the Genzyme speakers’ bureau.

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Figures

Fig. 1

Schedule of enrolment, interventions, and assessments of the MESEMS trial. *Optional studies as per sites desire; §MRI at week 0 and week 24 must be performed before the IV treatment with MSC or placebo

Fig. 2

Study design and patient flow in the MESEMS trial