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:BackgroundMultiple 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/designThis 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.DiscussionResults 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 registrationAndalusia: 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.

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.

Project description:BACKGROUND: Spasticity is a common and poorly controlled symptom of multiple sclerosis. Our objective was to determine the short-term effect of smoked cannabis on this symptom. METHODS: We conducted a placebo-controlled, crossover trial involving adult patients with multiple sclerosis and spasticity. We recruited participants from a regional clinic or by referral from specialists. We randomly assigned participants to either the intervention (smoked cannabis, once daily for three days) or control (identical placebo cigarettes, once daily for three days). Each participant was assessed daily before and after treatment. After a washout interval of 11 days, participants crossed over to the opposite group. Our primary outcome was change in spasticity as measured by patient score on the modified Ashworth scale. Our secondary outcomes included patients' perception of pain (as measured using a visual analogue scale), a timed walk and changes in cognitive function (as measured by patient performance on the Paced Auditory Serial Addition Test), in addition to ratings of fatigue. RESULTS: Thirty-seven participants were randomized at the start of the study, 30 of whom completed the trial. Treatment with smoked cannabis resulted in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo (p < 0.0001). In addition, treatment reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo (p = 0.008). Scores for the timed walk did not differ significantly between treatment and placebo (p = 0.2). Scores on the Paced Auditory Serial Addition Test decreased by 8.67 points more with treatment than with placebo (p = 0.003). No serious adverse events occurred during the trial. INTERPRETATION: Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity. Future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact.

Project description:Background Type-1 diabetes (T1D) occurs following autoimmune-induced pancreatic beta cells death. Among several treatment modalities, mesenchymal stem cells (MSCs) transplantation is promising for autoimmune disorders due to immunomodulation, regeneration, and migration to damaged tissue upon systemic injection. This study assessed the safety and efficacy of intravenous injection of autologous bone marrow-derived MSCs in newly diagnosed T1D patients. Methods After receiving informed consent, 21 patients who met the study criteria were enrolled and randomly assigned to receive either MSCs or placebo. Each patient in the experimental group received two doses of MSCs and was followed for at least one-year post-transplantation. Results The results have shown that this transplantation is safe and significantly reduces the number of hypoglycemic episodes. MSCs transplantation improved glycated hemoglobin (HbA1c), shifted serum cytokine patterns from pro-inflammatory to anti-inflammatory, increased the number of regulatory T-cells in the peripheral blood, and improved quality of life. Early transplantation of MSCs significantly improved HbA1c and C-peptide levels and shifted pro-inflammatory cytokines to anti-inflammatory cytokines. Also, exercise combined with MSCs transplantation improved glycemic and immunologic indices. Conclusions Taken together, autologous MSC transplantation is safe and effective, and its early transplantation is a promising treatment in newly diagnosed T1D children suffering from hypoglycemic episodes. Trial registration: This clinical trial was registered at the Iranian Registry of Clinical Trials (IRCT) with the identifier IRCT ID: IRCT2016070428786N1 registered on August 20, 2016 (Retrospectively registered) (https://en.irct.ir/trial/23256) and at the U.S. National Institutes of Health (ClinicalTrials.gov) with the related identifier NCT04078308 registered on September 6, 2019 (Retrospectively registered). (https://clinicaltrials.gov/ct2/show/NCT04078308). Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02941-w.

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.

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