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. 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. 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. 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.

Objectives: This study was conducted to evaluate the effect of simvastatin (40 mg/day) as an adjuvant therapy to interferon beta (IFNb 1a, 30 µg once weekly) in relapsing—remitting multiple sclerosis patients, compared with placebo. Methods: We enrolled 85 patients with relapsing—remitting multiple sclerosis (71% female) who were already receiving IFNb 1a (Avonex), with Expanded Disability Status Scale score of less than 5.0. The patients were assigned (in random and double-blinded fashion) into the two groups of simvastatin and placebo. All patients continued to receive their current IFNb treatment. The outcome measures were total relapse rate, Expanded Disability Status Scale score, and the number of gadolinium-enhanced (Gd+) and new T2 lesions in magnetic resonance imaging after a 1-year follow-up. We used Mann—Whitney and one-way multivariate analysis of variances to analyze the data. Results: Four patients in the placebo and two in the simvastatin group prematurely withdrew from the study due to experiencing two attacks. The total attack number in the simvastatin group was significantly lower than placebo group (moderate effect size r = 0.29) (p = 0.01). The final Expanded Disability Status Scale scores were lower in the simvastatin group (1.01 ± 1.40, mean ± SD) than in the placebo group (1.73 ± 1.49, mean ± SD), but this difference was not significant after controlling the baseline Expanded Disability Status Scale score (p = 0.07). In the simvastatin group, the mean ± SD of gadolinium-enhanced and new T2 lesions were 0.66 ± 1.18 and 3.39 ± 3.55, respectively, (compared with 0.74 ± 1.21 and 3.39 ± 3.55 in the placebo group). Although there was a decreasing trend in lesions on magnetic resonance imaging, this difference was not statistically significant (p = 0.62). The combination therapy was safe and well tolerated, and no serious adverse effect was noted. Conclusion: Our study supports the safety and efficacy of simvastatin as an add-on therapy to INFb 1a in patients with relapsing—remitting multiple sclerosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00668343. This interventional study provides Class I evidence stating that adding simvastatin 40 mg/day to IFNb 1a 30 µg a week in patients with relapsing—remitting multiple sclerosis may reduce the relapse rate (moderate effect size r = 0.29) (p = 0.01) compared with treatment with IFNb 1a alone.

Background: Multiple Sclerosis (MS) is a demyelinating disease of the nervous system which has numerous disabling effects on patients. Objectives: This study aimed at investigating the short- and long-term effects of a period of combination exercise therapy on walking distance, balance, fatigue and quality of life in multiple sclerosis patients referred to the physiotherapy clinic of Iran's Multiple Sclerosis Society in 2013. Patients and Methods: This study was a randomized controlled clinical trial on 59 patients divided into the intervention (n = 39) and control groups (n = 20). The intervention group received 10 weeks of combination therapy including aerobic, strengthening, balancing and stretching exercises. A week before, a week later and a year after the beginning of the exercises, both groups of patients received BBSS, six minute walking, Family Support Services (FSS), Expanded Disability Status Scale (EDSS) and quality of life tests. The scores of two groups were then compared using statistical tests such as repeated measures ANOVA test. Results: The results indicated significant changes in the intervention group in comparison to the control group in the second phase of the study comparing to the first one for all tests except EDSS (Mean difference scores of EDSS: -0.13), P-value = 0.60; FSS: -6.9, P-value = 0.02, Mental Quality of Life (QOL): 16.36, P-value = 0.001; Physical QOL: 12.17, P-value = 0.001, six minute walking: 137.2, P-value < 0.0001; and Berg: 3.34, P-value < 0.0001. These changes were not significant in the second phase of the study comparing to the third one; however, they were again significant in the third phase comparing to the first phase of the study (P < 0.05). Conclusions: Exercise has significant effect on improving symptoms of multiple sclerosis, and cessation of exercise may cause recurrence of symptoms in the intervention group with a slope similar to that of the control group. Therefore, continuous rather than short period exercises have valuable symptomatic and supportive relief effects in patients. Keywords: Fatigue; Quality of Life; Multiple Sclerosis; Exercise Therapy