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Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study.

ABSTRACT: Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures.In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded.Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy.Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.

SUBMITTER: Fernandez O

PROVIDER: S-EPMC5955528 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study.

Fernández Oscar O Izquierdo Guillermo G Fernández Victoria V Leyva Laura L Reyes Virginia V Guerrero Miguel M León Antonio A Arnaiz Carlos C Navarro Guillermo G Páramo Maria Dolores MD Cuesta Antonio De la A Soria Bernat B Hmadcha Abdelkrim A Pozo David D Fernandez-Montesinos Rafael R Leal Maria M Ochotorena Itziar I Gálvez Patricia P Geniz Maria Angeles MA Barón Francisco Javier FJ Mata Rosario R Medina Cristina C Caparrós-Escudero Carlos C Cardesa Ana A Cuende Natividad N

PloS one 20180516 5

<h4>Background</h4>Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures.<h4>Patients and methods</h4>In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusio ...[more]

PMID: 29768414

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Project description:IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).Methods and analysisPatients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.Ethics and disseminationMS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numbersNCT01910259; 2012-005394-31; ISRCTN28440672.

Project description:Background Multiple sclerosis (MS) is an autoimmune and demyelinating inflammatory disease that affects the central nervous system (CNS). The etiology of the disease remains unknown. Multiple theories highlight genetic, environmental, and infectious factors that may a role. MS is considered as the main cause of disability in young people. Cladribine, known chemically as (2-Chloro-2'-deoxyadenosine), is a purine analog chemotherapy used for hairy cell leukemia and other B-cell lymphomas. The goal of this study was to evaluate the safety and efficacy of cladribine in patients with rapidly evolving or early secondary progressive MS. Methods This observational, single-center, retrospective chart review at the MS Clinic in the Ottawa General Hospital, Ottawa, Canada. A total of 24 patients (median Expanded Disability Status Scale (EDSS) of 4.5) received cladribine (0.07 mg/kg/day) for four consecutive days every six months for ? 2 cycles with further cycles depending on lymphocyte recovery or disease activity to a maximum of eight cycles from 2005 until 2016 were included. Four patients who were already diagnosed with rapidly evolving or early secondary progressive multiple sclerosis (SPMS) were induced with cladribine. We evaluated relapse, EDSS, and magnetic resonance imaging (MRI) results. Results Out of 24 patients (ages ranging from 30 - 60), 80% were female. Median follow-up time was seven years. The mean relapse rate in the two years before patients were given cladribine was 1.25. Twenty patients had previously received multiple disease-modifying therapies (DMTs) (? 2) prior to receiving cladribine. Following cladribine, eight patients suffered 10 relapses (33.3% of the cohort). Annualized relapse rates (ARRs) were reduced from 1.25 to 0.42, which was statistically significant (p-value = 0.002). There was no mean difference in EDSS (p-value = 0.06): 16% deteriorated, 62% did not change, and 12.5% improved. New MRI activity (new T2 or Gad+ lesions) was noted in only seven of 24 patients. Conclusion Parenteral cladribine reduced the relapse rate from 1.25 to 0.42, which was statistically significant (p-value = 0.002). MRI activity in patients with rapidly evolving or early secondary progressive multiple sclerosis had a reasonable safety profile.

Project description:BackgroundWhile disease progression can be readily monitored in early stage relapsing multiple sclerosis (MS), it is more challenging for secondary progressive multiple sclerosis (SPMS). This advanced stage of disease has distinct pathophysiology due to compartmentalization of neuroinflammatory activity within the central nervous system, resulting in increased incidence and severity of cognitive dysfunction. The shift in the dominant disease pathways is underscored by the failure of relapsing therapies to benefit SPMS patients, highlighting the need for novel treatment strategies and clinical trial endpoints that are well-aligned with potential benefits. The Expanded Disability Status Scale (EDSS) is widely used but is weighted towards ambulatory ability, lacking sensitivity to other aspects of neurological impairment experienced in more severely disabled SPMS patients, so may not effectively capture their clinical status.To investigate the feasibility of an alternative clinical trial endpoint model for a phase 2B trial of an immune modulator for SPMS, the potential for treatment efficacy-based patient-centered outcomes was assessed within the context of a before and after, 12-week clinical trial of safety and tolerability.MethodsPatients treated with MIS416 for 12 weeks were evaluated for clinical status at baseline and end of dosing, using the established Multiple Sclerosis Functional Composite, Short Form Health Survey, and Expanded Disability Status Scale. Responder status was determined for eight outcome measures based on minimally important change, defined using published studies. To evaluate the patients' immune response to MIS416, blood plasma samples collected at baseline and pre- and 24-h post doses 1-4 were analyzed using multiplex cytokine quantification assays.ResultsUsing a combination of patient-centered outcomes, MIS416 treatment was associated with improved clinical status for 10/11 patients: eight patients showed improvement on two to five outcome measures, five of which also showed improvement by EDSS. Multi-dimensional scaling analysis of MIS416-induced factors quantified in individual patients, revealed immune response patterns which had a strong concordance with the extent of the patients' clinical response.ConclusionsThe data support the feasibility of using patient-centered outcomes as additional clinical trial endpoints, for determining the efficacy of disease-modifying therapies, in secondary progressive multiple sclerosis patients.Trial registrationClinicalTrial.gov, NCT01191996.

Dataset Information

Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study.

Publications

Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study.

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