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Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS): study protocol for a randomised controlled trial.

ABSTRACT: We have recently completed an evaluation of the safety and feasibility of intravenous delivery of autologous bone marrow in patients with progressive multiple sclerosis (MS). The possibility of repair was suggested by improvement in the neurophysiological secondary outcome measure seen in all participants. The current study will examine the efficacy of intravenous delivery of autologous marrow in progressive MS. Laboratory studies performed in parallel with the clinical trial will further investigate the biology of bone marrow-derived stem cell infusion in MS, including mechanisms underlying repair.A prospective, randomised, double-blind, placebo-controlled, stepped wedge design will be employed at a single centre (Bristol, UK). Eighty patients with progressive MS will be recruited; 60 will have secondary progressive disease (SPMS) but a subset (n = 20) will have primary progressive disease (PPMS). Participants will be randomised to either early or late (1 year) intravenous infusion of autologous, unfractionated bone marrow. The placebo intervention is infusion of autologous blood. The primary outcome measure is global evoked potential derived from multimodal evoked potentials. Secondary outcome measures include adverse event reporting, clinical (EDSS and MSFC) and self-assessment (MSIS-29) rating scales, optical coherence tomography (OCT) as well as brain and spine MRI. Participants will be followed up for a further year following the final intervention. Outcomes will be analysed on an intention-to-treat basis.Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS) is the first randomised, placebo-controlled trial of non-myeloablative autologous bone marrow-derived stem cell therapy in MS. It will determine whether bone marrow cell therapy can, as was suggested by the phase I safety study, improve conduction in multiple central nervous system pathways affected in progressive MS. Furthermore, laboratory studies performed in parallel with the clinical trial will inform our understanding of the cellular pharmacodynamics of bone marrow infusion in MS patients and the mechanisms underlying cell therapy.ISRCTN27232902 Registration date 11/09/2012. NCT01815632 Registration date 19/03/2013.

SUBMITTER: Rice CM

PROVIDER: S-EPMC4606493 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS): study protocol for a randomised controlled trial.

Rice Claire M CM Marks David I DI Ben-Shlomo Yoav Y Evangelou Nikos N Morgan Paul S PS Metcalfe Chris C Walsh Peter P Kane Nick M NM Guttridge Martin G MG Miflin Gail G Blackmore Stuart S Sarkar Pamela P Redondo Juliana J Owen Denise D Cottrell David A DA Wilkins Alastair A Scolding Neil J NJ

Trials 20151014

<h4>Background</h4>We have recently completed an evaluation of the safety and feasibility of intravenous delivery of autologous bone marrow in patients with progressive multiple sclerosis (MS). The possibility of repair was suggested by improvement in the neurophysiological secondary outcome measure seen in all participants. The current study will examine the efficacy of intravenous delivery of autologous marrow in progressive MS. Laboratory studies performed in parallel with the clinical trial ...[more]

PMID: 26467901

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Project description:Objective: To evaluate the sensitivity to change of differently calculated quantitative scores from motor evoked potentials (MEP) in patients with primary progressive multiple sclerosis (PPMS). Methods: Twenty patients with PPMS had MEP to upper and lower limbs at baseline, years 1 and 2 measured in addition to clinical assessment [Expanded Disability Status Scale (EDSS), ambulation score]; a subsample (n = 9) had a nine-hole peg test (NHPT) and a timed 25-foot walk (T25FW). Quantitative MEP scores for upper limbs (qMEP-UL), lower limbs (qMEP-LL), and all limbs (qMEP) were calculated in three different ways, based on z-transformed central motor conduction time (CMCT), shortest corticomuscular latency (CxM-sh), and mean CxM (CxM-mn). Changes in clinical measures and qMEP metrics were analyzed by repeated-measures analysis of variance (rANOVA), and a factor analysis was performed on change in qMEP metrics. Results: Expanded Disability Status Scale and ambulation score progressed in the rANOVA model (p < 0.05; post-hoc comparison baseline-year 2, p < 0.1). Lower limb and combined qMEP scores showed significant deterioration of latency (p < 0.01, MEP-LL_CxM-sh: p < 0.05) and in post-hoc comparisons (baseline-year 2, p < 0.05), qMEP_CxM-mn even over 1 year (p < 0.05). Effect sizes were higher for qMEP scores than for clinical measures, and slightly but consistently higher when based on CxM-mn compared to CxM-sh or CMCT. Subgroup analysis yielded no indication of higher sensitivity of timed clinical measures over qMEP scores. Two independent factors were detected, the first mainly associated with qMEP-LL, the second with qMEP-UL, explaining 65 and 29% of total variability, respectively. Conclusions: Deterioration in qMEP scores occurs earlier than EDSS progression in patients with PPMS. Upper and lower limb qMEP scores contribute independently to measuring change, and qMEP scores based on mean CxM are advantageous. The capability to detect subclinical changes longitudinally is a unique property of EP and complementary to clinical assessment. These features underline the role of EP as candidate biomarkers to measure effects of therapeutic interventions in PPMS.

Dataset Information

Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS): study protocol for a randomised controlled trial.

Publications

Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS): study protocol for a randomised controlled trial.

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