Repeat Infusion of Autologous Bone Marrow Cells in Multiple Sclerosis

Study Overview
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Brief Summary
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There is no cure for Multiple Sclerosis (MS) and we are always looking at new ways to stop the disease process and/or promote repair. We hypothesise that autologous bone marrow cellular therapy in chronic MS offers durable benefit. The purpose of this study is to test the safety of repeated bone marrow stem cell infusion in patients with MS. We want to find out what effects, good and/or bad, it has on you and your disability. You have previously participated in a safety study of bone marrow stem cell infusion in patients with MS. The results raised the possibility of some early partial repair; measurements of the speed of neurological impulses in the brain and spinal cord improved. The current study seeks to determine whether those benefits have persisted and whether they can be repeated or enhanced by repeating the procedure.

Detailed Description
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On the background of our own and others' experimental BM stem cell studies, we recently completed a phase 1 feasibility/safety trial of BM cell therapy in 6 patients with longstanding progressive MS (www.nature.com/clpt/journal/v87/n6/full/clpt201044a.html). Safety was confirmed, and intensive serial neurophysiological tests showed statistically significant improvements at 12 months. While highly preliminary and entirely uncontrolled, these results at least raise the possibility of a beneficial effect within the damaged central nervous system (CNS). A phase 2 clinical trial to formally assess efficacy of intravenous infusion of autologous bone marrow cells in progressive MS will commence in the near future (ACTiMuS trial). This trial comprises a programme of translational and clinical stem cell research, aiming (1) to continue translation with a phase two controlled trial of autologous bone marrow cells (BMCs) in chronic MS; and (2) to explore in parallel the potential mechanisms of action by studying BM cells from treated patients and controls, aiming to establish which BM sub-population(s) contribute(s) to efficacy, and which reparative mechanism(s) are important. It is not known whether repeated infusion of autologous bone marrow offers additional benefit or how long improvements might be expected to last. The current proposal seeks to explore whether the neurophysiological improvements observed in the phase I study persist several years after the initial single infusion and whether these can be either replicated or augmented by an additional infusion of autologous bone marrow cells. Hypothesis and aims We hypothesise that intravenously-delivered autologous bone marrow cellular therapy (BMCT) in chronic MS offers significant benefit. We hypothesize also that the mechanisms are multiple, and include immunomodulation and reparative and/or neuroprotective effects within the CNS; and are offered by one or more BM stem cell sub-populations, jointly contributing to the therapeutic impact. Exploring and understanding these mechanisms, and the biology of the cells responsible, will allow the development of more effective reparative cell therapy in MS. The current study seeks to examine whether the observed improvements noted in conduction times in central nervous system pathways in the phase I 'Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS)' persist several years following the initial single infusion and whether these can be either replicated or augmented by an additional infusion of autologous bone marrow cells and analysis of research samples will be performed as per samples included in the concurrent phase 2 clinical trial 'Assessment of bone marrow-derived cellular therapy in progressive multiple sclerosis (ACTiMuS)' (REC 12/SW/0358, ISRCTN27232902, NCT01815632).

Official Title
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Repeat Infusion of Autologous Bone Marrow Cells in Multiple Sclerosis (SIAMMS-II)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Procedure: Infusion of autologous bone marrow


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participation in the phase I safety and feasibility 'Study of Intravenous Autologous Marrow in Multiple Sclerosis' (SIAMMS) (REC reference number number 05/Q1704/137 Clin Pharmacol Ther. 2010 Jun;87(6):679-85) Exclusion Criteria: pregnancy, breastfeeding or lactation bone marrow insufficiency history of lymphoproliferative disease or previous total lymphoid irradiation immune deficiency history of current or recent (<5 years) malignancy chronic or frequent drug-resistant bacterial infections or presence of active - infection requiring antimicrobial treatment frequent and/or serious viral infection systemic or invasive fungal disease within 2 years of entry to study significant renal, hepatic, cardiac or respiratory dysfunction contraindication to anaesthesia bleeding or clotting diathesis current or recent (within preceding 12 months) immunomodulatory therapy other than corticosteroid therapy treatment with corticosteroids within the preceding 3 months radiation exposure in the past year other than chest / dental x-rays previous claustrophobia the presence of any implanted metal or other contraindication to MRI participation in another experimental study or treatment within previous 24 months

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: autologous bone marrow cells
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infusion of autologous bone marrow<br>Bone marrow harvest under general anaesthetic and intravenous infusion of filtered but otherwise unselected autologous bone marrow | Procedure: Infusion of autologous bone marrow<br>* Bone marrow harvest under general anaesthetic and intravenous infusion of filtered but otherwise unselected autologous bone marrow<br>|
| Placebo Comparator: Placebo<br> | Procedure: Infusion of autologous bone marrow<br>* Bone marrow harvest under general anaesthetic and intravenous infusion of filtered but otherwise unselected autologous bone marrow<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Number of adverse events | 1 year post-infusion of autologous bone marrow | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global evoked potential | The 'global evoked potential (GEP)' has been developed as a tool that, by combining multimodal evoked potential recordings to a single score, may be used to monitor the evolution of MS in individual patients, and as a surrogate end point in clinical trials. | Baseline then 6 months and 12 months post-infusion of autologous bone marrow | 
| MRI brain | MRI brain scan | Baseline and 6 months post-infusion of autologous bone marrow | 
| Expanded disability status scale (EDSS) | Expanded disability status scale - clinical scale of disability used in MS trials | Baseline then 6 months and 12 months post-infusion of autologous bone marrow | 
| Multiple sclerosis functional composite (MSFC) | The MSFC is a three-part quantitative assessment of disability and includes a timed walk, the nine-hole peg test and the Paced Auditory Serial Addition Test (PASAT). | Baseline then 6 months and 12 months post-infusion of autologous bone marrow | 
| Multiple sclerosis impact scale (MSIS-29) | Self-reporting questionnaire re impact of MS | Baseline then 6 months and 12 months post-infusion of autologous bone marrow | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis, bone marrow, stem cell therapy