BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-009090 on 11 September 2015. Downloaded from Repeat infusion of autologous bone marrow cells in multiple sclerosis – protocol for a phase I extension study (SIAMMS- II) For peer review only Journal: BMJ Open Manuscript ID: bmjopen-2015-009090 Article Type: Protocol Date Submitted by the Author: 15-Jun-2015 Complete List of Authors: Rice, Claire; University of Bristol, School of Clinical Sciences Marks, David; Bristol Royal Hospital for Children, Adult BMT Unit; University of Bristol, School of Clinical Sciences Walsh, Peter; North Bristol NHS Trust, Neurosciences Kane, Nick; North Bristol NHS Trust, Neurosciences Guttridge, Martin; NHS Blood and Transplant, Redondo, Juliana; University of Bristol, School of Clinical Sciences Sarkar, Pamela; University of Bristol, School of Clinical Sciences; North Bristol NHS Trust, Neurosciences Owen, Denise; North Bristol NHS Trust, Neurosciences Wilkins, Alastair; University of Bristol, School of Clinical Sciences; North Bristol NHS Trust, Neurosciences Scolding, Neil; University of Bristol Institute of Clinical Neurosciences, Neurology http://bmjopen.bmj.com/ <b>Primary Subject Neurology Heading</b>: Secondary Subject Heading: Haematology (incl blood transfusion) Multiple sclerosis < NEUROLOGY, IMMUNOLOGY, Bone marrow Keywords: transplantation < HAEMATOLOGY on September 30, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 11 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-009090 on 11 September 2015. Downloaded from 1 2 3 Repeat infusion of autologous bone marrow cells in multiple sclerosis – a 4 phase I extension study (SIAMMS-II) 5 6 7 8 Claire M. Rice1,2*, David I. Marks3, Peter Walsh2, Nick M. Kane2, Martin G. 9 4 1 1,2 2 1,2 10 Guttridge , Juliana Redondo , Pamela Sarkar , Denise Owen , Alastair Wilkins , 11 and Neil J. Scolding1,2 12 13 14 15 For peer review only 16 1School of Clinical 3Adult BMT Unit 4NHS Blood and 17 Sciences, Bristol Royal Hospital Transplant 18 19 University of Bristol, for Children Filton, 20 Southmead Hospital, University Hospitals North Bristol Park 21 Bristol, BS10 5NB, UK Bristol NHS Foundation Northway, Filton, 22 Trust & University of Bristol, BS34 7QH, UK 23 2Bristol Institute of Bristol, 24 Clinical Neurosciences, St Michael's Hill, 25 Southmead Hospital, Bristol, 26 Bristol, BS16 1JB, UK BS2 8BJ, UK 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 * Correspondence: [email protected] 36 37 38 39 Keywords: cell therapy 40 bone marrow 41 multiple sclerosis 42 reparative therapy on September 30, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 11 BMJ Open: first published as 10.1136/bmjopen-2015-009090 on 11 September 2015. Downloaded from 1 2 3 Abstract 4 5 Introduction: The ‘Study of Intravenous Autologous Marrow in Multiple Sclerosis 6 (SIAMMS)’ trial was a safety and feasibility study which examined the effect of 7 8 intravenous infusion of autologous bone marrow without myeloablative therapy. This 9 trial was well-tolerated and improvement was noted in the global evoked potential 10 (GEP) - a neurophysiological secondary outcome measure recording speed of 11 conduction in central nervous system pathways. The efficacy of intravenous delivery 12 of autologous marrow in progressive MS will be examined in the phase II study the 13 ‘Assessment of Bone Marrow-Derived Cellular Therapy in Progressive Multiple 14 Sclerosis (ACTiMuS; NCT01815632)’. In parallel with the ‘ACTiMuS’ study, the 15 current studyFor ‘SIAMMS-II’ peer will explore review the feasibility of repeated,only non-myeloablative 16 autologous bone marrow-derived cell therapy in progressive MS. Furthermore, 17 18 information will be obtained regarding the persistence or otherwise of improvements 19 in conduction in central nervous system pathways observed in the original ‘SIAMMS’ 20 study and whether these can be reproduced or augmented by a second infusion of 21 autologous bone marrow-derived cells. 22 23 24 Methods and analysis: An open, prospective, single centre phase I extension study. 25 The 6 patients with progressive MS who participated in the ‘SIAMMS’ study will be 26 invited to undergo repeat bone marrow harvest and receive an intravenous infusion 27 28 of autologous, unfractionated bone marrow as a day-case procedure. The primary 29 outcome measure is the number of adverse events and secondary outcome 30 measures will include change in clinical rating scales of disability, global evoked 31 potential and cranial MRI. 32 33 34 Ethics and dissemination: The study has UK National Research Ethics Committee http://bmjopen.bmj.com/ 35 approval (13/SW/0255). Study results will be disseminated via peer-reviewed 36 publications and conference presentations. 37 38 39 40 Trial Registration: ClinicalTrials.gov registry NCT01932593 41 42 on September 30, 2021 by guest. Protected copyright. 43 44 Strengths and limitations of this study 45 46 47 Strengths: 48 Regulated clinical trial of cell therapy for progressive MS 49 Extension data for phase I clinical trial 50 51 Limitations: 52 Open label trial 53 Small sample size 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 11 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-009090 on 11 September 2015. Downloaded from 1 2 3 Introduction 4 5 Although effective treatments for relapsing remitting multiple sclerosis (MS) are 6 available, there are no proven therapies available to halt or reverse the progressive 7 8 phase of the disease which ultimately affects the majority of people with MS. There is 9 preclinical evidence to support a reparative role for bone marrow-derived cells in 10 demyelinating disease and, following on from this, we have begun to explore the 11 potential of autologous, unselected bone marrow cells for repair in progressive MS. 12 ‘SIAMMS’ was a safety and feasibility study of intravenous autologous bone marrow 13 (BM) infusion in patients with progressive MS 1. This study was well tolerated and 14 also raised the possibility of partial repair; conduction times in multiple central 15 nervous systemFor (CNS) peer pathways collated review as a composite onlyscore (GEP) 2 3 improved in 16 all patients studied (n=6) 1. A randomised, placebo-controlled trial will determine 17 whether autologous bone marrow infusion exerts genuine reparative effects in 18 4 19 progressive MS (‘ACTiMuS’; NCT01815632) but the purpose of ‘SIAMMS-II’ is to 20 explore whether the improvements observed in the initial study performed over 5 21 years ago have persisted and whether these can be repeated or augmented. 22 23 24 Methods and design 25 26 27 Objective and hypothesis 28 29 Our hypothesis is that intravenously-delivered autologous bone marrow cell therapy 30 in chronic MS has reparative properties. We postulate that bone marrow-derived cells 31 contribute to repair within the CNS via a multiplicity of mechanisms including 32 immunomodulation and reparative and/or neuroprotective effects. Furthering our 33 understanding of these processes will enable development and refinement of cell 34 therapy for progressive MS. http://bmjopen.bmj.com/ 35 36 37 The phase II ‘ACTiMuS’ trial will explore the efficacy of intravenous infusion of 38 autologous bone marrow-derived cell therapy in progressive MS and its laboratory 39 arm will explore the underlying mechanisms of any observed effect. ‘SIAMMS-II’ will 40 run in parallel with ‘ACTiMuS’ and will investigate whether the previously observed 41 effects can be replicated and/or augmented. 42 on September 30, 2021 by guest. Protected copyright. 43 Trial design 44 45 46 ‘SIAMMS-II’ is an open, prospective, single centre, safety and feasibility extension 47 study. The study schema is presented in figure 1. The study has UK National 48 Research Ethics Committee approval (13/SW/0255). 49 50 Sample size, eligibility & enrolment 51 52 The study is limited to the 6 people who participated in the original ‘SIAMMS’ study, 53 all of whom are under active follow up at the Bristol and Avon Multiple Sclerosis 54 (BrAMS) Unit, North Bristol NHS Trust, Bristol, UK. All participants have progressive 55 56 MS and must fulfil the inclusion and exclusion criteria as detailed in table 1. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 11 BMJ Open: first published as 10.1136/bmjopen-2015-009090 on 11 September 2015. Downloaded from 1 2 3 Trial interventions 4 5 Participants will have a bone marrow harvest and re-infusion of autologous marrow 6 as a daycase procedure. A short general anaesthesic will be given for the bone 7 marrow harvest which will be taken from the posterior iliac crests. Approximately 8 600ml marrow will be collected together with a single bone marrow trephine. The 9 10 marrow aspirate will be processed by NHSBT (filtered, bagged and labelled) prior to 11 intravenous infusion. 12 13 Assuming specific written informed consent is granted, a bone marrow trephine and a 14 small sample of the bone marrow aspirate will be retained for research. Additional 15 blood samplesFor for research peer purposes review may be requested only throughout the duration of 16 the study. 17 18 Outcome Measures 19 20 21 Primary outcome measure 22 23 The primary outcome measure is the number of adverse events (AE). For the 24 purposes of the study, an AE is defined as any unfavourable and unintended sign, 25 symptom or illness that develops or worsens during the period of the study. This is 26 irrespective of the likelihood that the AE is related to study interventions.