title: Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS): study protocol for a randomised controlled trial.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ISRCTN27232902 Registration date 11/09/2012. NCT01815632 Registration date 19/03/2013.
authors.affiliation: School of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, UK. c.m.rice@bristol.ac.uk.|Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, BS10 5NB, UK. c.m.rice@bristol.ac.uk.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Adult BMT Unit, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust & University of Bristol, St Michael's Hill, Bristol, BS2 8BJ, UK. david.marks@uhbristol.nhs.uk.
authors.forename: David I
authors.initials: DI
authors.lastname: Marks
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK. Y.Ben-Shlomo@bristol.ac.uk.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.affiliation: Queen's Medical Centre, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK. Nikos.Evangelou@nottingham.ac.uk.
authors.forename: Nikos
authors.initials: N
authors.lastname: Evangelou
authors.affiliation: Queen's Medical Centre, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK. Paul.Morgan@nottingham.ac.uk.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Morgan
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK. Chris.Metcalfe@bristol.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Metcalfe
authors.affiliation: Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, BS10 5NB, UK. Peter.walsh@nbt.nhs.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Walsh
authors.affiliation: Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, BS10 5NB, UK. Nick.kane@nbt.nhs.uk.
authors.forename: Nick M
authors.initials: NM
authors.lastname: Kane
authors.affiliation: NHS Blood and Transplant, North Bristol Park, Bristol, BS34 7QH, UK. martin.guttridge@nhsbt.nhs.uk.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Guttridge
authors.affiliation: NHS Blood and Transplant, North Bristol Park, Bristol, BS34 7QH, UK. gail.miflin@nhsbt.nhs.uk.
authors.forename: Gail
authors.initials: G
authors.lastname: Miflin
authors.affiliation: NHS Blood and Transplant, North Bristol Park, Bristol, BS34 7QH, UK. stuart.blackmore@nhsbt.nhs.uk.
authors.forename: Stuart
authors.initials: S
authors.lastname: Blackmore
authors.affiliation: School of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, UK. pamela.sarkar@bristol.ac.uk.|Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, BS10 5NB, UK. pamela.sarkar@bristol.ac.uk.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sarkar
authors.affiliation: School of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, UK. Juliana.redondo@bristol.ac.uk.
authors.forename: Juliana
authors.initials: J
authors.lastname: Redondo
authors.affiliation: Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, BS10 5NB, UK. Denise.owen@nbt.nhs.uk.
authors.forename: Denise
authors.initials: D
authors.lastname: Owen
authors.affiliation: Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, BS10 5NB, UK. David.cottrell@nbt.nhs.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Cottrell
authors.affiliation: School of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, UK. Alastair.wilkins@bristol.ac.uk.|Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, BS10 5NB, UK. Alastair.wilkins@bristol.ac.uk.
authors.forename: Alastair
authors.initials: A
authors.lastname: Wilkins
authors.affiliation: School of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, UK. n.j.scolding@bristol.ac.uk.|Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, BS10 5NB, UK. n.j.scolding@bristol.ac.uk.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Scolding
mesh_terms: D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002985:Clinical Protocols; D004311:Double-Blind Method; D004739:England; D005071:Evoked Potentials; D006801:Humans; D057194:Intention to Treat Analysis; D008279:Magnetic Resonance Imaging; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis / Q000503:physiopathology / Q000601:surgery*; D009431:Neural Conduction; D009460:Neurologic Examination; D011446:Prospective Studies; D011930:Reaction Time; D020127:Recovery of Function; D012107:Research Design; D013116:Spinal Cord / Q000503:physiopathology; D013997:Time Factors; D041623:Tomography, Optical Coherence; D014182:Transplantation, Autologous; D016896:Treatment Outcome