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Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis
  1. Peter Connick1,
  2. Floriana De Angelis2,
  3. Richard A Parker3,
  4. Domenico Plantone2,
  5. Anisha Doshi2,
  6. Nevin John2,
  7. Jonathan Stutters2,
  8. David MacManus2,
  9. Ferran Prados Carrasco2,4,
  10. Frederik Barkhof2,5,
  11. Sebastien Ourselin4,
  12. Marie Braisher2,
  13. Moira Ross3,
  14. Gina Cranswick3,
  15. Sue H Pavitt6,
  16. Gavin Giovannoni7,
  17. Claudia Angela Gandini Wheeler-Kingshott2,8,
  18. Clive Hawkins9,
  19. Basil Sharrack10,
  20. Roger Bastow11,
  21. Christopher J Weir3,
  22. Nigel Stallard12,
  23. Siddharthan Chandran1,
  24. Jeremy Chataway2
  25. on behalf of The UK Multiple Sclerosis Society Clinical Trials Network
    1. 1 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
    2. 2 Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK
    3. 3 Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
    4. 4 Department of Medical Physics and Biomedical Engineering, Translational Imaging Group (TIG), Centre for Medical Image Computing (CMIC), UCL, London, UK
    5. 5 Department of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, The Netherlands
    6. 6 Dental Translational and Clinical Research Unit (part of the NIHR Leeds CRF), University of Leeds, Leeds, UK
    7. 7 Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    8. 8 Brain MRI 3T Research Center, IRCCS Mondino Foundation, Pavia, Italy
    9. 9 Keele Medical School and Institute for Science and Technology in Medicine, Keele University, Keele, UK
    10. 10 Department of Neuroscience, Royal Hallamshire Hospital, Sheffield, UK
    11. 11 MS Society Patient Representative, London, UK
    12. 12 Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
    1. Correspondence to Dr Jeremy Chataway; j.chataway{at}


    Introduction The 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 analysis Patients 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 dissemination MS-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 numbers NCT01910259; 2012-005394-31; ISRCTN28440672.

    • progressive multiple sclerosis
    • neuroprotection
    • clinical trial
    • drug repurposing
    • mechanistic evaluation

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    • Contributors JC, SC, CJW, GG, CAGW-K, SHP, NS, CH, BS, GC, RB, MB researched and wrote the original grant application. All are involved in the set-up and running of the trial. PC, FDA, DP, AD, NJ set-up the trial and are involved in the measurement and quality assurance of the clinical and MRI outcomes. CJW and RAP have written the statistical analysis plan. JS, DMCM, FB, FP, SO have set-up and quality assured the MRI acquisition and analysis pipelines. MR and GC are the Edinburgh Clinical Trials Unit (ECTU) managers responsible for the trial.

    • Funding MS-SMART is an investigator-led project sponsored by University College London (UCL). This independent research is awarded by the Efficacy and Mechanism Evaluation Programme (EME) and funded by the Medical Research Council (MRC), the UK Multiple Sclerosis Society and the National Multiple Sclerosis Society (USA NMSS) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership. Additional support comes from the University of Edinburgh; the National Institute for Health Research University College London Hospitals (NIHR-UCLH) Biomedical Research Centre (BRC) and University College London; NIHR Leeds CRF (DenTCRU). CJW and RAP were supported in this work by NHS Lothian via the Edinburgh Clinical Trials Unit.

    • Competing interests PC, FDA, DP, AD, NJ, JS, SHP, CH, CJW, RAP, NS, SC, GC, RB, DMCM, MR declare no conflict of interests with respect to this work. MB has received funding from the UK Multiple Sclerosis Society and NIHR Local Clinical Research Network. FP receives a Guarantors of Brain fellowship. SO receives funding from the EPSRC (EP/H046410/1, EP/J020990/1, EP/K005278), the MRC (MR/J01107X/1), the EU-FP7 (FP7-ICT-2011-9-601055) and NIHR UCLH BRC ( FB serves on the editorial boards of Brain, European Radiology, Journal of Neurology, Neurosurgery & Psychiatry, Neurology, Multiple Sclerosis and Neuroradiology, and serves as consultant for Bayer Shering Pharma, Sanofi-Aventis, Biogen-Idec, TEVA Pharmaceuticals, Genzyme, Merck-Serono, Novartis, Roche, Synthon, Jansen Research and Lundbeck. CGKW receives research grants (PI and co-applicant) from Spinal Research, Craig H. Neilsen Foundation, EPSRC, Wings for Life, UK MS Society, Horizon2020, NIHR/MRC. JC has received support from the Efficacy and Mechanism Evaluation Programme and Health Technology Assessment Programme (NIHR); UK Multiple Sclerosis Society and National Multiple Sclerosis Society. In the last 3 years, he has been a local principal investigator for trials in multiple sclerosis funded by: Receptos, Novartis, Roche and Biogen-Idec, and has received an investigator grant from Novartis outside this work. He has taken part in Advisory Boards/consultancy for Roche, Merck, MedDay, Biogen and Apitope. BS has received funding from NIHR and the UK MS Society, has been a principal investigator for trials in multiple sclerosis funded by: Receptos, Novartis, Biogen, Merck, Genzyme, Roche and Teva. GG is a steering committee member on the daclizumab trials for AbbVie, the BG12 and daclizumab trials for Biogen-Idec, the fingolimod and siponimod trials for Novartis, the laquinimod trials for Teva and the ocrelizumab trials for Roche. He has also received consultancy fees for advisory board meetings for oral cladribine trials for Merck-Serono, Genzyme-Sanofi and in relation to DSMB activities for Synthon BV, as well as honoraria for speaking at the Physicians’ summit and several medical education meetings. He is also the co-chief editor of Multiple Sclerosis and Related Disorders (Elsevier).

    • Patient consent Obtained.

    • Ethics approval MS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators The MS-SMART Collaborators are: Jeremy Chataway, Claudia Gandini Wheeler-Kingshott, Floriana De Angelis, Domenico Plantone, Anisha Doshi, Nevin John, Thomas Williams; Siddharthan Chandran, Peter Connick,James Cameron, Daisy Mollison, Baljean Dhillon; Christopher J Weir, Richard Parker; Gavin Giovannoni, Sharmilee Gnanapavan; Richard Nicholas; Waqar Rashid, Julia Aram; Helen Ford; James Overell; Carolyn Young; Martin Duddy, Joe Guadagno; Nikolaos Evangelou; Matthew Craner, Jacqueline Palace; Jeremy Hobart; Basil Sharrack, David Paling; Clive Hawkins, Seema Kalra; Brendan McLean.

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