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

BMJ Open

Volumn 8, Issue 8, 2018, Pages

  Connick, Peter ^a   De Angelis, Floriana ^b   Parker, Richard A ^a   Plantone, Domenico ^b   Doshi, Anisha ^b   John, Nevin ^b   Stutters, Jonathan ^b   Macmanus, David ^b   Prados Carrasco, Ferran ^b,c   Barkhof, Frederik ^b,d   Ourselin, Sebastien ^c   Braisher, Marie ^b   Ross, Moira ^a   Cranswick, Gina ^a   Pavitt, Sue H ^e   Giovannoni, Gavin ^f   Gandini Wheeler Kingshott, Claudia Angela ^b,g   Hawkins, Clive ^h   Sharrack, Basil ⁱ   Bastow, Roger ^j   Weir, Christopher J ^a   Stallard, Nigel ^k   Chandran, Siddharthan ^a   Chataway, Jeremy ^b   more..

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

^d VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^e UNIVERSITY OF LEEDS   (United Kingdom)

^f QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^g C MONDINO NATIONAL NEUROLOGICAL INSTITUTE   (Italy)

^h KEELE UNIVERSITY SCHOOL OF MEDICINE   (United Kingdom)

ⁱ ROYAL HALLAMSHIRE HOSPITAL   (United Kingdom)

^j Public and Patient Representative   (United Kingdom)

^k UNIVERSITY OF WARWICK   (United Kingdom)

more..

Author keywords

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

Indexed keywords

AMILORIDE; FLUOXETINE; PLACEBO; RILUZOLE; NEUROPROTECTIVE AGENT;

ADULT; AGED; ARTICLE; BRAIN SIZE; COMPARATIVE EFFECTIVENESS; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; FEMALE; HUMAN; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; MULTIPLE SCLEROSIS; NEUROIMAGING; NUCLEAR MAGNETIC RESONANCE IMAGING; OUTCOME ASSESSMENT; PHASE 2 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL; CLINICAL TRIAL; COMPARATIVE STUDY; MIDDLE AGED; TREATMENT OUTCOME;

ADULT; AMILORIDE; DOUBLE-BLIND METHOD; FEMALE; FLUOXETINE; HUMANS; MALE; MIDDLE AGED; MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE; NEUROPROTECTIVE AGENTS; RILUZOLE; TREATMENT OUTCOME;

EID: 85053108653     PISSN: None     EISSN: 20446055     Source Type: Journal    
DOI: 10.1136/bmjopen-2018-021944     Document Type: Article

References (46)

1. Brownlee WJ, Hardy TA, Fazekas F, et al. Diagnosis of multiple sclerosis: progress and challenges. Lancet 2017; 389: 1336-46.
2. MS International Federation. 2013. Atlas of MS http://www. atlasofms. org (Accessed 11 Apr 2018.).
3. Stadelmann C, Wegner C, Bruck W. Inflammation, demyelination, and degeneration-recent insights from MS pathology. Biochim Biophys Acta 2011; 1812: 275-82.
4. Rovaris M, Confavreux C, Furlan R, et al. Secondary progressive multiple sclerosis: current knowledge and future challenges. Lancet Neurol 2006; 5: 343-54.
5. Ransohoff RM, Hafler DA, Lucchinetti CF. Multiple sclerosis-a quiet revolution. Nat Rev Neurol 2015; 11: 134-42.
6. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med 2017; 376: 209-20.
7. Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 2018; 391: 1263-73.
8. Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol 2015; 14: 208-23.
9. Mullard A. Drug repurposing programmes get lift off. Nat Rev Drug Discov 2013; 505-6.
10. Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 2004; 3: 673-83.
11. Gold R, Linington C, Lassmann H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 2006; 129: 1953-71.
12. Baker D, Gerritsen W, Rundle J, et al. Critical appraisal of animal models of multiple sclerosis. Mult Scler 2011; 17: 647-57.
13. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 2015; 14: 183-93.
14. Salvetti M, Landsman D, Schwarz-Lam P, et al. Progressive MS: from pathophysiology to drug discovery. Mult Scler 2015; 21: 1376-84.
15. Lassmann H. Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer's disease. J Neural Transm 2011; 118: 747-52.
16. Vesterinen HM, Connick P, Irvine CM, et al. Drug repurposing: a systematic approach to evaluate candidate oral neuroprotective interventions for secondary progressive multiple sclerosis. PLoS One 2015; 10: e0117705.
17. Plantone D, De Angelis F, Doshi A, et al. Secondary Progressive Multiple Sclerosis: Definition and Measurement. CNS Drugs 2016; 30: 517-26.
18. Hobart J, Freeman J, Thompson A. Kurtzke scales revisited: the application of psychometric methods to clinical intuition. Brain 2000; 123 (Pt 5): 1027-40.
19. Bosma LV, Kragt JJ, Brieva L, et al. Progression on the Multiple Sclerosis Functional Composite in multiple sclerosis: what is the optimal cut-off for the three components? Mult Scler 2010; 16: 862-7.
20. McGhee D, Parker A, Fielding S, et al. Using "dead or dependent" as an outcome measure in clinical trials in Parkinson's disease. JNNP 2015; 86: 180-5.
21. Altmann DR, Jasperse B, Barkhof F, et al. Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis. Neurology 2009; 72: 595-601.
22. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213-21.
23. Chataway J, Fox R. Special issue: Advancing Trial Design in Progressive Multiple Sclerosis. MSJ 2017; 23: 1572-655.
24. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005; 58: 840-6.
25. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292-302.
26. Lublin FD, Reingold SC. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46: 907-11.
27. Friese MA, Craner MJ, Etzensperger R, et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med 2007; 13: 1483-9.
28. Vergo S, Craner MJ, Etzensperger R, et al. Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Brain 2011; 134: 571-84.
29. Arun T, Tomassini V, Sbardella E, et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain 2013; 136: 106-15.
30. Mostert JP, Koch MW, Heerings M, et al. Therapeutic potential of fluoxetine in neurological disorders. CNS Neurosci Ther 2008; 14: 153-64.
31. Mostert JP, Sijens PE, Oudkerk M, et al. Fluoxetine increases cerebral white matter NAA/Cr ratio in patients with multiple sclerosis. Neurosci Lett 2006; 402: 22-4.
32. Cambron M, Mostert J, Haentjens P, et al. Fluoxetine in progressive multiple sclerosis (FLUOX-PMS). 2016. ECTRIMS Online Library https://onlinelibrary. ectrimscongress. eu/ectrims/2016/32nd/147080/melissa. cambron. fluoxetine. in. progressive. multiple. sclerosis. 28fluoxpms29. html? f=m1 (accessed 22 July 2017).
33. Bellingham MC. A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci Ther 2011; 17: 4-31.
34. Killestein J, Kalkers NF, Polman CH, et al. Glutamate inhibition in MS: the neuroprotective properties of riluzole. J Neurol Sci 2005; 233: 113-5.
35. Smith SM, Zhang Y, Jenkinson M, et al. Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 2002; 17: 479-89.
36. Smith SM, Jenkinson M, Woolrich MW, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004; 23 Suppl 1 (Suppl 1): S208-S219.
37. Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol 2006; 5: 158-70.
38. Barkhof F, Simon JH, Fazekas F, et al. MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials. Nat Rev Neurol 2011; 8: 13-21.
39. Mostert JP, Koch MW, Steen C, et al. T2 lesions and rate of progression of disability in multiple sclerosis. Eur J Neurol 2010; 17: 1471-5.
40. De Stefano N, Arnold DL. Towards a better understanding of pseudoatrophy in the brain of multiple sclerosis patients. Mult Scler 2015; 21: 675-6.
41. Cohen JA, Reingold SC, Polman CH, et al. Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects. Lancet Neurol 2012; 11: 467-76.
42. Barkhof F, Calabresi PA, Miller DH, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009; 5: 256-66.
43. van Walderveen MA, Kamphorst W, Scheltens P, et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 1998; 50: 1282-8.
44. Horakova D, Dwyer MG, Havrdova E, et al. Gray matter atrophy and disability progression in patients with early relapsingremitting multiple sclerosis: a 5-year longitudinal study. J Neurol Sci 2009; 282: 112-9.
45. Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, doubleblind, placebo-controlled, parallel-group trial. Lancet Neurol 2010; 9: 681-8.
46. Cardoso MJ, Modat M, Wolz R, et al. Geodesic Information Flows: Spatially-Variant Graphs and Their Application to Segmentation and Fusion. IEEE Trans Med Imaging 2015; 34: 1976-88.