title: Treatment trials in progressive MS--current challenges and future directions.
abstract: The introduction of immunomodulatory treatments has transformed the management of patients with relapsing-remitting multiple sclerosis (MS), but has had no consistent benefit in progressive MS. Patients with primary or secondary progressive MS, therefore, are faced with relentless functional decline that remains without treatment. Clinical trials in progressive MS are clearly needed, but their design and conduct is challenging, and different from that of trials in relapsing-remitting MS. Challenges to reliable measurement of clinical progression, uncertainties about the natural history of progressive MS, and the unclear role of imaging outcomes all impede optimal trial design. Clinical trials in progressive MS have used time to a predefined change on the Expanded Disability Status Scale as their main outcome measure, which has had important consequences for trial duration and has led to inclusion of only a highly selected minority of patients. Here, we review the current approach to clinical trial design in progressive MS, outline key ongoing challenges, and suggest strategies to overcome such hurdles.
authors.affiliation: Multiple Sclerosis Clinic, Foothills Hospital, AC137A, SSB, 1403-29 ST NW, Calgary, AB T2N 2T9, Canada. mwkoch@ucalgary.ca
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Koch
authors.forename: Gary
authors.initials: G
authors.lastname: Cutter
authors.forename: Peter K
authors.initials: PK
authors.lastname: Stys
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
authors.forename: Luanne M
authors.initials: LM
authors.lastname: Metz
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods / Q000639:trends*; D006801:Humans; D020528:Multiple Sclerosis, Chronic Progressive / Q000628:therapy*; D016896:Treatment Outcome
references.citation: Lancet. 1998 Nov 7;352(9139):1491-7
references.pmid: 9820296
references.citation: Ann Neurol. 2002 Oct;52(4):421-8
references.pmid: 12325070
references.citation: Neurology. 2009 Dec 8;73(23):1996-2002
references.pmid: 19996074
references.citation: Arch Neurol. 1988 Jul;45(7):746-8
references.pmid: 3390030
references.citation: Ann Neurol. 2007 Jan;61(1):14-24
references.pmid: 17262850
references.citation: CNS Neurosci Ther. 2008 Summer;14(2):153-64
references.pmid: 18482027
references.citation: Arch Neurol. 2005 Sep;62(9):1345-56
references.pmid: 16157741
references.citation: Lancet Neurol. 2012 Dec;11(12):1082-92
references.pmid: 23153407
references.citation: Clin Neuropsychol. 2010 Oct;24(7):1131-45
references.pmid: 20830649
references.citation: Brain. 1999 May;122 ( Pt 5):871-82
references.pmid: 10355672
references.citation: Mult Scler. 2012 Aug;18(8):1074-80
references.pmid: 22740488
references.citation: Acta Neuropathol. 2012 Sep;124(3):411-24
references.pmid: 22766690
references.citation: Nat Rev Neurol. 2012 Nov 5;8(11):647-56
references.pmid: 23007702
references.citation: Cochrane Database Syst Rev. 2010 May 12;(5):CD004678
references.pmid: 20464733
references.citation: Proc Natl Acad Sci U S A. 2013 May 21;110(21):8714-9
references.pmid: 23650361
references.citation: Mult Scler. 2010 Jul;16(7):862-7
references.pmid: 20488826
references.citation: Lancet Neurol. 2012 May;11(5):467-76
references.pmid: 22516081
references.citation: Lancet Neurol. 2009 Mar;8(3):254-60
references.pmid: 19201654
references.citation: J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):767-72
references.pmid: 19240050
references.citation: Neurology. 2001 Apr 10;56(7):934-7
references.pmid: 11294932
references.citation: Mult Scler. 2009 Jun;15(6):715-20
references.pmid: 19383646
references.citation: Control Clin Trials. 1989 Mar;10(1):1-10
references.pmid: 2702835
references.citation: J Neuroinflammation. 2011 Jul 05;8:76
references.pmid: 21729281
references.citation: Ann Neurol. 2009 Feb;65(2):160-6
references.pmid: 19224531
references.citation: J Neuroinflammation. 2010 May 19;7:30
references.pmid: 20482831
references.citation: Mult Scler. 2004 Feb;10(1):55-60
references.pmid: 14760953
references.citation: Lancet. 2004 Sep 25-Oct 1;364(9440):1149-56
references.pmid: 15451222
references.citation: J Neurol Sci. 2008 Nov 15;274(1-2):48-53
references.pmid: 18684473
references.citation: Neurology. 2004 Nov 23;63(10):1788-95
references.pmid: 15557491
references.citation: Neurotherapeutics. 2013 Jan;10(1):44-54
references.pmid: 23070731
references.citation: Lancet Neurol. 2011 Nov;10(11):1026-34
references.pmid: 22014437
references.citation: Brain Res. 2009 Aug 4;1283:177-85
references.pmid: 19497309
references.citation: Cochrane Database Syst Rev. 2012 Jan 18;1:CD005181
references.pmid: 22258960
references.citation: N Engl J Med. 2000 Nov 16;343(20):1430-8
references.pmid: 11078767
references.citation: Neurology. 2006 Jan 24;66(2):172-7
references.pmid: 16434648
references.citation: Brain. 1999 Apr;122 ( Pt 4):625-39
references.pmid: 10219776
references.citation: Neurology. 2001 Jun 12;56(11):1496-504
references.pmid: 11402106
references.citation: Acta Neuropathol. 2012 May;123(5):627-38
references.pmid: 22327362
references.citation: Nature. 2005 Dec 22;438(7071):1167-71
references.pmid: 16372012
references.citation: Lancet Neurol. 2006 Apr;5(4):343-54
references.pmid: 16545751
references.citation: Neurology. 2002 Apr 23;58(8):1294-6
references.pmid: 11971105
references.citation: Neurology. 1983 Nov;33(11):1444-52
references.pmid: 6685237
references.citation: Brain. 2010 Jul;133(Pt 7):1914-29
references.pmid: 20534650
references.citation: Brain. 2011 Sep;134(Pt 9):2703-21
references.pmid: 21908875
references.citation: J Neurol. 2007 May;254 Suppl 2:II26-9
references.pmid: 17503125
references.citation: Mult Scler. 2006 Oct;12(5):594-8
references.pmid: 17086905
references.citation: N Engl J Med. 2006 Mar 2;354(9):899-910
references.pmid: 16510744
references.citation: Neurology. 2010 Apr 27;74 Suppl 3:S16-23
references.pmid: 20421569
references.citation: Lancet Neurol. 2010 Jul;9(7):681-8
references.pmid: 20621711
references.citation: Mult Scler. 2000 Jun;6(3):163-71
references.pmid: 10871827
references.citation: Neurology. 2002 Sep 10;59(5):679-87
references.pmid: 12221157
references.citation: Mult Scler. 2005 Apr;11(2):149-58
references.pmid: 15794387
references.citation: Neurology. 2009 Feb 24;72(8):705-11
references.pmid: 19073945
references.citation: Neurol Sci. 2013 Feb;34(2):181-6
references.pmid: 22362332
references.citation: Expert Opin Biol Ther. 2008 Oct;8(10):1561-70
references.pmid: 18774923
references.citation: Neurology. 1995 Jul;45(7):1268-76
references.pmid: 7617181
references.citation: Neurology. 2010 Apr 27;74 Suppl 3:S8-15
references.pmid: 20421572
references.citation: Mult Scler. 2007 Jan;13(1):52-7
references.pmid: 17294611
references.citation: Arch Neurol. 1991 Mar;48(3):299-301
references.pmid: 2001188
references.citation: Brain. 2005 Nov;128(Pt 11):2705-12
references.pmid: 16230320
references.citation: Lancet Neurol. 2004 Dec;3(12):744-51
references.pmid: 15556807
references.citation: Brain. 2010 Jul;133(Pt 7):1900-13
references.pmid: 20423930
references.citation: Neurology. 2009 Feb 17;72(7):595-601
references.pmid: 19005170
references.citation: Ann Neurol. 2001 Nov;50(5):646-57
references.pmid: 11706971
references.citation: Lancet. 2002 Apr 6;359(9313):1221-31
references.pmid: 11955556
references.citation: Lancet Neurol. 2007 Oct;6(10):903-12
references.pmid: 17884680
references.citation: Stat Med. 2011 Jun 15;30(13):1528-40
references.pmid: 21341301
references.citation: Mult Scler. 2001 Oct;7(5):305-12
references.pmid: 11724446
references.citation: Nature. 2006 Feb 23;439(7079):988-92
references.pmid: 16372019
references.citation: Arch Neurol. 2000 Sep;57(9):1319-24
references.pmid: 10987899
references.citation: Arch Clin Neuropsychol. 2006 Jan;21(1):53-76
references.pmid: 16290063
references.citation: Brain. 1991 Apr;114 ( Pt 2):1057-67
references.pmid: 2043941
references.citation: Brain. 2008 Jun;131(Pt 6):1464-77
references.pmid: 18490361
references.citation: Mult Scler. 2011 Jan;17(1):81-8
references.pmid: 20798135
references.citation: Brain. 2003 Apr;126(Pt 4):770-82
references.pmid: 12615637
references.citation: J Neurol Sci. 2005 Jan 15;228(1):71-4
references.pmid: 15607213
references.citation: Nat Rev Neurol. 2013 Jan;9(1):35-43
references.pmid: 23165337
references.citation: Neurology. 1990 Jun;40(6):971-5
references.pmid: 2189084
references.citation: Brain. 2012 Oct;135(Pt 10):2952-61
references.pmid: 23065788
references.citation: Lancet. 1998 Nov 7;352(9139):1498-504
references.pmid: 9820297
references.citation: Trends Mol Med. 2013 Jan;19(1):23-30
references.pmid: 23153574
references.citation: Neurotox Res. 2003;5(1-2):157-64
references.pmid: 12832230
references.citation: J Neurol Sci. 2003 Feb 15;206(2):165-71
references.pmid: 12559505
references.citation: Curr Pharm Des. 2012;18(29):4489-97
references.pmid: 22612746
references.citation: Lancet Neurol. 2011 Apr;10(4):329-37
references.pmid: 21397565
references.citation: J Neuroimmunol. 2012 Jul 15;248(1-2):66-72
references.pmid: 22381245