Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis.
Multiple sclerosis
progression
progressive multiple sclerosis
relapses
secondary progressive multiple sclerosis
siponimod
Journal
Multiple sclerosis (Houndmills, Basingstoke, England)
ISSN: 1477-0970
Titre abrégé: Mult Scler
Pays: England
ID NLM: 9509185
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
pubmed:
19
11
2020
medline:
26
10
2021
entrez:
18
11
2020
Statut:
ppublish
Résumé
In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses. To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial. Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses. Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively. By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.
Sections du résumé
BACKGROUND
In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.
OBJECTIVE
To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.
METHODS
Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.
RESULTS
Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.
CONCLUSION
By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.
Identifiants
pubmed: 33205682
doi: 10.1177/1352458520971819
pmc: PMC8414818
doi:
Substances chimiques
Azetidines
0
Benzyl Compounds
0
siponimod
RR6P8L282I
Types de publication
Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1564-1576Références
J Neuroinflammation. 2016 Feb 08;13:31
pubmed: 26856814
Lancet. 2018 Mar 31;391(10127):1263-1273
pubmed: 29576505
Mult Scler. 2018 Oct;24(11):1421-1432
pubmed: 28752787
Neurology. 2004 Nov 23;63(10):1788-95
pubmed: 15557491
Lancet. 1998 Nov 7;352(9139):1491-7
pubmed: 9820296
JAMA Neurol. 2015 Aug;72(8):897-904
pubmed: 26053119
Neurology. 2014 Jul 15;83(3):278-86
pubmed: 24871874
Ann Neurol. 2016 Oct;80(4):499-510
pubmed: 27464262
Neurology. 2017 Sep 5;89(10):1050-1059
pubmed: 28794248
Curr Opin Neurol. 2019 Jun;32(3):365-377
pubmed: 30985372
Ann Neurol. 2019 May;85(5):653-666
pubmed: 30851128
Lancet. 2016 Mar 12;387(10023):1075-1084
pubmed: 26827074
Lancet Neurol. 2018 May;17(5):405-415
pubmed: 29545067
Neurology. 2011 Nov 1;77(18):1684-90
pubmed: 21975200
Stat Med. 2019 Oct 15;38(23):4761-4771
pubmed: 31386219
Lancet. 2017 Apr 1;389(10076):1357-1366
pubmed: 27889191
Curr Opin Neurol. 2002 Jun;15(3):239-45
pubmed: 12045719
Mult Scler. 1999 Aug;5(4):283-6
pubmed: 10467389
J Epidemiol Community Health. 2006 Jul;60(7):578-86
pubmed: 16790829
Cochrane Database Syst Rev. 2012 Jan 18;1:CD005181
pubmed: 22258960
Neurology. 1996 Apr;46(4):907-11
pubmed: 8780061
J Neuroinflammation. 2016 Aug 26;13(1):207
pubmed: 27566665
J Neurol Neurosurg Psychiatry. 2000 Apr;68(4):450-7
pubmed: 10727480
Ann Neurol. 2014 Oct;76(4):568-80
pubmed: 25087920