The timed 25-foot walk is a more sensitive outcome measure than the EDSS for PPMS trials: an analysis of the PROMISE clinical trial dataset.
Clinical trial
Contrast-enhancing lesions
MRI
Multiple sclerosis
Outcome measure
Primary progressive multiple sclerosis
Journal
Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161
Informations de publication
Date de publication:
Oct 2022
Oct 2022
Historique:
received:
01
03
2022
accepted:
01
05
2022
revised:
29
04
2022
pubmed:
16
5
2022
medline:
15
9
2022
entrez:
15
5
2022
Statut:
ppublish
Résumé
Clinical trials in primary progressive MS (PPMS) generally use the Expanded Disability Status Scale (EDSS) as their primary outcome measure, although different clinical outcomes may be more useful. Disability worsening in PPMS trials may be influenced by baseline factors, such as age, sex, and contrast-enhancing lesions. We used the dataset of PROMISE, a large randomized controlled trial of glatiramer acetate (GA) versus placebo, to compare the clinical outcomes EDSS, timed 25-foot walk (T25FW), and nine-hole peg test (NHPT). We used Cox regression analyses to investigate the association of the baseline factors age, sex, treatment arm, contrast-enhancing lesions (CELs), and EDSS on the time to 3-month confirmed disability worsening (3MCDW) on the EDSS and the T25FW. PROMISE included 943 participants. Worsening on the T25FW or EDSS or occurred much more frequently than on the NHPT. Having CELs at baseline was associated with a shorter time to 3MCDW on both the EDSS and T25FW. An additional resampling experiment using the PROMISE dataset showed that increasing representation of participants with CELs at baseline increases the likelihood of having a positive trial result in favor of GA treatment. Our investigation suggests that the T25FW may be a more useful primary outcome measure than the EDSS in PPMS trials, and that its use may shorten clinical trials. Our findings on the impact of CELs at baseline on disability outcomes inform the critical appraisal of clinical trials in PPMS.
Sections du résumé
BACKGROUND
BACKGROUND
Clinical trials in primary progressive MS (PPMS) generally use the Expanded Disability Status Scale (EDSS) as their primary outcome measure, although different clinical outcomes may be more useful. Disability worsening in PPMS trials may be influenced by baseline factors, such as age, sex, and contrast-enhancing lesions.
METHODS
METHODS
We used the dataset of PROMISE, a large randomized controlled trial of glatiramer acetate (GA) versus placebo, to compare the clinical outcomes EDSS, timed 25-foot walk (T25FW), and nine-hole peg test (NHPT). We used Cox regression analyses to investigate the association of the baseline factors age, sex, treatment arm, contrast-enhancing lesions (CELs), and EDSS on the time to 3-month confirmed disability worsening (3MCDW) on the EDSS and the T25FW.
RESULTS
RESULTS
PROMISE included 943 participants. Worsening on the T25FW or EDSS or occurred much more frequently than on the NHPT. Having CELs at baseline was associated with a shorter time to 3MCDW on both the EDSS and T25FW. An additional resampling experiment using the PROMISE dataset showed that increasing representation of participants with CELs at baseline increases the likelihood of having a positive trial result in favor of GA treatment.
CONCLUSION
CONCLUSIONS
Our investigation suggests that the T25FW may be a more useful primary outcome measure than the EDSS in PPMS trials, and that its use may shorten clinical trials. Our findings on the impact of CELs at baseline on disability outcomes inform the critical appraisal of clinical trials in PPMS.
Identifiants
pubmed: 35570237
doi: 10.1007/s00415-022-11171-2
pii: 10.1007/s00415-022-11171-2
doi:
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
5319-5327Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.
Références
Miller DH, Leary SM (2007) Primary-progressive multiple sclerosis. Lancet Neurol 6:903–912. https://doi.org/10.1016/S1474-4422(07)70243-0
doi: 10.1016/S1474-4422(07)70243-0
pubmed: 17884680
Montalban X, Hauser SL, Kappos L et al (2017) Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 376:209–220. https://doi.org/10.1056/NEJMoa1606468
doi: 10.1056/NEJMoa1606468
pubmed: 28002688
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452
doi: 10.1212/WNL.33.11.1444
Koch MW, Cutter G, Stys PK et al (2013) Treatment trials in progressive MS–current challenges and future directions. Nat Rev Neurol 9:496–503. https://doi.org/10.1038/nrneurol.2013.148
doi: 10.1038/nrneurol.2013.148
pubmed: 23897406
Koch MW, Cutter GR, Giovannoni G et al (2017) Comparative utility of disability progression measures in PPMS Analysis of the PROMiSe data set. Neurol Neuroimmunol Neuroinflamm 4:e358. https://doi.org/10.1212/NXI.0000000000000358
doi: 10.1212/NXI.0000000000000358
pubmed: 28680915
pmcid: 5489138
Koch MW, Mostert JP, Uitdehaag B, Cutter G (2021) A comparison of clinical outcomes in PPMS in the INFORMS original trial data set. Mult Scler 27:1864–1874. https://doi.org/10.1177/1352458520987539
doi: 10.1177/1352458520987539
pubmed: 33464149
pmcid: 8521359
Motl RW, Cohen JA, Benedict R et al (2017) Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis. Mult Scler 23:704–710. https://doi.org/10.1177/1352458517690823
doi: 10.1177/1352458517690823
pubmed: 28206828
pmcid: 5405807
Kalinowski A, Cutter G, Bozinov N et al (2021) The timed 25-foot walk in a large cohort of multiple sclerosis patients. Mult Scler. https://doi.org/10.1177/13524585211017013
doi: 10.1177/13524585211017013
pubmed: 34100297
pmcid: 8795230
Wolinsky JS, Narayana PA, O’Connor P et al (2007) Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 61:14–24. https://doi.org/10.1002/ana.21079
doi: 10.1002/ana.21079
pubmed: 17262850
Feys P, Lamers I, Francis G et al (2017) The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis. Mult Scler 23:711–720. https://doi.org/10.1177/1352458517690824
doi: 10.1177/1352458517690824
pubmed: 28206826
pmcid: 5405844
Schwid SR, Goodman AD, McDermott MP et al (2002) Quantitative functional measures in MS: what is a reliable change? Neurology 58:1294–1296
doi: 10.1212/WNL.58.8.1294
R Core Team (2021) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna
Ebers GC, Heigenhauser L, Daumer M et al (2008) Disability as an outcome in MS clinical trials. Neurology 71:624–631. https://doi.org/10.1212/01.wnl.0000313034.46883.16
doi: 10.1212/01.wnl.0000313034.46883.16
pubmed: 18480462
Koch MW, Mostert J, Repovic P et al (2021) Reliability of outcome measures in clinical trials in secondary progressive multiple sclerosis. Neurology 96:e111–e120. https://doi.org/10.1212/WNL.0000000000011123
doi: 10.1212/WNL.0000000000011123
pubmed: 33106389
Koch MW, Mostert J, Greenfield J et al (2020) Gadolinium enhancement on cranial MRI in multiple sclerosis is age dependent. J Neurol 267:2619–2624. https://doi.org/10.1007/s00415-020-09895-0
doi: 10.1007/s00415-020-09895-0
pubmed: 32388832
Lublin F, Miller DH, Freedman MS et al (2016) Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 387:1075–1084. https://doi.org/10.1016/S0140-6736(15)01314-8
doi: 10.1016/S0140-6736(15)01314-8
pubmed: 26827074
Hawker K, O’Connor P, Freedman MS et al (2009) Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 66:460–471. https://doi.org/10.1002/ana.21867
doi: 10.1002/ana.21867
pubmed: 19847908
Frischer JM, Bramow S, Dal-Bianco A et al (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132:1175–1189. https://doi.org/10.1093/brain/awp070
doi: 10.1093/brain/awp070
pubmed: 19339255
pmcid: 2677799
Kutzelnigg A, Lucchinetti CF, Stadelmann C et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712. https://doi.org/10.1093/brain/awh641
doi: 10.1093/brain/awh641
pubmed: 16230320
Frischer JM, Weigand SD, Guo Y et al (2015) Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol 78:710–721. https://doi.org/10.1002/ana.24497
doi: 10.1002/ana.24497
pubmed: 26239536
pmcid: 4623970
Koch MW, Zabad R, Giuliani F et al (2015) Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis. J Neurol Sci 358:131–137. https://doi.org/10.1016/j.jns.2015.08.1525
doi: 10.1016/j.jns.2015.08.1525
pubmed: 26344560
Koch MW, Kaur S, Sage K et al (2021) Hydroxychloroquine for primary progressive multiple sclerosis. Ann Neurol 90:940–948. https://doi.org/10.1002/ana.26239
doi: 10.1002/ana.26239
pubmed: 34590328