Table 2.
Published and ongoing phase III trials in patients with progressive MS
| Trial name/group [registry numbera] | Publication date [start datea] | Treatment | MS phenotype [EDSS inclusion criterion] | Primary outcome measure(s) | Secondary and other outcome measures (disability-related) |
|---|---|---|---|---|---|
| Published studies | |||||
| European Trial Group [40] | Nov 1998 [1994] | Interferon β-1b vs. placebo | SPMS [3.0–6.5] | Time to sustained (3-month) disability progression on EDSSb | Time to/proportion of patients becoming wheelchair-bound (EDSS ≥ 7) Sustained (3-month) disability progression on EDSS (proportion of patients)b Change in EDSS EDSS score at endpoint |
| Cladribine Clinical Trial Group [41] | Mar 2000 [Dec 1994] | Cladribine vs. placebo | Progressive MS [3.0–6.5] | Change in EDSS | Change in SNRS Time to sustained (2-month) progression on EDSSd |
| SPECTRIMS [42]c | Jun 2001 | Interferon β-1a SC vs. placebo | SPMS [3.0–6.5] | Time to sustained (3-month) disability progression on EDSSd | Sustained (3-month) disability progression on EDSS (proportion of patients)d Area under the EDSS–time curve |
| IMPACT [43]c | Sep 2002 | Interferon β-1a IM vs. placebo | SPMS [3.5–6.5] | Change in MSFC z-score | Sustained (3-month) disability progression on EDSSb Change in EDSS score Proportion of patients categorised as stable, worse or better based on EDSS change |
| MIMS [44] | Dec 2002 | Mitoxantrone vs. placebo | Progressive MS (progressive-relapsing MS or SPMS) [3.0–6.0] | Five clinical measures: change in EDSS, change in ambulation index, number of corticosteroid-treated relapses, time to first treated relapse, change in standardised neurological status | Disability progression on EDSS (proportion of patients)e Sustained (3- and 6-month) disability progression on EDSS (proportion of patients)e Time to first sustained EDSS deterioration Use of wheelchair assistance |
| Andersen et al. [45] | May 2004 | Interferon β-1a SC vs. placebo | SPMS [< 7.0] | Time to sustained (6-month) disability progression on EDSSd | Progression in RFSSf Tertiary: Proportion of progression-free patients Ambulation index Arm index |
| ESIMS [46, 47] | Sep 2004 | IVIG vs. placebo | SPMS [3.0–6.5] | Co-primary: Treatment failure (sustained [3–month] disability progression on EDSS)d Deterioration of EDSS and/or confirmed 20% worsening in 9HPT |
Treatment failure after 3 and 6 months Difference in mean slope of progression Confirmed 20% worsening in 9HPT Change in EDSS score Time to deterioration in EDSS, 9HPT, pyramidal, visual and brainstem function scales and composite outcome scores Change in visual function Change in 9HPT results |
| North American Trial Group [48]c | Nov 2004 | Interferon β-1b vs. placebo | SPMS [3.0–6.5] | Sustained (6-month) disability progression on EDSSb | Change in EDSS score Cognition (change in composite neuropsychological test score) |
| PROMISE [49]c | Jan 2007 | Glatiramer acetate vs. placebo | PPMS [3.0–6.5] | Time to sustained (3-month) disability progression on EDSSd | Sustained (3-month) disability progression on EDSS (proportion of patients)d Change in EDSS score Change in MSFC score |
| Poehlau et al. [50, 51] | Nov 2007 | IVIG vs. placebo | PPMS or SPMS [3.0–7.0] | Sustained (3-month) improvement in disability on EDSSg Sustained (3-month) disability progression on EDSSd |
Visual function Upper extremity function (box and block test; 9HPT) Cognitive function (neuropsychological battery) |
| OLYMPUS [52] [NCT00087529] Note that this is a phase II/III trial | Oct 2009 [Jun 2004] | Rituximab vs. placebo | PPMS [2.0–6.5] | Sustained (3-month) disability progression on EDSSb | None Exploratory: Sustained (6-month) improvement in disability on EDSS Change in MSFC total and component scale scores |
| MAESTRO [53] [NCT00869726] | Oct 2011 [Dec 2004] | MBP8298 (dirucotide) vs. placebo | SPMS [3.5–6.5] | Sustained (6-month) disability progression on EDSSd | Change in MSFC z-scores |
| INFORMS [54] [NCT00731692] | Mar 2016 [Jul 2008] | Fingolimod vs. placebo | PPMS [3.5–6] | Clinical disease progression (at least one of the following): sustained [3-month] disability progression on EDSSd; ≥ 20% increase on T25FW; or ≥ 20% increase in time taken to complete 9HPT | Sustained [3-month] disability progression on EDSSd Clinical disease progression according to T25FW and 9HPT Ambulation (MSWS-12) |
| ORTARIO [55] [NCT01194570] | Jan 2017 [Mar 2011] | Ocrelizumab vs. placebo | PPMS [3.0–6.5] | Sustained (3-month) disability progression on EDSSb | Sustained (6-month) disability progression on EDSS Change in performance on T25FW Change in Physical Component Summary score of SF-36 |
| PROMESS [56] [NCT00241254] | Jan 2017 [Dec 2005] | Cyclophosphamide vs. methylprednisolone | SPMS [4.0–6.5] | Time to sustained (4-month) disability progression on EDSSh | Sustained (4-month) disability progression on EDSS (proportion of patients)h Progression of MSFC z-scores |
| Ongoing studies | |||||
| EXPAND [NCT01665144] | NA [Dec 2012] | Siponimod vs. placebo | SPMS [3.0–6.5] | Sustained (3-month) disability progression on EDSSd | Sustained (3-month) deterioration ≥ 20% on T25FW Sustained (6-month) disability progression on EDSSd MSWS-12 response rate |
| MS-SPI [NCT02220933] | NA [Oct 2013] | MD1003 (biotin) vs. placebo | Spinal progressive MS [4.5–7.0] | Sustained (3-month) improvement in disability on EDSSj or T25FW (≥ 20%) [proportion of patients] | MSWS CGI-/PGI-improvement 9HPT |
| MS-SPI2 [NCT02936037] | NA [Dec 2016] | MD1003 (biotin) vs. placebo | PPMS or SPMS [3.5–6.5] | Sustained (3-month) improvement in disability on EDSSi or T25FW (≥ 20%) [proportion of patients] | Time to sustained (3-month) disability progression on EDSSi CGI-Improvement Change in T25FW Other: Remote monitoring of ambulation Kurtzke functional subscores Cognition (SDMT) |
Endpoints measuring the following parameters are not included as they do not necessarily capture disability: quality of life, fatigue, depression, psychological impairment, social impairment, hospitalisations and interventions for disease-related events
Trials published from 1997 to 2017; ongoing trials were sourced from ClinicalTrials.gov
9HPT 9-hole peg test, CGI Clinical Global Impression, EDSS Expanded Disability Status Scale, IM intramuscular, IVIG intravenous immunoglobulin, MS multiple sclerosis, MSFC Multiple Sclerosis Functional Composite, MSWS Multiple Sclerosis Walking Scale, NA not applicable, PGI Patient Global Impression, PPMS primary progressive multiple sclerosis, RFSS Regional Functional System Score, SC subcutaneous, SDMT, Symbol Digit Modalities Test, SF-36 Medical Outcomes Study Short-Form (36-item) Health Survey, SNRS Scripps Neurological Rating Scale, SPMS secondary progressive multiple sclerosis, T25FW timed 25-foot walk
aIf available
bEDSS score increase ≥ 1.0 if baseline score ≤ 5.5, or ≥ 0.5 if baseline score ≥ 6.0
cPublication does not specify that trial is phase III (assumption based on trial design [randomised, controlled and double-blind] and sample size [n > 400])
dEDSS score increase ≥ 1.0 if baseline score ≤ 5.0, or ≥ 0.5 if baseline score ≥ 5.5
eIncrease ≥ 1.0
fIncrease ≥ 2%
gEDSS score decrease ≥ 1.0 if baseline score ≤ 5.0, or ≥ 0.5 if baseline score ≥ 5.5
hEDSS score increase ≥ 1 if baseline score 4.0 or 4.5, or ≥ 0.5 if baseline score ≥ 5.0
iEDSS score decrease ≥ 1.0 if baseline score ≤ 5.5, or ≥ 0.5 if baseline score ≥ 6.0