Composite Confirmed Disability Worsening/Progression Is a Useful Clinical Endpoint for Multiple Sclerosis Clinical Trials.

BACKGROUND AND OBJECTIVES

Sensitive and meaningful disability worsening measures remain an unmet medical need in multiple sclerosis (MS). Composite confirmed disability worsening/progression (cCDW/cCDP) combines the Expanded Disability Status Scale (EDSS) with performance tests of ambulation and dexterity (Timed 25-Foot Walk Test [T25FWT] and Nine-Hole Peg Test [9HPT]). We assessed the relation of changes in these measures to understand the utility of cCDW/cCDP as an endpoint for MS trials.

METHODS

Clinical trials measuring all components of cCDW were selected for the analysis of (i) individual patient-level data from Roche-sponsored MS studies to characterize the association between performance-test changes and subsequent EDSS changes and (ii) population-level data from published studies reporting treatment effects on EDSS and either cCDP or T25FWT or 9HPT events to examine the relationship between treatment effects on T25FWT and EDSS events.

RESULTS

Analysis (i): 6 Roche-sponsored Phase III trials comprising 4,979 patients with relapsing-remitting MS (RRMS; n = 1,225), relapsing MS (RMS; n = 1,656), progressive MS (PMS; n = 922), and primary progressive MS (PPMS; n = 1,171), with a data cutoff of November 2022, were included in the individual patient analyses. For all trials, T25FWT events were associated with increased risk of subsequent EDSS events (hazard ratios [HRs], values: 2.11-5.20, 0.07-<0.001); similar associations were found for 9HPT events with HRs for later EDSS events ranging from 1.47 to 2.66 ( values from 0.24-<0.001). For patients without EDSS events in the first 96 study weeks, T25FWT or 9HPT events in the first 96 study weeks were associated with increased risk of subsequent EDSS events (HRs, values: T25FWT 1.74-3.26, 0.01-<0.001; 9HPT 1.45-3.08, 0.45-<0.001). Patients with T25FWT or 9HPT events were more likely to experience a ≥8-point change from baseline at the final visit in the 29-item Multiple Sclerosis Impact Scale physical subscale (risk ratios, values: T25FWT 1.45-2.17, 0.004-<0.001; 9HPT 1.26-1.87, 0.15-0.03). Analysis (ii): In the 9 studies included, treatment effects on T25FWT events were predictive of treatment effects on EDSS events (Spearman correlation [95% CI] = 0.82 [0.34-0.96], = 0.005).

DISCUSSION

In this post hoc analysis, worsening on T25FWT or 9HPT was a harbinger of EDSS worsening and treatment effects on T25FWT correlated with those on EDSS. These results establish the predictive validity and clinical relevance of performance-test worsening, thus supporting use of cCDW/cCDP as a primary outcome for progression in MS trials.

CLINICAL TRIAL IDENTIFIERS

ClinicalTrials.gov Identifiers: NCT01247324 (OPERA I); first submitted November 23, 2010; first patient enrolled: August 31, 2011; available at clinicaltrials.gov/study/NCT01247324. NCT01412333 (OPERA II); first submitted August 8, 2011; first patient enrolled: September 20, 2011; available at clinicaltrials.gov/study/NCT01412333. NCT03085810 (ENSEMBLE); first submitted March 16, 2017; first patient enrolled: March 27, 2017; available at clinicaltrials.gov/study/NCT03085810. NCT01194570 (ORATORIO); first submitted August 28, 2010; first patient enrolled: March 3, 2011; available at clinicaltrials.gov/study/NCT01194570. NCT03523858 (CONSONANCE); first submitted April 16, 2018; first patient enrolled: May 28, 2018; available at clinicaltrials.gov/study/NCT03523858. NCT00087529 (OLYMPUS); first submitted July 9, 2004; first patient enrolled: July 9, 2004; available at clinicaltrials.gov/study/NCT00087529.