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

Abstract

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], p 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 (p 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, p 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, p 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], p = 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.

Figure 1. Kaplan-Meier Estimates of the Proportion of Patients With EDSS Events Confirmed for At Least 24 Weeks Regarding Patients With and Without T25FWT Events Confirmed for At Least 12 Weeks (OPERA [A, B] and ORATORIO [E, F]) or 24 Weeks (ENSEMBLE [C] and CONSONANCE [D]) in the First 96 Weeks of the Studies

CDP = confirmed disability progression; CDW = confirmed disability worsening; EDSS = Expanded Disability Status Scale; HR = hazard ratio; IFN = interferon β-1a; OCR = ocrelizumab; PBO = placebo; T25FWT = Timed 25-Foot Walk Test.

Figure 2. Plot of Treatment Effects on (A) T25FWT and EDSS Events and (B) cCDW/cCDP and EDSS Events on the Log-Hazard Ratio Scale From Nine/Seven Studies Across Multiple Sclerosis Phenotypes

9HPT = Nine-Hole Peg Test; cCDP = composite confirmed disability progression; cCDW = composite confirmed disability worsening; CDW12 = confirmed disability worsening at 12 weeks; CDW24 = confirmed disability worsening at 24 weeks; EDSS = Expanded Disability Status Scale; HR = hazard ratio; PPMS = primary progressive multiple sclerosis; RMS = relapsing multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; T25FWT = Timed 25-Foot Walk Test. Note that treatment effects for AFFIRM are based on CDW24, and treatment effects on T25FWT-CDW for PROMISE are based on a composite between T25FWT-CDW and 9HPT-CDW. Otherwise, all other treatment effects are for T25FWT-CDW12 and EDSS-CDW12.