Original Article
Neurology
Objective: To evaluate a novel functional composite endpoint (CEP) based on disability progression and cognitive processing speed (CPS) to characterize disease progression in patients with secondary progressive multiple sclerosis (SPMS) more effectively.
Background: Physical disability, as measured by the Expanded Disability Status Scale (EDSS) score, and CPS as measured by the Symbol Digit Modalities Test (SDMT), are functional domains of high clinical relevance for patients with SPMS. EDSS and SDMT cover different aspects of progression. A clinically meaningful CEP, using information from both EDSS- and SDMT-based events, will utilize clinical trial data more effectively thus yielding useful information while minimizing patients’ exposure to trial risks.
Design/Methods: We analyzed time to clinically meaningful changes in EDSS and SDMT, i.e., 6-month confirmed disability progression on EDSS (1.0-point worsening from ≤5.0 baseline score or 0.5-point worsening from >5.0 baseline score; 6mCDPEDSS), SDMT (4.0-point confirmed worsening from baseline; 6mCWSDMT), and on the proposed CEP in patients from placebo-controlled trial of siponimod in SPMS (EXPAND). We present hazard ratios (HR) and 95% confidence intervals (CI) using a Cox proportional hazards model and the corresponding Kaplan-Meier estimates.
Results: Of 1645 patients: 358 had EDSS-progression, of which 279 (78%) had no progression on SDMT; 287 had SDMT-progression, of which 208 (72%) had no progression on EDSS; 79 patients progressed on both EDSS and SDMT. Compared to placebo, siponimod reduced the risk of progression (HR [95% CI]: 6mCDPEDSS 0.74 [0.60; 0.92], p=0.0058, 6mCWSDMT 0.75 [0.59; 0.95], p=0.0163 and CEP 0.75 [0.63; 0.88], p=0.0008). At the end of the core study, 62% of siponimod-treated patients versus 52% on placebo remained CEP free.
Conclusions: Combining SDMT and EDSS resulted in higher sensitivity for change and therapeutic effects in a large SPMS clinical trial. If confirmed in further patient samples, introduction of this compound measure would allow for lower sample sizes in future clinical trials.
