Comparison of the EDSS, Timed 25-Foot Walk, and the 9-Hole Peg Test as Clinical Trial Outcomes in Relapsing-Remitting Multiple Sclerosis

Abstract

Background and objectives: Clinical trials in relapsing-remitting multiple sclerosis (RRMS) usually use the Expanded Disability Status Scale (EDSS) as their primary disability outcome measure, while the more recently developed outcomes timed 25-ft walk (T25FW) and 9-hole peg test (NHPT) may be more useful and patient relevant. The objective of this work was to compare the EDSS to the T25FW and NHPT in a large RRMS randomized controlled trial (RCT) dataset.

Methods: We used the dataset from Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) (clinicaltrials.gov identifier NCT00211887), a large phase 3 RCT, to compare the EDSS to the alternative outcomes T25FW and NHPT. We investigated disability worsening vs similarly defined improvement, unconfirmed vs confirmed and sustained disability change, and the presentation methods cumulative Kaplan-Meier survival curves vs cross-sectional disability worsening.

Results: CombiRx included 1,008 participants. A comparison of confirmed and sustained worsening events showed that, throughout the trial, there were substantially fewer sustained than confirmed events, with a positive predictive value of confirmed for sustained worsening at 24 months of 0.73 for the EDSS, 0.73 for the T25FW, and 0.8 for the NHPT. More concerning were the findings that worsening on the EDSS occurred as frequently as similarly defined improvement throughout the 3 years of follow-up and that improvement rates increased in parallel with worsening rates. The T25FW showed low improvement rates of <10% throughout the trial. We also found that Kaplan-Meier survival analysis, the standard presentation and analysis method in modern RRMS trials, yields exaggerated estimates of disability worsening. With the Kaplan-Meier method, the proportion of patients with worsening events steadily increases until it reaches several-fold the number of events seen with more conservative analysis methods. For 3-month confirmed disability worsening up to 36 months, the Kaplan-Meier method yields 2.6-fold higher estimates for the EDSS, 2.9-fold higher estimates for the T25FW, and 5.1-fold higher estimates for the NHPT compared to a more conservative presentation of the same data.

Discussion: Our analyses raise concerns about using the EDSS as the standard disability outcome in RRMS trials and suggest that the T25FW may be a more useful measure. These findings are relevant for the design and critical appraisal of RCTs.

© 2021 American Academy of Neurology.

Figures

Figure 1. Confirmed vs Sustained Disability Worsening

Difference between confirmed and sustained disability worsening. For both the Expanded Disability Status Scale (EDSS) (A) and timed 25-ft walk (T25FW) (B), confirmed disability worsening yields more worsening events that sustained disability worsening. There is only a little change in the 9-hole peg test (NHPT) (C), suggesting that it may not be a useful clinical outcome in relapsing-remitting multiple sclerosis trials. CDP = confirmed disability progression; SDP = sustained disability progression; 3M = 3-month.

Figure 2. Disability Worsening vs Similarly Defined Improvement

Comparison of worsening with similarly defined improvement on the 3 outcome measures shows that the risk of worsening on the Expanded Disability Status Scale (EDSS) is similar to the risk of improvement throughout the trial (A). For the timed 25-ft walk (T25FW), there are meaningfully more worsening than improvement events, suggesting that the T25FW does reflect and measure disability accumulation (C). There is little difference between worsening and improvement on the 9-hole peg test (NHPT); however, this is difficult to interpret given the overall low number of events. 3MC = 3-month confirmed.

Figure 3. Comparison of Ways to Present Disability Worsening

Black line shows the currently most commonly used presentation 3-month (3M) confirmed disability worsening based on the Kaplan-Meier curve; red bars show the most conservative 3-month sustained disability worsening presentation. There is a striking difference in worsening events between these 2 ways to present the same data. At 24 months, for example, estimates using the Kaplan-Meier presentation are 2- to 3-fold higher than those using the cross-sectional method for each outcome. EDSS = Expanded Disability Status Scale; NHPT = 9-hole peg test; T25FW = timed 25-ft walk.