Outcome measures in MS trials require more research ‘to improve clinical trial design’

The timed 25-foot walk test and the nine-hole peg test demonstrated lower rates of improvement than the Expanded Disability Scale Status, which is consistent with less measurement error, according to findings published in Neurology.

The timed 25-foot walk test (T25FW) and the nine-hole peg test (9HPT) also showed larger differences between progression and improvement rates than the EDSS. These results suggested that the T25FW and the 9HPT represent more reliable outcomes than the EDSS, the researchers noted, adding that the reason for this difference “may simply lie in the fact that both the T25FW and 9HPT are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.”

The results have relevance regarding the design and assessment of clinical trials in secondary progressive MS, Marcus W. Koch, MD, PhD, assistant professor of clinical neurosciences and full member of the Hotchkiss Brain Institute at the University of Calgary, and colleagues wrote.

Koch and colleagues demonstrated in previous research that the T25FW showed higher rates of progression than the EDSS in two large randomized controlled clinical trials in SPMS, suggesting that the T25FW — rather than the EDSS — could be a more useful primary outcome for clinical trials in SPMS. Another factor in selecting the most relevant primary outcome in these trials is whether that outcome “really and precisely measures the process of disability progression,” according to the researchers.

“Since disability progression in MS is generally understood to be unremitting, Ebers and coworkers reasoned that an ideal outcome measure would only show worsening of disability over time, whereas measuring ‘improvement’ of disability over the course of the trial would be ‘noise’ due to random variation or measurement error,” Koch and colleagues wrote. “Based on this idea, we investigated rates of disability progression and ‘improvement’ on the EDSS, the T25FW, the 9HPT and their combinations in the original trial datasets from two large [randomized controlled trials] in SPMS.

The researchers used data from the placebo arms of the IMPACT and ASCEND randomized controlled trials, both of which looked at SPMS. They compared disability progression and defined “improvement” with and without 3 or 6 month confirmation on the following outcome measures: EDSS, T25FW, 9HPT and their combinations.

The IMPACT dataset included patient-level data on 219 individuals and the ASCEND dataset included patient-level data on 449 patients. Baseline patient characteristics in each trial were similar regarding sex (female, 64.3% in IMPACT vs. 63.4% in ASCEND), mean age (47.9 years in IMPACT vs. 47.13 in ASCEND), EDSS (median, 6 in IMPACT vs. 6 in ASCEND), T25FW (9.1 in IMPACT vs. 11.2 in ASCEND) and 9HPT (27.6 in IMPACT vs. 29.8 in ASCEND).

Disability increased steadily over time on all measures, as did the ratio of worsening to “improvement,” Koch and colleagues found, though they also noted that both results were expected.

In both IMPACT and ASCEND, EDSS demonstrated the greatest rates of “improvement” over time, as well as the least difference between disability progression and “improvement” rates, followed by the T25FW and the 9HPT. Confirmation of disability progression or “improvement” at 3 or 6 months reduced rates of both disability progression and “improvement.” The researchers observed little difference between 3 and 6 month confirmation regarding both disability progression and “improvement.”

Throughout the study, disability progression rates for the T25FW and 9HPT continually increased, while “improvement” rates remained at, below or around the 10% level. Regarding EDSS, “improvement” rates increased in parallel with disability progression rates throughout the course of the trial, though more noticeably so in the IMPACT dataset, Koch and colleagues found.

“The combined measures showed a mixed pattern, with both disability progression and ‘improvement’ rates rising over the course of the trial,” the researchers wrote. “‘Improvement’ rates among the combined measures were generally higher than for single outcome measures and higher for the ‘EDSS or T25FW or 9HPT’ outcome compared to ‘EDSS or T25FW.’”

In addition to clinical trial design, the findings of the current study are relevant for evaluating randomized controlled trials in SPMS, Koch and colleagues reported.

“Over the last few years, there have been [randomized control trials] in which the clinical results did not match between outcome measures,” the researchers wrote. “In light of our findings, treatment effects would seem more robust and convincing if derived from an effect on both outcome measures, or on T25FW performance alone.”

Finally, Koch and colleagues pointed to the impact of reliable clinical trial results on the ability to find better therapies for patients with progressive MS. Such therapies represent “a large unmet need,” the researchers noted.

“Clinical outcome measures are the most patient relevant and will therefore likely remain the primary outcome measures in [randomized controlled trials]. However, their reliability is not well researched,” Koch and colleagues wrote. “Further research into such outcome measures in existing original trial datasets and clinical cohorts of patients with SPMS and [primary progressive MS] remains necessary to improve clinical trial design.”