A recent study published in the European Journal of Neurology suggests that the traditional change threshold for the timed 25-foot walk (T25FW) and 9-hole peg test (NHPT) outcome measures represents a fair compromise between minimizing the number of false change events and attaining the largest number of change events in people with primary progressive multiple sclerosis (PPMS).

The study findings suggest that the traditional 20% threshold prevented a reasonable number of false change events while providing many change events at the follow-up period.

Read more about multiple sclerosis experimental therapies

The present study aimed to investigate the short-term variation in T25FW and NHPT and to compare its extent with disability change at the 12-month follow-up period in patients with PPMS.

The researchers used authentic patient-level data from the PROMISE PPMS trial conducted by Teva Pharmaceutical Industries. Patients between 30 and 65 years of age and diagnosed with PPMS were included in the trial.

In addition, the team performed 3 separate T25FW and NHPT measurements 1 week apart during screening. These repeated measures were then used to describe the extent of short-term variation. Moreover, binary logistic regression models with an established threshold of 20% or greater were employed to assess the relationship between unacceptable short-term variation and screening characteristics.

Study results of short-term variation analysis revealed the presence of short-term variation in both the T25FW and NHPT. Moreover, the improvement events on the “either hand” NHPT outnumbered the worsening events at lower thresholds (44.6% vs. 22%).

Additionally, logistic regression model analysis indicated that only the index measure of T25FW or standard NHPT was associated with a higher risk of being beyond the ≥20% improvement or worsening threshold. Furthermore, it was observed that the PROMISE participants were much more likely to experience disability worsening than disability improvement during the 12-month follow-up period.

“Based on the comparison of short-term variation in the repeated measures and disability change at 12 months, it appears that the standard 20% cut-off for disability worsening is a reasonable compromise for PPMS trials,” the authors added.

Preventing the worsening of disability is considered the most important treatment goal in PPMS, the researchers noted. The Expanded Disability Status Scale was the primary outcome measure used in PPMS clinical trials; however, studies have suggested that EDSS might not be the best choice since the newer outcome measures, such as T25FW and NHPT, are found to be more sensitive and robust.

All clinical performance measures show variability in the short term; however, selecting the threshold of change on the T25FW and NHPT best representing the true worsening of disability is still challenging. Traditionally, a 20% cut-off has been used, but it is unclear whether this applies to PPMS and across different levels of disability.


Koch MW, Repovic P, Mostert J, et al. Threshold definitions for significant change on the timed 25-foot walk and nine-hole peg test in primary progressive multiple sclerosis. Eur J Neurol. Published online Jun 12, 2023. doi:10.1111/ene.15920.