Comparative utility of disability progression measures in PPMS

Abstract

Objective:To assess the comparative utility of disability progression measures in primary progressive MS (PPMS) using the PROMiSe trial data set.Methods:Data for patients randomized to placebo (n = 316) in the PROMiSe trial were included in this analysis. Disability was assessed using change in single (Expanded Disability Status Scale [EDSS], timed 25-foot walk [T25FW], and 9-hole peg test [9HPT]) and composite disability measures (EDSS/T25FW, EDSS/9HPT, and EDSS/T25FW/9HPT). Cumulative and cross-sectional unconfirmed disability progression (UDP) and confirmed disability progression (CDP; sustained for 3 months) rates were assessed at 12 and 24 months.Results:CDP rates defined by a ≥20% increase in T25FW were higher than those defined by EDSS score at 12 and 24 months. CDP rates defined by T25FW or EDSS score were higher than those defined by 9HPT score. The 3-part composite measure was associated with more CDP events (41.4% and 63.9% of patients at 12 and 24 months, respectively) than the 2-part measure (EDSS/T25FW [38.5% and 59.5%, respectively]) and any single measure. Cumulative UDP and CDP rates were higher than cross-sectional rates.Conclusions:The T25FW or composite measures of disability may be more sensitive to disability progression in patients with PPMS and should be considered as the primary endpoint for future studies of new therapies. CDP may be the preferred measure in classic randomized controlled trials in which cumulative disability progression rates are evaluated; UDP may be feasible for cross-sectional studies.

Fluoxetine in progressive multiple sclerosis: The FLUOX-PMS trial

“…Interestingly, this corresponds, using the same combined endpoint, to the reported 2-year cumulative confirmed disease progression rate of 56.7% in the placebo cohort of the PPMS patients in the PROMiSe trial. 15 However, the confirmed disease progression rate in our trial for the placebo group was only 38.2%, which in our design approached the anticipated 30% progression rate for the fluoxetine group. Given the unexpected slow rate of progression in the placebo arm, there is insufficient statistical power to detect a potential treatment effect of fluoxetine.…”

“…Adding the traditional EDSS to the composite endpoint might have led to the registration of more progression events. 15 However, we decided not to include the EDSS because clinical assessments were performed by study nurses visiting the patients at their home. The study nurses were well trained to assess the T25-FW and 9-HPT but not to perform and register the EDSS.…”

Disability Outcome Measures in Phase III Clinical Trials in Multiple Sclerosis

“…In a recent analysis of data from the placebo arm of the PROMiSe trial, which was conducted in patients with primary progressive MS [ 49 ], sustained (3-month) worsening of the EDSS was less sensitive to disability progression than sustained (3-month) changes in the T25FW (≥ 20% increase) or composite measures (EDSS or T25FW; EDSS or 9HPT [≥ 20% increase]; EDSS, T25FW or 9HPT). The authors concluded that T25FW or composite measures should be considered as the primary endpoint for future studies of new disease-modifying therapies [ 66 ].…”

Patient selection for trials

“…Subsequent modeling of the trial's database supported the use of composite endpoints to include patients evidencing a 12-week 20% sustained change from baseline for the timed 25-foot walk test (T25FWT), or 9-hole peg test (9HPT), or CDP based on EDSS as a full set, or paired sets compared to the standard CDP by EDSS alone; comparisons were also done for more stringent 24-week CDP. 19 Others have explored the power of these endpoints as well; 20 but to date, these composite outcomes have not been explored by baseline patient characteristics that might improve the outcome sensitivity by study enrichment.…”