Clinical staging in amyotrophic lateral sclerosis: analysis of Edaravone Study 19

Abstract

Objective: This was a post hoc analysis of the Edaravone Phase III Study MCI186-19 ('Study 19') to examine the utility of clinical staging systems as end points in clinical trials in amyotrophic lateral sclerosis (ALS).

Methods: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised item scores from Study 19 were retrospectively mapped to King's stage and Milano-Torino staging (MiToS) stage. We assessed the percentage of patients who experienced progression in King's and MiToS stages during Study 19. We also assessed disease progression in subgroups of patients according to baseline King's stage.

Results: During double-blind treatment, the percentage of patients who experienced a progression in King's stage was lower for edaravone (42.0%, 95% CI 30.4% to 53.6%) than placebo (55.9%, 95% CI 44.1% to 67.6%). The most pronounced effect was noted among patients who were in stage 1 and was maintained throughout open-label treatment. An analysis of a ≥2-stage progression in MiToS stage showed no difference between treatment arms during double-blind treatment, but during the open-label period, more rapid progression was noted among patients in the placebo-edaravone arm than among those in the edaravone-edaravone arm (log-rank test, p<0.001).

Conclusions: The King's and MiToS staging systems provided utility in assessing clinical progression in Edaravone Study 19. These findings may support the use of staging systems as end points in ALS clinical trials and to understand the timing of benefit as measured by these scales.

Figure 1

King’s and MiToS stages at study entry. Percentages of patients in each treatment arm corresponding to each clinical stage are shown (edaravone, blue columns; placebo, yellow columns). ALS, amyotrophic lateral sclerosis; MiToS, Milano-Torino staging.

Figure 2

Number of patients lost to follow-up. The number of patients lost to follow-up is shown for each assessment. The blue lines represent patients receiving edaravone and edaravone–edaravone; the yellow lines represent patients receiving placebo, and the blue dashed lines represent patients receiving placebo–edaravone. ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised; MiToS, Milano-Torino staging.

Figure 3

Kaplan-Meier analysis of time to any decline in King’s ALS clinical stage. Kaplan-Meier curves are shown for time to any decline in King’s ALS clinical stage for patients in the double-blind period (blue line, edaravone; yellow line, placebo) and in the active-treatment period (blue line, edaravone–edaravone; dashed blue line, placebo–edaravone). Plus symbols represent patients who were censored from the analysis due to loss to follow-up (a plus symbol may represent more than one patient). The number of patients at risk is listed under the graph at each time point for each arm. ALS, amyotrophic lateral sclerosis.

Figure 4

Kaplan-Meier analyses of patients remaining in each King’s stage. Kaplan-Meier curves show time to event analyses for proportions of patients remaining in King’s stage 1 (A), stage 2 (B), stage 3 (C) or stage 4 (D). All analyses are for time points during the 24-week double-blind treatment period. Plus symbols represent patients who were censored from the analysis (a plus symbol may represent more than one patient). The number of patients at risk is listed under the graph at each time point for each arm.

Figure 5

Kaplan-Meier analysis of time to any decline in MiToS stage. Kaplan-Meier curves are shown for time to any decline in MiToS stage for patients in the double-blind period (blue line, edaravone; yellow line, placebo) and in the active-treatment period (blue line, edaravone–edaravone; dashed blue line, placebo–edaravone). Plus symbols represent patients who were censored from the analysis due to loss to follow-up (a plus symbol may represent more than one patient). The number of patients at risk is listed under the graph at each time point for each arm. MiToS, Milano-Torino staging.

Figure 6

Kaplan-Meier analysis of time to a ≥2-stage decline in MiToS. Kaplan-Meier curves are shown for time to a ≥2-stage decline in MiToS for patients in the double-blind period (blue line, edaravone; yellow line, placebo) and in the active-treatment period (blue line, edaravone–edaravone; dashed blue line, placebo–edaravone). Plus symbols represent patients who were censored from the analysis due to loss to follow-up (a plus symbol may represent more than one patient). The number of patients at risk is listed under the graph at each time point for each arm. MiToS, Milano-Torino staging.

Figure 7

Change in ALSFRS-R scores by King’s stage at baseline and treatment group. Trends in changes in ALSFRS-R score over time were plotted for patients in the following King’s stages at baseline: stage 1 (edaravone, n=29; placebo, n=21), stage 2 (edaravone, n=27; placebo, n=36) and stage 3 (edaravone, n=11; placebo, n=9). Least squares means treatment differences from baseline to cycle 6, as assessed by MMRM analysis, were as follows: stage 1, 2.33 units (p=0.043); stage 2, 3.5 units (p=0.0057), and stage 3, 0.81 units (p=0.69). ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised; MMRM, mixed-effects model for repeated measures.