ABSTRACT
Introduction/Aims
On/Off dosing of intravenous (IV) edaravone and edaravone oral suspension was US Food and Drug Administration (FDA)‐approved for Amyotrophic Lateral Sclerosis (ALS) treatment. Placebo‐controlled trials showed that IV edaravone slows the rate of physical functional decline in patients with ALS. Here, the impact of edaravone oral suspension on function and survival was assessed.
Methods
Edaravone oral suspension was investigated in clinical trials MT‐1186‐A01/A02/A03/A04. Patients from Studies MT‐1186‐A02/A04 (prespecified analysis) and Studies MT‐1186‐A01/A02/A03/A04 (post hoc analysis) were propensity score matched 1:1 on 10 baseline variables with historical Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) placebo patients (not receiving active investigational treatment in their trials) to assess the impact of edaravone oral suspension on function and survival.
Results
In the prespecified analysis, 78 edaravone oral suspension–treated patients from Studies MT‐1186‐A02/A04 demonstrated a survival benefit versus 78 matched PRO‐ACT placebo patients (p = 0.005). Baseline risk‐adjusted hazard ratio showed an 84% decreased risk of death in edaravone oral suspension versus PRO‐ACT placebo patients (p = 0.005). ALS Functional Rating Scale‐Revised (ALSFRS‐R) total score change from baseline at Week 48 was −8.4 points for edaravone oral suspension versus −14.1 points for PRO‐ACT placebo patients (p < 0.001). In the post hoc analysis, patients from Studies MT‐1186‐A01/A02/A03/A04 (n = 210) propensity score matched to PRO‐ACT placebo patients (n = 210) showed statistically significantly longer time to death and smaller ALSFRS‐R change from baseline at Week 48; restricted mean survival time showed a 7.3‐month improvement (p < 0.001).
Discussion
This suggests edaravone oral suspension significantly increases survival time and decreases physical functional decline versus PRO‐ACT placebo patients.
Keywords: amyotrophic lateral sclerosis, clinical trial, edaravone, efficacy, survival
Abbreviations
- ALS
amyotrophic lateral sclerosis
- ALSFRS‐R
ALS Functional Rating Scale‐Revised
- BMI
body mass index
- CI
confidence interval
- E‐E
edaravone‐edaravone
- ENCALS
European Network for the Cure of ALS
- FDA
Food and Drug Administration
- FVC
forced vital capacity
- HR
hazard ratio
- IV
intravenous
- LS
least squares
- MMRM
mixed model for repeated measures
- n/a
not applicable
- OLE
open‐label extension
- PAV
permanent assisted ventilation
- PB‐TURSO
sodium phenylbutyrate and taurursodiol
- P‐E
placebo‐edaravone
- PRO‐ACT
Pooled Resource Open‐Access ALS Clinical Trials
- PSM
propensity score matching
- RMST
restricted mean survival time
- SAP
statistical analysis plan
- SD
standard deviation
- SE
standard error
- Study 19
Study MCI186‐19
- SVC
slow vital capacity
- US
United States
- VA
Veterans Affairs
- VC
vital capacity
1. Introduction
Intravenous (IV) edaravone received United States (US) Food and Drug Administration (FDA) approval for use in Amyotrophic Lateral Sclerosis (ALS) in 2017 [1] based on the results of a pivotal, placebo‐controlled, phase 3 trial (MCI186‐19; Study 19) in which IV edaravone was shown to slow the rate of functional decline by 33% (p = 0.0013), as measured by the ALS Functional Rating Scale‐Revised (ALSFRS‐R), versus placebo at 24 weeks [2]. Edaravone oral suspension was FDA‐approved in May 2022 [1, 3, 4]. A global, multicenter, open‐label, phase 3 study (MT‐1186‐A01) investigated the safety and tolerability of On/Off dosing of edaravone oral suspension in adults with ALS through 48 weeks and found that edaravone oral suspension was well tolerated, with no new safety concerns identified [5].
Several post hoc analyses of Study 19 have helped establish the longer‐term effects of edaravone treatment and generalizability to a broader ALS population [6, 7]. Beyond the initial 24‐week, double‐blind, placebo‐controlled period of Study 19, there was a 24‐week, open‐label extension (OLE) that included patients who originally received IV edaravone and continued receiving it (edaravone‐edaravone [E‐E] group, n = 65) and patients who originally received placebo and switched to IV edaravone (placebo‐edaravone [P‐E] group, n = 58) [8]. ALSFRS‐R score change (mean ± standard deviation [SD]) from baseline was −8.0 ± 5.6 in the E‐E group and −10.9 ± 6.9 in the P‐E group over 48 weeks. Because the OLE did not have statistical tests prospectively planned, a post hoc analysis using a mixed model for repeated measures (MMRM) showed significantly less ALSFRS‐R total score decline in the E‐E versus P‐E group at 48 weeks, demonstrating that ALSFRS‐R score differences were maintained through the OLE [9]. In addition, a Study 19 post hoc analysis showed a 53% relative risk reduction for death, tracheostomy, permanent assisted ventilation (PAV), or hospitalization in the E‐E versus P‐E group at 48 weeks (p = 0.02) [10]. Finally, data from a US administrative claims database showed that IV edaravone treatment was associated with significantly prolonged median overall survival versus propensity score–matched patients not treated with IV edaravone (p = 0.005) [11].
There are no longer‐term studies that have provided information relating to the effect of edaravone oral suspension treatment versus placebo on function and survival. The Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) database can provide a source for historical, external placebo controls in analyses of ALS clinical trials [12, 13]. Here, using ALSFRS‐R scores and survival data versus propensity score–matched, external, historical PRO‐ACT placebo control group patients (who did not receive active investigational treatment, but may have received riluzole in their respective clinical trials, hereafter referred to as the “PRO‐ACT placebo group”), we prospectively planned to examine efficacy of edaravone oral suspension treatment through 24 months from patients with ALS enrolled in Studies MT‐1186‐A02 and MT‐1186‐A04 before the database lock of Study MT‐1186‐A02, and retrospectively evaluated efficacy in a broader ALS population enrolled in Studies MT‐1186‐A01/A02/A03/A04.
2. Methods
2.1. Studies MT‐1186‐A01/A02/A03/A04
Study MT‐1186‐A01 (NCT04165824) was a phase 3, global, multicenter, open‐label study that evaluated the long‐term safety and tolerability of the approved edaravone oral suspension (Mitsubishi Tanabe Pharma America) 105‐mg On/Off dosing regimen over 48 weeks [5], and Study MT‐1186‐A03 (NCT04577404) was its extension study, which provided up to 96 weeks of additional treatment. Study MT‐1186‐A02 (NCT04569084) was a phase 3b, multicenter, double‐blind, parallel‐group, randomized study that evaluated whether investigational Once Daily edaravone oral suspension dosing was superior to the approved On/Off dosing based on Combined Assessment of Function and Survival, and assessed safety and tolerability over 48 weeks in patients with ALS; and Study MT‐1186‐A04 (NCT05151471) was its extension study, which provided up to 48 weeks of additional treatment. Studies MT‐1186‐A01/A02/A03 [5, 14, 15] have been previously described.
2.2. Standard Protocol Approvals, Registrations, and Patient Consent
Protocol approval, registration, and patient consent information for Studies MT‐1186‐A01/A02/A03 [5, 14, 15] have been previously described. These and Study MT‐1186‐A04 were initiated only after Institutional Review Board/Independent Ethics Committee approval of the necessary essential documents, and only after patients provided informed consent.
2.3. PRO‐ACT Database
Data for the historical, external control patients with ALS who had not received active investigational treatment, but may have received riluzole in their respective clinical trials, were obtained from the PRO‐ACT database [12], which contains > 10 million longitudinally collected data points from phase 2/3 clinical trials [13]. Protocols of included PRO‐ACT database trials were approved by the participating medical centers. Trial data are de‐identified and provided for research purposes only [13]. Data used in the preparation of this article were obtained from the PRO‐ACT Database. The data available in the PRO‐ACT Database have been volunteered by PRO‐ACT Consortium members. [Correction added after first online publication on 06 August 2025. This section has been updated.]
2.4. Analysis Cohorts
The follow‐up period was designed to 98 weeks for Studies MT‐1186‐A02/A04 and 144 weeks for Studies MT‐1186‐A01/A03. The primary analysis examined the efficacy of edaravone oral suspension–treated patients with ALS enrolled in Studies MT‐1186‐A02/A04 through approximately 24 months versus propensity score–matched PRO‐ACT placebo group patients. To confirm the robustness of the primary cohort analysis results, the broader ALS population post hoc analysis similarly examined the efficacy of edaravone oral suspension–treated patients with ALS enrolled in Studies MT‐1186‐A01/A02/A03/A04 through approximately 35 months versus PRO‐ACT placebo group.
In the primary analysis cohort, the following key inclusion criteria in Studies MT‐1186‐A02/A04 were applied for both treated and PRO‐ACT placebo groups: definite ALS or probable ALS per El Escorial revised Airlie House diagnostic criteria; ≥ 18 to 75 years of age; ≥ 2 points on each individual ALSFRS‐R item at baseline; ≥ 70% respiratory function (baseline % forced vital capacity [FVC] or % slow vital capacity [SVC]); ≤ 2 years between first symptom of ALS and informed consent; and 1‐ to 4‐point decline in total ALSFRS‐R score during 8 weeks (±7 days) between screening and baseline visits (edaravone oral suspension–treated group only). Propensity score matching, described in the Results, was applied for the edaravone oral suspension–treated and PRO‐ACT placebo groups.
In the broader ALS population post hoc analysis, for all treated and PRO‐ACT placebo groups, the following criteria were applied: available baseline data for age, sex, body weight, El Escorial revised Airlie House Diagnostic Criteria (definite ALS, probable ALS, probable laboratory‐supported ALS, or possible ALS), disease duration between ALS symptom onset date and informed consent date, baseline ALSFRS‐R total score, baseline % vital capacity (VC) (either %FVC or %SVC), initial symptom (bulbar or limb onset), concomitant use of riluzole, pre–ALSFRS‐R slope per month [16], available time to death, and post‐baseline ALSFRS‐R total score; similar propensity score matching was also applied. This analysis cohort removed the above key inclusion criteria for Studies MT‐1186‐A02 and MT‐1186‐A04.
2.5. Endpoints
The primary endpoint was time to death, and the secondary endpoint was change in ALSFRS‐R score from baseline up to Week 48.
2.6. Statistical Methods
The statistical analysis plan (SAP) for the comparison between the edaravone oral suspension and historical PRO‐ACT placebo groups was finalized before the Study MT‐1186‐A02 database lock.
To account for any potential imbalances in participant baseline characteristics or other variables between each edaravone oral suspension treatment group and PRO‐ACT placebo group, patients were propensity score matched to adjust for baseline covariates, including age, sex, body weight, El Escorial revised Airlie House diagnostic criteria, disease duration between ALS symptom onset date and screening visit, baseline ALSFRS‐R total score, baseline %VC (either %FVC or %SVC), initial symptom, concomitant use of riluzole, and pre–ALSFRS‐R slope per month. Propensity score matching was conducted in a 1:1 ratio using greedy‐matching algorithm and a caliper width of 0.3 (for the prespecified primary analysis cohort including Studies MT‐1186‐A02/A04) or 0.15 (for the broader ALS post hoc analysis cohort including Studies MT‐1186‐A01/A02/A03/A04) of the SD of the logit of the propensity score, referring to a caliper width of 0.2 [17], 0.25 [18], and 0.4 [19]. Balance after matching was assessed by a standardized mean difference of ≤ 0.1 [20].
The primary analysis for time to death applied the log‐rank test with Kaplan–Meier estimates with 95% confidence intervals (CIs). Secondary analysis of a Cox proportional hazards model with treatment and propensity score for this endpoint was also performed according to the SAP. ALSFRS‐R total score change from baseline to Week 48 was analyzed using the MMRM with treatment regimen, visit, and treatment regimen by visit interaction as fixed factors, and propensity score as the covariate. An unstructured covariance structure was assumed for the covariance of within‐patient scores, and denominator degrees of freedom were computed using the Kenward–Roger method. All statistical tests were 2‐sided at the 5% significance level. Point estimates of treatment differences were accompanied by 2‐sided 95% CIs where applicable. No multiplicity adjustments were made. The main statistical comparison was made between the Combined (On/Off + Once Daily) edaravone oral suspension group versus PRO‐ACT placebo group.
3. Results
3.1. PRO‐ACT Database Patient Cohorts
For the primary analysis cohort, there were 82 PRO‐ACT placebo group patients meeting the key inclusion criteria for the MT‐1186‐A02/A04 analysis population and having available time to death and ALSFRS‐R data out of 11,675 patients overall (Figure 1a). For the broader ALS post hoc analysis cohort without the above key inclusion criteria, there were 297 PRO‐ACT placebo group patients with available background information, time to death, and ALSFRS‐R data out of 11,675 patients overall (Figure 1b).
FIGURE 1.
Selection of PRO‐ACT external placebo group for (a) Studies MT‐1186‐A02 and MT‐1186‐A04 and (b) Studies MT‐1186‐A01/A02/A03/A04. ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; PSM, propensity score matching.
3.2. Propensity Score Matching of Baseline Characteristics
Patients with ALS in Studies MT‐1186‐A02 and MT‐1186‐A04 on 2 different edaravone oral suspension regimens were propensity score matched as follows with patients with ALS administered placebo in the PRO‐ACT database (Table 1):
Combined (On/Off + Once Daily) edaravone oral suspension group (n = 78) versus PRO‐ACT placebo group (n = 78).
On/Off edaravone oral suspension regimen (n = 65) versus PRO‐ACT placebo group (n = 65).
Once Daily edaravone oral suspension regimen (n = 65) versus PRO‐ACT placebo group (n = 65).
TABLE 1.
Demographic and baseline characteristics of the primary propensity score–matched analysis cohorts of the MT‐1186‐A02 and MT‐1186‐A04 Combined edaravone oral suspension group versus PRO‐ACT placebo group and broader post hoc propensity score–matched analysis cohorts of the MT‐1186‐A01/A02/A03/A04 edaravone oral suspension groups versus PRO‐ACT placebo group.
| Primary propensity score–matched cohort | Post hoc propensity score–matched cohort | |||
|---|---|---|---|---|
| MT‐1186‐A02 and MT‐1186‐A04 | MT‐1186‐A01/A02/A03/A04 | |||
| Edaravone oral suspension Combined group (n = 78) | PRO‐ACT placebo group (n = 78) | Edaravone oral suspension On/Off and Once Daily group (n = 210) | PRO‐ACT placebo group (n = 210) | |
| Sex, n (%) | ||||
| Male | 54 (69.2) | 51 (65.4) | 121 (57.6) | 126 (60.0) |
| Female | 24 (30.8) | 27 (34.6) | 89 (42.4) | 84 (40.0) |
| Age (years) | ||||
| n | 78 | 78 | 210 | 210 |
| Mean (SD) | 56.0 (9.2) | 56.1 (9.6) | 57.9 (10.0) | 57.7 (10.1) |
| Median (min, max) | 57.0 (34, 72) | 56.5 (36, 74) | 59.0 (29, 75) | 58.0 (24, 80) |
| < 65 years, n (%) | 61 (78.2) | 61 (78.2) | 153 (72.9) | 155 (73.8) |
| ≥ 65 years, n (%) | 17 (21.8) | 17 (21.8) | 57 (27.1) | 55 (26.2) |
| On/Off or Once Daily, n (%) | ||||
| Edaravone oral suspension On/Off | 40 (51.3) | n/a | 125 (59.5) | n/a |
| Edaravone oral suspension Once Daily | 38 (48.7) | n/a | 85 (40.5) | n/a |
| Body weight (kg) | ||||
| n | 78 | 78 | 210 | 210 |
| Mean (SD) | 76.2 (17.0) | 78.1 (16.1) | 72.2 (16.7) | 74.6 (15.5) |
| Median (min, max) | 79.7 (41.5, 124.2) | 76.7 (49.4, 123.8) | 73.0 (39.2, 125.9) | 73.0 (40.0, 123.8) |
| BMI (kg/m2) | ||||
| n | 78 | 71 | 210 | 191 |
| Mean (SD) | 25.8 (5.0) | 25.8 (3.8) | 25.0 (4.6) | 25.7 (3.9) |
| Median (min, max) | 25.2 (16.8, 40.9) | 25.6 (19.2, 36.0) | 24.5 (16.8, 40.9) | 25.7 (15.9, 36.2) |
| El Escorial revised Airlie House diagnostic criteria, n (%) | ||||
| Definite ALS | 39 (50.0) | 45 (57.7) | 99 (47.1) | 94 (44.8) |
| Probable ALS | 39 (50.0) | 33 (42.3) | 94 (44.8) | 78 (37.1) |
| Probable laboratory‐supported ALS | 0 | 0 | 16 (7.6) | 30 (14.3) |
| Possible ALS | 0 | 0 | 1 (0.5) | 8 (3.8) |
| Disease duration from onset of symptoms to screening visit (years) | ||||
| n | 78 | 78 | 210 | 210 |
| Mean (SD) | 1.1 (0.4) | 1.1 (0.4) | 1.3 (0.6) | 1.3 (0.6) |
| Median (min, max) | 1.0 (0.4, 1.9) | 1.1 (0.4, 2.0) | 1.2 (0.1, 2.9) | 1.2 (0.3, 3.4) |
| < 1 year, n (%) | 37 (47.4) | 33 (42.3) | 74 (35.2) | 71 (33.8) |
| ≥ 1 year, n (%) | 41 (52.6) | 45 (57.7) | 136 (64.8) | 139 (66.2) |
| ≤ 2 years, n (%) | 78 (100.0) | 78 (100.0) | 189 (90.0) | 183 (87.1) |
| > 2 years, n (%) | 0 | 0 | 21 (10.0) | 27 (12.9) |
| Initial symptom, n (%) | ||||
| Bulbar onset | 38 (48.7) | 41 (52.6) | 82 (39.0) | 84 (40.0) |
| Limb onset | 40 (51.3) | 37 (47.4) | 128 (61.0) | 126 (60.0) |
| Baseline ALSFRS‐R score | ||||
| n | 78 | 78 | 210 | 210 |
| Mean (SD) | 41.0 (3.2) | 41.0 (3.1) | 39.1 (4.0) | 38.9 (4.7) |
| Median (min, max) | 42.0 (30, 47) | 41.0 (34, 47) | 40.0 (22, 47) | 39.5 (23, 47) |
| Change in ALSFRS‐R score during screening period (between screening and baseline visits) for studies MT‐1186‐A02/A04 only, n (%) | ||||
| (−1, −2) | 60 (76.9) | n/a | 103 (49.0) | n/a |
| (−3, −4) | 18 (23.1) | n/a | 43 (20.5) | n/a |
| Pre–ALSFRS‐R slope per month (for comparison with PRO‐ACT placebo group) | ||||
| n | 78 | 78 | 210 | 210 |
| Mean (SD) | −0.6 (0.3) | −0.6 (0.4) | −0.7 (0.5) | −0.7 (0.6) |
| Median (min, max) | −0.5 (−1.8, −0.2) | −0.5 (−2.0, −0.1) | −0.6 (−3.9, −0.1) | −0.6 (−4.6, −0.04) |
| Concomitant use of riluzole, n (%) | ||||
| Yes | 57 (73.1) | 53 (67.9) | 163 (77.6) | 161 (76.7) |
| No | 21 (26.9) | 10 (12.8) | 47 (22.4) | 18 (8.6) |
| Missing | 0 | 15 (19.2) | 0 | 31 (14.8) |
Abbreviations: ALS, Amyotrophic Lateral Sclerosis; ALSFRS‐R, ALS Functional Rating Scale‐Revised; BMI, body mass index; n/a, not applicable; PB‐TURSO, sodium phenylbutyrate and taurursodiol; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SD, standard deviation.
Baseline characteristics were well balanced overall in the comparison between MT‐1186‐A02/A04 Combined edaravone oral suspension versus PRO‐ACT placebo groups (Table 1, Figure S1a). Similar baseline characteristics were observed in the On/Off edaravone oral suspension regimen versus PRO‐ACT placebo and the Once Daily edaravone oral suspension regimen versus PRO‐ACT placebo group (Table S1). A broader population of patients with ALS in Studies MT‐1186‐A01/A02/A03/A04 (n = 210 per arm) was post hoc propensity score matched with PRO‐ACT placebo group patients with baseline characteristics well balanced overall except for the proportion of %VC < 70% at baseline (edaravone oral suspension: 0.5%; PRO‐ACT placebo: 10.5%) (Table 1, Figure S1b). Vital capacity data for the groups are compared in Table S2.
3.3. Time to Death
In the primary propensity score–matched analysis cohort (N = 156), the Combined edaravone oral suspension group (n = 78) demonstrated a survival benefit versus PRO‐ACT placebo group (n = 78) over 670 days (approximately 22 months). The log‐rank test showed a statistically significant difference between groups (p = 0.005). Fewer patients died in the Combined edaravone oral suspension group (3/78 patients, 3.8%) versus PRO‐ACT placebo group (14/78 patients, 17.9%) (Figure 2a, Table 2). The baseline risk‐adjusted hazard ratio (HR) was statistically significant and showed an 84% decreased risk of death (HR = 0.16, 95% CI [0.043, 0.562]; p = 0.005), indicating longer survival for patients in the Combined edaravone oral suspension versus PRO‐ACT placebo groups (Table 2). Additionally, differences comparing both the Once Daily (n = 65) and On/Off edaravone oral suspension (n = 65) groups versus PRO‐ACT placebo group (n = 65), which were not statistically significant, are shown for time to death in Table S3 and Figure S2a,b.
FIGURE 2.
Overall survival in the (a) propensity score–matched Combined MT‐1186‐A02 and MT‐1186‐A04 edaravone oral suspension group versus PRO‐ACT placebo group and (b) broader post hoc propensity score–matched analysis cohorts of the MT‐1186‐A01/A02/A03/A04 edaravone oral suspension groups versus PRO‐ACT placebo group. PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials.
TABLE 2.
Overall survival in the primary propensity score–matched cohorts of the MT‐1186‐A02 and MT‐1186‐A04 Combined edaravone oral suspension group versus the PRO‐ACT placebo group and broader post hoc propensity score–matched analysis cohorts of the MT‐1186‐A01/A02/A03/A04 edaravone oral suspension groups versus PRO‐ACT placebo group.
| Primary propensity score–matched cohort | Post hoc propensity score–matched cohort | |||
|---|---|---|---|---|
| MT‐1186‐A02 and MT‐1186‐A04 | MT‐1186‐A01/A02/A03/A04 | |||
| Edaravone oral suspension Combined group (n = 78) | PRO‐ACT placebo group (n = 78) | Edaravone oral suspension On/Off and Once Daily group (n = 210) | PRO‐ACT placebo group (n = 210) | |
| Number of events (%) | 3 (3.8) | 14 (17.9) | 29 (13.8) | 69 (32.9) |
| Median (months) | — | — | — | 20.70 |
| 95% CI | — | (18.4, −) | — | 18.43, 23.59 |
| Min, max | 9.6, 19.0 | 7.6, 20.9 | 3.5, 32.9 | 2.1, 32.8 |
| p a | 0.005 | < 0.001 | ||
| Hazard ratio (SE) b | 0.16 (0.65) | 0.34 (0.22) | ||
| 95% CI b | (0.04, 0.56) | (0.22, 0.52) | ||
| p b | 0.005 | < 0.001 | ||
Abbreviations: CI, confidence interval; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SE, standard error.
Statistics are from the log‐rank test.
Statistics are from the Cox proportional hazard regression model with treatment and propensity score.
In the post hoc propensity score–matched analysis cohort that included the broader ALS population encompassing patients from Studies MT‐1186‐A01/A02/A03/A04 (n = 420) versus PRO‐ACT placebo group, the log‐rank test showed a statistically significant difference in time to death between the 2 groups over 1059 days (approximately 35 months; p < 0.001). The proportion of events in the edaravone oral suspension group (29/210 patients, 13.8%) was significantly smaller than the PRO‐ACT placebo group (69/210 patients, 32.9%) (Figure 2b, Table 2). The baseline risk‐adjusted HR was statistically significant and showed a 66% decreased risk of death in the On/Off and Once Daily edaravone oral suspension groups versus PRO‐ACT placebo group (HR = 0.34, 95% CI [0.22, 0.52]; p < 0.001) (Table 2). Post hoc restricted mean survival time (RMST) analysis [21] was performed for this population to confirm the average survival time over 1041 days (approximately 34 months) and showed an additional mean 7.3 months of survival (On/Off and Once Daily edaravone oral suspension: 29.6 months; PRO‐ACT placebo group: 22.2 months; p < 0.001).
3.4. ALSFRS‐R Functional Change
In the primary propensity score–matched analysis cohort (N = 156), change from baseline ALSFRS‐R score in patients in the Combined edaravone oral suspension (n = 78) versus PRO‐ACT placebo (n = 78) groups was examined. Patients in both groups had a mean baseline ALSFRS‐R score of 41.0 points (Table 1, Figure 3). The least squares (LS) mean ± standard error (SE) ALSFRS‐R total score change from baseline to Week 48 was smaller in the Combined edaravone oral suspension group (−8.4 ± 1.0 points) versus PRO‐ACT placebo group (−14.1 ± 1.0 points), a statistically significant difference of 5.6 points (95% CI [2.8, 8.4]; p < 0.001) (Table 3). In the primary propensity score–matched analysis cohort, when comparing the Once Daily edaravone oral suspension group (n = 65) versus PRO‐ACT placebo group (n = 65), a statistically significant difference was also observed in LS mean difference ± SE ALSFRS‐R total score change from baseline to Week 48 (4.5 ± 1.5 points; p = 0.003); a comparison of the On/Off edaravone oral suspension group versus the PRO‐ACT placebo group, which was not statistically significant, is shown in Table S4.
FIGURE 3.
ALSFRS‐R total score change over 48 weeks in the propensity score–matched Combined MT‐1186‐A02 and MT‐1186‐A04 edaravone oral suspension group versus PRO‐ACT placebo group. ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; CI, confidence interval; LS, least squares; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials.
TABLE 3.
Baseline ALSFRS‐R total score change in the primary propensity score–matched cohorts of the MT‐1186‐A02 and MT‐1186‐A04 Combined edaravone oral suspension group versus PRO‐ACT placebo group at Week 48 and broader post hoc propensity score–matched analysis cohorts of the MT‐1186‐A01/A02/A03/A04 edaravone oral suspension groups versus PRO‐ACT placebo group at Week 48.
| Primary propensity score–matched cohort | Post hoc propensity score–matched cohort | |||
|---|---|---|---|---|
| MT‐1186‐A02 and MT‐1186‐A04 | MT‐1186‐A01/A02/A03/A04 | |||
| Edaravone oral suspension Combined group (n = 78) | PRO‐ACT placebo group (n = 78) | Edaravone oral suspension On/Off and Once Daily group (n = 210) | PRO‐ACT placebo group (n = 210) | |
| Baseline | ||||
| n | 78 | 78 | 210 | 210 |
| Mean (SD) | 41.0 (3.2) | 41.0 (3.1) | 39.1 (4.0) | 38.9 (4.7) |
| Median (min, max) | 42.0 (30, 47) | 41.0 (34, 47) | 40.0 (22, 47) | 39.5 (23, 47) |
| Week 48 | ||||
| n | 49 | 52 | 137 | 146 |
| Mean (SD) | 34.8 (7.6) | 28.1 (9.3) | 30.1 (9.4) | 28.5 (9.3) |
| Median (min, max) | 37.0 (12, 46) | 30.0 (2, 44) | 32.0 (9, 46) | 30.0 (2, 47) |
| Change from baseline at Week 48 | ||||
| n | 49 | 52 | 137 | 146 |
| Mean (SD) | −6.6 (5.4) | −13.0 (8.2) | −9.4 (7.8) | −11.0 (7.6) |
| Median (min, max) | −5.0 (−24, 3) | −12.0 (−38, 2) | −7.0 (−29, 3) | −10.0 (−38, 2) |
| LS mean (SE) | −8.4 (1.0) | −14.1 (1.0) | −10.5 (0.7) | −12.9 (0.6) |
| LS mean difference (SE) | 5.6 (1.4) | 2.4 (0.9) | ||
| 95% CI | 2.8, 8.4 | 0.6, 4.2 | ||
| p | < 0.001 | 0.008 | ||
Note: Statistics are from the mixed model for repeated measures (MMRM) that included treatment group, visit, and treatment‐by‐visit interaction as fixed factors and propensity score in the model. An unstructured covariance structure and the denominator degrees of freedom are computed using the Kenward–Roger method.
Abbreviations: ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; CI, confidence interval; LS, least squares; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SD, standard deviation; SE, standard error.
In the post hoc propensity score–matched analysis cohort that included the broader ALS population from Studies MT‐1186‐A01/A02/A03/A04, change from baseline ALSFRS‐R score in patients in the On/Off and Once Daily edaravone oral suspension groups (n = 210) versus PRO‐ACT placebo group (n = 210) was examined, with patients in the edaravone oral suspension and PRO‐ACT placebo groups starting at a mean baseline ALSFRS‐R score of 39.1 and 38.9 points, respectively (Table 1). The LS mean ± SE ALSFRS‐R total score change from baseline to Week 48 was smaller in the edaravone oral suspension group (−10.5 ± 0.7 points) versus PRO‐ACT placebo group (−12.9 ± 0.6 points), a statistically significant difference of 2.4 points (95% CI [0.6, 4.2]; p = 0.008) (Table 3).
4. Discussion
Fewer deaths and longer overall survival were observed in the primary propensity score–matched analysis of the MT‐1186‐A02/A04 Combined edaravone oral suspension group versus PRO‐ACT placebo group. Additionally, the Combined and Once Daily edaravone oral suspension groups showed significantly less ALSFRS‐R score decline from baseline to Week 48 versus the PRO‐ACT placebo group. Similarly, statistically significant survival and ALSFRS‐R score results were also seen in the broader ALS population post hoc comparisons of Studies MT‐1186‐A01/A02/A03/A04 versus the PRO‐ACT placebo group.
The data here expand on the existing evidence from Study 19 which showed the benefit of IV edaravone versus placebo [2], and are consistent with the favorable survival outcome shown in a previous administrative claims database study of IV edaravone [11].
Previously published observational studies investigating treatment with edaravone have reported mixed results [22, 23, 24]. These results may have been limited by certain confounding variables, since capturing all prognostic factors associated with functional and survival outcomes in observational studies is very difficult. IV edaravone treatment of patients in the US Veterans Affairs (VA) healthcare system was associated with a lower death rate, but was not statistically significant, using predefined baseline confounders of IV edaravone receipt and ALS progression [22]. Two single‐arm, observational studies found no significant differences between edaravone‐treated groups versus patients not receiving edaravone in terms of disease progression or survival [23, 24]. In contrast to these studies, use of a PRO‐ACT placebo group may provide higher quality control data versus external data since clinical trial data are generated in a well‐controlled setting.
Study 19 demonstrated a baseline change in ALSFRS‐R LS mean difference of 2.49 points in favor of IV edaravone versus placebo group at 24 weeks [2]. In a Study 19 post hoc analysis, ALSFRS‐R score change was significantly lower for IV edaravone versus placebo through Week 48 [7]. In another Study 19 post hoc analysis, the IV edaravone group ALSFRS‐R score change at Week 48 was −10.2 points [9]. Castrillo‐Viguera et al. found all the clinicians/clinical researchers they surveyed considered an ALSFRS‐R score change of ≥ 25% at least somewhat clinically meaningful [25]. In the current study, the difference in the change from baseline ALSFRS‐R score between the Combined edaravone oral suspension versus PRO‐ACT placebo groups was 40% (5.6‐point difference between edaravone oral suspension and PRO‐ACT placebo group divided by the 14.1‐point change in PRO‐ACT placebo group), although this comparison between our study and the clinician survey requires careful consideration due to different study designs. The current study results agree with those of Study 19 [2] and suggest that edaravone oral suspension slows ALS functional decline.
The main limitation of our analysis is non‐randomized comparison. A second potential limitation is a time bias between our current analysis of edaravone oral suspension clinical trials and the PRO‐ACT historical placebo group. Previous studies investigating the survival of patients with ALS, with comparisons ranging from 1990 to 2010, have shown improved median survival over time, due in part to improvements in clinical practice and medical care [26, 27, 28]. There is a potential influence of a time bias in our analyses since literature investigating patients treated with riluzole suggest a difference of 0.33 years of median survival time to the riluzole‐free group between 2006 and 2013 [29, 30].
No multiplicity adjustments were made for these analyzed data. According to recommendations pertaining to use of an external placebo group [31], PRO‐ACT placebo group patients were extracted based on the same eligibility criteria used for the edaravone oral suspension treatment groups in Study MT‐1186‐A02, using a propensity score–matched methodology on relevant prognostic factors associated with ALS. While less preferred than the inclusion of an internal, contemporaneous randomized control group, propensity score–matched edaravone oral suspension–treated patients versus a historical PRO‐ACT placebo group allows for the exclusion of a concurrent placebo group due to ethical considerations [32]. Although the external PRO‐ACT placebo groups were propensity score matched to edaravone oral suspension treatment groups on established prognostic factors in ALS to minimize bias due to imbalance among background variables associated with clinical outcome, this cannot account for unknown confounders and does not match the gold standard of evidence generated by randomized controlled trials. Finally, genetic variables, such as C9orf72 status suggested by the European Network for the Cure of ALS (ENCALS) survival prediction model [33], could not be incorporated.
In summary, these results provide evidence for a slowing of functional decline and improved survival with long‐term edaravone oral suspension treatment versus PRO‐ACT placebo in patients with ALS. Post hoc RMST analysis of patients from Studies MT‐1186‐A01/A02/A03/A04 propensity score matched to PRO‐ACT placebo group patients showed a mean survival prolongation of 7.3 months. These findings are consistent with and provide additional supporting evidence to previously published studies. Future analyses using other external placebo groups based on the ENCALS prediction model [33] could be undertaken to assess the efficacy of edaravone oral suspension in patients with ALS.
Author Contributions
Fumihiro Takahashi: conceptualization, data curation, formal analysis, methodology, validation, writing – original draft, writing – review and editing. Angela Genge: conceptualization, investigation, writing – original draft, writing – review and editing. Manabu Hirai: conceptualization, writing – original draft, writing – review and editing. Daniel Selness: conceptualization, funding acquisition, methodology, project administration, supervision, writing – original draft, writing – review and editing. Vesna Todorovic: writing – original draft, writing – review and editing. Art Wamil: conceptualization, methodology, project administration, supervision, writing – original draft, writing – review and editing. Nissim Sasson: conceptualization, data curation, formal analysis, writing – original draft, writing – review and editing, methodology, validation. Stephen Apple: project administration, writing – original draft, writing – review and editing, supervision. Yoshiteru Ushirogawa: conceptualization, writing – original draft, writing – review and editing.
Ethics Statement
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Conflicts of Interest
F.T., M.H., D.S., A.W., and S.A. are employees of Mitsubishi Tanabe Pharma America Inc.; A.G. has served as a consultant for Mitsubishi Tanabe Pharma Inc.; Y.U. is an employee of Mitsubishi Tanabe Pharma Corporation; V.T. is an employee of Mitsubishi Tanabe Pharma Europe Ltd.; N.S. has served as a consultant for NeuroDerm and Mitsubishi Tanabe Pharma Inc.
Supporting information
Figure S1. Standardized mean difference of background variables of (a) propensity score–matched Combined MT‐1186‐A02 and MT‐1186‐A04 edaravone oral suspension group versus PRO‐ACT placebo group and (b) broader post hoc propensity score–matched analysis cohorts of the MT‐1186‐A01/A02/A03/A04 edaravone oral suspension groups versus PRO‐ACT placebo group, before and after propensity score matching. Abbreviations: ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials.
Figure S2. Overall survival in the propensity score–matched On/Off (a) and Once Daily (b) MT‐1186‐A02 and MT‐1186‐A04 edaravone oral suspension groups versus PRO‐ACT placebo groups. Abbreviations: PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials.
Table S1. Demographic and baseline characteristics of the primary propensity score–matched analysis cohorts of Studies MT‐1186‐A02 and MT‐1186‐A04 On/Off and Once Daily edaravone oral suspension groups versus PRO‐ACT placebo groups. Abbreviations: ALS, Amyotrophic Lateral Sclerosis; ALSFRS‐R, ALS Functional Rating Scale‐Revised; BMI, body mass index; FVC, functional vital capacity; PB‐TURSO, sodium phenylbutyrate and taurursodiol; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SD, standard deviation; SVC, slow vital capacity.
Table S2. Baseline vital capacity of the primary propensity score–matched analysis cohorts of the MT‐1186‐A02 and MT‐1186‐A04 Combined edaravone oral suspension group versus PRO‐ACT placebo group and broader post hoc propensity score–matched analysis cohorts of the MT‐1186‐A01/A02/A03/A04 edaravone oral suspension groups versus PRO‐ACT placebo group. Abbreviations: FVC, forced vital capacity; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SD, standard deviation; SVC, slow vital capacity.
Table S3. Overall survival in the primary propensity score–matched cohorts of Studies MT‐1186‐A02 and MT‐1186‐A04 On/Off and Once Daily edaravone oral suspension groups versus the PRO‐ACT placebo groups. aStatistics are from the log‐rank test. bStatistics are from the Cox proportional hazard regression model with treatment and propensity score from the primary propensity score–matched analysis cohort. Abbreviations: CI, confidence interval; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SE, standard error.
Table S4. Baseline ALSFRS‐R total score change in the primary propensity score–matched cohorts of the MT‐1186‐A02 and MT‐1186‐A04 On/Off and Once Daily edaravone oral suspension groups versus PRO‐ACT placebo groups at Week 48. Statistics are from the mixed model for repeated measures (MMRM) that included treatment group, visit, and treatment‐by‐visit interaction as fixed factors and propensity score in the model. An unstructured covariance structure and the denominator degrees of freedom is computed using the Kenward–Roger method. Abbreviations: ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; CI, confidence interval; LS, least squares; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SD, standard deviation; SE, standard error.
Acknowledgments
The authors thank Irene Brody, VMD, PhD, of p‐value communications, Cedar Knolls, NJ, USA, for providing medical writing support. Editorial support was also provided by p‐value communications. This support was funded by Mitsubishi Tanabe Pharma America, Inc., Jersey City, NJ, USA, in accordance with Good Publication Practice Guidelines 2022.
Data used in the preparation of this article were obtained from the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) Database. As such, the following organizations and individuals within the PRO‐ACT Consortium contributed to the design and implementation of the PRO‐ACT Database and/or provided data, but did not participate in the analysis of the data or the writing of this report:
ALS Therapy Alliance Cytokinetics, Inc. Amylyx Pharmaceuticals, Inc. Knopp Biosciences Neuraltus Pharmaceuticals, Inc. Neurological Clinical Research Institute, MGH Northeast ALS Consortium Novartis Orion Corporation Prize4Life Israel Regeneron Pharmaceuticals, Inc. Sanofi Teva Pharmaceutical Industries, Ltd. The ALS Association The Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital [Correction added after first online publication on 06 August 2025. This section has been updated.]
Takahashi F., Genge A., Hirai M., et al., “Analysis of Long‐Term Function and Survival of Edaravone Oral Suspension–Treated Patients With Amyotrophic Lateral Sclerosis Using PRO‐ACT Data as Historical Placebo Controls,” Muscle & Nerve 72, no. 4 (2025): 586–596, 10.1002/mus.28462.
Funding: This work was supported by Mitsubishi Tanabe Pharma America, Inc.
Fumihiro Takahashi and Angela Genge should be considered co‐lead authors.
Congresses where part or all of the material has been presented: Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS), Clearwater, 23 October 2024.
[Correction added after first online publication on 06 August 2025. “the Pooled Resource Open‐Access ALS Clinical Trials Consortium” has been added in author byline.]
Data Availability Statement
All relevant data are contained within the manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. Standardized mean difference of background variables of (a) propensity score–matched Combined MT‐1186‐A02 and MT‐1186‐A04 edaravone oral suspension group versus PRO‐ACT placebo group and (b) broader post hoc propensity score–matched analysis cohorts of the MT‐1186‐A01/A02/A03/A04 edaravone oral suspension groups versus PRO‐ACT placebo group, before and after propensity score matching. Abbreviations: ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials.
Figure S2. Overall survival in the propensity score–matched On/Off (a) and Once Daily (b) MT‐1186‐A02 and MT‐1186‐A04 edaravone oral suspension groups versus PRO‐ACT placebo groups. Abbreviations: PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials.
Table S1. Demographic and baseline characteristics of the primary propensity score–matched analysis cohorts of Studies MT‐1186‐A02 and MT‐1186‐A04 On/Off and Once Daily edaravone oral suspension groups versus PRO‐ACT placebo groups. Abbreviations: ALS, Amyotrophic Lateral Sclerosis; ALSFRS‐R, ALS Functional Rating Scale‐Revised; BMI, body mass index; FVC, functional vital capacity; PB‐TURSO, sodium phenylbutyrate and taurursodiol; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SD, standard deviation; SVC, slow vital capacity.
Table S2. Baseline vital capacity of the primary propensity score–matched analysis cohorts of the MT‐1186‐A02 and MT‐1186‐A04 Combined edaravone oral suspension group versus PRO‐ACT placebo group and broader post hoc propensity score–matched analysis cohorts of the MT‐1186‐A01/A02/A03/A04 edaravone oral suspension groups versus PRO‐ACT placebo group. Abbreviations: FVC, forced vital capacity; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SD, standard deviation; SVC, slow vital capacity.
Table S3. Overall survival in the primary propensity score–matched cohorts of Studies MT‐1186‐A02 and MT‐1186‐A04 On/Off and Once Daily edaravone oral suspension groups versus the PRO‐ACT placebo groups. aStatistics are from the log‐rank test. bStatistics are from the Cox proportional hazard regression model with treatment and propensity score from the primary propensity score–matched analysis cohort. Abbreviations: CI, confidence interval; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SE, standard error.
Table S4. Baseline ALSFRS‐R total score change in the primary propensity score–matched cohorts of the MT‐1186‐A02 and MT‐1186‐A04 On/Off and Once Daily edaravone oral suspension groups versus PRO‐ACT placebo groups at Week 48. Statistics are from the mixed model for repeated measures (MMRM) that included treatment group, visit, and treatment‐by‐visit interaction as fixed factors and propensity score in the model. An unstructured covariance structure and the denominator degrees of freedom is computed using the Kenward–Roger method. Abbreviations: ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; CI, confidence interval; LS, least squares; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SD, standard deviation; SE, standard error.
Data Availability Statement
All relevant data are contained within the manuscript.