Post-hoc analyses of the edaravone clinical trials Study 16 and Study 19: a step toward more efficient clinical trial designs in amyotrophic lateral sclerosis.

Objectives: The edaravone development program established a study design in which a treatment effect slowing functional loss in amyotrophic lateral sclerosis (ALS) could be documented within a 24-week time frame. This report elucidates the strategic enrichment design utilized to create efficiency and precision in the development program. Methods: Post-hoc analyses describe learning, sequential iteration, and evolution in study design. Results: The first Phase 3 study of edaravone in ALS (Study MCI186-16) included a large proportion (35%) of placebo patients who were minimal progressors. These patients demonstrated high heterogeneity in change in ALSFRS-R score (-4 median with interquartile range [IQR] 7.5) and a modal distribution score of 0, suggesting evidence of minimal change in ALSFRS-R during the study. This level of variability and rate of progression may have made it difficult to detect a prospective treatment effect in the study. A strategic enrichment strategy provided the second Phase 3 study (Study MCI186-19) with the ability to detect a treatment effect. In Study MCI186-19, only 13% of the placebo patients were minimal progressors. Further, these placebo patients demonstrated less heterogeneity and greater functional progression of ALS, thereby providing greater likelihood of detecting a treatment effect. The enrichment strategy may have excluded some rapidly progressing patients, potentially supporting the detection of a treatment effect. As previously published, Study MCI186-19 prospectively documented a 33% reduction in rate of progression of ALS (p = 0.0013). Conclusions: Strategic choices in the design of Study MCI186-19 reduced the proportion of minimally progressing patients and supported detection of a treatment effect.

Post-hoc analysis of MCI186-17, the extension study to MCI186-16, the confirmatory double-blind, parallel-group, placebo-controlled study of edaravone in amyotrophic lateral sclerosis.

In the 24-week double-blind study of edaravone in ALS (MCI186-16), edaravone did not show a statistically significant difference versus placebo for the primary efficacy endpoint. For post-hoc analyses, two subpopulations were identified in which edaravone might be expected to show efficacy: the efficacy-expected subpopulation (EESP), defined by scores of ≥2 points on all 12 items of the ALS Functional Rating Scale-Revised (ALSFRS-R) and a percent predicted forced vital capacity (%FVC) ≥80% at baseline; and the definite/probable EESP 2 years (dpEESP2y) subpopulation which, in addition to EESP criteria, had definite or probable ALS diagnosed by El Escorial revised criteria, and disease duration of ≤2 years. In the 36-week extension study of MCI186-16, a 24-week double-blind comparison followed by 12 weeks of open-label edaravone (MCI186-17; NCT00424463), analyses of ALSFRS-R scores of the edaravone-edaravone group and edaravone-placebo group for the full analysis set (FAS) and EESP, as prospectively defined, were reported in a previous article. Here we additionally report results in patients who met dpEESP2y criteria at the baseline of MCI186-16. In the dpEESP2y, the difference in ALSFRS-R changes from 24 to 48 weeks between the edaravone-edaravone and edaravone-placebo groups was 2.79 (p = 0.0719), which was greater than the differences previously reported for the EESP and the FAS. The pattern of adverse events in the dpEESP2y did not show any additional safety findings to those from the earlier prospective study. In conclusion, this post-hoc analysis suggests a potential effect of edaravone between 24 and 48 weeks in patients meeting dpEESP2y criteria at baseline.

Post-hoc analysis of open-label extension period of study MCI186-19 in amyotrophic lateral sclerosis.

Study MCI186-19 investigated the safety and efficacy of edaravone in the treatment of ALS. The 24-week, double-blind period was followed by a 24-week, open-label, active extension period. Patients originally receiving edaravone continued edaravone (E-E group, n = 65), and patients originally receiving placebo switched to edaravone (P-E group, n = 58). Because no statistical tests had been prospectively planned in the open-label period, we performed post-hoc analyses to assist in the interpretation of efficacy data. A mixed model for repeated measures (MMRM) and the Combined Assessment of Function and Survival (CAFS) were assessed. Additionally, slopes of time-dependent change between baseline in cycle 1 and the end of cycle 6 (24 weeks double-blind) and between the end of cycle 6 and end of cycle 12 (24 weeks open-label) were calculated using a random coefficient model including all available data during each period. At week 48, the MMRM analysis showed significantly less decline in ALS Functional Rating Scale-Revised (ALSFRS-R) total score in the E-E group than in the P-E group (least-squares mean change from baseline ± standard error, 4.17 ± 1.40, p = 0.0037), meaning that the differences in the ALSFRS-R total score during the 24-week double-blind period were maintained in patients receiving edaravone for an additional 24 weeks. The CAFS endpoint (p = 0.0089) supported this finding. The slope analysis during the double-blind period showed a significant difference between the treatment groups, while there was no significant difference between the groups during the active extension period. These analyses suggest a potential benefit of early and continued edaravone treatment over delayed edaravone treatment.

An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe.

BACKGROUND: There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between different countries and regions. OBJECTIVE: To assess similarities and differences in clinical practice and treatment guidelines for ALS, and also to compare the demographics and rate of progression of disease in patients with ALS enrolled in clinical trials in Japan, the US, and Europe. METHODS: We performed a review of clinical studies published since 2000 to compare the demographics and characteristics of patients with ALS. Progression of ALS disease was assessed in patients receiving placebo. The changes per month in ALSFRS-R score were calculated and compared between the studies. RESULTS: Overall, diagnostic criteria, recognition of ALS symptoms, comorbidities, use of riluzole, and nutritional, and respiratory support were similar. Regarding demographics and characteristics, there were no clear differences in the incidence of sporadic ALS (range 91-98%), bulbar onset (range 11-41%), and median time from onset to diagnosis (range 9-14 months) among the populations despite the difference in race between regions. However, use of tracheostomy-based invasive respiratory support was higher in Japan (29-38%) than in the US (4%) and Europe (1-31%). Rate of progression of disease was similar between the US and Europe study populations (range -0.89 to -1.60 points/month), and the Japanese study populations (range -1.03 to -1.21 points/month). CONCLUSION: There is evidence to support the generalisability of data from the Japanese ALS trial experience to the US and Europe populations in early to mid-stage of ALS.

Post-hoc analysis of randomised, placebo-controlled, double-blind study (MCI186-19) of edaravone (MCI-186) in amyotrophic lateral sclerosis.

Post-hoc analyses of the ALS Functional Rating Scale-Revised (ALSFRS-R) score data, the primary endpoint in the 24-week double-blind placebo-controlled study of edaravone (MCI186-19, NCT01492686), were performed to confirm statistical robustness of the result. The previously reported original analysis had used a last observation carried forward (LOCF) method and also excluded patients with fewer than three completed treatment cycles. The post-hoc sensitivity analyses used different statistical methods as follows: 1) including all patients regardless of treatment cycles received (ALL LOCF); 2) a mixed model for repeated measurements (MMRM) analysis; and 3) the Combined Assessment of Function and Survival (CAFS) endpoint. Findings were consistent with the original primary analysis in showing superiority of edaravone over placebo. We also investigated the distribution of change in ALSFRS-R total score across all patients in the study as well as which ALSFRS-R items and domains may have contributed to the overall efficacy findings. The distribution of changes in ALSFRS-R total score from baseline to the end of cycle 6 (ALL LOCF) shifted in favour of edaravone compared to placebo. Edaravone was descriptively favoured for each ALSFRS-R item and each of the four ALSFRS-R domains at the end of cycle 6 (ALL LOCF), suggesting a generalised effect of edaravone in slowing functional decline across all anatomical regions. The effect of edaravone appeared to be similar in patients with bulbar onset and limb onset. Together, these observations would be consistent with its putative neuroprotective effects against the development of oxidative damage unspecific to anatomical regions.