Slowing the loss of physical function in amyotrophic lateral sclerosis with edaravone: Post hoc analysis of ALSFRS-R item scores in pivotal study MCI186-19.

INTRODUCTION: Phase 3 study MCI186-19 demonstrated less loss of physical function with edaravone versus placebo, as measured by the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score. A 1-point drop in an individual ALSFRS-R item may be clinically meaningful. We assessed ALSFRS-R item score changes to identify clinical features protected by edaravone treatment. METHODS: Time-to-event analysis was used to assess the cumulative probabilities of reductions in ALSFRS-R item scores and Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) subdomain scores. RESULTS: Edaravone use was accompanied by: (1) delayed drop of ≥1 point in ALSFRS-R item score for four items: salivation, walking, climbing stairs, orthopnea (unadjusted), or for two items: walking, climbing stairs (after Bonferroni correction for multiple comparisons); (2) delayed score transition from 4 or 3 at baseline to ≤2 for five items: swallowing, eating motion, walking, climbing stairs, orthopnea (unadjusted), or for one item: climbing stairs (after Bonferroni correction for multiple comparisons); and (3) delayed worsening of ALSAQ-40 domain scores representing daily living/independence, eating and drinking (unadjusted). DISCUSSION: These post-hoc analyses identified the ALSFRS-R item scores and ALSAQ-40 domain scores that were associated with preserved gross motor function and health-related quality of life, respectively, after edaravone treatment. Limitations of post-hoc analyses should be considered when interpreting these results. We recommend that clinical trials employing the ALSFRS-R include this type of analysis as a pre-specified secondary outcome measure.

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.

Edaravone and its clinical development for amyotrophic lateral sclerosis.

The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.

Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) affects persons of all races, and there continues to be a need for effective therapies to treat the disease. OBJECTIVE: To compare the pharmacokinetics (PK) of edaravone between Japanese and Caucasian populations. METHODS: Data from five PK studies among Japanese and Caucasian healthy volunteers were pooled and evaluated. In population PK (PPK) modelling, compartment models and other models with linear elimination were evaluated for appropriateness. Covariate effects by race, sex, weight, and age were investigated to explain variability in PK parameters. Simulations of the final PPK model were performed using a virtual population based on ALS clinical trials. RESULTS: The analysis included 86 subjects. A three-compartment model with Michaelis-Menten plus linear elimination was selected as the best fit model. Race was statistically detected as a covariate for the second peripheral volume of distribution (V2), indicating a 26% increase for Caucasian subjects compared to Japanese subjects. However, based on simulation of PPK model for a virtual ALS population, the small difference of V2 was associated with a difference of Ctau around 1 ng/mL after infusion, which was minimal compared to Cmax of approximately 1000 ng/ml. CONCLUSION: The PPK analyses demonstrated no clinically relevant difference in the PK profiles of edaravone by race, sex, weight, or age.

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.

Absorption and excretion of colestilan in healthy subjects.

Colestilan, an anion-exchange resin binding both phosphate and bile-acid anions, is under development for the treatment of hyperphosphataemia and dyslipidaemia, which occur in the majority of end-stage renal disease patients. This study using 14C-colestilan was conducted to investigate the absorption and excretion of colestilan in humans. Following a 28-day run-in period with administration of colestilan 3 g three times daily, 12 subjects received a single oral dose of 14C-colestilan 100 mg (approximately 4.0 MBq) and colestilan 3 g under fasted conditions on the morning of day 1. A total of 9 g of colestilan was administered three times daily on days 1-4. Total radioactivity levels in whole blood (at 4, 8, 12 and 24 hours and then at 24-hour intervals) and in the urine and faeces (from 0 to 24 hours and then at 24-hour intervals) were monitored up to 216 hours postdose (day 10). Total radioactivity measured in all whole-blood samples was below the lower limit of quantification (0.025 microg equivalent of 14C-labelled colestilan/mL of whole blood). Total radioactivity assessed in all urine samples was also below the lower limit of quantification (0.003 microg equivalent/mL for urine), except at 0-24 hours postdose, when 0.01% of the radioactive dose was excreted by all subjects. This level was below the predetermined water soluble impurity level of 0.04%. The mean cumulative excretion of total radioactivity in the faeces was 99.66% by 216 hours postdose, excluding one subject with incomplete collection of faecal samples. These results demonstrate that colestilan is not absorbed from the gastrointestinal tract and is completely excreted in the faeces.

Norepinephrine triggers Ca2+-dependent exocytosis of 5-hydroxytryptamine from rat pinealocytes in culture.

5-hydroxytryptamine (5-HT) is a precursor and a putative modulator for melatonin synthesis in mammalian pinealocytes. 5-HT is present in organelles distinct from l-glutamate-containing synaptic-like microvesicles as well as in the cytoplasm of pinealocytes, and is secreted upon stimulation by norepinephrine (NE) to enhance serotonin N-acetyltransferase activity via the 5-HT2 receptor. However, the mechanism underlying the secretion of 5-HT from pinealocytes is unknown. In this study, we show that NE-evoked release of 5-HT is largely dependent on Ca2+ in rat pinealocytes in culture. Omission of Ca2+ from the medium and incubation of pineal cells with EGTA-tetraacetoxymethyl-ester inhibited by 59 and 97% the NE-evoked 5-HT release, respectively. Phenylephrine also triggered the Ca2+-dependent release of 5-HT, which was blocked by phentolamine, an alpha antagonist, but not by propranolol, a beta antagonist. Botulinum neurotoxin type E cleaved 25 kDa synaptosomal-associated protein and inhibited by 50% of the NE-evoked 5-HT release. Bafilomycin A1, an inhibitor of vacuolar H+-ATPase, and reserpine and tetrabenazine, inhibitors of vesicular monoamine transporter, all decreased the storage of vesicular 5-HT followed by inhibition of the NE-evoked 5-HT release. Agents that trigger L-glutamte exocytosis such as acetylcholine did not trigger any Ca2+-dependent 5-HT release. Vice versa neither NE nor phenylephrine caused synaptic-like microvesicle-mediated l-glutamate exocytosis. These results indicated that upon stimulation of a adrenoceptors pinealocytes secrete 5-HT through a Ca2+-dependent exocytotic mechanism, which is distinct from the exocytosis of synaptic-like microvesicles.