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

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.

Current and Future Projections of Amyotrophic Lateral Sclerosis in the United States Using Administrative Claims Data.

BACKGROUND: Various methodologies have been reported to assess the real-world epidemiology of amyotrophic lateral sclerosis (ALS) in the United States. The aim of this study was to estimate the prevalence, incidence, and geographical distribution of ALS using administrative claims data and to model future trends in ALS epidemiology. METHODS: We performed a retrospective analysis of deidentified administrative claims data for >100 million patients, using 2 separate databases (IBM MarketScan Research Databases and Symphony Health Integrated DataVerse [IDV]), to identify patients with ALS. We evaluated disease prevalence, annual incidence, age- and population-controlled geographical distribution, and expected future trends. RESULTS: From 2013 to 2017, we identified 7,316 and 35,208 ALS patients from the MarketScan databases and IDV, respectively. Average annual incidence estimates were 1.48 and 1.37 per 100,000 and point prevalence estimates were 6.85 and 5.16 per 100,000 and in the United States for the MarketScan databases and IDV, respectively. Predictive modeling estimates are reported out to the year 2060 and demonstrate an increasing trend in both incident and prevalent cases. CONCLUSIONS: This study provides incidence and prevalence estimates as well as geographical distribution for what the authors believe to be the largest ALS population studied to date. By using 2 separate administrative claims data sets, confidence in our estimates is increased. Future projections based on either database demonstrate an increase in ALS cases, which has also been seen in other large-scale ALS studies. These results can be used to help improve the allocation of healthcare resources in the future.

Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19).

BACKGROUND: In a Phase 3 study, amyotrophic lateral sclerosis (ALS) patients experienced significantly less physical functional decline with 24-week edaravone vs placebo, followed by open-label treatment for an additional 24 weeks. METHODS: Outcome (the change in ALS Functional Rating Scale-Revised, ALSFRS-R, from baseline) was projected for placebo patients through 48 weeks and compared with 48-week edaravone or 24-week edaravone after switching from placebo. RESULTS: A total of 123 patients received open-label treatment (65 edaravone-edaravone; 58 placebo-edaravone). The projected ALSFRS-R decline for placebo from baseline through week 48 was greater than for 48-week edaravone (P < .0001). For patients switching from placebo to edaravone, ALSFRS-R slope approached that of continued edaravone for 48 weeks. ALSFRS-R decline did not differ between actual and projected edaravone through week 48. CONCLUSIONS: Compared with placebo, these analyses suggest that edaravone is beneficial in ALS patients even after 6 mo of receiving placebo, and efficacy is maintained for up to 1 year.

Evidence for generalizability of edaravone efficacy using a novel machine learning risk-based subgroup analysis tool.

Introduction: The edaravone development program for amyotrophic lateral sclerosis (ALS) included trials MCI186-16 (Study 16) and MCI186-19 (Study 19). A cohort enrichment strategy was based on a Study 16 post hoc analysis and applied to Study 19 to elucidate a treatment effect in that study. To determine whether the Study 19 results could be generalized to a broader ALS population, we used a machine learning (ML) model to create a novel risk-based subgroup analysis tool. Methods: A validated ML model was used to rank order all Study 16 participants by predicted time to 50% expected vital capacity. Subjects were stratified into nearest-neighbor risk-based subgroups that were systematically expanded to include the entire Study 16 population. For each subgroup, a statistical analysis generated heat maps that revealed statistically significant effect sizes. Results: A broad region of the Study 16 heat map with significant effect sizes was identified, including up to 70% of the trial population. Incorporating participants identified in the cohort enrichment strategy yielded a broad group comprising 76% of the original participants with a statistically significant treatment effect. This broad group spanned the full range of the functional score progression observed in Study 16. Conclusions: This analysis, applying predictions derived using an ML model to a novel methodology for subgroup identification, ascertained a statistically significant edaravone treatment effect in a cohort of participants with broader disease characteristics than the Study 19 inclusion criteria. This novel methodology may assist clinical interpretation of study results and potentially inform efficient future clinical trial design strategies.

Engaging ALS patients and caregivers (the ALS research ambassadors) to help design the REFINE-ALS biomarker study.

In the planning and design of the Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS) study, we sought to elicit feedback from patients with ALS and their caregivers to ensure that patient-centric issues would be addressed. Ten ALS Clinical Research Learning Institute (ALS-CRLI) Research Ambassadors participated in 2 meetings. They provided perspectives on patients' interest in the study, the schedule of study visits, and data sharing. The findings were used to help revise the study design, as appropriate. Key concerns identified were (1) the frequency of sample collections, (2) participant travel burden, (3) enrollment criteria, and (4) data reporting and sharing with participants. Several of the identified issues were promptly addressed. The number of visits was reduced, travel optimized, entry criteria clarified, and plans for sharing participants' data with them were codified. The feedback from the Ambassadors was substantive and resulted in constructive patient-centric changes to the study protocol.

Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design.

OBJECTIVES: To identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes. METHODS: This is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration-approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale-Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported. RESULTS: The study is estimated to be completed in 2022 with an interim analysis planned. CONCLUSIONS: Findings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment.

Radicava (edaravone) for amyotrophic lateral sclerosis: US experience at 1 year after launch.

Background: Radicava® (edaravone), approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2017, may be administered intravenously at clinic sites, infusion centers or at home. Objective: To gain insights into the utilization of Radicava® at 1 year post-launch. Methods: Radicava® usage data were collected, and a survey was conducted among 75 physicians. Adverse events (AEs) were identified from a post-marketing safety database from 8 August 2017 through 3 August 2018 (cutoff date). Results: As of 6 August 2018, 3007 ALS patients were treated with Radicava®. Survey results indicated that 43% of patients received infusions at home, 32% in a clinician's office, and 26% at a referred site. Infusions were administered mainly via implanted port. The most commonly reported AEs were drug ineffective, death (not specified), therapeutic response unexpected, asthenia, fatigue, gait disturbance, disease progression, muscular weakness, fall, and dyspnea. Conclusions: The first year of Radicava® availability to ALS patients in the US provided many key learnings that will help shape strategies for improved patient care.

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.

Edaravone in the treatment of amyotrophic lateral sclerosis: efficacy and access to therapy - a roundtable discussion.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease affecting approximately 5 out of every 100,000 individuals living in the United States. ALS is associated with 50% mortality within 30 months of initial symptom onset. The rarity of the disease, along with the significant inter- and intra-patient variability in clinical course and a lack of reliable biomarkers, have rendered the development of effective agents to treat ALS a challenge. Because oxidative stress is considered a contributing factor to ALS onset and progression, drugs that eliminate free radicals may protect motor neurons from damage potentially caused by free-radical and oxidative stress. Edaravone is an antioxidant free-radical scavenger approved by the FDA in 2017 for the treatment of ALS. A review of the edaravone clinical development program offers a clearer view of the clinical utility of this agent. Broader treatment success is also influenced by factors such as limited patient access and the restrictive payer environment. Cooperation within the healthcare community, among clinicians, patient advocacy groups, pharmaceutical companies, and managed care payers, must occur to advance ALS management and treatment and improve patient access. Moreover, collaborative discussions are useful in identifying potential solutions to problems currently surrounding patient access.

Application of pharmacoeconomics to formulary decision making in managed care organizations.

OBJECTIVE: To discuss the apparent value of incorporating pharmacoeconomic studies into pharmacy and therapeutic committee decision making; current internal and external barriers to the use of pharmacoeconomic studies; and possible solutions to the problems. STUDY DESIGN: Literature review. RESULTS: The formulary system assists healthcare providers in the evaluation, appraisal, and selection of drugs. Unfortunately, managed care organizations usually evaluate drugs exclusively on clinical efficacy, safety, and daily acquisition cost without considering overall cost effectiveness. Factors that have been impeding the use of pharmacoeconomic data include departmental budgetary constraints, tardy publications, limited reliability of available studies, and a lack of knowledge required to evaluate such studies. CONCLUSIONS: To remain competitive, managed care organizations need to incorporate pharmacoeconomic consideration into their formulary decision-making process. Performing an institutionwide economic evaluation; conducting pharmacoeconomic studies earlier, perhaps along with clinical trials; using decision analysis; developing standardized guidelines; and increasing education can help overcome current barriers.

An epidemiologic model to project the impact of changes in glomerular filtration rate on quality of life and survival among persons with chronic kidney disease.

PURPOSE: Predicting the timing and number of end-stage renal disease (ESRD) cases from a population of individuals with pre-ESRD chronic kidney disease (CKD) has not previously been reported. The objective is to predict the timing and number of cases of ESRD occurring over the lifetime of a cohort of hypothetical CKD patients in the US based on a range of baseline estimated glomerular filtration rate (eGFR) values and varying rates of eGFR decline. METHODS: A three-state Markov model - functioning kidney, ESRD, and death - with an annual cycle length is used to project changes in baseline eGFR on long-term health outcomes in a hypothetical cohort of CKD patients. Using published eGFR-specific risk equations and adjusting for predictive characteristics, the probability of ESRD (eGFR <10), time to death, and incremental cost-effectiveness ratios for hypothetical treatments (costing US$10, $5, and $2/day), are projected over the cohort's lifetime under two scenarios: an acute drop in eGFR (mimicking acute kidney injury) and a reduced hazard ratio for ESRD (mimicking an effective intervention). RESULTS: Among CKD patients aged 50 years, an acute eGFR decrement from 45 mL/minute to 35 mL/minute yields decreases of 1.6 life-years, 1.5 quality-adjusted life-years (QALYs), 0.8 years until ESRD, and an increase of 183 per 1,000 progressing to ESRD. Among CKD patients aged 60 years, lowering the hazard ratio of ESRD to 0.8 yields values of 0.2, 0.2, 0.2, and 46 per 1,000, respectively. Incremental cost-effectiveness ratios are higher (ie, less favorable) for higher baseline eGFR, indicating that interventions occurring later in the course of disease are more likely to be economically attractive. CONCLUSION: Both acute kidney injury and slowing the rate of eGFR decline produce substantial shifts in expected numbers and timing of ESRD among CKD patients. This model is a useful tool for planning management of CKD patients.

Clinical characteristics and outcomes of end-stage renal disease patients with self-reported pruritus symptoms.

One of the most common conditions affecting end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) is pruritus. Studies report that itchy and dry skin, symptoms of pruritus, affect 40%-90% of ESRD patients. Yet, in clinical practice the condition is often underdiagnosed resulting in inadequate management and an underappreciated impact on patient outcomes. Two retrospective analyses were conducted: a preliminary analysis of ESRD patients with pruritus symptoms (n=73,124) undergoing HD or peritoneal dialysis at a large dialysis provider and a subsequent detailed analysis of a homogenous subset of patients undergoing in-center HD (n=38,315). The goal was to better understand the clinical burden of pruritus as it relates to patient characteristics, quality of life, medication use, and HD compliance. This population is commonly burdened by multiple comorbidities and related polypharmaceutical management; identifying the relationship of pruritus to these ailments can help guide future research and resource allocation. The detailed analysis confirmed trends observed in the preliminary analysis: 30% reported being "moderately" to "extremely bothered" by itchiness. The HD patient population with the highest severity of self-reported pruritus also had a consistent trend in overall increased resource utilization - higher monthly doses of erythropoietin-stimulating agents (53,397.1 to 63,405.4 units) and intravenous (IV) iron (237.2 to 247.6 units) and higher use of IV antibiotics (14.1% to 20.7%), as well as poorer quality-of-life measures (25-point reductions in Burden of Disease Score and Effects on Daily Life subscales of the Kidney Disease Quality of Life-36 survey). These results highlight the need to better identify and manage ESRD patients impacted by pruritus, as this symptom is associated with negative clinical outcomes and increased resource utilization. Further studies are needed to evaluate the current economic burden of pruritus in ESRD patients and create possible options for an improved pharmacoeconomic profile in this patient population.