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Introduction/aims: Riluzole improves survival in amyotrophic lateral sclerosis (ALS), but optimal time and duration of treatment are unknown. The aim of this study was to examine if timing of riluzole initiation and duration of treatment modified its effect on survival., Methods: Patients from the PRO-ACT dataset with information on ALS Functional Rating Scale, time from onset to enrollment (TFOE), and riluzole use were selected for analysis. Survival from enrollment was the outcome. Multivariable Cox proportional hazard models were examined for interactions between riluzole and TFOE. Inverse probability of treatment weighting (IPTW) was used to assess average treatment effect., Results: Of 4778 patients, 3446 (72.1%) had received riluzole. In unadjusted analyses, riluzole improved median survival significantly (22.6 vs. 20.2 months, log-rank p < 0.001). In multivariable analyses, no significant interaction between TFOE and riluzole was found. Riluzole effect was uniform during follow-up. By IPTW, estimated riluzole hazard ratio was 0.798 (95% confidence interval 0.686-0.927). Delaying riluzole initiation by 1 y (6 to 18 months from onset) may translate to reducing median survival from onset by 1.9 months (40.1 to 38.2 months)., Discussion: Riluzole appears to reduce risk of death uniformly, regardless of time from onset to treatment, and duration of treatment. Earlier treatment with riluzole may be associated with greater absolute survival gain from onset. Early diagnosis of ALS will facilitate early treatment and is expected to improve survival., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Objective : Examine sequence of weakness in arm muscles from longitudinal hand-held dynamometry (HHD) data in ALS for congruence with contiguous spread of neurodegeneration along spinal cord segments. Methods : Longitudinal HHD data from the Ceftriaxone clinical trial were examined using nonlinear mixed models, assuming a logistic trajectory from normal to zero strength. Unobserved baseline normal strength of weak muscles was assumed using strength of the best-preserved muscle. A novel metric called "time from onset to midway strength" (TOMS) was estimated for each muscle group, and TOMS ratios were examined to identify sequence of weakness, overall and by onset site. Results : Shoulder flexion (SF), elbow flexion (EF), elbow extension (EE), wrist extension (WE), and first dorsal interosseous (FDI) were measured on each side. Over a median of 36 weeks, 513 subjects provided 2589 sets of HHD measures. TOMS increased sequentially in the following order: FDI, WE, SF, EF, and EE. TOMS ratios estimates with 95% CIs (adjusted for multiple comparisons) were: WE/FDI 1.32 (1.24-1.41), SF/WE 1.06 (1.01-1.10), EF/SF 1.06 (1.02-1.10), and EE/EF 1.18 (1.12-1.23). Elbow and shoulder flexors weakened sooner than did elbow extensors. The sequence of arm muscle weakness progression was similar regardless of onset site. Conclusion : Nonsegmental progression of arm muscle weakness that is similar for different onset sites favors cortical influence/network spread over contiguous spread of neurodegeneration in the spinal cord. Furthermore, this study confirms the "split elbow" pattern. TOMS and other proposed methods may have value as outcome measures in clinical research.

Objectives: Reexamine cost-effectiveness of riluzole in the treatment of amyotrophic lateral sclerosis (ALS) in light of recent advances in disease staging and understanding of stage-specific drug effect., Methods: ALS was staged according to the "fine'til 9" (FT9) staging method. Stage-specific health utilities (EQ-5D, US valuation) were estimated from an institutional cohort, whereas literature informed costs and transition probabilities. Costs at 2018 prices were disaggregated into recurring costs (RCs) and "one-off" transition/"tollgate" costs (TCs). Five- and 10-year horizons starting in stage 1 disease were examined from healthcare sector and societal perspectives using Markov models to evaluate riluzole use, at a threshold of $100 000/quality-adjusted life year (QALY). Probabilistic and deterministic sensitivity analyses were conducted., Results: Mean EQ-5D utilities for stages 0 to 4 were 0.79, 0.74, 0.63, 0.54, and 0.46, respectively. From the healthcare sector perspective at the 5-year horizon, riluzole use contributed to 0.182 QALY gained at the cost difference of $12 348 ($5403 riluzole cost, $8870 RC and -$1925 TC differences), translating to an incremental cost-effectiveness ratio (ICER) of $67 658/QALY. Transition probability variation contributed considerably to ICER uncertainty (-30.2% to +90.0%). ICER was sensitive to drug price and RCs, whereas higher TCs modestly reduced ICER due to delayed tollgates., Conclusion: This study provides a framework for health economic studies of ALS treatments using FT9 staging. Prospective stage-specific and disaggregated cost measurement is warranted for accurate future cost-effectiveness analyses. Appropriate separation of TCs from RCs substantially mitigates the high burden of background cost of care on the ICER., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Objectives : To estimate the effect of riluzole on the stage-specific risk of progression of ALS. Methods : Patients from the PRO-ACT dataset were staged employing two methods (King's and FT9). Hazard ratios associated with riluzole treatment were estimated for forward transition between stages, using unadjusted and adjusted Markov multistate models. Results : Of 1903 patients, 1587 had received riluzole. Riluzole-treated patients survived non-significantly longer than those who did not (median 22.9 months vs. 18.3 months from time of initial observation, log rank p  = 0.16). After adjusting for age and ALSFRS-R slope at first visit, riluzole significantly reduced risk of the following transitions: (1) King's stages: 1->2 (hazard ratio (HR) = 0.81), and 2->3 (HR = 0.82), 4->death (HR = 0.57), and (2) FT9 stages: 1->2 (HR = 0.84), 3->4 (HR = 0.71), and 4->death (HR = 0.67). In contrast, the beneficial effect of riluzole in bulbar-onset patients was in early rather than late King's stages. Conclusions : This examination of cohorts closely followed in clinical trials finds a beneficial effect of riluzole that is predominantly but not exclusively in later stages of ALS. This analytic framework has utility to discern stage-specific treatment effects, and for refined health economic analyses.

Objective: We sought to examine prevalence and predictors of noninvasive ventilation (NIV) in a composite cohort of patients with amyotrophic lateral sclerosis (ALS) followed in a clinical trials setting (Pooled Resource Open-Access ALS Clinical Trials database)., Methods: NIV initiation and status were ascertained from response to question 12 of the revised ALS Functional Rating Scale (ALSFRS-R). Factors affecting NIV use in patients with forced vital capacity (FVC) ≤50% of predicted were examined. Predictors of NIV were evaluated by Cox proportional hazard models and generalized linear mixed models., Results: Among 1,784 patients with 8,417 simultaneous ALSFRS-R and FVC% measures, NIV was used by 604 (33.9%). Of 918 encounters when FVC% ≤50%, NIV was reported in 482 (52.5%). Independent predictors of NIV initiation were lower FVC% (hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.17-1.37 for 10% drop), dyspnea (HR 2.62, 95% CI 1.87-3.69), orthopnea (HR 4.09, 95% CI 3.02-5.55), lower bulbar and gross motor subscores of ALSFRS-R (HRs 1.09 [95% CI 1.03-1.14] and 1.13 [95% CI 1.07-1.20], respectively, per point), and male sex (HR 1.73, 95% CI 1.31-2.28). Adjusted for other variables, bulbar onset did not significantly influence time to NIV (HR 0.72, 95% CI 0.47-1.08). Considerable unexplained variability in NIV use was found., Conclusion: NIV use was lower than expected in this ALS cohort that was likely to be optimally managed. Absence of respiratory symptoms and female sex may be barriers to NIV use. Prospective exploration of factors affecting adoption of NIV may help bridge this gap and improve care in ALS., (© 2019 American Academy of Neurology.)

Objectives: Propose an empirical amyotrophic lateral sclerosis (ALS) staging approach called Fine'til 9 (FT9) based on how many of the patient's ALS functional rating scale (ALSFRS-R) subscores are 9 or less (of normal 12). Gain insights into progression of ALS by applying Markov models to ALS stages by multiple systems (King's, Milan-Torino system (MITOS) and FT9)., Methods: Patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) dataset were staged using ALSFRS-R responses. Risks of progression through stages and death were estimated, as were effects of prognostic variables on these risks., Results: A total of 29,947 time points in 3199 patients from the PRO-ACT dataset were assigned stages. Although the three systems were moderately correlated, MITOS stages were heavily skewed toward advanced disease, whereas King's and FT9 stages were more balanced. Non-sequential progression was observed with King's system. Markov models adequately described transitions from stage to stage in the first year of observation, but underestimated risks beyond that point. Regardless of staging method, initial rate of ALSFRS-R decline had a powerful effect on rate of progression through sequential stages, whereas age predominantly influenced stage-specific mortality., Conclusion: King's and FT9 are more sensitive to observed progression of disease in clinical trials than MITOS. FT9 can partition the course similar to King's, and may have advantages of sequential progression and easy applicability to retrospective data. Markov transition intensity estimates may be of value for counseling, health economic studies, and research design. In particular, this framework permits estimation of multidimensional effects of variables (including treatment) on outcome.

Introduction: Rate of decline of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score is a common outcome measure and a powerful predictor of mortality in ALS., Methods: Observed rate of decline (postslope) of ALSFRS-R, its linearity, and its relationship to decline at first visit (preslope) were examined in the Pooled Resource Open-Access ALS Clinical Trials cohort by using longitudinal mixed effects models., Results: Mean ALSFRS-R postslope in 3,367 patients was -0.99 points/month. Preslope and postslope were correlated and had powerful effects on survival. ALSFRS-R trajectories were slightly accelerated overall, but slope and direction/degree of curvature varied. Subscore decline was sequential by site of onset. Respiratory subscore decline was the least steep., Discussion: Variable curvilinearity of ALSFRS-R trajectories confounds interpretation in clinical studies that assume linear decline. Subscore trajectories recapitulate phenotypic diversity and topographical progression of ALS. ALSFRS-R is better used as a multidimensional measure. Muscle Nerve 57: 937-945, 2018., (© 2017 Wiley Periodicals, Inc.)