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In amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), it is necessary to communicate difficult news during the initial diagnosis and throughout the disease trajectory as the condition progresses. However, delivering difficult news to people with ALS/MND is an emotionally demanding task for healthcare and allied health professionals-one for which many feel ill-prepared because of limited training in this area. Ineffective communication of difficult news damages the patient-provider relationship and negatively impacts patient quality of life (QoL). To address this issue, we developed the A-L S-PIKES protocol based on available literature and our extensive clinical experience. It provides easy-to-follow, stepwise guidelines to effectively deliver difficult news to people with ALS/MND (PALS) that includes: A dvance Preparation (preparing for the discussion logistically and emotionally); L ocation & S etting (creating a comfortable setting that fosters rapport); P atient's Perceptions (assessing PALS' understanding and perception of their condition); I nvitation (seeking PALS' permission to share information); K nowledge (sharing information in a clear, understandable manner); E motion/ E mpathy (addressing emotions with empathy and providing emotional support); and S trategy & S ummary (summarizing the discussion and collaboratively developing a plan of action). A-L S-PIKES provides practical guidelines on how to prepare for and conduct these challenging conversations. It emphasizes effective communication tailored to the individual needs of PALS and their families, empathy, sensitivity, and support for PALS' emotional well-being and autonomy. The aim of A-L S-PIKES is to both enhance skills and confidence in delivering difficult news and to improve the QoL of PALS and their families. Future studies should systematically evaluate the feasibility and effectiveness of A-L S-PIKES to establish its utility in clinical practice.

The International Network for Amyotrophic Lateral Sclerosis (ALS) Research and Care (INARC) was founded in 2022. INARC's main goals are to offer a platform dedicated to staff members for ALS clinics and research teams who are not physicians. By nurturing experience and expertise exchanges to improve problem solving skills, the ultimate goal is to increase the standard ALS care and research. This brief report aims to describe the formation of INARC, the 2023 INARC meeting, as well as to report topics discussed, lessons learned and challenges raised by INARC members.

Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.

The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures.

Purpose: The primary objective of this study was to determine if speech and pause measures obtained using a passage reading task and timing measures from a monosyllabic diadochokinesis (DDK) task differ across speakers of Canadian French diagnosed with amyotrophic lateral sclerosis (ALS) presenting with and without bulbar symptoms, and healthy controls. The secondary objective was to determine if these measures can reflect the severity of bulbar symptoms., Method: A total of 29 Canadian French speakers with ALS (classified as bulbar symptomatic [ n  = 14] or pre-symptomatic [ n  = 15]) and 17 age-matched healthy controls completed a passage reading task and a monosyllabic DDK task (/pa/ and /ta/), for up to three follow-up visits. Measures of speaking rate, total duration, speech duration, and pause events were extracted from the passage reading recordings using a semi-automated speech and pause analysis procedure. Manual analysis of DDK recordings provided measures of DDK rate and variability., Result: Group comparisons revealed significant differences ( p = < .05) between the symptomatic group and the pre-symptomatic and control groups for all passage measures and DDK rates. Only the DDK rate in /ta/ differentiated the pre-symptomatic and control groups. Repeated measures correlations revealed moderate correlations (r rm = > 0.40; p = < 0.05) between passage measures of total duration, speaking rate, speech duration, and number of pauses, and ALSFRS-R total and bulbar scores, as well as between DDK rate and ALSFRS-R total score., Conclusion: Speech and pause measures in passage and timing measures in monosyllabic DDK tasks might be suitable for monitoring bulbar functional symptoms in French speakers with ALS, but more work is required to identify which measures are sensitive to the earliest stages of the disease.

The ALS Functional Rating Scale-Revised is the most commonly used primary outcome measure in current ALS clinical trials. While rigorous training and certification is generally recognized as critical to reliable performance, differences have existed between training in the two groups responsible for most training in ALS outcome measures. We present a harmonized standard operating procedure which is intended to further reduce response variability by the use of identical training in North America and Europe.

Objective : To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS). Methods : We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial. Results : In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort. Conclusions : In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv , the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS).

Introduction/Aims . Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods . The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK ® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results . In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion . We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug Administration (FDA) approved intravenous (IV) and oral edaravone for the treatment of ALS in 2017 and 2022, respectively. With the addition of oral edaravone, patients with ALS may exclusively use oral medications., Areas Covered: The authors performed a review of the published literature using the United States (US) National Library of Medicine's PubMed.gov resource to describe the pharmacokinetics, pharmacodynamics, safety, and efficacy of oral edaravone, as well as pertinent completed and ongoing clinical trials, including the oral edaravone clinical trial development program. The clinical profile of oral edaravone is also discussed., Expert Opinion: Edaravone has been shown to slow the rate of motor function deterioration experienced by patients with ALS. As the oral formulation has been approved, patients with ALS may use it alone or in combination with other approved therapeutics. Additional clinical trials and real-world evidence are ongoing to gain further understanding of the clinical profile of oral edaravone.

Objective: To evaluate the Milano-Torino staging (MiToS) and King's staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS., Methods: This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16. Patients were retrospectively classified into MiToS and King's stages. Outcomes were the mean time maintaining baseline stage and risk of progression from the baseline stage to a later stage., Results: The full analysis set consisted of 456 patients randomized 3:1 ( reldesemtiv n  = 342, placebo n  = 114) who received at least one dose of double-blind study drug and had at least one post-baseline assessment. At baseline, MiToS and King's stages were balanced between the reldesemtiv and placebo groups: >99% of patients were in MiToS stage 0 or 1 and King's stage 1, 2 or 3. Time of maintaining the baseline stage was similar in both groups, for each staging system. The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King's., Conclusion: This exploratory analysis showed the feasibility of MiToS and King's staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials.

Amyotrophic lateral sclerosis (ALS) is a rare, progressive multi-system neurodegenerative disorder. Its clinical presentation varies considerably leading to delays in diagnosis, which has dire consequences in a disease where early intervention is key to optimize outcomes and limit care giver burden. There are a range of diagnostic criteria available to aid ALS diagnosis, as well staging methods to assess disease progression. However, they all suffer from inter-rater variability, complexity, and confusion in use. Such difficulties, when medical appointment times are limited and becoming more virtually based, have the potential to amplify uncertainty and errors in ALS diagnosis and prognosis. This review provides a clinical overview of the best way to balance the needs of evidence-based medicine and the patient. We focus on ALS diagnostic criteria and staging systems currently in use in clinical practice and explore factors that could enhance diagnostic efficiency and assessment of disease progression.

The absence of disease modifying treatments for amyotrophic lateral sclerosis (ALS) is in large part a consequence of its complexity and heterogeneity. Deep clinical and biological phenotyping of people living with ALS would assist in the development of effective treatments and target specific biomarkers to monitor disease progression and inform on treatment efficacy. The objective of this paper is to present the Comprehensive Analysis Platform To Understand Remedy and Eliminate ALS (CAPTURE ALS), an open and translational platform for the scientific community currently in development. CAPTURE ALS is a Canadian-based platform designed to include participants' voices in its development and through execution. Standardized methods will be used to longitudinally characterize ALS patients and healthy controls through deep clinical phenotyping, neuroimaging, neurocognitive and speech assessments, genotyping and multisource biospecimen collection. This effort plugs into complementary Canadian and international initiatives to share common resources. Here, we describe in detail the infrastructure, operating procedures, and long-term vision of CAPTURE ALS to facilitate and accelerate translational ALS research in Canada and beyond.

Aims: To estimate the health utilities and quality-adjusted life years (QALYs) in patients with amyotrophic lateral sclerosis (ALS) receiving reldesemtiv versus placebo in FORTITUDE-ALS., Materials and Methods: We performed a post hoc analysis of clinical trial data from FORTITUDE-ALS (NCT03160898). This Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial evaluated reldesemtiv in patients with ALS. Health utilities from the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) were estimated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores collected during the trial. QALYs were estimated using the area under the curve method., Results: The full analysis set consisted of 456 patients ( reldesemtiv n  = 342, placebo n  = 114), who received at least one dose of the double-blind study drug, and had ALSFRS-R assessed at baseline and at least one post-baseline assessment. The difference in EQ-5D-5L utility least-squares (LS) mean change from baseline to week 12 for reldesemtiv versus placebo, adjusted for baseline values, was statistically significant (0.03, 95% confidence interval [CI]: 0.01, 0.05; p = .0008). The incremental QALY of reldesemtiv versus placebo adjusted for baseline utility values showed a modest, but statistically significant, difference (0.004, 95% CI: 0.001, 0.007; p = .0058)., Conclusions: This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALYs compared with placebo. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings., Clinicaltrials.gov Identifier: NCT03160898.

Objective : Amyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized primarily by motor neuron degeneration, but may be accompanied by cognitive dysfunction. Statistically appropriate criteria for establishing cognitive impairment (CI) in ALS are lacking. We evaluate quantile regression (QR), that accounts for age and education, relative to a traditional two standard deviation (SD) cutoff for defining CI. Methods : QR of cross-sectional data from a multi-center North American Control (NAC) cohort of 269 healthy adults was used to model the 5 th percentile of cognitive scores on the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). The QR approach was compared to traditional two SD cutoff approach using the same NAC cohort (2SD-NAC) and to existing UK-based normative data derived using the 2SD approach (2SD-UK) to assess the impact of cohort selection and statistical model in identifying CI in 182 ALS patients. Results : QR-NAC models revealed that age and education impact cognitive performance on the ECAS. Based on QR-NAC normative cutoffs, the frequency of CI in the 182 PENN ALS patients was 15.9% for ALS specific, 12.6% for ALS nonspecific, and 15.4% for ECAS total. This frequency of CI is substantially more conservative in comparison to the 2SD-UK (20.3%-34.6%) and modestly more conservative to the 2SD-NAC (14.3%-16.5%) approaches for estimating CI. Conclusions : The choice of normative cohort has a substantial impact and choice of statistical method a modest impact on defining CI in ALS. This report establishes normative ECAS thresholds to identify whether ALS patients in the North American population have CI.

Objective: To understand current genetic testing practices at Canadian ALS clinics. Methods: An online survey and phone interviews, with clinicians practicing in 27 ALS clinics in Canada, were employed to collect data. Quantitative and qualitative analyses were conducted. Results: Ninety-three percent (25/27) of ALS clinics in Canada are routinely ordering genetic testing for familial ALS, while 33% (9/27) of clinics are routinely ordering genetic testing for sporadic ALS. Barriers to genetic testing include a perceived lack of an impact on treatment plan, difficulty in obtaining approvals, primarily from provincial Ministries of Health, and limited access to genetic counseling. Predictive testing practices were found to be the most variable across the country. The average wait time for a symptomatic patient living with ALS to see a genetic counselor in Canada is 10 months (range 0-36 months). Conclusions: Access to genetic testing, and testing practices, vary greatly across Canadian ALS clinics. There may be patients with a monogenetic etiology to their ALS who are not being identified given that genetic testing for patients diagnosed with ALS is not routinely performed at all clinics. This study highlights potential inequities for patients with ALS that can arise from variability in health care delivery across jurisdictions, in a federally-funded, but provincially-regulated, health care system. Clinical trials for both symptomatic ALS patients and pre-symptomatic ALS gene carriers are ongoing, and ALS clinicians in Canada are motivated to improve access to genetic testing for ALS.

Objective : To evaluate the possible effect of reldesemtiv , a fast skeletal muscle troponin activator, on prescription and acceptance of durable medical equipment (DME) in the FORTITUDE-ALS trial. Methods: Health economic outcome information was collected in FORTITUDE-ALS (NCT03160898); sites recorded if and when DME, specifically manual or power wheelchairs, gastrostomy tubes, noninvasive ventilators, or augmentative language devices, was prescribed by a physician and accepted by the patient (DME-PAP) during the trial. Acceptance was defined as the patient agreeing the item was needed. Cox regression analysis compared time to DME-PAP for each reldesemtiv dose with placebo. Post hoc analyses evaluated all reldesemtiv doses compared with placebo. Results: At least one DME item was prescribed and accepted by 33/114 (28.9%) of placebo patients, 19/112 (17.0%) of patients receiving reldesemtiv 150 mg bid, 24/113 (21.2%) receiving 300 mg bid, and 29/117 (24.8%) receiving 450 mg bid. The proportion of new DME-PAP was significantly lower in patients receiving reldesemtiv 150 mg bid vs placebo (17.0% vs 28.9%, p  = 0.032). The hazard ratio versus placebo for accepting at least one DME item for all reldesemtiv doses combined was 0.61 (confidence interval: 0.39, 0.96, p  = 0.032). 25% of placebo patients were prescribed and agreed to obtain a DME item by 84 days; this threshold was met for reldesemtiv -treated patients at 120 days. Conclusions: Results suggest ALS patients receiving reldesemtiv may have lower risk of and delayed need for DME related to impaired mobility, breathing, swallowing, or speaking; this delay is consistent with other measures indicating delay in disease progression.

Objective: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients ( N  = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance ( p  = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p  = 0.09; muscle strength mega-score, p  = 0.31). Post hoc analyses pooling all active reldesemtiv -treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).

Background and Objective: Primary lateral sclerosis (PLS) is a neurodegenerative disease characterized by progressive upper motor neuron dysfunction. Because PLS patients represent only 1 to 4% of patients with adult motor neuron diseases, there is limited information about the disease's natural history. The objective of this study was to establish a large multicenter retrospective longitudinal registry of PLS patients seen at Northeast ALS Consortium (NEALS) sites to better characterize the natural progression of PLS. Methods: Clinical characteristics, electrophysiological findings, laboratory values, disease-related symptoms, and medications for symptom management were collected from PLS patients seen between 2000 and 2015. Results: The NEALS registry included data from 250 PLS patients. Median follow-up time was 3 years. The mean rate of functional decline measured by ALSFRS-R total score was -1.6 points/year (SE:0.24, n  = 124); the mean annual decline in vital capacity was -3%/year (SE:0.55, n  = 126). During the observational period, 18 patients died, 17 patients had a feeding tube placed and 7 required permanent assistive ventilation. Conclusions: The NEALS PLS Registry represents the largest available aggregation of longitudinal clinical data from PLS patients and provides a description of expected natural disease progression. Data from the registry will be available to the PLS community and can be leveraged to plan future clinical trials in this rare disease.

Objective: The use of speech measures is becoming a common practice in the assessment of bulbar disease progression in amyotrophic lateral sclerosis (ALS). This study aimed to establish psychometric properties (e.g. reliability, validity, sensitivity, specificity) of speech and pause timing measures during a standardized passage . Methods: A large number of passage recordings (ALS N  = 775; Neurotypical controls N  = 323) was analyzed using a semi-automatic method (Speech and Pause Analysis, SPA). Results: The results revealed acceptable reliability of the speech and pause measures across repeated recording by the control participants. Strong construct validity was established via significant group differences between patients and controls and correlation statistics with clinical measures of overall ALS and bulbar disease severity. Speaking rate, pause events, and mean pause duration were able to detect ALS participants at the presymptomatic stage of bulbar disease with a good discrimination ability (AUC 0.81). Conclusions: Based on the current psychometric evaluation, performing passage recording and speech and pause timing analysis was deemed useful for detecting early and progressive changes associated with bulbar ALS.

Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib ( n  = 99) showed significant benefit over placebo ( n  = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.

Objective: As declining respiratory muscle function commonly leads to disability and death in amyotrophic lateral sclerosis (ALS), respiratory measurements such as slow vital capacity (SVC) may predict disease progression. This study evaluated the relationship between SVC and symptoms measured by the revised ALS Functional Rating Scale (ALSFRS-R)., Methods: About 453 ALS placebo-treated patients from the EMPOWER trial (NCT01281189) were evaluated. Correlations between %predicted SVC and individual respiratory ALSFRS-R subdomain items, respiratory subdomain score (maximum score of 12), and total ALSFRS-R score (maximum score of 48) were evaluated using the Pearson correlation coefficient. Pearson's chi-squared test was used to evaluate changes from baseline to week 48 in ALSFRS-R respiratory symptom and respiratory subdomain scores in patients with baseline %predicted SVC above/below the median at baseline and with more slowly/more rapidly decreasing %predicted SVC., Results: The %predicted SVC showed significant correlations with dyspnea, orthopnoea, respiratory insufficiency, respiratory subdomain score, and total ALSFRS-R score (all p < 0.0001). Patients with baseline SVC values < median were significantly more likely than those with baseline SVC ≥ median to have a change in total ALSFRS-R respiratory subdomain score from 12 to <12 (40.9% vs. 30.2%, p = 0.0358) and from ≥10 to <10 (41.6% vs. 24.4%, p = 0.0005). Additionally, patients with smaller declines in SVC over time were significantly more likely to have smaller decreases in their respiratory subdomain scores (p < 0.0001)., Conclusions: The higher correlation between %predicted SVC and specific ALSFRS-R symptom scores in patients with rapidly versus more slowly progressing disease reinforces the importance of continually monitoring respiratory function throughout the disease course.

Objective: To identify common practices of noninvasive ventilation (NIV) use among ALS specialists and how they follow respiratory status in their patients., Methods: A 25-item questionnaire on NIV indications/initiation was sent via SurveyMonkey® to ALS specialists identified through membership in NEALS (114 sites in the US) and ENCALS (39 sites in Europe). Descriptive statistics and Cochran-Mantel-Haenszel test for general association were performed., Results: In their initial evaluation, US and European specialists (n = 186) use upright forced vital capacity (FVC) most (92.8% vs 91.1%; p = 0.752). Upright FVC results are most important for US respondents when deciding to prescribe NIV; European respondents consider symptoms of orthopnea and/or dyspnea as most important. European respondents use overnight pulse oximetry (69.8% vs 7.9%; p < 0.001) and arterial blood gas analyses (62.8% vs 3.2%; p < 0.001) more than US respondents. Insurance regulations/national health care coverage impact NIV initiation more in the US than in Europe (70.0% vs 47.5%; p = 0.025). When asked if insurance/other financial constraints affects when they prescribe NIV, more US respondents answered positively (77.2% vs 15.4%; p < 0.001). In patients with no respiratory symptoms, most US specialists (68.3%) initiated NIV at VC <50% predicted; European responses showed greater variability., Conclusions: Given the impact of NIV on respiratory function and the importance of respiratory function to quality of life and survival, understanding differences that influence NIV prescribing is critical. This information may inform future study design and identify areas warranting additional research to develop best practices for NIV implementation.

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that causes skeletal muscle weakness, including muscles involved with respiration. Death often results from respiratory failure within 3-5 years. Monitoring respiratory status is therefore critical to ALS management, as respiratory/pulmonary function tests (PFTs) are used to make decisions including when to initiate noninvasive ventilation. Understanding the different respiratory and PFTs as they relate to disease progression and survival may help determine which tests are most suitable., Methods: This review describes the tests used to assess respiratory muscle and pulmonary function in patients with ALS and the correlations between different respiratory measures and clinical outcomes measures., Results: The most commonly used measurement, forced vital capacity (VC), has been shown to correlate with clinical milestones including survival, but also requires good motor coordination and facial strength to form a tight seal around a mouthpiece. Other tests such as slow VC, sniff inspiratory pressure, or transdiaphragmatic pressure with magnetic stimulation are also associated with distinct advantages and disadvantages., Conclusions: Therefore, how and when to use different tests remains unclear. Understanding how each test relates to disease progression and survival may help determine which is best suited for specific clinical decisions.

Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, p = 0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, p < 0.0001). In conclusion, engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial.