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A roundtable convened in July 2020 examined issues concerning respiratory support in amyotrophic lateral sclerosis (ALS), with reference to the potential for an early-phase orally administered medication that might either postpone the introduction of noninvasive ventilation (NIV) and/or enhance the benefits to be gained from it. Attention was also given to the impact of the COVID-19 pandemic on usual practice in the assessment and management of ALS-related respiratory difficulties. Implementation of NIV marks a step-change in clinical status for patients and a major increase in burden for caregivers. All means to ease this transition should be explored: an oral therapy that supported respiratory function and patients' independence and sense of well-being would aid discussions to facilitate the eventual successful introduction of NIV. Assessment of a candidate oral therapy that might support respiratory function in ALS patients would be aided by the development of improved patient-reported outcome measures for robust quantification of treatment effect and quality of life. Such instruments could also be used to monitor patients' status during the COVID-19 pandemic, averting some of the risks of face-to-face assessment plus the patient burden and costs of traditional methods. Several oral candidate therapies have recently failed to meet their primary endpoints in clinical trials. However, understanding of the underlying physiology and appropriate trial design have grown and will inform future developments in this field.

Objectives: To evaluate the prescribing practices of noninvasive ventilation (NIV) and patient compliance during VITALITY-ALS. Methods: VITALITY-ALS enrolled patients with a slow vital capacity (SVC) ≥70% of predicted who were not using NIV at screening. Physicians prescribed NIV without restriction following randomization. Reason(s) for NIV prescription, dates prescribed and initiated, and compliance were recorded. Compliance was recorded as prescribed but never initiated, used ≥2 h/24 h, used ≥4 h/24 h, or used ≥22 h/24 h. In addition to other outcome measures, SVC and the revised ALS functional rating scale (ALSFRS-R) were performed at all visits. Patients were followed up to 56 weeks. Results: 565 patients were randomized and dosed with placebo or tirasemtiv in VITALITY-ALS; 195 (34.5%) were prescribed NIV: of these, 78.5% used it for ≥2 h/24 h, 71.3% for ≥4 h/24 h, and 11.8% for ≥22 h/24 h. The three most common reasons NIV was prescribed were decline in vital capacity, respiratory symptoms, and sleep-related symptoms. During the trial, 179/565 (31.7%) patients had a decline of SVC below 50%; of these patients, 122/179 (68.2%) were prescribed NIV. Reasons for prescribing NIV were different for patients from North America compared with Europe. Conclusions: Despite allowing for NIV initiation at any point following randomization in VITALITY-ALS, only slightly more than two out of three patients whose SVC fell below 50% were prescribed NIV; this was similar in Europe and in North America. Underutilization of NIV could influence survival outcomes in patients with ALS including those involved in clinical trials.

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.

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.

Importance: The prognostic value of slow vital capacity (SVC) in relation to respiratory function decline and disease progression in patients with amyotrophic lateral sclerosis (ALS) is not well understood., Objective: To investigate the rate of decline in percentage predicted SVC and its association with respiratory-related clinical events and mortality in patients with ALS., Design, Setting, and Participants: This retrospective study included 893 placebo-treated patients from 2 large clinical trials (EMPOWER and BENEFIT-ALS, conducted from March 28, 2011, to November 1, 2012, and from October 23, 2012, to March 21, 2014, respectively) and an ALS trial database (PRO-ACT, containing studies completed between 1990 and 2010) to investigate the rate of decline in SVC. Data from the EMPOWER trial (which enrolled adults with possible, probable, or definite ALS; symptom onset within 24 months before screening; and upright SVC at least 65% of predicted value for age, height, and sex) were used to assess the relationship of SVC to respiratory-related clinical events; 456 patients randomized to placebo were used in this analysis. The 2 clinical trials included patients from North America, Australia, and Europe., Main Outcomes and Measures: Clinical events included the earlier of time to death or time to decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) respiratory subdomain, time to onset of respiratory insufficiency, time to tracheostomy, and all-cause mortality., Results: Among 893 placebo-treated patients with ALS, the mean (SD) patient age was 56.7 (11.2) years, and the mean (SD) SVC was 90.5% (17.1%) at baseline; 65.5% (585 of 893) were male, and 20.5% (183 of 893) had bulbar-onset ALS. In EMPOWER, average decline of SVC from baseline through 1.5-year follow-up was -2.7 percentage points per month. Steeper declines were found in patients older than 65 years (-3.6 percentage points per month [P = .005 vs <50 years and P = .007 vs 50-65 years) and in patients with an ALSFRS-R total score of 39 or less at baseline (-3.1 percentage points per month [P < .001 vs >39]). When the rate of decline of SVC was slower by 1.5 percentage points per month in the first 6 months, risk reductions for events after 6 months were 19% for decline in the ALSFRS-R respiratory subdomain or death after 6 months, 22% for first onset of respiratory insufficiency or death after 6 months, 23% for first occurrence of tracheostomy or death after 6 months, and 23% for death at any time after 6 months (P < .001 for all)., Conclusions and Relevance: The rate of decline in SVC is associated with meaningful clinical events in ALS, including respiratory failure, tracheostomy, or death, suggesting that it is an important indicator of clinical progression.

Objectives: Death in amyotrophic lateral sclerosis (ALS) patients is related to respiratory failure, which is assessed in clinical settings by measuring vital capacity. We developed ALS-VC, a modeling tool for longitudinal prediction of vital capacity in ALS patients. Methods: A gradient boosting machine (GBM) model was trained using the PRO-ACT (Pooled Resource Open-access ALS Clinical Trials) database of over 10,000 ALS patient records. We hypothesized that a reliable vital capacity predictive model could be developed using PRO-ACT. Results: The model was used to compare FVC predictions with a 30-day run-in period to predictions made from just baseline. The internal root mean square deviations (RMSD) of the run-in and baseline models were 0.534 and 0.539, respectively, across the 7L FVC range captured in PRO-ACT. The RMSDs of the run-in and baseline models using an unrelated, contemporary external validation dataset (0.553 and 0.538, respectively) were comparable to the internal validation. The model was shown to have similar accuracy for predicting SVC (RMSD = 0.562). The most important features for both run-in and baseline models were “Baseline forced vital capacity” and “Days since baseline.” Conclusions: We developed ALS-VC, a GBM model trained with the PRO-ACT ALS dataset that provides vital capacity predictions generalizable to external datasets. The ALS-VC model could be helpful in advising and counseling patients, and, in clinical trials, it could be used to generate virtual control arms against which observed outcomes could be compared, or used to stratify patients into slowly, average, and rapidly progressing subgroups. [ABSTRACT FROM AUTHOR]