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To determine the feasibility, reliability, and sensitivity of remotely monitoring muscle strength loss of knee extensors using a novel portable fixed dynamometer (PFD) in patients with amyotrophic lateral sclerosis (ALS). We conducted a pilot study with a newly developed device to measure knee extension strength. Patients performed unsupervised PFD measurements, biweekly, for 6 months at home. We evaluated feasibility using adherence and a device-specific questionnaire. Reliability was assessed by (1) comparing unsupervised and supervised measurements to identify systematic bias, and (2) comparing consecutive unsupervised measurements to determine test-retest reliability expressed as intraclass correlation coefficient (ICC) and standard error of measurement (SEM). Sensitivity to detect longitudinal change was described using linear mixed-effects models. We enrolled 18 patients with ALS. Adherence was 86%, where all patients found that the device suitable to measure muscle strength at home; 4 patients (24%) found the measurements burdensome. The correlation between (un)supervised measurements was excellent (Pearson’s r 0.97, 95%CI; 0.94 − 0.99) and no systematic bias was present (mean difference 0.13, 95%CI; −2.22 − 2.48, p = 0.91). Unsupervised measurements had excellent test-retest reliability with an average ICC of 0.97 (95%CI: 0.94 − 0.99) and SEM of 5.8% (95%CI: 4.8 − 7.0). Muscle strength declined monthly by 1.9 %predicted points (95%CI; −3.0 to −0.9, p = 0.001). Using the PFD, it proved feasible to perform knee extension strength measurements at home which were reliable and sensitive for detecting muscle strength loss. Larger studies are warranted to compare the device with conventional outcomes.

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population.