Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers

Abstract

ImportanceClinical trial activity in amyotrophic lateral sclerosis (ALS) is dramatically increasing; as a result, trial modifications have been introduced to improve efficiency, outcome measures have been reassessed, and considerable discussion about the level of data necessary to advance a drug to approval has occurred. This review discusses what recent pivotal studies can teach the community about these topics.ObservationsBy restricting inclusion and exclusion criteria, recent trials have enrolled populations distinct from previous studies. This has led to efficacy signals being observed in studies that are smaller and shorter than was thought feasible previously. However, such trials raise questions about generalizability of results. Small trials with equivocal clinical results also raise questions about the data necessary to lead to regulatory approval. The ALS Functional Rating Scale–Revised remains the most commonly used primary outcome measure; this review discusses innovations in its use. Blood neurofilament levels can predict prognosis in ALS and may be a sensitive indicator of biologic effect; current knowledge does not yet support its use as a primary outcome.Conclusions and RelevanceIt is now possible to use specific inclusion criteria to recruit a homogeneous patient population progressing at a specific rate; this will likely impact trials in the future. Generalizability of results on limited populations remains a concern. Although clinical outcomes remain the most appropriate primary outcome measures, fluid markers reflecting biologically important processes will assume more importance as more is learned about the association between such markers and clinical end points. The benefit of use of analytic strategies, such as responder analyses, is still uncertain.

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

“…However, the post hoc analyses showed that the drug slowed the progression of those within 12 months’ duration ( Kaji et al, 2019 ). The criteria that selectively enroll patients with rapid or slow progression rates also increase the homogeneity of the population and thus have a better chance of efficacy being observed ( Shefner et al, 2022 ). Therefore, using more specific inclusion criteria to recruit homogenous patients, especially those with a rapid progression rate, may increase the chance of finding effective drugs, although whether the results can be translated to a more general population remains a concern.…”

“…Stringent disease and diagnosis may also influence the rate. However, the short observation period may be remedied by assessing the longer follow-up or use of demographic cofactors ( Shefner et al, 2022 ).…”

“…It is a 12-item functional assessment evaluated from four domains. Although the analysis of the total score is widely used and has proven effective, some concerns have been raised regarding whether it will act poorly when the drug selectively improves one function ( Shefner et al, 2022 ). Van Eijk et al suggested analyzing on a subscale level to determine the benefit may avoid the pitfalls of the total score and enlarge the chance of observing effective outcomes ( van Eijk et al, 2021 ).…”

“…Van Eijk et al suggested analyzing on a subscale level to determine the benefit may avoid the pitfalls of the total score and enlarge the chance of observing effective outcomes ( van Eijk et al, 2021 ). However, the different decline rates of individual subdomains are not addressed by this method ( Shefner et al, 2022 ).…”

“…The analysis strategies of endpoints may affect the results. The ALSFRS-R score is most commonly analyzed as a continuous variable, using group statistics, in the form of slope of the rate of decline or mean change from baseline to the end ( Shefner et al, 2022 ). Time to events such as death or tracheostomy are also used as the main endpoint.…”