Scientists propose delta-FS as new measure of disease severity in ALS
Easy-to-obtain tool may help predict patient prognosis: Study
A new amyotrophic lateral sclerosis (ALS) assessment called delta-FS — defined as the rate of decline over time in the ALS Functional Rating Scale-Revised (ALSFRS-R) — has been proposed as an attractive, easily obtainable tool to monitor disease severity and predict patient prognosis.
The assessment also could be used to identify certain groups of patients who could benefit the most from an experimental treatment, helping to optimize patient selection in clinical trials, the researchers said.
“[Delta]-FS is a clinically relevant, independent predictor of survival, capable of distinguishing patient subgroups that have a different course of disease progression,” Albert Ludolph, MD, PhD, a professor at the University Hospital and Medical Faculty of Ulm, in Germany, and the study’s senior author, said in a press release.
“Categorization of the ALS population via post-onset [delta]-FS is therefore an important study design consideration that may facilitate optimization of drug effectiveness and patient management, and as such is recommended for inclusion in the design of clinical trials,” Ludolph said.
The merits of delta-FS was discussed by researchers in the study “Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice,” which was published in the journal Muscle & Nerve.
Seeking new, more nuanced measures of disease severity in ALS
Early symptoms of ALS can vary substantially from person to person. Most patients first experience weakness in their limb muscles (known as limb-onset ALS), while others have such symptoms in the muscles around the face and throat (bulbar-onset disease). Over time, muscle weakness often develops into paralysis and breathing difficulties, with many patients dying of respiratory failure.
As ALS is a progressive disease, its symptoms are known to worsen over time. However, the rate of decline to eventual death can vary between patients, from a matter of months to more than a decade.
The most widely used measure of ALS severity in clinical practice and clinical trials is the ALS Functional Rating Scale-Revised, known more simply as ALSFRS-R. But despite its widespread acceptance, ALSFRS-R has certain limitations, including its inability to distinguish between patients with very severe or very mild disability and the absence of a cognitive function domain, or area of assessment.
ALSFRS-R also doesn’t capture non-linear decline, or periods of rapid or slow decline that may sometimes occur over time.
Now, researchers in Germany, France, and the U.S. are proposing delta-FS, defined by the rate of decline in ALSFRS-R scores, as a new measure of disease severity in ALS.
Use of Delta-FS urged for selecting patients for clinical trials
Delta-FS has been shown to be a sensitive and independent clinical outcome measure. This makes it a predictor of survival and capable of distinguishing patient subgroups with different disease courses.
“In this article we discuss the merits of post-onset [delta]-FS as a tool for innovative ALS study design,” Ludolph said.
To capture the non-linear features of ALS, delta-FS values can be calculated differently at each stage of the disease, the researchers noted. Early, or post-onset delta-FS measures the initial ALSFRS-R rate of decline from symptom onset, while late, or interval delta-FS considers the decline between follow-up assessments.
Another distinguishing feature is the timeframe differences in calculating delta-FS. Post-onset delta-FS is measured about 11 to 24 months after symptom onset, so it is less affected by short-term variations in ALSFRS-R scores. Moreover, post-onset delta-FS can be measured as part of routine clinical practice, providing physicians who treat ALS with a patient selection tool.
According to the researchers, post-onset delta-FS can be used to classify and select participants in clinical trials, providing more homogeneous patient populations. It also allows for subgroup analysis based on variations in ALS severity, which may detect differences in treatment response, as well as underlying disease-related processes, across the overall ALS population.
The team noted two limitations of post-onset delta-FS. First, it is a retrospective measure, meaning it collects data from the past. Second, as a subjective assessment of functional disability, regular training of assessors is required to ensure reliability, the team stressed.
To date, several clinical trials have applied delta-FS in patient selection. One is AB10015 (NCT02588677), a Phase 2/3 study that evaluated AB Science’s masitinib, an add-on oral medication meant to slow ALS progression.
“Although this article is not specifically directed towards the masitinib study AB10015 in ALS, it describes very well the design philosophy behind that study and as such is a strong validation of this approach,” said Olivier Hermine, MD, PhD, president of the scientific committee of AB Science.
There are no insurmountable barriers regarding the application of post-onset [delta]-FS in clinical practice, making it [a] very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.
The researchers suggested that delta-FS be put into use as soon as possible as a measure of disease severity.
“Overall, there are no insurmountable barriers regarding the application of post-onset [delta]-FS in clinical practice, making it [a] very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design,” the researchers concluded.
Hermine added that this study, sponsored by AB, “shows that there is consensus among … key opinion leaders that post-onset [delta]-FS is a simple-to-use instrument for patient selection, with no obvious barriers regarding its application in clinical practice.”
About the Author
