Questionnaires, such as the ALS Functional Rating Scale (ALSFRS), play an important role in ALS clinical trials. They are used to evaluate whether treatments have an effect on functional decline. However, if questions are not selected appropriately, they can miss important treatment effects. 20 years ago, the ALSFRS scale was revised. Whether this revision resulted in an improved outcome measure for clinical trials, remains questionable. A new study by researchers from the UMC Utrecht shows that the original ALSFRS is actually better able than the revised ALSFRS (ALSFRS-R) to detect small treatment effects.
The intention of the ALSFRS is to monitor disease progression. It contains questions regarding daily functioning, such as eating and drinking, getting dressed and sleeping. Traditionally, the ALSFRS was designed as a 10-item questionnaire, addressing four domains: bulbar functions (swallowing and speech), fine motor functioning, gross motor functioning, and respiratory functioning. Since it was believed that the components of the scale were not equally weighted, the ALSFRS scale was revised in 1999 and two respiratory items were added. However, whether the revision has resulted in an improved clinical trial endpoint remains a matter of debate.
Researchers at the UMC Utrecht analysed >21,000 measurements from 2,590 patients that were obtained during various clinical trials. They found that the original ALSFRS questionnaire was actually more sensitive to detect treatment effects compared to the revised version. This means that a smaller group of participants needs to be monitored in a clinical trial in order to determine if a drug slows disease progression.
There may be several explanations. Respiratory symptoms can be related to a person’s mobility. Since mobility is often decreased in the final stages of ALS, this may reduce respiratory symptoms. In addition, non-invasive ventilation may not be tolerated by some patients, causing considerable patient-to-patient variability. This could perhaps explain the negative impact of the ALSFRS revision.
For future clinical trials it can therefore be considered to use the classical ALSFRS as a primary outcome measure, complemented with more objective lung function tests. More efforts are also underway to develop better, more sensitive questionnaires. This will be key to accelerate the development of more effective treatments for ALS.
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Reconsidering the revised amyotrophic lateral sclerosis functional rating scale for ALS clinical trials. The scientific paper can be found here.