JNNP: Rethinking of the functional evaluation scale for amyotrophic lateral sclerosis in ALS clinical trials

Clinical trials of amyotrophic lateral sclerosis (ALS) are designed to identify treatments that can slow functional decline or prolong survival.
in the absence of objective biomarkers, questionnaires such as the ALSFRS Functional Assessment Scale (ALSFRS) were used in clinical trials to assess the effectiveness of treatment.
originally designed to have a breath function score of 10, which can also be used as a sports function score.
alSFRS was revised in 1999 with the addition of two projects.
it is not clear whether this revision leads to improvements, as the structural effectiveness of the questionnaire may deteriorate, resulting in a weakening of the correlation with respiratory function and survival rates.
, the ultimate practical application of ALSFRS is as the end point of efficacy.
the effectiveness of the assessment alone may not be sufficient to evaluate the revision.
, it is particularly important to evaluate vertical biomarkers and questionnaires, not only in terms of effectiveness, but also in terms of experimental design.
, this strategy may help select the best outcome for clinical trials of ALS or other neurodegenerative diseases.
use 12 months of data from PRO-ACT to compare alSFRS and ALSFRS revisions (ALSFRS-R).
PRO-ACT contains anonymous data from 23 clinical trials conducted since 1990.
only use data from tests including ALSFRS-R.
in order to compare the PRO-ACT dataset with the general trial population, we excluded patients with symptom duration of 36 months, lung capacity of 60 per cent or over 80 years of age.
alSFRS and ALSFRS-R are calculated as the sum of items 1 to 10 or 1 to 12, respectively.
sensitivity of ALSFRS and ALSFRS-R to detect therapeutic effects with the signal-to-noise ratio and the required sample size.
signal-to-noise ratio is directly related to the required sample size, and a higher signal-to-noise ratio increases the ability to detect therapeutic effects.
to compare questionnaires directly, divide the scores by 10 (ALSFRS) and 12 (ALSFRS-R).
this linear transformation does not affect the signal-to-noise ratio.
the signal-to-noise ratio is defined as the average monthly decrease divided by the variability between patients.
the sample size calculation is based on 90% power, the monthly follow-up detection progress rate is reduced by 30%, and the two-α is 5%.
as a sensitivity analysis, we repeatedly analyzed ALSFRS Plus Project 11, ALSFRS Plus Project 12, and excluded slow-moving patients (i.e., SFS-lt;0.50 d/month).
95% confidence interval is calculated by using the self-lift method (n-25 000).
the study included 2,590 patients and conducted 21,497 ALSFRS-R measurements (an average of 8.8 measurements and 10.1 months of follow-up time).
average monthly score of ALSFRS-R decreased to 1.07 points (95% CI, 1.04-1.11), while the average monthly score of ALSFRS decreased to 0.96 points (95% CI, 0.93-0.99).
average ALSFRS per item is falling faster (0.096 to 0.090 d/month) than ALSFRS-R, so the signal-to-noise ratio is better.
, ALSFRS requires fewer patients to detect a given treatment than ALSFRS-R.
to illustrate this point: 270 patients with a sample size required to reduce alSFRS-R reduction by 30% over 12 months at 90% of the power, and 252 patients with ALSFRS (up 7.1%, 95% credible) Ranges from 5.3% to 9.6%), or, in this case, 200 patients will provide 79.6% of the power when using ALSFRS-R, and 82.3% when using ALSFRS as the primary endpoint.
possible explanation for the negative effects of the ALSFRS revision is that a decrease in the activity of ALS at the end of the period may lead to a reduction in respiratory symptoms.
addition, some patients may not be able to withstand non-invasive breathing, resulting in significant differences between patients.
, breath testing may be an alternative to breathing and a better option.
, drug efficacy is usually determined based on subjective endpoints, such as ALSFRS-R.
it may be beneficial to evaluate the therapeutic effects of each weight scale, and efforts are being made to develop better questionnaires, which may result in more sensitive endpoints.
, however, the performance of the questionnaire as the end of the experiment still needs to be considered during the development phase.
study, a relatively simple assessment is presented that can be used as a tool in addition to classic re-belief and effectiveness measurements.
this assessment can reduce the risk of losing important treatment leads.
important, the proposed method can be used to optimize and select any vertical endpoint over time, as shown elsewhere.
, this may speed up the identification of effective treatments for ALS and other neurodegenerative diseases.
de Jongh AD, van den Berg LH, van Eijk RPA Reshding the revised amyotrophic lateral sclerosis functional rating scale for ALS clinical trials Journal of Neurology, Neurosurgery Psython Published Online First: 23 November 2020. doi:10.1136/jnnp-2020-325253MedSci Original Source: MedSci Original Copyright Notice: All notes on this website "Source: Met Medical" or "Source: MedSci Original" text, images and audio-visual materials, copyrighted by Mace Medical, not authorized by any media Websites or individuals may not be reproduced, and the authorizing reprints must include "Source: Metz Medicine".
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