Table 1.

Summary of ALS outcome measures and examples of use in clinical trials

Outcome measure	Strengths	Weaknesses	Examples of use in ALS clinical trials
Survival	-Objective -Clinically relevant	-Requires studies of long duration and higher sample size -Can be defined in multiple ways	-Phase 3 riluzole study: positive outcome, but required 959 participants in an 18-month study [123]
The revised Amyotrophic Lateral Sclerosis Rating Scale (ALSFRS-R)	-Clinically relevant -Correlates with survival -Accepted by regulatory agencies for drug development -Easy to administer -Large existing datasets available for prediction purposes -Reliable	-Not linearly weighted (1 point is not a specific unit measurement of function) -Not unidimensional (captures domains other than functional status) -Limited responsiveness	-Phase 3 study of Nurown mesenchymal stem cells: defined a “responder” as a post-treatment improvement in ALSFRS-R score, but 28% of placebo and 33% of treated patients met the responder criteria in this negative study [124] -Phase 3 study of edarvone and a selected population met the primary outcome of change in ALSFRS-R slope, but ambiguity remained regarding clinical relevance, and worldwide regulatory approval was mixed [32, 33, 89]
Combined Assessment of Function and Survival (CAFS)	-Allows assessment of survival data when present, but allows surviving patients to also be analyzed by functional status -Supported by FDA in drug development	-Has same limitations as ALSFRS-R -Rank-order approach makes clinical interpretation difficult	-Used as the primary outcome measure in the negative phase 3 study of dexpramipexole in ALS, required 942 participants for up to 18 months [54]
The Rasch-built Overall ALS Disability Scale (ROADS)	-Easy to administer patient reported outcome measure -Correlates with validated ALS outcome measures -Linearly weighted and unidimensional, providing a mathematically valid sum score -High reliability	-Real-world clinical trial data lacking to date
Motor unit number estimation (MUNE) and motor unit number index (MUNIX)	-Marker of lower motor neuron loss -Correlates with validate ALS outcomes	-Requires specialized training -Results can be limited by technique variability	-A prospective observational study of ALS patients showed significant variation between raters and required a complex training process for MUNIX [43]
Electrical impedance myography (EIM)	-Painless and simple to administer -Objective	-Does not provide real-time data -Difficult to interpret clinically	-Used as a secondary outcome measure in a phase 1 study of intraspinal stem cell injections, correlated with other validated outcome measures [125]
Transcranial magnetic stimulation (TMS)	-A marker of cortical excitability that could demonstrate target engagement	-Technically difficult	-In a phase 2 study of ezogabine, 24/103 participants screened were excluded due to inability to measure TMS, primary TMS outcome measure not met, but several secondary electrophysiologic outcome measures showed dose-dependent decreases in excitability
Hand-held dynamometry (HHD)	-Loss of muscle strength is a clinically relevant outcome of interest -Can be performed at the bedside	-Has floor and ceiling effects -Requires standardization against healthy controls and calculation of a megascore for analysis -Requires training for reproducibility	-Used as a secondary outcome measure in the negative Phase 3 dexpramipexole study and adaptive ceftriaxone trial; findings were concordant with primary outcome measures [55, 56]
Accurate Test of Limb Isometric Strength (ATLIS)	-Loss of muscle strength is a clinically relevant outcome of interest -Use of a fixed dynamometry avoids ceiling effects	-Requires cumbersome equipment that is not readily available -Requires standardization against healthy controls and calculation of a megascore for analysis -Requires training for reproducibility -Requires participant to transfer to the ATLIS chair	-Did not meet statistical significance as a secondary outcome measure in the phase 2 study of AMX0035 despite positive ALSFRS-R result on the primary outcome measure
Vital capacity (VC)	-Correlates with survival and validated functional outcome measurements -Clinically relevant and used routinely in practice	-Can be limited by bulbar dysfunction or spasticity -Infection prevention concerns raised during COVID-19 pandemic -Typically shows more variability compared to functional outcome measures	-Used as the primary outcome measure for reldesemtiv and tirasemtiv clinical trials testing selective skeletal muscle troponin activators with mixed results to date
At-home outcome measures	-Can potentially reduce participant burden -Allows for more frequent measurements	-Optimization and data interpretation still in progress