Predicting ALS Disease Progression With Respiratory Function Decline

Illustration of a health lung with bronchi
Illustration of a health lung with bronchi
Patients older than 65 were more likely to have steeper declines in slow vital capacity.

In patients with amyotrophic lateral sclerosis (ALS), the rate of decline in respiratory function, which is measured by percentage predicted slow vital capacity (SVC), is an important indicator of disease progression that helps inform clinical management, according to the results of a recent retrospective study published in JAMA Neurology.1

The study used placebo data from 2 large randomized, double-blind clinical trials2,3 and data from an ALS trial database (PRO-ACT [Pooled Resource Open-Access ALS Clinical Trials])4 containing studies completed between 1990 and 2010 designed to investigate the natural history of respiratory function decline in patients with ALS as assessed by SVC. The studies included the phase 3 EMPOWER trial2 ( Identifier: NCT01281189) of dexpramipexole in ALS and the phase 2 BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and Functional Improvement With Tirasemtiv in ALS) trial3 ( Identifier: NCT01709149). Patients from North America, Europe, and Australia were enrolled in the 2 clinical studies. Of the 893 patients evaluated, 456 were from EMPOWER, 210 were from BENEFIT-ALS, and 227 were from the PRO-ACT database.

Main outcome measures included time to death or time to decline in the Amyotrophic Lateral Sclerosis Functioning Rating Scale-Revised (ALSFRS-R) respiratory subdomain, time to onset of respiratory insufficiency, time to tracheostomy, and all-cause mortality. Mean patient age was 56.7±11.2, 65.5% (585 of 893) of the participants were men, and 20.5% (183 of 893) of the patients had bulbar-onset ALS. Mean SVC at baseline was 90.5%±17.1%.

In the EMPOWER group, the average decline in SVC from baseline through 1.5 years of follow-up was –2.7 percentage points per month. Significantly steeper declines were reported in individuals aged >65 years (–3.6% per month; P =.005 vs patients aged <50 years; P =.007 vs patients aged 50 to 65 years ), as well as in patients with an ALSFRS-R total score of ≤39 at baseline (–3.1% per month; P <.001 vs patients with ALSFRS-R total scores of >39 at baseline).

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When the rate of decline in SVC was slower by 1.5 percentage points per month in the initial 6 months, risk reductions for events occurring after 6 months were as follows: 19% for decline in ALSFRS-R respiratory subdomain or death after 6 months (95% CI, 12%-25%), 22% for first onset of respiratory insufficiency or death after 6 months (95% CI, 18%-27%), 23% for first occurrence of tracheostomy or death after 6 months (95% CI, 19%-27%), and 23% for death at any time after 6 months (95% CI, 18%-27%; P <.001 for all comparators).

The investigators concluded that the rate of decline in SVC in patients with ALS is associated with clinically meaningful events, including respiratory failure, tracheostomy, or death, implying that it is a key indicator of the clinical progression of disease. This might prove to be a useful end point to consider in future ALS clinical studies.


  1. Andrews JA, Meng L, Kulke SF, et al. Association between decline in slow vital capacity and respiratory insufficiency, use of assisted ventilation, tracheostomy, or death in patients with amyotrophic lateral sclerosis [published online November 27, 2017]. JAMA Neurol. doi:10.1001/jamaneurol.2017.3339
  2. Cudkowicz ME, van den Berg LH, Shefner JM, et al; EMPOWER Investigators. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol. 2013;12(11):1059-1067.
  3. Shefner JM, Wolff AA, Meng L, et al; on behalf of the BENEFIT-ALS Study Group. A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17(5-6):426-435.
  4. Atassi N, Berry J, Shui A, et al. The PRO-ACT database: design, initial analyses, and predictive features. Neurology. 2014;83(19):1719-1725.