Decline In Slow Vital Capacity Predicts Respiratory Insufficiency, Use Of Assisted Ventilation, Tracheostomy Or Death In Als

Objective: to determine the relationship between pulmonary measures commonly used in ALS.Background: Tirasemtiv, a selective skeletal muscle activator, significantly reduced the decline in slow vital capacity (SVC) over 12 weeks in the Phase 2b clinical trial, BENEFIT-ALS. To understand this finding, we investigated the natural history of SVC and its relationship to other measures of respiratory function in placebo patients from the dexpramipexole Phase 3 clinical trial, EMPOWER.Methods: 469 patients randomized to placebo in EMPOWER were included; follow-up was 1.5 years. Slope of decline in SVC was calculated overall and in different subgroups. Cox regression modelled the time to clinical events from Month 6 visit to the end of follow-up using the slope of SVC change from baseline to the Month 6 visit as an explanatory variable. Pearson Product Moment correlation coefficient (r) assessed associations between SVC and other variables.Results: Slope of SVC was -0.090[percnt]/day (95[percnt]CIs: -0.098, -0.082). Older subjects, subjects with initial ALSFRS-R less than 39, and bulbar onset subjects all had a steeper slope of decline (-0.12[percnt]/day, -0.10[percnt]/day, and -0.10[percnt]/day respectively). Patients with SVC decline by 0.05[percnt]/day from baseline to the Month 6 visit had a reduced risk for the earlier of death or any decline in the respiratory subdomain of ALSFRS-R (19[percnt]); or onset of respiratory insufficiency (22[percnt]); or tracheostomy (23[percnt]); and for the risk of death (23[percnt]) after the Month 6 visit (all pu003c0.0001). The correlation of change from baseline in SVC and the respiratory subdomain of the ALSFRS-R (r = 0.26) was weak (pu003c0.0001).Conclusion: Decline of SVC predicted the risk of meaningful clinical events, including the decline in the respiration subdomain of ALSFRS-R, respiratory insufficiency, tracheostomy or death. The weak correlation of change in SVC with the ALSFRS-R respiratory questions suggests that they may not be sensitive indicators of respiratory dysfunction. Disclosure: Dr. Shefner has received personal compensation for activities with Cytokinetics, Inc, Biogen, Voyager and Isis Pharmaceuticals as a consultant. Dr. Meng holds stock and/or stock option in Cytokinetics, Inc., which sponsored research in which Dr. Meng was involved as an investigator. Ms. Kulke has received personal compensation for activities with Cytokinetics as an employee. Dr. Wolff holds stock and/or stock options in Cytokinetics, Inc. Dr. Bozik has received personal compensation for activities with Knopp Biosciences, LLC as an employee. Dr. Malik has received personal compensation for activities with Cytokinetics, Inc. as an employee. Dr. Andrews has received personal compensation for activities with Cytokinetics, Inc. as an employee.