title: A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis.
abstract: Our objectives were to evaluate the safety and tolerability of tirasemtiv over 12 weeks and its effect on the revised ALS Functional Rating Scale (ALSFRS-R) and other secondary functional measures. This randomized, double-blind, placebo-controlled trial enrolled adults with ALS and slow vital capacity (SVC) > 50% from 73 centers in eight countries. Patients who tolerated open-label tirasemtiv 125 mg b.i.d. for one week were randomized to double-blind treatment either to placebo or tirasemtiv, escalating to a maximum tolerated dose up to 250 mg b.i.d. The primary endpoint was the change from baseline in ALSFRS-R; secondary endpoints included SVC, maximum voluntary ventilation, sniff nasal inspiratory pressure, isometric muscle strength, and sub-maximum handgrip fatigue. Of 711 patients enrolled, 596 were randomized and received at least one dose of double-blind treatment. The primary endpoint showed no treatment effect (tirasemtiv: -2.98 ± 0.28, placebo: -2.40 ± 0.25, p = 0.114); however, SVC and muscle strength declined significantly more slowly on tirasemtiv (95% CI p = 0.0006, p = 0.0158, respectively). Dropouts and serious adverse events occurred more frequently in the tirasemtiv group. In conclusion, this was a negative study with respect to the primary endpoint; however, the effects on SVC and muscle strength suggest a potentially important effect of tirasemtiv warranting further evaluation over a longer period in ALS.
authors.affiliation: Barrow Neurological Institute , Phoenix , Arizona and.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Shefner
authors.affiliation: Cytokinetics, Inc. , South San Francisco , California , USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wolff
authors.affiliation: Cytokinetics, Inc. , South San Francisco , California , USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Meng
authors.affiliation: Cytokinetics, Inc. , South San Francisco , California , USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Bian
authors.affiliation: Cytokinetics, Inc. , South San Francisco , California , USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lee
authors.affiliation: Cytokinetics, Inc. , South San Francisco , California , USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Barragan
authors.affiliation: Cytokinetics, Inc. , South San Francisco , California , USA.
authors.forename: Jinsy A
authors.initials: JA
authors.lastname: Andrews
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D018737:Hand Strength; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000627:therapeutic use*; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D053580:Muscle Strength; D011719:Pyrazines / Q000009:adverse effects* / Q000627:therapeutic use*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014797:Vital Capacity / Q000187:drug effects
chemical_list: C572767:CK-2017357; D007093:Imidazoles; D011719:Pyrazines
keywords: Clinical trial; amyotrophic lateral sclerosis; tirasemtiv; troponin activator