VITALITY-ALS, a phase III trial of tirasemtiv, a selective fast skeletal muscle troponin activator, as a potential treatment for patients with amyotrophic lateral sclerosis: study design and baseline characteristics

<p><i>Objective</i>: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo on respiratory function and other functional measures in patients with amyotrophic lateral sclerosis (ALS). This study was designed to confirm and extend results from a large phase IIb trial and maximize tolerability with a slower dose escalation. <i>Methods</i>: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled, parallel-group study in ALS patients. Participants who tolerated two weeks of open-label tirasemtiv (125 mg twice a day) were randomized 3:2:2:2 to placebo or one of three target total daily dose levels of tirasemtiv (250, 375, or 500 mg). Participants randomized to tirasemtiv escalated their dose every two weeks to their target dose level or maximum tolerated dose. The primary outcome measure was change in slow vital capacity from baseline to 24 weeks. Secondary endpoints assessed the effect of tirasemtiv on muscle strength and certain respiratory milestones of disease progression. A four-week randomized withdrawal phase followed 48 weeks of treatment to evaluate the possibility of sustained benefit or rebound decline. <i>Results</i>: Data collection will be complete in the fourth quarter of 2017. <i>Conclusions</i>: VITALITY-ALS was a phase III trial designed to evaluate the efficacy, safety, and tolerability of tirasemtiv in ALS.</p

Effect of Drug Holiday on CSF Drug Levels.

<p>Predictive illustration of the effect of “drug holidays” at steady-state. Drug holiday began at the arrow (24 hours). Dosing then resumed as usual at 72 hours. Despite the holiday, CSF levels remained above 1 micromolar in the 4 gm/day group, and fell slightly below 1 micromolar in the 2 gm/day group.</p

Enrollment, Randomization, Follow-Up and Analysis.

<p>Enrollment, Randomization, Follow-Up and Analysis.</p

Time to Discontinuation of Study Drug by Treatment Arm (until 20 weeks).

<p>Kaplan-Meyer curve showing time to discontinuation of study drug within the first 20 weeks for patients who discontinued study drug within this time frame. Time to discontinuation of study drug was not significantly different between treatment arms (p = 0.90; Log-Rank). LD – Low Dose Ceftriaxone Arm; HD - High Dose Ceftriaxone Arm.</p

Demographics.

<p>VC – Vital Capacity; HHD - Hand-Held Dynamometry; ALSFRS-R – Revised ALS Functional Rating Scale; ALSQOL – ALS Quality of Life Questionnaire; V_d – Volume of Distribution; T_1/2– Half-life; mL – milliliters; min – minutes; kg - kilograms.</p

Reasons for Drug Discontinuation in Stages 1 and 2.

*<p>Pseudomembranous colitis, Pruritis, Neutropenia.</p>**<p>Pulmonary edema, Cholelithiasis.</p

Cholelithiasis and Biliary Sludging by Treatment Arm.

<p>(a) Biliary sludging and cholelithiasis were more common in the low dose (LD) and high dose (HD) treatment arms than in the placebo treatment arm (p<0.01; Jonckheere-Terpstra). (b) Treatment with ursodiol significantly shortened event duration when used to treat cholelithiasis and biliary sludging (p,0.001; Log-Rank).</p

Serious Adverse Events.

<p>Serious Adverse Events.</p