A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis

Abstract

Objective: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. Results: Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: À16.8, À11.9) in the placebo group and 13.4% (95% CI: À15.3, À11.6) in the tirasemtiv group (p ¼ 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p ¼ 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups. Conclusions: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898).

Improved ALS clinical trials through frequent at‐home self‐assessment: a proof of concept study

“…Clinical trials in ALS have in fact have evolved to be more efficient, with the most significant change being a transition from studies based on survival as a primary endpoint to measures based on function. [1][2][3][4] In addition, modeling studies and recent clinical trials have suggested that cohort enrichment to select for rapidly progressive patients may reduce sample size and trial duration. However, clinical trials still require many months to complete, and participants must travel to the study center frequently, limiting involvement to those in close proximity to study sites and who are not too debilitated to travel.…”

“…This variability in measurement mandates a sample size on the order of 120-150 per treatment arm in order to have sufficient power to appreciate a moderate effect size. 2,4 Variability in rates of decline with respect to any measure come from three major sources: 1. "noise" related to inevitable nondisease-related factors, such as subject motivation or fatigue (for clinical measures); 2. measurement error and inconsistencies due to the tool or technique itself or: 3. deviations from the assumption that ALS progresses in a linear manner.…”

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS

“…The characteristics resemble those of most previous and current ALS trials, with the exception that time from first symptom to screening was 22.8 ± 19.1 months, which is longer than in many recent trials. (6,(11)(12)(13)(14) For some trials, symptom onset and not time since diagnosis was the basis of the inclusion criteria, which may contribute to at least some of the differences related to this patient characteristic. (11)(12)(13)(14) In addition, 113/457 (24.7%) of patients were on edaravone, either alone or in combination with riluzole.…”

“…As the lowest dose appeared to be active in all three key efficacy measures, this multiple contrast approach may not have been the best analysis to demonstrate a treatment effect of reldesemtiv versus placebo. Finally, this trial enrolled more slowly progressing patients than several recent trials (6,(11)(12)(13)(14), which may have somewhat diluted an efficacy signal by some patients not progressing appreciably during the relatively short 12-week duration of active treatment. Indeed, there appeared to be clear evidence of benefit of reldesemtiv among those patients progressing more rapidly prior to randomization and during the course of the trial.…”

Calcium sensitivity and muscle disease

“…A feature of the studies of tirasemtiv is a substantial incidence of side-effects, particularly dizziness, euphoria, fatigue and gait disturbances, and it is likely that these side-effects contributed to the deterioration in the 6 min walk. Tirasemtiv has also been evaluated for the treatment of amyotrophic lateral sclerosis, a neurodegenerative disease causing progressive weakness and death due to respiratory failure typically 3-5 years after diagnosis (Shefner et al 2019). This was a randomised, double-blind trial with placebo and three drug levels evaluated after 24 weeks.…”