TY - JOUR
T1 - A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis
AU - on behalf of the VITALITY-ALS STUDY GROUP
AU - Shefner, Jeremy M.
AU - Cudkowicz, Merit E.
AU - Hardiman, Orla
AU - Cockroft, Bettina M.
AU - Lee, Jacqueline H.
AU - Malik, Fady I.
AU - Meng, Lisa
AU - Rudnicki, Stacy A.
AU - Wolff, Andrew A.
AU - Andrews, Jinsy A.
AU - Hanemann, Oliver
N1 - Publisher Copyright:
© 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2019/5/13
Y1 - 2019/5/13
N2 - 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: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −11.6) in the tirasemtiv group (p = 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 = 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).
AB - 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: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −11.6) in the tirasemtiv group (p = 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 = 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).
KW - amyotrophic lateral sclerosis
KW - Randomized clinical trial
KW - tirasemtiv
UR - http://www.scopus.com/inward/record.url?scp=85065802152&partnerID=8YFLogxK
UR - https://pearl.plymouth.ac.uk/context/pms-research/article/2114/viewcontent/Sheffner_et_al_Tirasemtiv.pdf
U2 - 10.1080/21678421.2019.1612922
DO - 10.1080/21678421.2019.1612922
M3 - Article
C2 - 31081694
AN - SCOPUS:85065802152
SN - 2167-8421
VL - 20
SP - 584
EP - 594
JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
IS - 7-8
ER -