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Jeremy M Shefner - One of the best experts on this subject based on the ideXlab platform.
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A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis.
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019Co-Authors: Jeremy M Shefner, William Camu, Lisa Meng, Fady I Malik, Stacy A Rudnicki, Orla Hardiman, Jacqueline H Lee, Merit E. Cudkowicz, Bettina M. Cockroft, Andrew A WolffAbstract: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).
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relationships between Slow Vital Capacity and measures of respiratory function on the alsfrs r
Amyotrophic Lateral Sclerosis, 2018Co-Authors: Carlayne E Jackson, Mamede De Carvalho, Angela Genge, Terry Heimanpatterson, Jeremy M Shefner, Jenny Wei, Andrew A WolffAbstract:Objective: As declining respiratory muscle function commonly leads to disability and death in amyotrophic lateral sclerosis (ALS), respiratory measurements such as Slow Vital Capacity (SVC) may pre...
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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
Amyotrophic Lateral Sclerosis, 2018Co-Authors: Jinsy A Andrews, Andrew A Wolff, Lisa Meng, Fady I Malik, Merit Cudkowicz, Orla Hardiman, Amy Bian, Jacqueline H Lee, Jeremy M ShefnerAbstract:AbstractObjective: 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. Methods: 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 mi...
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association between decline in Slow Vital Capacity and respiratory insufficiency use of assisted ventilation tracheostomy or death in patients with amyotrophic lateral sclerosis
JAMA Neurology, 2018Co-Authors: Jinsy Andrews, Andrew A Wolff, Lisa Meng, Sarah Kulke, Michael E Bozik, Fady I Malik, Stacy A Rudnicki, Jeremy M ShefnerAbstract:Importance The prognostic value of Slow Vital Capacity (SVC) in relation to respiratory function decline and disease progression in patients with amyotrophic lateral sclerosis (ALS) is not well understood. Objective To investigate the rate of decline in percentage predicted SVC and its association with respiratory-related clinical events and mortality in patients with ALS. Design, Setting, and Participants This retrospective study included 893 placebo-treated patients from 2 large clinical trials (EMPOWER and BENEFIT-ALS, conducted from March 28, 2011, to November 1, 2012, and from October 23, 2012, to March 21, 2014, respectively) and an ALS trial database (PRO-ACT, containing studies completed between 1990 and 2010) to investigate the rate of decline in SVC. Data from the EMPOWER trial (which enrolled adults with possible, probable, or definite ALS; symptom onset within 24 months before screening; and upright SVC at least 65% of predicted value for age, height, and sex) were used to assess the relationship of SVC to respiratory-related clinical events; 456 patients randomized to placebo were used in this analysis. The 2 clinical trials included patients from North America, Australia, and Europe. Main Outcomes and Measures Clinical events included the earlier of time to death or time to decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) respiratory subdomain, time to onset of respiratory insufficiency, time to tracheostomy, and all-cause mortality. Results Among 893 placebo-treated patients with ALS, the mean (SD) patient age was 56.7 (11.2) years, and the mean (SD) SVC was 90.5% (17.1%) at baseline; 65.5% (585 of 893) were male, and 20.5% (183 of 893) had bulbar-onset ALS. In EMPOWER, average decline of SVC from baseline through 1.5-year follow-up was −2.7 percentage points per month. Steeper declines were found in patients older than 65 years (−3.6 percentage points per month [P = .005 vs 39]). When the rate of decline of SVC was Slower by 1.5 percentage points per month in the first 6 months, risk reductions for events after 6 months were 19% for decline in the ALSFRS-R respiratory subdomain or death after 6 months, 22% for first onset of respiratory insufficiency or death after 6 months, 23% for first occurrence of tracheostomy or death after 6 months, and 23% for death at any time after 6 months (P Conclusions and Relevance The rate of decline in SVC is associated with meaningful clinical events in ALS, including respiratory failure, tracheostomy, or death, suggesting that it is an important indicator of clinical progression.
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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
2018Co-Authors: Jinsy A Andrews, Andrew A Wolff, Lisa Meng, Fady I Malik, Orla Hardiman, Amy Bian, Merit E. Cudkowicz, Jacqueline Lee, Jeremy M ShefnerAbstract:Objective: 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. Methods: 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. Results: Data collection will be complete in the fourth quarter of 2017. Conclusions: VitalITY-ALS was a phase III trial designed to evaluate the efficacy, safety, and tolerability of tirasemtiv in ALS.
Andrew A Wolff - One of the best experts on this subject based on the ideXlab platform.
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A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis.
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019Co-Authors: Jeremy M Shefner, William Camu, Lisa Meng, Fady I Malik, Stacy A Rudnicki, Orla Hardiman, Jacqueline H Lee, Merit E. Cudkowicz, Bettina M. Cockroft, Andrew A WolffAbstract: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).
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relationships between Slow Vital Capacity and measures of respiratory function on the alsfrs r
Amyotrophic Lateral Sclerosis, 2018Co-Authors: Carlayne E Jackson, Mamede De Carvalho, Angela Genge, Terry Heimanpatterson, Jeremy M Shefner, Jenny Wei, Andrew A WolffAbstract:Objective: As declining respiratory muscle function commonly leads to disability and death in amyotrophic lateral sclerosis (ALS), respiratory measurements such as Slow Vital Capacity (SVC) may pre...
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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
Amyotrophic Lateral Sclerosis, 2018Co-Authors: Jinsy A Andrews, Andrew A Wolff, Lisa Meng, Fady I Malik, Merit Cudkowicz, Orla Hardiman, Amy Bian, Jacqueline H Lee, Jeremy M ShefnerAbstract:AbstractObjective: 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. Methods: 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 mi...
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association between decline in Slow Vital Capacity and respiratory insufficiency use of assisted ventilation tracheostomy or death in patients with amyotrophic lateral sclerosis
JAMA Neurology, 2018Co-Authors: Jinsy Andrews, Andrew A Wolff, Lisa Meng, Sarah Kulke, Michael E Bozik, Fady I Malik, Stacy A Rudnicki, Jeremy M ShefnerAbstract:Importance The prognostic value of Slow Vital Capacity (SVC) in relation to respiratory function decline and disease progression in patients with amyotrophic lateral sclerosis (ALS) is not well understood. Objective To investigate the rate of decline in percentage predicted SVC and its association with respiratory-related clinical events and mortality in patients with ALS. Design, Setting, and Participants This retrospective study included 893 placebo-treated patients from 2 large clinical trials (EMPOWER and BENEFIT-ALS, conducted from March 28, 2011, to November 1, 2012, and from October 23, 2012, to March 21, 2014, respectively) and an ALS trial database (PRO-ACT, containing studies completed between 1990 and 2010) to investigate the rate of decline in SVC. Data from the EMPOWER trial (which enrolled adults with possible, probable, or definite ALS; symptom onset within 24 months before screening; and upright SVC at least 65% of predicted value for age, height, and sex) were used to assess the relationship of SVC to respiratory-related clinical events; 456 patients randomized to placebo were used in this analysis. The 2 clinical trials included patients from North America, Australia, and Europe. Main Outcomes and Measures Clinical events included the earlier of time to death or time to decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) respiratory subdomain, time to onset of respiratory insufficiency, time to tracheostomy, and all-cause mortality. Results Among 893 placebo-treated patients with ALS, the mean (SD) patient age was 56.7 (11.2) years, and the mean (SD) SVC was 90.5% (17.1%) at baseline; 65.5% (585 of 893) were male, and 20.5% (183 of 893) had bulbar-onset ALS. In EMPOWER, average decline of SVC from baseline through 1.5-year follow-up was −2.7 percentage points per month. Steeper declines were found in patients older than 65 years (−3.6 percentage points per month [P = .005 vs 39]). When the rate of decline of SVC was Slower by 1.5 percentage points per month in the first 6 months, risk reductions for events after 6 months were 19% for decline in the ALSFRS-R respiratory subdomain or death after 6 months, 22% for first onset of respiratory insufficiency or death after 6 months, 23% for first occurrence of tracheostomy or death after 6 months, and 23% for death at any time after 6 months (P Conclusions and Relevance The rate of decline in SVC is associated with meaningful clinical events in ALS, including respiratory failure, tracheostomy, or death, suggesting that it is an important indicator of clinical progression.
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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
2018Co-Authors: Jinsy A Andrews, Andrew A Wolff, Lisa Meng, Fady I Malik, Orla Hardiman, Amy Bian, Merit E. Cudkowicz, Jacqueline Lee, Jeremy M ShefnerAbstract:Objective: 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. Methods: 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. Results: Data collection will be complete in the fourth quarter of 2017. Conclusions: VitalITY-ALS was a phase III trial designed to evaluate the efficacy, safety, and tolerability of tirasemtiv in ALS.
William Camu - One of the best experts on this subject based on the ideXlab platform.
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Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial
EBioMedicine, 2020Co-Authors: William Camu, Marius Mickunas, Jean-luc Veyrune, Christine Payan, Cecilia Garlanda, Massimo Locati, Raul Juntas-morales, Nicolas Pageot, Andrea Malaspina, Ulf AndreassonAbstract:Abstract Background Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects. Methods We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age 3 months, and a Slow Vital Capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), Slow Vital Capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759. Findings All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p Interpretation Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on Slowing ALS disease progression. Funding : The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA).
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rock als protocol for a randomized placebo controlled double blind phase iia trial of safety tolerability and efficacy of the rho kinase rock inhibitor fasudil in amyotrophic lateral sclerosis
Frontiers in Neurology, 2019Co-Authors: William Camu, Paul Lingor, Markus Weber, Tim Friede, Reinhard Hilgers, Andreas Leha, Christoph Neuwirth, Rene GuntherAbstract:Objectives: Disease-modifying therapies for amyotrophic lateral sclerosis (ALS) are still not satisfactory. The Rho kinase (ROCK) inhibitor fasudil has demonstrated beneficial effects in cell culture and animal models of ALS. For many years, fasudil has been approved in Japan for the treatment of vasospasm in patients with subarachnoid hemorrhage with a favorable safety profile. Here we describe a clinical trial protocol to repurpose fasudil as a disease-modifying therapy for ALS patients. Methods: ROCK-ALS is a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of fasudil in ALS patients (EudraCT: 2017-003676-31, NCT: 03792490). Safety and tolerability are the primary endpoints. Efficacy is a secondary endpoint and will be assessed by the change in ALSFRS-R, ALSAQ-5, Slow Vital Capacity (SVC), ECAS, and the motor unit number index (MUNIX), as well as survival. Efficacy measures will be assessed before (baseline) and immediately after the infusion therapy as well as on days 90 and 180. Patients will receive a daily dose of either 30 or 60 mg fasudil, or placebo in two intravenous applications for a total of 20 days. Regular assessments of safety will be performed throughout the treatment period, and in the follow-up period until day 180. Additionally, we will collect biological fluids to assess target engagement and evaluate potential biomarkers for disease progression. A total of 120 patients with probable or definite ALS (revised El Escorial criteria) and within 6-18 months of the onset of weakness shall be included in 16 centers in Germany, Switzerland and France. Results and conclusions: The ROCK-ALS trial is a phase IIa trial to evaluate the ROCK-inhibitor fasudil in early-stage ALS-patients that started patient recruitment in 2019.
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A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis.
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019Co-Authors: Jeremy M Shefner, William Camu, Lisa Meng, Fady I Malik, Stacy A Rudnicki, Orla Hardiman, Jacqueline H Lee, Merit E. Cudkowicz, Bettina M. Cockroft, Andrew A WolffAbstract: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).
Luc Dupuis - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of rasagiline as an add on therapy to riluzole in patients with amyotrophic lateral sclerosis a randomised double blind parallel group placebo controlled phase 2 trial
Lancet Neurology, 2018Co-Authors: Albert C Ludolph, Luc Dupuis, Jan Kassubek, Joachim Schuster, Johannes Dorst, Jens Dreyhaupt, Jochen H Weishaupt, Ulrike Weiland, Susanne Petri, Thomas MeyerAbstract:Summary Background Rasagiline, a monoamine oxidase B inhibitor with neuroprotective potential in Parkinson's disease, has shown a disease-modifying effect in the SOD1-Gly93Ala low-expressing mouse model of amyotrophic lateral sclerosis, both alone and in combination with riluzole. We sought to test whether or not rasagiline 1 mg/day can prolong survival in patients with amyotrophic lateral sclerosis also receiving riluzole. Methods Patients with possible, probable, or definite amyotrophic lateral sclerosis were enrolled to our randomised, placebo-controlled, parallel-group, double-blind, phase 2 trial from 15 German network for motor neuron diseases (MND-NET) centres (university hospitals or clinics). Eligible patients were aged at least 18 years, had onset of progressive weakness within the 36 months before the study, had disease duration of more than 6 months and less than 3 years, and had a best-sitting Slow Vital Capacity of at least 50%. After a 4-week screening period, eligible patients were randomly assigned (1:1) to receive either rasagiline (1 mg/day) or placebo in addition to riluzole (100 mg/day), after stratification for site of onset (bulbar or spinal) and study centre. Patients and all personnel assessing outcome parameters were masked to treatment allocation. Patients were followed up 2, 6, 12, and 18 months after randomisation. The primary endpoint was survival time, defined as the time to death or time to study cutoff date (ie, the last patient's last visit plus 14 days). Analyses of primary outcome and safety measures were done in all patients who received at least one dose of trial treatment (intention-to-treat population). The trial is registered with ClinicalTrials.gov, number NCT01879241. Findings Between July 2, 2013, and Nov 11, 2014, 273 patients were screened for eligibility, and 252 patients were randomly assigned to receive rasagiline (n=127) or placebo (n=125). 126 patients taking rasagiline and 125 taking placebo were included in the intention-to-treat analysis. For the primary outcome, the survival probability at the end of the study was 0·43 (95% CI 0·25–0·59) in the rasagiline group (n=126) and 0·53 (0·43–0·62) in the placebo group (n=125). The estimated effect size (hazard ratio) was 0·91 (one-sided 97·5% CI –infinity to 1·34; p=0·31). Rasagiline was well tolerated, and most adverse events were due to amyotrophic lateral sclerosis disease progression rather than treatment; the most frequent of these were dysphagia (32 [25%] taking rasagiline vs 24 [19%] taking placebo) and respiratory failure (25 [20%] vs 31 [25%]). Frequency of adverse events were comparable between both groups. Interpretation Rasagiline was safe in patients with amyotrophic lateral sclerosis. There was no difference between groups in the primary outcome of survival, although post-hoc analysis suggested that rasagiline might modify disease progression in patients with an initial slope of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised greater than 0·5 points per month at baseline. This should be confirmed in another clinical trial. Funding Teva Pharmaceutical Industries.
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a randomized double blind placebo controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis
PLOS ONE, 2012Co-Authors: Luc Dupuis, R Dengler, Michael T Heneka, Thomas Meyer, Stephan Zierz, Jan Kassubek, Wilhelm Fischer, Franziska SteinerAbstract:BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, Slow Vital Capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118.
Fady I Malik - One of the best experts on this subject based on the ideXlab platform.
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A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis.
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019Co-Authors: Jeremy M Shefner, William Camu, Lisa Meng, Fady I Malik, Stacy A Rudnicki, Orla Hardiman, Jacqueline H Lee, Merit E. Cudkowicz, Bettina M. Cockroft, Andrew A WolffAbstract: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).
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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
Amyotrophic Lateral Sclerosis, 2018Co-Authors: Jinsy A Andrews, Andrew A Wolff, Lisa Meng, Fady I Malik, Merit Cudkowicz, Orla Hardiman, Amy Bian, Jacqueline H Lee, Jeremy M ShefnerAbstract:AbstractObjective: 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. Methods: 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 mi...
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association between decline in Slow Vital Capacity and respiratory insufficiency use of assisted ventilation tracheostomy or death in patients with amyotrophic lateral sclerosis
JAMA Neurology, 2018Co-Authors: Jinsy Andrews, Andrew A Wolff, Lisa Meng, Sarah Kulke, Michael E Bozik, Fady I Malik, Stacy A Rudnicki, Jeremy M ShefnerAbstract:Importance The prognostic value of Slow Vital Capacity (SVC) in relation to respiratory function decline and disease progression in patients with amyotrophic lateral sclerosis (ALS) is not well understood. Objective To investigate the rate of decline in percentage predicted SVC and its association with respiratory-related clinical events and mortality in patients with ALS. Design, Setting, and Participants This retrospective study included 893 placebo-treated patients from 2 large clinical trials (EMPOWER and BENEFIT-ALS, conducted from March 28, 2011, to November 1, 2012, and from October 23, 2012, to March 21, 2014, respectively) and an ALS trial database (PRO-ACT, containing studies completed between 1990 and 2010) to investigate the rate of decline in SVC. Data from the EMPOWER trial (which enrolled adults with possible, probable, or definite ALS; symptom onset within 24 months before screening; and upright SVC at least 65% of predicted value for age, height, and sex) were used to assess the relationship of SVC to respiratory-related clinical events; 456 patients randomized to placebo were used in this analysis. The 2 clinical trials included patients from North America, Australia, and Europe. Main Outcomes and Measures Clinical events included the earlier of time to death or time to decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) respiratory subdomain, time to onset of respiratory insufficiency, time to tracheostomy, and all-cause mortality. Results Among 893 placebo-treated patients with ALS, the mean (SD) patient age was 56.7 (11.2) years, and the mean (SD) SVC was 90.5% (17.1%) at baseline; 65.5% (585 of 893) were male, and 20.5% (183 of 893) had bulbar-onset ALS. In EMPOWER, average decline of SVC from baseline through 1.5-year follow-up was −2.7 percentage points per month. Steeper declines were found in patients older than 65 years (−3.6 percentage points per month [P = .005 vs 39]). When the rate of decline of SVC was Slower by 1.5 percentage points per month in the first 6 months, risk reductions for events after 6 months were 19% for decline in the ALSFRS-R respiratory subdomain or death after 6 months, 22% for first onset of respiratory insufficiency or death after 6 months, 23% for first occurrence of tracheostomy or death after 6 months, and 23% for death at any time after 6 months (P Conclusions and Relevance The rate of decline in SVC is associated with meaningful clinical events in ALS, including respiratory failure, tracheostomy, or death, suggesting that it is an important indicator of clinical progression.
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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
2018Co-Authors: Jinsy A Andrews, Andrew A Wolff, Lisa Meng, Fady I Malik, Orla Hardiman, Amy Bian, Merit E. Cudkowicz, Jacqueline Lee, Jeremy M ShefnerAbstract:Objective: 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. Methods: 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. Results: Data collection will be complete in the fourth quarter of 2017. Conclusions: VitalITY-ALS was a phase III trial designed to evaluate the efficacy, safety, and tolerability of tirasemtiv in ALS.
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decline in Slow Vital Capacity predicts respiratory insufficiency use of assisted ventilation tracheostomy or death in als p3 186
Neurology, 2016Co-Authors: Jeremy M Shefner, Andrew A Wolff, Lisa Meng, Sarah Kulke, Michael E Bozik, Fady I Malik, Jinsy A AndrewsAbstract: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 p<0.0001). The correlation of change from baseline in SVC and the respiratory subdomain of the ALSFRS-R (r = 0.26) was weak (p<0.0001). 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.