Two unblinded interim analyses by the Data Monitoring Committee are planned to assess the futility of reldesemtiv, with the first occurring 12 weeks after one-third of the sample size is randomized.
Following promising results from a phase 2 clinical trial, Cytokinetics announced open enrollment for a new phase 3 trial dubbed COURAGE-ALS (NCT04944784), which will evaluate the efficacy and safety of its investigational agent reldesemtiv in patients with amyotrophic lateral sclerosis (ALS).
COURAGE-ALS (Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation in ALS) is a double-blind, placebo-controlled trial expected to enroll approximately 555 patients using the ALS Functional Rating Scale-Revised (ALSFRS-R) as the primary outcome measure. Participants will be randomized 2:1 to receive 300-mg reldesemtiv or matching placebo dosed twice daily for 24 weeks, followed by a 24-week period in which all patients will receive reldesemtiv twice daily.
Two unblinded interim analysis by the Independent Data Monitoring Committee are planned, the first assessing futility of the drug 12 weeks after approximately one-third or more of the planned sample size is randomized. The second interim analysis will also assess for futility, with an option for a fixed increase in total enrollment, if necessary, to augment the statistical power of the trial.
Reldesemtiv, a next-generation fast skeletal muscle troponin activator (FSTA), slows the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers, which sensitizes the sarcomere to calcium, leading to an increase in skeletal muscle contractility. The drug has previously demonstrated pharmacological activity that may lead to new therapeutic options for diseases associated with muscle weakness and fatigue.
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"We recognize the profound urgency to deliver new treatments to people with ALS and are pleased to open COURAGE-ALS after gathering important input from patients, regulators, advocates and the clinical community," Fady I. Malik, MD, PhD, executive vice president of Research & Development, Cytokinetics, said in a statement. "As pioneers in muscle biology, we have been pursuing fast skeletal muscle activation for the potential treatment of ALS for over a decade and, based on the results from FORTITUDE-ALS, we believe there is a compelling rationale to advance reldesemtiv into this pivotal Phase 3 clinical trial, as it potentially may add to current standard of care and improve patients’ functional status and overall quality of life."
FORTITUDE-ALS (NCT03160898) was a phase 2, double-blind, randomized, dose-ranging, placebo-controlled, parallel group study that assessed reldesemtiv in 458 eligible patients with ALS. Investigators used change from baseline in the percent predicted slow vital capacity (SVC), a measure of respiratory function, as the primary end point. After 12 weeks of dosing, the study did not achieve statistical significance for a pre-specified dose-response relationship in change from baseline in SVC (P = .11).
Similar analyses of ALSFRS-R and slope of Muscle Strength Mega-Score, key secondary end points, yielded P values of 0.09 and 0.31, respectively. Investigators did note that patients across all dose groups (150 mg, 300 mg, and 450 mg) declined less than patients on placebo for SVC and ALSFRS-R, with larger and clinically meaningful differences emerging over time.
A post-hoc analysis of FORTITUDE-ALS showed that the differences between reldesemtiv and placebo on SVC and ALSFRS-R total score following the 12-week study period remained evident at follow-up, 4 weeks after the last dose of the study drug.
"We are also working toward our goal to provide continued access to reldesemtiv for participants who complete dosing in COURAGE-ALS, as well as make it available to participants from our previously completed ALS trials," Malik said in a statement.
The company is planning to provide continued access to reldesemtiv for participants who complete COURAGE-ALS, as well as for those who participated in prior ALS trials through the ALS Patient and Caregiver Advisory Council (ALS-PAC). The access program will be developed with the objective to ensure safe, ethical and equitable access to reldesemtiv.
Feedback from ALS-PAC, as well as a series of meetings with patients, caregivers, advocates, payors, and healthcare professionals helped shape the design of COURAGE-ALS. It now incorporates elements designed to remove barriers to clinical trial participation, including remote clinic visits, home nursing visits, and mobile app based end point measurements. Furthermore, 1 patient will serve on the steering committee of COURAGE-ALS to provide patient perspective on the trial.