A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of reldesemtiv versus placebo on functional outcomes in ALS.

Detailed Description
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COURAGE-ALS is a Phase 3, double-blind, randomized, placebo-controlled trial of reldesemtiv in patients aged 18 to 80 with ALS. The screening and qualification period for the trial will be no more than 14 days in duration. Approximately 555 eligible ALS patients will be randomized (2:1) to receive the following dose of reldesemtiv or placebo (stratified by riluzole use/non-use and edaravone use/non-use) for the first 24 weeks (double-blind, placebo-controlled period): 300 mg reldesemtiv twice a day for a 600 mg total daily dose (TDD) Placebo twice daily At the end of the 24-week double-blind, placebo-controlled period, patients will transition to the active drug period, where all patients will receive the following dose of reldesemtiv for the next 24 weeks: 300 mg reldesemtiv twice a day for a 600 mg TDD for patients who were not down titrated during the 24 weeks of blinded dosing 150 mg reldesemtiv twice a day for a 300 mg TDD for patients who were down titrated during the 24 weeks of blinded dosing

Official Title
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A Phase 3, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Reldesemtiv
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males or Females between the ages of 18 and 80 years of age, inclusive Diagnosis of familial or sporadic ALS (defined as meeting the laboratory-supported probable, probable, or definite criteria for ALS according to the World Federation of Neurology El Escorial criteria). Patients who meet the possible criteria are eligible if they have lower motor neuron findings; those who have purely upper motor neuron findings are ineligible. First symptom of ALS ≤ 24 months prior to screening. The qualifying first symptoms of ALS are limited to manifestations of weakness in extremity, bulbar, or respiratory muscles. ALSFRS-R total score ≤ 44 at screening. Patients with a total score of 45 or higher may be rescreened 60±7 days following the original screening date. Upright FVC ≥ 65.0% of predicted for age, height, sex and ethnicity at screening according to Global Lung Initiative equation Must be either on riluzole for ≥ 30 days prior to screening or have not taken it for at least 30 days prior to screening Must have completed at least 2 cycles of edaravone at the time of screening or have not received it for at least 30 days prior to screening Able to swallow whole tablets Exclusion Criteria: eGFRCysC < 45.0 mL/min/1.73 m2 at screening Urine protein/creatinine ratio > 1 mg/mg (113 mg/mmol) at screening Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3-times the upper limit of normal (ULN) Total bilirubin (TBL), direct or indirect bilirubin above the ULN. Cognitive impairment, related to ALS or otherwise that impairs the patient's ability to understand and/or comply with study procedures and provide informed consent Other medically significant neurological conditions that could interfere with the assessment of ALS symptoms, signs or progression. Has a tracheostomy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 300 mg reldesemtiv twice daily for a 600 mg total daily dose, from Day 1 until Week 24<br>Patients in this arm take 2 reldesemtiv 150 mg oral tablets twice a day for a 600 mg total daily dose from Day 1 until Week 24. | Drug: Reldesemtiv<br>* Reldesemtiv Oral Tablet<br>|
| Placebo Comparator: Placebo twice daily, from Day 1 until Week 24<br>Patients in this arm take 2 placebo oral tablets twice a day from Day 1 until Week 24. | Drug: Placebo<br>* Placebo Oral Tablet<br>|
| Experimental: 300 mg reldesemtiv twice daily for a 600 mg total daily dose, from Week 24 until Week 48<br>Patients in this arm take 2 reldesemtiv 150 mg oral tablets twice a day for a 600 mg total daily dose from Week 24 until Week 48 for patients who were not down titrated during the 24 weeks of blinded dosing. | Drug: Reldesemtiv<br>* Reldesemtiv Oral Tablet<br>|
| Experimental: 150 mg reldesemtiv twice daily for a 300 mg total daily dose, from Week 24 until Week 48<br>Patients in this arm take 1 reldesemtiv 150 mg oral tablet twice a day for a 300 mg total daily dose from Week 24 until Week 48 for patients who were down titrated for any reason during the 24 weeks of blinded dosing. | Drug: Reldesemtiv<br>* Reldesemtiv Oral Tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of reldesemtiv versus placebo on functional outcomes in ALS | Change from baseline to Week 24 in ALS Functional Rating Scale-Revised (ALSFRS-R) total score; rating scale 0 to 48; higher scores indicate better functional status | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of reldesemtiv versus placebo on combined functional and survival outcomes in ALS | Combined assessment of change in ALSFRS-R total score, time to onset of respiratory insufficiency, and survival time up to Week 24. In this joint rank test each individual patient is ranked compared to all other patients based on survival time, time to onset of respiratory insufficiency, and changes from baseline to Week 24 in ALSFRS-R total score. Deaths have the worst rank (with earlier deaths being ranked worse than later deaths); patients with onset of respiratory insufficiency have the next worst rank; and the more favorable changes from baseline at week 24 in ALSFRS-R total score have the best rank using this process. | 24 Weeks | 
| Effect of reldesemtiv versus placebo on ventilatory function | Change from baseline to Week 24 in the percent predicted FVC | Baseline to Week 24 | 
| Effect of reldesemtiv versus placebo on quality of life | Change from baseline to Week 24 in the ALS Assessment Questionnaire-40 (ALSAQ-40) total score; rating scale 0 to 100; higher scores indicate worse quality of life | Baseline to Week 24 | 
| Effect of reldesemtiv versus placebo on handgrip strength | Change from baseline to Week 24 in handgrip strength (average of both hands) | Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyotrophic Lateral Sclerosis, ALS, CK-2127107, Reldesemtiv, COURAGE-ALS