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

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)

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

Study Overview

• Status: Terminated
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Reldesemtiv

Detailed Description

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 21 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

• Study Type: Interventional
• Enrollment (Actual): 489
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Brain and Mind Centre
    • Concord, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • The Perron Institute
• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg, Department of Neurology
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary - Heritage Medical Research Clinic
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta
  • New Brunswick
    • Fredericton, New Brunswick, Canada, E3B 0C7
      • Stan Cassidy Centre for Rehabilitation
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University Medical Centre
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Hospital Research Institute - Civic Campus
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Research Institute
  • Quebec
    • Montréal, Quebec, Canada, H2X 0A9
      • Centre de recherche du CHUM
    • Montréal, Quebec, Canada, H3A 2B4
      • McGill University, Montreal Neurological Institute & Hospital
    • Québec, Quebec, Canada, G1J 1Z4
      • CHU de Quebec-Universite Laval
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7K 0M7
      • Saskatoon City Hospital
• Denmark
  • Copenhagen, Denmark, 2400
    • Deparment of Neurology Bispebjerg University Hospital
• France
  • Bron, France, 69677
    • CRC SLA de Lyon
  • Lille, France, 59037
    • CHRU de Lille Hopital Roger Salengro
  • Limoges, France, 87 042
    • CHU de Limoges - Hôpital Dupuytren
  • Marseille, France, 13005
    • CHU de la Timone
  • Nice, France, 06 001
    • CHU de Nice - Hôpital Pasteur 2
  • Paris, France, 75013
    • Hôpital La Pitié Salpêtrière
  • Tours, France, 37044
    • CHRU de Tours, Hopital Bretonneau, Clinical Research Center
• Germany
  • Berlin, Germany, 13353
    • Charité - Universitätsmedizin Berlin
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn
  • Hanover, Germany, 30625
    • Medical School Hannover - Department of Neurology
  • Jena, Germany, 07747
    • Universitatsklinikum Jena
  • Lübeck, Germany, 23538
    • Universitatsklinikum Schleswig Holstein
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
• Ireland
  • Dublin
    • Beaumont, Dublin, Ireland, 9
      • RSCI Education and Research Centre, Beaumont Hospital
• Italy
  • Milan, Italy, 20149
    • Ospedale San Luca
  • Milan, Italy, 20162
    • Centro Clinical Nemo - Fondazione Serena Onlus
  • Milano, Italy, 20138
    • Instituti Clinici Scientifici Maugeri
  • Turin, Italy, 10126
    • AOU Città della Salute e Scienza (Molinette),
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • UMC Utrecht, Department of Neurology, ALS Center
• Poland
  • Warsaw, Poland, 02-473
    • City Clinic Research
• Portugal
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar Universitario Lisboa Norte, Department of Neurology
• Spain
  • Barcelona, Spain, 08907
    • Hospital Universitari de Bellvitge
  • Bilbao, Spain, 48013
    • Hospital Universitario Basurto
  • Madrid, Spain, 28016
    • Hospital San Rafael
  • Valencia, Spain, 46026
    • Hospital Universitari i Politècnic La Fe
• Sweden
  • Malmö, Sweden, 21428
    • Neurologimottagningen Skane University Hospital
  • Stockholm, Sweden, 11361
    • Studieenheten Akademiskt Specialistcentrum, Sabbatsberg Hospital
• Switzerland
  • Saint Gallen, Switzerland, 9007
    • Muskelzentrum/ALS Clinic
• United Kingdom
  • Liverpool, United Kingdom, L9 7LJ
    • The Walton Centre NHS Foundation Trust
  • London, United Kingdom, SE5 9RX
    • Maurice Wohl Clinical Neuroscience Institute
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital & Medical Center - Barrow Neurological Institute
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Orange, California, United States, 92868
      • University of California Irvine - ALS & Neuromuscular Center
    • San Francisco, California, United States, 94109
      • California Pacific Medical Center - Forbes Norris MDA/ALS Research Center
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital Anschutz Outpatient Pavilion
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • GW Medical Faculty Associates
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Jacksonville
    • Tampa, Florida, United States, 33612
      • University of South Florida - Carol and Frank Morsani Center for Advanced Health Care
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Duchossois Center for Advanced Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • The University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Outpatient Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital - Neurological Clinical Research Institute
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center/Medical School
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Michigan Medicine
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Missouri
    • Saint Louis, Missouri, United States, 63108
      • Washington University School of Medicine - Center for Advance Medicine
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Neurology Associates, PC
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Atrium Health Neuroscience Institute - Charlotte
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97213
      • Providence ALS Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Health Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Lewis Katz School of Medicine at Temple University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center - Clinical Research Center
  • Texas
    • Dallas, Texas, United States, 75206
      • Texas Neurology, P.A.
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont Medical Center
  • Virginia
    • Henrico, Virginia, United States, 23233
      • VCU Neuroscience Orthopaedic and Wellness Center (NOW)
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reldesemtiv Group, Double-Blind Period; Participants 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; Reldesemtiv Oral Tablet
Placebo Comparator: Placebo Group, Double-Blind Period; Participants in this arm take 2 placebo oral tablets twice a day from Day 1 until Week 24.	Drug: Placebo; Placebo Oral Tablet
Experimental: Delayed Start Group, Active Drug Period; Participants in this arm were those who received placebo in the double-blind period and reldesemtiv in the active drug period. Participants take 2 reldesemtiv 150 mg oral tablets twice a day for a 600 mg total daily dose from Week 24 until Week 48. Patients who were down-titrated for any reason during the 24 weeks of blinded dosing take 1 reldesemtiv 150 mg oral tablet twice a day for a 300 mg total daily dose from Week 24 until Week 48.	Drug: Reldesemtiv; Reldesemtiv Oral Tablet
Experimental: Early Start Group, Active Drug Period; Participants in this arm were those who received reldesemtiv in the double-blind and active drug periods. Participants take 2 reldesemtiv 150 mg oral tablets twice a day for a 600 mg total daily dose from Week 24 until Week 48. Patients who were down-titrated for any reason during the 24 weeks of blinded dosing take 1 reldesemtiv 150 mg oral tablet twice a day for a 300 mg total daily dose from Week 24 until Week 48.	Drug: Reldesemtiv; Reldesemtiv Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Reldesemtiv Versus Placebo on Functional Outcomes in Amyotrophic Lateral Sclerosis (ALS)	Change from baseline to Week 24 in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score using MMRM without multiple imputation; 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 Amyotrophic Lateral Sclerosis (ALS)	Composite Assessment of Function and Survival (CAFS) compares ranked outcomes based on change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) score (0-48; higher scores indicate better function), time in months to dependence on assisted ventilation (DOAV) and time in months to death. Deceased participants are ranked by time-to-death; earliest deaths ranked the lowest. DOAV survivors are ranked more favorably than those who have died but lower than those alive and not DOAV. Non-DOAV survivors are ranked based on change in ALSFRS-R (largest decline in ALSFRS-R ranked lower than less decline or improvement in ALSFRS-R). Unitless ranked scores range from 1-482 (Full Analysis Set) with larger rank scores associated with a better outcome. Ranks were analyzed using stratified Wilcoxon test comparing the ranked scores between reldesemtiv and placebo, adjusting for baseline riluzole and edaravone use. The win probability and the ratio (reldesemtiv vs placebo) are presented.	Baseline to Week 24
Effect of Reldesemtiv Versus Placebo on Ventilatory Function	Change from baseline in percent predicted forced vital capacity (FVC) using an in-clinic spirometer; a negative number for change from baseline indicates respiratory function decline relative to baseline	Baseline to Week 24
Effect of Reldesemtiv Versus Placebo on Quality of Life	Change from baseline in ALSAQ-40 total score. ALSAQ-40 = Amyotrophic Lateral Sclerosis Assessment Questionnaire; summary scores range from 0 (best health status) to 100 (worst health status); ALSAQ-40 total score is calculated as the sum of the summary scores from the 5 domains; lower score corresponds to better health-related quality of life.	Baseline to Week 24
Effect of Reldesemtiv Versus Placebo on Handgrip Strength	Change from baseline in maximum handgrip strength (average of both hands) measured bilaterally by an electronic hand dynamometer	Baseline to Week 24

Collaborators and Investigators

• Sponsor: Cytokinetics
• Investigators: Study Director: Cytokinetics, MD, Cytokinetics

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2021
• Primary Completion (Actual): July 18, 2023
• Study Completion (Actual): July 18, 2023

Study Registration Dates

• First Submitted: June 16, 2021
• First Submitted That Met QC Criteria: June 24, 2021
• First Posted (Actual): June 30, 2021

Study Record Updates

• Last Update Posted (Estimated): December 5, 2024
• Last Update Submitted That Met QC Criteria: November 27, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; ALS; CK-2127107; Reldesemtiv; COURAGE-ALS
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: CY 5031; 2020-004040-29 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No