A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS)
- Registration Number
- NCT04944784
- Lead Sponsor
- Cytokinetics
- Brief Summary
The purpose of this study is to assess the effect of reldesemtiv versus placebo on functional outcomes in ALS.
- 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
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 489
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Reldesemtiv Group, Double-Blind Period Reldesemtiv 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. Placebo Group, Double-Blind Period Placebo Participants in this arm take 2 placebo oral tablets twice a day from Day 1 until Week 24. Delayed Start Group, Active Drug Period Reldesemtiv 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. Early Start Group, Active Drug Period Reldesemtiv 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.
- Primary Outcome Measures
Name Time Method Effect of Reldesemtiv Versus Placebo on Functional Outcomes in Amyotrophic Lateral Sclerosis (ALS) Baseline to Week 24 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
- Secondary Outcome Measures
Name Time Method Effect of Reldesemtiv Versus Placebo on Combined Functional and Survival Outcomes in Amyotrophic Lateral Sclerosis (ALS) Baseline to Week 24 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.
Effect of Reldesemtiv Versus Placebo on Ventilatory Function Baseline to Week 24 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
Effect of Reldesemtiv Versus Placebo on Quality of Life Baseline to Week 24 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.
Effect of Reldesemtiv Versus Placebo on Handgrip Strength Baseline to Week 24 Change from baseline in maximum handgrip strength (average of both hands) measured bilaterally by an electronic hand dynamometer
Trial Locations
- Locations (84)
Johns Hopkins Outpatient Center
🇺🇸Baltimore, Maryland, United States
Royal Brisbane and Women's Hospital
🇦🇺Herston, Queensland, Australia
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
University of California Irvine - ALS & Neuromuscular Center
🇺🇸Orange, California, United States
Duchossois Center for Advanced Medicine
🇺🇸Chicago, Illinois, United States
Massachusetts General Hospital - Neurological Clinical Research Institute
🇺🇸Boston, Massachusetts, United States
Michigan Medicine
🇺🇸Ann Arbor, Michigan, United States
Atrium Health Neuroscience Institute - Charlotte
🇺🇸Charlotte, North Carolina, United States
Stanford Hospital and Clinics
🇺🇸Stanford, California, United States
Hospital for Special Surgery
🇺🇸New York, New York, United States
University of Massachusetts Memorial Medical Center/Medical School
🇺🇸Worcester, Massachusetts, United States
GW Medical Faculty Associates
🇺🇸Washington, District of Columbia, United States
Mayo Clinic Florida
🇺🇸Jacksonville, Florida, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
University of Vermont Medical Center
🇺🇸Burlington, Vermont, United States
UZ Leuven Gasthuisberg, Department of Neurology
🇧🇪Leuven, Belgium
Ottawa Hospital Research Institute - Civic Campus
🇨🇦Ottawa, Ontario, Canada
University of Alberta
🇨🇦Edmonton, Alberta, Canada
University of Calgary - Heritage Medical Research Clinic
🇨🇦Calgary, Alberta, Canada
Saskatoon City Hospital
🇨🇦Saskatoon, Saskatchewan, Canada
Medical School Hannover - Department of Neurology
🇩🇪Hanover, Germany
Universitatsklinikum Jena
🇩🇪Jena, Germany
UMC Utrecht, Department of Neurology, ALS Center
🇳🇱Utrecht, Netherlands
Universitatsklinikum Ulm
🇩🇪Ulm, Germany
RSCI Education and Research Centre, Beaumont Hospital
🇮🇪Beaumont, Dublin, Ireland
Centro Hospitalar Universitario Lisboa Norte, Department of Neurology
🇵🇹Lisboa, Portugal
City Clinic Research
🇵🇱Warsaw, Poland
Hopital La Pitie Salpetriere
🇫🇷Paris, France
Ospedale San Luca
🇮🇹Milan, Italy
CHU de Limoges - Hopital Dupuytren
🇫🇷Limoges, France
CHRU de Tours, Hopital Bretonneau, Clinical Research Center
🇫🇷Tours, France
Universitatsklinikum Bonn
🇩🇪Bonn, Germany
Hospital Universitario Basurto
🇪🇸Bilbao, Spain
Charité - Universitätsmedizin Berlin
🇩🇪Berlin, Germany
Hospital San Rafael
🇪🇸Madrid, Spain
CRC SLA de Lyon
🇫🇷Bron, France
CHRU de Lille Hopital Roger Salengro
🇫🇷Lille, France
CHU de la Timone
🇫🇷Marseille, France
CHU de Nice - Hôpital Pasteur 2
🇫🇷Nice, France
Universitätsklinikum Schleswig Holstein
🇩🇪Lübeck, Germany
AOU Città della Salute e Scienza (Molinette),
🇮🇹Turin, Italy
Hospital Universitari de Bellvitge
🇪🇸Barcelona, Spain
Muskelzentrum/ALS Clinic
🇨🇭Saint Gallen, Switzerland
Studieenheten Akademiskt Specialistcentrum, Sabbatsberg Hospital
🇸🇪Stockholm, Sweden
The Walton Centre NHS Foundation Trust
🇬🇧Liverpool, United Kingdom
Deparment of Neurology Bispebjerg University Hospital
🇩🇰Copenhagen, Denmark
Neurologimottagningen Skane University Hospital
🇸🇪Malmö, Sweden
Maurice Wohl Clinical Neuroscience Institute
🇬🇧London, United Kingdom
London Health Sciences Centre
🇨🇦London, Ontario, Canada
McMaster University Medical Centre
🇨🇦Hamilton, Ontario, Canada
Sunnybrook Research Institute
🇨🇦Toronto, Ontario, Canada
Centre de recherche du CHUM
🇨🇦Montréal, Quebec, Canada
CHU de Quebec-Université Laval
🇨🇦Québec, Quebec, Canada
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Flinders Medical Centre
🇦🇺Bedford Park, South Australia, Australia
Brain and Mind Centre
🇦🇺Camperdown, New South Wales, Australia
St. Joseph's Hospital & Medical Center - Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
Vanderbilt University Medical Center - Clinical Research Center
🇺🇸Nashville, Tennessee, United States
Froedtert Hospital
🇺🇸Milwaukee, Wisconsin, United States
California Pacific Medical Center - Forbes Norris MDA/ALS Research Center
🇺🇸San Francisco, California, United States
University of Colorado Hospital Anschutz Outpatient Pavilion
🇺🇸Aurora, Colorado, United States
University of South Florida - Carol and Frank Morsani Center for Advanced Health Care
🇺🇸Tampa, Florida, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Providence ALS Center
🇺🇸Portland, Oregon, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
Penn State Health Milton S. Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
SUNY Upstate Medical University
🇺🇸Syracuse, New York, United States
Lewis Katz School of Medicine at Temple University
🇺🇸Philadelphia, Pennsylvania, United States
VCU Neuroscience Orthopaedic and Wellness Center (NOW)
🇺🇸Henrico, Virginia, United States
McGill University, Montreal Neurological Institute & Hospital
🇨🇦Montréal, Quebec, Canada
The Perron Institute
🇦🇺Nedlands, Western Australia, Australia
Stan Cassidy Centre for Rehabilitation
🇨🇦Fredericton, New Brunswick, Canada
Concord Repatriation General Hospital
🇦🇺Concord, New South Wales, Australia
Instituti Clinici Scientifici Maugeri
🇮🇹Milano, Italy
Centro Clinical Nemo - Fondazione Serena Onlus
🇮🇹Milan, Italy
Neurology Associates, PC
🇺🇸Lincoln, Nebraska, United States
The University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States
University of Florida Jacksonville
🇺🇸Jacksonville, Florida, United States
Washington University School of Medicine - Center for Advance Medicine
🇺🇸Saint Louis, Missouri, United States
Texas Neurology, P.A.
🇺🇸Dallas, Texas, United States