Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
REFALS
1 other identifier
interventional
496
13 countries
101
Brief Summary
This study will evaluate whether prolonged oral levosimendan can preserve respiratory function more effectively than placebo, resulting in better patient functionality as measured by the ALSFRS-R scale. In this randomized, double-blind, placebo-controlled, parallel-group, multicenter study, subjects are allocated in a 2:1 ratio to receive either levosimendan (1 -2 mg daily) or placebo for 48 weeks. The primary endpoint is slow vital capacity (SVC) at 12 weeks, with the impact on patient function assessed through 48 weeks, adjusted for patient outcome, using ALSFRS-R (combined assessment of function and survival, CAFS). Other important efficacy measures include time to respiratory events, clinical global impression (CGI), assessment of dyspnea using the Borg scale and sleep scales (Pittsburgh sleep quality index and Epworth sleepiness scale). Patient safety is monitored using conventional methods including adverse events, safety laboratory tests, vital signs and 12-lead EKG. Following screening and baseline visits, patients attend the clinic at 2, 4, 8, 12, 24, 36 and 48 weeks, with telephone assessments conducted at weeks 18, 30 and 42. An end of study visit is performed 14-25 days after the last study treatment administration. The study will be monitored by an independent data and safety monitoring board. A long-term extension study will be available for patients completing the study.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Jun 2018
101 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 16, 2018
CompletedFirst Posted
Study publicly available on registry
April 20, 2018
CompletedStudy Start
First participant enrolled
June 21, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
July 23, 2020
CompletedStudy Completion
Last participant's last visit for all outcomes
July 23, 2020
CompletedResults Posted
Study results publicly available
August 31, 2021
CompletedMay 11, 2022
April 1, 2022
2.1 years
April 16, 2018
July 1, 2021
April 22, 2022
Conditions
Outcome Measures
Primary Outcomes (1)
Supine Slow Vital Capacity (SVC)
Change from baseline to 12 weeks, expressed as % of predicted normal.
The change from baseline at 12 weeks
Secondary Outcomes (5)
Combined Assessment of Function and Survival Through 48 Weeks
Mean rank at 48 weeks
Time to Respiratory Event Through 48 Weeks
Time to event through 48 weeks
Change From the Baseline in Clinical Global Impression CGI at 48 Weeks
The change from baseline at 48 weeks
Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks
Slope of decline at 48 weeks
Supine Borg Category Ratio 10 Scale at 12 Weeks
Change from baseline at 12 weeks
Study Arms (2)
Levosimendan
EXPERIMENTALLevosimendan 1 mg capsules for oral administration, once to twice a day. The total duration of treatment 48 weeks
Placebo for levosimendan
PLACEBO COMPARATORPlacebo capsule for oral administration, once to twice a day. The total duration of treatment 48 weeks.
Interventions
Placebo capsule for oral administration
Eligibility Criteria
You may qualify if:
- Written or verbal informed consent (IC) for participation in the study
- Male or female subjects with diagnosis of laboratory supported probable, probable or definite ALS according to El Escorial revised criteria. Full electromyogram (EMG) report available consistent with ALS (but not necessarily fulfilling the electrodiagnostic criteria for ALS) from an experienced neurophysiologist
- Able to swallow study treatment capsules, and in the opinion of the investigator, is expected to continue to do so during the study
- Sitting SVC between 60-90% of the predicted value for age, height and sex at screening visit
- Disease duration from symptom onset (defined by first muscle weakness or dysarthria) 12-48 months at the time of visit 1 (baseline)
- Able to perform supine SVC in an adequate and reliable way at screening and baseline visits as judged by the investigator
- Subjects with or without riluzole and/or edaravone. If using riluzole (any daily dose up to 100 mg), the dose must have been stable for at least 4 weeks before the screening visit and should not be changed during the study. If using edaravone, the treatment should have been started at least 4 weeks before the screening visit (at least one 28-day treatment cycle as indicated) and should not be changed during the study. If not on riluzole and/or edaravone, the respective treatments should not be started during the study
You may not qualify if:
- Subject in whom other causes of neuromuscular weakness have not been excluded
- Subject with a diagnosis of another neurodegenerative disease (e.g. Parkinson's or Alzheimer's disease)
- Assisted ventilation of any type within 3 months before the screening visit or at screening
- Any use of a diaphragm pacing system (DPS) within 3 months before the screening visit
- Any form of stem cell or gene therapy for the treatment of ALS
- Known hypersensitivity to levosimendan
- Administration of levosimendan within 3 months before the screening visit or previous participation in the present phase III study or earlier study with oral levosimendan in ALS patients (LEVALS)
- Any use of tirasemtiv or reldesemtiv within 1 month before the screening visit.
- Participation in a clinical trial with any experimental treatment within 30 days or within 5 half-lives of that treatment (whichever is longer) before the screening visit
- Any botulinum toxin use within 3 months before the screening visit
- Recorded diagnosis or evidence of major psychiatric diagnosis, significant cognitive impairment or clinically evident dementia that may interfere with the patient's ability to comply with study procedures
- Pulmonary illness (e.g. asthma or COPD) requiring regular treatment
- Haemodynamically significant uncorrected valve disease or hypertrophic cardiomyopathy or restrictive cardiomyopathy
- Any cardiovascular event (e.g. myocardial infarction, HF, arrhythmia or stroke) requiring hospitalisation within 3 months before the screening visit
- History of Torsades de Pointes (TdP) or diagnosed long QT-syndrome
- +13 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (104)
Phoenix Neurological Associates
Phoenix, Arizona, 85006, United States
Neuromuscular Research Center and Neuromuscular Clinic of Arizona
Phoenix, Arizona, 85028, United States
University of California San Diego
La Jolla, California, 92037-0886, United States
Cedars-Sinai Medical Center
Los Angeles, California, 90048, United States
University of California Irvine
Orange, California, 92868, United States
California Pacific Medical Center
San Francisco, California, 94115, United States
Colorado Springs Neurological Associates
Colorado Springs, Colorado, 80907, United States
Hospital for Special Care
New Britain, Connecticut, 06053, United States
Georgetown University
Washington D.C., District of Columbia, 20007, United States
The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion
Washington D.C., District of Columbia, 20037, United States
Providence Holy Cross Medical Center
Fort Lauderdale, Florida, 33308, United States
University of Florida
Gainesville, Florida, 32611, United States
University of Florida Health - Jacksonville
Jacksonville, Florida, 32209, United States
Mayo Clinic - Jacksonville
Jacksonville, Florida, 32224, United States
University of South Florida
Tampa, Florida, 33612, United States
Emory University School of Medicine
Atlanta, Georgia, 30322, United States
Augusta University
Augusta, Georgia, 30912, United States
Northwestern University Feinberg School of Medicine
Chicago, Illinois, 60611, United States
University of Chicago
Chicago, Illinois, 60637, United States
University of Kentucky Chandler Medical Center
Lexington, Kentucky, 40536, United States
Kentucky Neuroscience Research
Louisville, Kentucky, 40202, United States
The Johns Hopkins Hospital
Baltimore, Maryland, 21205, United States
Massachusetts General Hospital
Boston, Massachusetts, 02114, United States
University of Michigan
Ann Arbor, Michigan, 49007, United States
Mayo Clinic - Rochester
Rochester, Minnesota, 55905, United States
HealthPartners Specialty Center
Saint Paul, Minnesota, 55130-5302, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Neurology Associates
Lincoln, Nebraska, 68506, United States
Mount Sinai Beth Israel
New York, New York, 10003, United States
Hospital for Special Surgery
New York, New York, 10021, United States
Columbia Presbyterian Hospital
New York, New York, 10032, United States
Neurosciences Institute - Neurology Charlotte
Charlotte, North Carolina, 28207, United States
Duke University Medical Center
Durham, North Carolina, 27705, United States
Wake Forest University Baptist Medical Center
Winston-Salem, North Carolina, 27157-1023, United States
The Ohio State University
Columbus, Ohio, 43210, United States
Oregon Health and Science University
Portland, Oregon, 97201-3098, United States
Providence Brain and Spine Institute
Portland, Oregon, 97213, United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, 19107, United States
Temple University School of Medicine
Philadelphia, Pennsylvania, 19140, United States
Allegheny General Hospital
Pittsburgh, Pennsylvania, 15212, United States
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15213, United States
Texas Neurology
Dallas, Texas, 75214, United States
Nerve and Muscle Center of Texas
Houston, Texas, 77030, United States
University of Utah - Imaging & Neurosciences Center
Salt Lake City, Utah, 84108, United States
University of Vermont Medical Center
Burlington, Vermont, 05401, United States
Swedish Neuroscience Institute
Seattle, Washington, 98122, United States
University of Washington Medical Center
Seattle, Washington, 98195, United States
Froedtert Hospital
Milwaukee, Wisconsin, 53226, United States
Brain and Mind Centre
Camperdown, New South Wales, 2050, Australia
Royal Brisbane and Women's Hospital
Brisbane, Queensland, 4029, Australia
Flinders Medical Centre
Bedford Park, South Australia, 5042, Australia
Calvary Health Care Bethlehem
Caulfield South, Victoria, 3162, Australia
Perron Institute for Neurological and Translational Science
Murdoch, Western Australia, 6150, Australia
Universität Innsbruck
Innsbruck, Tyrol, 6020, Austria
Salzkammergut-Klinikum Vöcklabruck
Vöcklabruck, Upper Austria, 4840, Austria
Medizinische Universität Wien
Vienna, 1090, Austria
Universitaire Ziekenhuis Leuven
Leuven, Flemish Brabant, 3000, Belgium
Centre Hospitalier Régional de la Citadelle
Liège, Liege, 4000, Belgium
Algemeen Ziekenhuis St. Lucas Gent
Ghent, Oost-Vlaanderen, 9000, Belgium
Alberta Health Services - Neuromuscular Clinic
Calgary, Alberta, T3M 1M4, Canada
University of Alberta
Edmonton, Alberta, T6G 2G3, Canada
Stan Cassidy Centre for Rehabilitation
Fredericton, New Brunswick, E3B 0C7, Canada
Moncton Hospital, Southeast Regional Health Authority
Moncton, New Brunswick, E1C 2Z3, Canada
McMaster University Medical Centre
Hamilton, Ontario, L8N 3Z5, Canada
Sunnybrook Health Sciences Centre
Toronto, Ontario, M4N 3M5, Canada
Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame
Montreal, Quebec, H2L 4M1, Canada
Montreal Neurological Institute and Hospital
Montreal, Quebec, H3A 2B4, Canada
Centre Hospitalier Affilie Universitaire de Quebec
Québec, Quebec, G1J 1Z4, Canada
Neurologian Poliklinikka - Meilahden Tornisairaala 3
Helsinki, 00029, Finland
Etelä-Karjalan keskussairaala
Lappeenranta, 53130, Finland
Turku University Hospital
Turku, 20521, Finland
Centre Hospitalier Universitaire de Limoges
Limoges, 87042, France
Hôpital Gui de Chauliac
Montpellier, 34295, France
Hôpital Pasteur
Nice, 06202, France
Centre Hospitalier Régional et Universitaire de Tours Hôpital Bretonneau
Tours, 37044, France
Universitätsklinikum Ulm
Ulm, Baden-Wurttemberg, 89081, Germany
Deutsche Klinik für Diagnostik
Wiesbaden, Hesse, 65191, Germany
Medizinische Hochschule Hannover
Hanover, Lower Saxony, 30625, Germany
Universitätsmedizin Rostock
Rostock, Mecklenburg-western-pommerania, 18147, Germany
Alfried Krupp Krankenhaus Rüttenscheid
Essen, North Rhine-Westphalia, 45131, Germany
Universitätsklinikum Münster
Münster, North Rhine-Westphalia, 48149, Germany
Universitätsklinikum Carl Gustav Carus
Dresden, Saxony, 01307, Germany
Universitätsklinikum Jena
Jena, Thuringia, 07747, Germany
Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum
Berlin, 13353, Germany
Beaumont Hospital - Ireland
Dublin, 9, Ireland
Azienda Ospedaliera Universitaria San Martino
Genova, 16132, Italy
Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara
Novara, 28100, Italy
ICS Maugeri Spa SB
Pavia, 27100, Italy
Azienda Ospedaliero-Universitaria Pisana Ospedale Santa Chiara
Pisa, 56126, Italy
Policlinico Umberto I di Roma
Roma, 0016, Italy
Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino
Torino, 10126, Italy
Academisch Medisch Centrum
Amsterdam, North Holland, 1105 AZ, Netherlands
Universitair Medisch Centrum Utrecht - Rudolf Magnus Instituut voor Neurowetenschappen
Utrecht, 3584 CG, Netherlands
Hospital de Basurto
Bilbao, Vizcaya, 48013, Spain
Hospital Universitari de Bellvitge
Barcelona, 08207, Spain
Hospital Universitario Reina Sofia
Córdoba, 14011, Spain
Hospital San Rafael - Madrid
Madrid, 28016, Spain
Hospital Universitario y Politécnico de La Fe
Valencia, 46026, Spain
Norrlands Universitetssjukhus
Umeå, Västerbotten County, 90737, Sweden
Centralsjukhuset Karlstad
Karlstad, 651 85, Sweden
Karolinska Universitetssjukhuset
Stockholm, 14186, Sweden
Barts Health NHS Trust
London, England, E1 1BB, United Kingdom
King's College Hospital NHS Foundation Trust
London, England, SE5 9RS, United Kingdom
The Walton Centre NHS Foundation Trust
Liverpool, L9 7LJ, United Kingdom
Related Publications (1)
Cudkowicz M, Genge A, Maragakis N, Petri S, van den Berg L, Aho VV, Sarapohja T, Kuoppamaki M, Garratt C, Al-Chalabi A; REFALS investigators. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2021 Oct;20(10):821-831. doi: 10.1016/S1474-4422(21)00242-8.
PMID: 34536404DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Director, Clinical Operations
- Organization
- Orion Corporation
Study Officials
- STUDY DIRECTOR
Merja Mäkitalo, CSD
Orion Corporation, Orion Pharma
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
April 16, 2018
First Posted
April 20, 2018
Study Start
June 21, 2018
Primary Completion
July 23, 2020
Study Completion
July 23, 2020
Last Updated
May 11, 2022
Results First Posted
August 31, 2021
Record last verified: 2022-04