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Trial record 1 of 2 for:    NCT03505021 | ALS
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Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS (REFALS)

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ClinicalTrials.gov Identifier: NCT03505021
Recruitment Status : Completed
First Posted : April 20, 2018
Results First Posted : August 31, 2021
Last Update Posted : May 11, 2022
Information provided by (Responsible Party):
Orion Corporation, Orion Pharma

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.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: Levosimendan Drug: Placebo for levosimendan Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 496 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
Actual Study Start Date : June 21, 2018
Actual Primary Completion Date : July 23, 2020
Actual Study Completion Date : July 23, 2020

Arm Intervention/treatment
Experimental: Levosimendan
Levosimendan 1 mg capsules for oral administration, once to twice a day. The total duration of treatment 48 weeks
Drug: Levosimendan
Levosimendan 1 mg capsule for oral administration
Other Name: ODM-109

Placebo Comparator: Placebo for levosimendan
Placebo capsule for oral administration, once to twice a day. The total duration of treatment 48 weeks.
Drug: Placebo for levosimendan
Placebo capsule for oral administration
Other Name: Placebo for ODM-109

Primary Outcome Measures :
  1. Supine Slow Vital Capacity (SVC) [ Time Frame: The change from baseline at 12 weeks ]
    Change from baseline to 12 weeks, expressed as % of predicted normal.

Secondary Outcome Measures :
  1. Combined Assessment of Function and Survival Through 48 Weeks [ Time Frame: Mean rank at 48 weeks ]
    Scale: The ALS Functional Rating Scale - Revised. This scale includes 12 items. Each item was scored from 0 to 4. Total score is the sum of the scores of all 12 items. Each subject is ranked according to time-to-death (earlier deaths ranked lower than later deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than after deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than less worsening or an improvement in ALSFRS-R). The ranked scores range from 001 to 496 (the number of participants assessed for the Outcome Measure) with larger rank score numbers associated with a better outcome.

  2. Time to Respiratory Event Through 48 Weeks [ Time Frame: Time to event through 48 weeks ]
    ALSFRS-R scale contains 3 items that relate to respiratory function: severity of dyspnoea, occurrence of orthopnoea (shortness of breath when lying flat) and the use of mechanical ventilation for respiratory insufficiency. A reduction in any one of these items was considered a respiratory event. Not all patients receive ventilatory support, despite respiratory insufficiency: meeting "protocolised" criteria for NIV relates to patients without NIV whose slow vital capacity declined to a level that would ordinarily trigger such treatment.

  3. Change From the Baseline in Clinical Global Impression CGI at 48 Weeks [ Time Frame: The change from baseline at 48 weeks ]
    Visual Analogue Scale 0-100 millimeters, rated by study subjects. Score 0 indicates that the subject is completely well without any disability and score 100 indicates the worst possible severity of the condition.

  4. Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks [ Time Frame: Slope of decline at 48 weeks ]
    ALSFRS-R scale contains 3 items that relate to respiratory function: severity of dyspnoea, occurrence of orthopnoea (shortness of breath when lying flat) and the use of mechanical ventilation for respiratory insufficiency. These are added together to created the respiratory domain with a score range 0-12 (where 12 represents normal function). Although individual items and patients vary, ALSFRS-R typically declines at a relatively constant rate over time. Plotted over time the slope of the line obtained indicates the speed of progression and thus an effective treatment might be expected to reduce the slope of decline.

  5. Supine Borg Category Ratio 10 Scale at 12 Weeks [ Time Frame: Change from baseline at 12 weeks ]
    Patients rated their perception of the severity of their dysnoea using the Borg scale. The scale ranges from 0 (no dyspnoea) to 10 (maximal). Each category is numbered and most (not all) have verbal cues. At each assessment the patient scored the category they felt best described their symptoms. The analysis measured change from baseline at 12 weeks, where a negative score indicates improvement and a positive score reflects worsening.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • History of life-threatening ventricular arrhythmia, unless treated with reliable measures to prevent recurrence (e.g. with placement of implantable cardioverter defibrillator [ICD] or catheter ablation)
  • History of second or third degree atrioventricular (AV) block or sinus node disease at screening, if not treated with pacemaker
  • HR repeatedly > 100 bpm in the 12-lead ECG after a 5-minute rest at screening. If the HR is > 100 bpm in the first recording, then the second recording must be done after another 5 min rest to confirm HR > 100 bpm
  • Systolic blood pressure (SBP) < 90 mmHg at screening
  • Potassium < 3.7 mmol/l or > 5.5 mmol/l at screening
  • Severe renal impairment (creatinine clearance < 30 ml/min at screening), creatinine > 170 μmol/l at screening or on dialysis
  • Blood haemoglobin < 10 g/dl at screening or blood donation or loss of significant amount of blood within 60 days before the screening visit
  • Clinically significant hepatic impairment at the discretion of the investigator
  • Body mass index (BMI) ≤ 18.5kg/m2 (BMI = weight/height2)
  • Women who are lactating or of reproductive age without a negative pregnancy test and without a commitment to using a highly effective method of contraception (e.g. oral hormonal contraceptives associated with inhibition of ovulation, intrauterine devices and long acting progestin agents), if sexually active during the study, and for 1 month after the last dose of the study treatment. Women who are postmenopausal (1 year since last menstrual cycle), surgically sterilised or who have undergone a hysterectomy are considered not to be reproductive and can be included
  • Patient judged to be actively suicidal by the investigator during 3 months before the screening visit
  • Patients with known history of human immunodeficiency virus (HIV) infection
  • Any other clinically significant cardiovascular, gastrointestinal, hepatic, renal, neurological or psychiatric disorder or any other major concurrent illness that in the opinion of the investigator could interfere with the interpretation of the study results or constitute a health risk for the subject if he/she took part in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03505021

Hide Hide 104 study locations
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United States, Arizona
Phoenix Neurological Associates
Phoenix, Arizona, United States, 85006
Neuromuscular Research Center and Neuromuscular Clinic of Arizona
Phoenix, Arizona, United States, 85028
United States, California
University of California San Diego
La Jolla, California, United States, 92037-0886
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
University of California Irvine
Orange, California, United States, 92868
California Pacific Medical Center
San Francisco, California, United States, 94115
United States, Colorado
Colorado Springs Neurological Associates
Colorado Springs, Colorado, United States, 80907
United States, Connecticut
Hospital for Special Care
New Britain, Connecticut, United States, 06053
United States, District of Columbia
Georgetown University
Washington, District of Columbia, United States, 20007
The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion
Washington, District of Columbia, United States, 20037
United States, Florida
Providence Holy Cross Medical Center
Fort Lauderdale, Florida, United States, 33308
University of Florida
Gainesville, Florida, United States, 32611
University of Florida Health - Jacksonville
Jacksonville, Florida, United States, 32209
Mayo Clinic - Jacksonville
Jacksonville, Florida, United States, 32224
University of South Florida
Tampa, Florida, United States, 33612
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
Augusta University
Augusta, Georgia, United States, 30912
United States, Illinois
Northwestern University Feinberg School of Medicine
Chicago, Illinois, United States, 60611
University of Chicago
Chicago, Illinois, United States, 60637
United States, Kentucky
University of Kentucky Chandler Medical Center
Lexington, Kentucky, United States, 40536
Kentucky Neuroscience Research
Louisville, Kentucky, United States, 40202
United States, Maryland
The Johns Hopkins Hospital
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 49007
United States, Minnesota
Mayo Clinic - Rochester
Rochester, Minnesota, United States, 55905
HealthPartners Specialty Center
Saint Paul, Minnesota, United States, 55130-5302
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, Nebraska
Neurology Associates
Lincoln, Nebraska, United States, 68506
United States, New York
Mount Sinai Beth Israel
New York, New York, United States, 10003
Hospital for Special Surgery
New York, New York, United States, 10021
Columbia Presbyterian Hospital
New York, New York, United States, 10032
United States, North Carolina
Neurosciences Institute - Neurology Charlotte
Charlotte, North Carolina, United States, 28207
Duke University Medical Center
Durham, North Carolina, United States, 27705
Wake Forest University Baptist Medical Center
Winston-Salem, North Carolina, United States, 27157-1023
United States, Ohio
The Ohio State University
Columbus, Ohio, United States, 43210
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97201-3098
Providence Brain and Spine Institute
Portland, Oregon, United States, 97213
United States, Pennsylvania
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19107
Temple University School of Medicine
Philadelphia, Pennsylvania, United States, 19140
Allegheny General Hospital
Pittsburgh, Pennsylvania, United States, 15212
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
United States, Texas
Texas Neurology
Dallas, Texas, United States, 75214
Nerve and Muscle Center of Texas
Houston, Texas, United States, 77030
United States, Utah
University of Utah - Imaging & Neurosciences Center
Salt Lake City, Utah, United States, 84108
United States, Vermont
University of Vermont Medical Center
Burlington, Vermont, United States, 05401
United States, Washington
Swedish Neuroscience Institute
Seattle, Washington, United States, 98122
University of Washington Medical Center
Seattle, Washington, United States, 98195
United States, Wisconsin
Froedtert Hospital
Milwaukee, Wisconsin, United States, 53226
Australia, New South Wales
Brain and Mind Centre
Camperdown, New South Wales, Australia, 2050
Australia, Queensland
Royal Brisbane and Women's Hospital
Brisbane, Queensland, Australia, 4029
Australia, South Australia
Flinders Medical Centre
Bedford Park, South Australia, Australia, 5042
Australia, Victoria
Calvary Health Care Bethlehem
Caulfield South, Victoria, Australia, 3162
Australia, Western Australia
Perron Institute for Neurological and Translational Science
Murdoch, Western Australia, Australia, 6150
Universität Innsbruck
Innsbruck, Tyrol, Austria, 6020
Salzkammergut-Klinikum Vöcklabruck
Vöcklabruck, Upper Austria, Austria, 4840
Medizinische Universität Wien
Wien, Austria, 1090
Universitaire Ziekenhuis Leuven
Leuven, Flemish Brabant, Belgium, 3000
Centre Hospitalier Régional de la Citadelle
Liège, Liege, Belgium, 4000
Algemeen Ziekenhuis St. Lucas Gent
Gent, Oost-Vlaanderen, Belgium, 9000
Canada, Alberta
Alberta Health Services - Neuromuscular Clinic
Calgary, Alberta, Canada, T3M 1M4
University of Alberta
Edmonton, Alberta, Canada, T6G 2G3
Canada, New Brunswick
Stan Cassidy Centre for Rehabilitation
Fredericton, New Brunswick, Canada, E3B 0C7
Moncton Hospital, Southeast Regional Health Authority
Moncton, New Brunswick, Canada, E1C 2Z3
Canada, Ontario
McMaster University Medical Centre
Hamilton, Ontario, Canada, L8N 3Z5
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada, M4N 3M5
Canada, Quebec
Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame
Montréal, Quebec, Canada, H2L 4M1
Montreal Neurological Institute and Hospital
Montréal, Quebec, Canada, H3A 2B4
Centre Hospitalier Affilie Universitaire de Quebec
Québec, Quebec, Canada, G1J 1Z4
Neurologian Poliklinikka - Meilahden Tornisairaala 3
Helsinki, Finland, 00029
Etelä-Karjalan keskussairaala
Lappeenranta, Finland, 53130
Turku University Hospital
Turku, Finland, 20521
Centre Hospitalier Universitaire de Limoges
Limoges, France, 87042
Hôpital Gui de Chauliac
Montpellier, France, 34295
Hôpital Pasteur
Nice, France, 06202
Centre Hospitalier Régional et Universitaire de Tours Hôpital Bretonneau
Tours, France, 37044
Universitätsklinikum Ulm
Ulm, Baden-Württemberg, Germany, 89081
Deutsche Klinik für Diagnostik
Wiesbaden, Hessen, Germany, 65191
Universitätsmedizin Rostock
Rostock, Mecklenburg-western-pommerania, Germany, 18147
Medizinische Hochschule Hannover
Hannover, Niedersachsen, Germany, 30625
Alfried Krupp Krankenhaus Rüttenscheid
Essen, Nordrhein-westfalen, Germany, 45131
Universitätsklinikum Münster
Münster, Nordrhein-Westfalen, Germany, 48149
Universitätsklinikum Carl Gustav Carus
Dresden, Sachsen, Germany, 01307
Universitätsklinikum Jena
Jena, Thuringen, Germany, 07747
Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum
Berlin, Germany, 13353
Beaumont Hospital - Ireland
Dublin, Ireland, 9
Azienda Ospedaliera Universitaria San Martino
Genova, Italy, 16132
Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara
Novara, Italy, 28100
ICS Maugeri Spa SB
Pavia, Italy, 27100
Azienda Ospedaliero-Universitaria Pisana Ospedale Santa Chiara
Pisa, Italy, 56126
Policlinico Umberto I di Roma
Roma, Italy, 0016
Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino
Torino, Italy, 10126
Academisch Medisch Centrum
Amsterdam, Noord-Holland, Netherlands, 1105 AZ
Universitair Medisch Centrum Utrecht - Rudolf Magnus Instituut voor Neurowetenschappen
Utrecht, Netherlands, 3584 CG
Hospital de Basurto
Bilbao, Vizcaya, Spain, 48013
Hospital Universitari de Bellvitge
Barcelona, Spain, 08207
Hospital Universitario Reina Sofia
Córdoba, Spain, 14011
Hospital San Rafael - Madrid
Madrid, Spain, 28016
Hospital Universitario y Politécnico de La Fe
Valencia, Spain, 46026
Norrlands Universitetssjukhus
Umeå, Vasterbotten, Sweden, 90737
Centralsjukhuset Karlstad
Karlstad, Sweden, 651 85
Karolinska Universitetssjukhuset
Stockholm, Sweden, 14186
United Kingdom
Barts Health NHS Trust
London, England, United Kingdom, E1 1BB
King's College Hospital NHS Foundation Trust
London, England, United Kingdom, SE5 9RS
The Walton Centre NHS Foundation Trust
Liverpool, United Kingdom, L9 7LJ
Sponsors and Collaborators
Orion Corporation, Orion Pharma
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Study Director: Merja Mäkitalo, CSD Orion Corporation, Orion Pharma
  Study Documents (Full-Text)

Documents provided by Orion Corporation, Orion Pharma:
Study Protocol  [PDF] March 26, 2020
Statistical Analysis Plan  [PDF] June 18, 2020

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Orion Corporation, Orion Pharma
ClinicalTrials.gov Identifier: NCT03505021    
Other Study ID Numbers: 3119002
First Posted: April 20, 2018    Key Record Dates
Results First Posted: August 31, 2021
Last Update Posted: May 11, 2022
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Amyotrophic Lateral Sclerosis
Motor Neuron Disease
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Cardiotonic Agents
Vasodilator Agents
Phosphodiesterase 3 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs