Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS (REFALS)

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.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Levosimendan; Drug: Placebo for levosimendan

• Study Type: Interventional
• Enrollment (Actual): 496
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 116 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Placebo for ODM-109

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Supine Slow Vital Capacity (SVC)	Change from baseline to 12 weeks, expressed as % of predicted normal.	The change from baseline at 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Combined Assessment of Function and Survival Through 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.	Mean rank at 48 weeks
Time to Respiratory 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.	Time to event through 48 weeks
Change From the Baseline in Clinical Global Impression CGI 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.	The change from baseline at 48 weeks
Change From Baseline in Respiratory Function of ALSFRS-R 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.	Slope of decline at 48 weeks
Supine Borg Category Ratio 10 Scale 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.	Change from baseline at 12 weeks

Collaborators and Investigators

• Sponsor: Orion Corporation, Orion Pharma
• Investigators: Study Director: Merja Mäkitalo, CSD, Orion Corporation, Orion Pharma

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2018
• Primary Completion (Actual): July 23, 2020
• Study Completion (Actual): July 23, 2020

Study Registration Dates

• First Submitted: April 16, 2018
• First Submitted That Met QC Criteria: April 16, 2018
• First Posted (Actual): April 20, 2018

Study Record Updates

• Last Update Posted (Actual): May 11, 2022
• Last Update Submitted That Met QC Criteria: April 22, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan
• Other Study ID Numbers: 3119002

Drug and device information, study documents

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