Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
- Conditions
- Amyotrophic Lateral Sclerosis
- Interventions
- Registration Number
- NCT03505021
- Lead Sponsor
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 496
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo for levosimendan Placebo for levosimendan Placebo capsule for oral administration, once to twice a day. The total duration of treatment 48 weeks. Levosimendan Levosimendan Levosimendan 1 mg capsules for oral administration, once to twice a day. The total duration of treatment 48 weeks
- Primary Outcome Measures
Name Time Method Supine Slow Vital Capacity (SVC) The change from baseline at 12 weeks Change from baseline to 12 weeks, expressed as % of predicted normal.
- Secondary Outcome Measures
Name Time Method Time to Respiratory Event Through 48 Weeks 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.
Change From the Baseline in Clinical Global Impression CGI at 48 Weeks 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.
Supine Borg Category Ratio 10 Scale at 12 Weeks 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.
Combined Assessment of Function and Survival Through 48 Weeks 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.
Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks 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.
Trial Locations
- Locations (104)
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Moncton Hospital, Southeast Regional Health Authority
🇨🇦Moncton, New Brunswick, Canada
Hospital for Special Care
🇺🇸New Britain, Connecticut, United States
Georgetown University
🇺🇸Washington, District of Columbia, United States
University of Florida
🇺🇸Gainesville, Florida, United States
Augusta University
🇺🇸Augusta, Georgia, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion
🇺🇸Washington, District of Columbia, United States
University of Florida Health - Jacksonville
🇺🇸Jacksonville, Florida, United States
Mayo Clinic - Jacksonville
🇺🇸Jacksonville, Florida, United States
The Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
Royal Brisbane and Women's Hospital
🇦🇺Brisbane, Queensland, Australia
Calvary Health Care Bethlehem
🇦🇺Caulfield South, Victoria, Australia
Centre Hospitalier Régional de la Citadelle
🇧🇪Liège, Liege, Belgium
Flinders Medical Centre
🇦🇺Bedford Park, South Australia, Australia
Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame
🇨🇦Montréal, Quebec, Canada
Centre Hospitalier Universitaire de Limoges
🇫🇷Limoges, France
Salzkammergut-Klinikum Vöcklabruck
🇦🇹Vöcklabruck, Upper Austria, Austria
Medizinische Universität Wien
🇦🇹Wien, Austria
Universitaire Ziekenhuis Leuven
🇧🇪Leuven, Flemish Brabant, Belgium
Stan Cassidy Centre for Rehabilitation
🇨🇦Fredericton, New Brunswick, Canada
University of Alberta
🇨🇦Edmonton, Alberta, Canada
Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum
🇩🇪Berlin, Germany
Algemeen Ziekenhuis St. Lucas Gent
🇧🇪Gent, Oost-Vlaanderen, Belgium
Centre Hospitalier Affilie Universitaire de Quebec
🇨🇦Québec, Quebec, Canada
McMaster University Medical Centre
🇨🇦Hamilton, Ontario, Canada
Centre Hospitalier Régional et Universitaire de Tours Hôpital Bretonneau
🇫🇷Tours, France
Medizinische Hochschule Hannover
🇩🇪Hannover, Niedersachsen, Germany
Hôpital Pasteur
🇫🇷Nice, France
Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara
🇮🇹Novara, Italy
ICS Maugeri Spa SB
🇮🇹Pavia, Italy
Universitätsmedizin Rostock
🇩🇪Rostock, Mecklenburg-western-pommerania, Germany
Alfried Krupp Krankenhaus Rüttenscheid
🇩🇪Essen, Nordrhein-westfalen, Germany
Universitätsklinikum Jena
🇩🇪Jena, Thuringen, Germany
Azienda Ospedaliero-Universitaria Pisana Ospedale Santa Chiara
🇮🇹Pisa, Italy
Policlinico Umberto I di Roma
🇮🇹Roma, Italy
Academisch Medisch Centrum
🇳🇱Amsterdam, Noord-Holland, Netherlands
Universitair Medisch Centrum Utrecht - Rudolf Magnus Instituut voor Neurowetenschappen
🇳🇱Utrecht, Netherlands
Centralsjukhuset Karlstad
🇸🇪Karlstad, Sweden
King's College Hospital NHS Foundation Trust
🇬🇧London, England, United Kingdom
University of Chicago
🇺🇸Chicago, Illinois, United States
University of California Irvine
🇺🇸Orange, California, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Emory University School of Medicine
🇺🇸Atlanta, Georgia, United States
Columbia Presbyterian Hospital
🇺🇸New York, New York, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Nerve and Muscle Center of Texas
🇺🇸Houston, Texas, United States
University of California San Diego
🇺🇸La Jolla, California, United States
Brain and Mind Centre
🇦🇺Camperdown, New South Wales, Australia
Hospital Universitario y Politécnico de La Fe
🇪🇸Valencia, Spain
Hospital Universitario Reina Sofia
🇪🇸Córdoba, Spain
Hospital Universitari de Bellvitge
🇪🇸Barcelona, Spain
Norrlands Universitetssjukhus
🇸🇪Umeå, Vasterbotten, Sweden
Hospital San Rafael - Madrid
🇪🇸Madrid, Spain
Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
Hospital de Basurto
🇪🇸Bilbao, Vizcaya, Spain
Alberta Health Services - Neuromuscular Clinic
🇨🇦Calgary, Alberta, Canada
Montreal Neurological Institute and Hospital
🇨🇦Montréal, Quebec, Canada
Temple University School of Medicine
🇺🇸Philadelphia, Pennsylvania, United States
Texas Neurology
🇺🇸Dallas, Texas, United States
Etelä-Karjalan keskussairaala
🇫🇮Lappeenranta, Finland
Turku University Hospital
🇫🇮Turku, Finland
Deutsche Klinik für Diagnostik
🇩🇪Wiesbaden, Hessen, Germany
Karolinska Universitetssjukhuset
🇸🇪Stockholm, Sweden
Neurologian Poliklinikka - Meilahden Tornisairaala 3
🇫🇮Helsinki, Finland
Hôpital Gui de Chauliac
🇫🇷Montpellier, France
Universitätsklinikum Carl Gustav Carus
🇩🇪Dresden, Sachsen, Germany
Beaumont Hospital - Ireland
🇮🇪Dublin, Ireland
Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino
🇮🇹Torino, Italy
University of Kentucky Chandler Medical Center
🇺🇸Lexington, Kentucky, United States
Hospital for Special Surgery
🇺🇸New York, New York, United States
California Pacific Medical Center
🇺🇸San Francisco, California, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
University of Utah - Imaging & Neurosciences Center
🇺🇸Salt Lake City, Utah, United States
HealthPartners Specialty Center
🇺🇸Saint Paul, Minnesota, United States
Perron Institute for Neurological and Translational Science
🇦🇺Murdoch, Western Australia, Australia
The Ohio State University
🇺🇸Columbus, Ohio, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Barts Health NHS Trust
🇬🇧London, England, United Kingdom
Phoenix Neurological Associates
🇺🇸Phoenix, Arizona, United States
Neuromuscular Research Center and Neuromuscular Clinic of Arizona
🇺🇸Phoenix, Arizona, United States
Mayo Clinic - Rochester
🇺🇸Rochester, Minnesota, United States
Providence Brain and Spine Institute
🇺🇸Portland, Oregon, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Froedtert Hospital
🇺🇸Milwaukee, Wisconsin, United States
University of South Florida
🇺🇸Tampa, Florida, United States
Kentucky Neuroscience Research
🇺🇸Louisville, Kentucky, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Wake Forest University Baptist Medical Center
🇺🇸Winston-Salem, North Carolina, United States
Providence Holy Cross Medical Center
🇺🇸Fort Lauderdale, Florida, United States
Northwestern University Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
Mount Sinai Beth Israel
🇺🇸New York, New York, United States
Neurology Associates
🇺🇸Lincoln, Nebraska, United States
Neurosciences Institute - Neurology Charlotte
🇺🇸Charlotte, North Carolina, United States
Swedish Neuroscience Institute
🇺🇸Seattle, Washington, United States
University of Vermont Medical Center
🇺🇸Burlington, Vermont, United States
Universitätsklinikum Münster
🇩🇪Münster, Nordrhein-Westfalen, Germany
Universitätsklinikum Ulm
🇩🇪Ulm, Baden-Württemberg, Germany
Azienda Ospedaliera Universitaria San Martino
🇮🇹Genova, Italy
The Walton Centre NHS Foundation Trust
🇬🇧Liverpool, United Kingdom
Colorado Springs Neurological Associates
🇺🇸Colorado Springs, Colorado, United States
Universität Innsbruck
🇦🇹Innsbruck, Tyrol, Austria