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

NCT ID: NCT03505021

Last Updated: 2022-05-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 496 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-21
• Study Completion Date: 2020-07-23

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.

Conditions

Amyotrophic Lateral Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Levosimendan

Levosimendan 1 mg capsules for oral administration, once to twice a day. The total duration of treatment 48 weeks

Group Type: EXPERIMENTAL

Levosimendan

Intervention Type: DRUG

Levosimendan 1 mg capsule for oral administration

Placebo for levosimendan

Placebo capsule for oral administration, once to twice a day. The total duration of treatment 48 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo for levosimendan

Intervention Type: DRUG

Placebo capsule for oral administration

Interventions

Levosimendan

Levosimendan 1 mg capsule for oral administration

Intervention Type: DRUG

Placebo for levosimendan

Placebo capsule for oral administration

Intervention Type: DRUG

Other Intervention Names

ODM-109; Placebo for ODM-109

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Orion Corporation, Orion Pharma

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Merja Mäkitalo, CSD

Role: STUDY_DIRECTOR

Orion Corporation, Orion Pharma

Locations

Phoenix Neurological Associates

Phoenix, Arizona, United States

Neuromuscular Research Center and Neuromuscular Clinic of Arizona

Phoenix, Arizona, United States

University of California San Diego

La Jolla, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

University of California Irvine

Orange, California, United States

California Pacific Medical Center

San Francisco, California, United States

Colorado Springs Neurological Associates

Colorado Springs, Colorado, United States

Hospital for Special Care

New Britain, Connecticut, United States

Georgetown University

Washington D.C., District of Columbia, United States

The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion

Washington D.C., District of Columbia, United States

Providence Holy Cross Medical Center

Fort Lauderdale, Florida, United States

University of Florida

Gainesville, Florida, United States

University of Florida Health - Jacksonville

Jacksonville, Florida, United States

Mayo Clinic - Jacksonville

Jacksonville, Florida, United States

University of South Florida

Tampa, Florida, United States

Emory University School of Medicine

Atlanta, Georgia, United States

Augusta University

Augusta, Georgia, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

University of Chicago

Chicago, Illinois, United States

University of Kentucky Chandler Medical Center

Lexington, Kentucky, United States

Kentucky Neuroscience Research

Louisville, Kentucky, United States

The Johns Hopkins Hospital

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Mayo Clinic - Rochester

Rochester, Minnesota, United States

HealthPartners Specialty Center

Saint Paul, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Neurology Associates

Lincoln, Nebraska, United States

Mount Sinai Beth Israel

New York, New York, United States

Hospital for Special Surgery

New York, New York, United States

Columbia Presbyterian Hospital

New York, New York, United States

Neurosciences Institute - Neurology Charlotte

Charlotte, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, United States

The Ohio State University

Columbus, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Providence Brain and Spine Institute

Portland, Oregon, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Temple University School of Medicine

Philadelphia, Pennsylvania, United States

Allegheny General Hospital

Pittsburgh, Pennsylvania, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Texas Neurology

Dallas, Texas, United States

Nerve and Muscle Center of Texas

Houston, Texas, United States

University of Utah - Imaging & Neurosciences Center

Salt Lake City, Utah, United States

University of Vermont Medical Center

Burlington, Vermont, United States

Swedish Neuroscience Institute

Seattle, Washington, United States

University of Washington Medical Center

Seattle, Washington, United States

Froedtert Hospital

Milwaukee, Wisconsin, United States

Brain and Mind Centre

Camperdown, New South Wales, Australia

Royal Brisbane and Women's Hospital

Brisbane, Queensland, Australia

Flinders Medical Centre

Bedford Park, South Australia, Australia

Calvary Health Care Bethlehem

Caulfield South, Victoria, Australia

Perron Institute for Neurological and Translational Science

Murdoch, Western Australia, Australia

Universität Innsbruck

Innsbruck, Tyrol, Austria

Salzkammergut-Klinikum Vöcklabruck

Vöcklabruck, Upper Austria, Austria

Medizinische Universität Wien

Vienna, , Austria

Universitaire Ziekenhuis Leuven

Leuven, Flemish Brabant, Belgium

Centre Hospitalier Régional de la Citadelle

Liège, Liege, Belgium

Algemeen Ziekenhuis St. Lucas Gent

Ghent, Oost-Vlaanderen, Belgium

Alberta Health Services - Neuromuscular Clinic

Calgary, Alberta, Canada

University of Alberta

Edmonton, Alberta, Canada

Stan Cassidy Centre for Rehabilitation

Fredericton, New Brunswick, Canada

Moncton Hospital, Southeast Regional Health Authority

Moncton, New Brunswick, Canada

McMaster University Medical Centre

Hamilton, Ontario, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame

Montreal, Quebec, Canada

Montreal Neurological Institute and Hospital

Montreal, Quebec, Canada

Centre Hospitalier Affilie Universitaire de Quebec

Québec, Quebec, Canada

Neurologian Poliklinikka - Meilahden Tornisairaala 3

Helsinki, , Finland

Etelä-Karjalan keskussairaala

Lappeenranta, , Finland

Turku University Hospital

Turku, , Finland

Centre Hospitalier Universitaire de Limoges

Limoges, , France

Hôpital Gui de Chauliac

Montpellier, , France

Hôpital Pasteur

Nice, , France

Centre Hospitalier Régional et Universitaire de Tours Hôpital Bretonneau

Tours, , France

Universitätsklinikum Ulm

Ulm, Baden-Wurttemberg, Germany

Deutsche Klinik für Diagnostik

Wiesbaden, Hesse, Germany

Medizinische Hochschule Hannover

Hanover, Lower Saxony, Germany

Universitätsmedizin Rostock

Rostock, Mecklenburg-western-pommerania, Germany

Alfried Krupp Krankenhaus Rüttenscheid

Essen, North Rhine-Westphalia, Germany

Universitätsklinikum Münster

Münster, North Rhine-Westphalia, Germany

Universitätsklinikum Carl Gustav Carus

Dresden, Saxony, Germany

Universitätsklinikum Jena

Jena, Thuringia, Germany

Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum

Berlin, , Germany

Beaumont Hospital - Ireland

Dublin, , Ireland

Azienda Ospedaliera Universitaria San Martino

Genova, , Italy

Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara

Novara, , Italy

ICS Maugeri Spa SB

Pavia, , Italy

Azienda Ospedaliero-Universitaria Pisana Ospedale Santa Chiara

Pisa, , Italy

Policlinico Umberto I di Roma

Roma, , Italy

Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino

Torino, , Italy

Academisch Medisch Centrum

Amsterdam, North Holland, Netherlands

Universitair Medisch Centrum Utrecht - Rudolf Magnus Instituut voor Neurowetenschappen

Utrecht, , Netherlands

Hospital de Basurto

Bilbao, Vizcaya, Spain

Hospital Universitari de Bellvitge

Barcelona, , Spain

Hospital Universitario Reina Sofia

Córdoba, , Spain

Hospital San Rafael - Madrid

Madrid, , Spain

Hospital Universitario y Politécnico de La Fe

Valencia, , Spain

Norrlands Universitetssjukhus

Umeå, Västerbotten County, Sweden

Centralsjukhuset Karlstad

Karlstad, , Sweden

Karolinska Universitetssjukhuset

Stockholm, , Sweden

Barts Health NHS Trust

London, England, United Kingdom

King's College Hospital NHS Foundation Trust

London, England, United Kingdom

The Walton Centre NHS Foundation Trust

Liverpool, , United Kingdom

Countries

United States; Australia; Austria; Belgium; Canada; Finland; France; Germany; Ireland; Italy; Netherlands; Spain; Sweden; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 34536404 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

3119002

Identifier Type: -

Identifier Source: org_study_id