Effect of Oral Levosimendan (ODM-109) on Respiratory Function in Patients with ALS (REFALS)
The purpose of the study is to evaluate safety and the effectiveness of levosimendan in preserving respiratory function in patients with amyotrophic lateral sclerosis (ALS).
Disease:Amyotrophic Lateral Sclerosis (ALS), Familial ALS, Sporadic ALS
Study Type:Interventional Trial
Study Category:Drug Trial
Study Chair(s)/Principal Investigator(s):
Merit Cudkowicz, MD, Massachusetts General Hospital
Clinicaltrials.gov ID (11 digit #):NCT03505021
Coordinating Center Contact InformationOrion Corporation/Orion Pharma
Turku , Finland
Full Study 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.
Study Sponsor:Orion Corporation, Orion Pharma
Total study duration for each subject will be 51-52 weeks, including the screening period, 48 weeks treatment and an end-of-study visit.
At screening, the visit length will be approximately 2 – 2.5hrs.
For visits 2, 3 and 8, the visit length will be approximately 3 – 5 hrs.
For visits 4 to 7, the visit length will be approximately 2 – 3hrs.
There will also be three telephone contacts made in-between sites visits that should not last longer than 30 minutes.
Depending on location of sites, the study participant may be required to travel.
Estimated Study Start Date:06/21/2018
Estimated Study Completion Date:10/30/2020
Posting Last Modified Date:07/13/2018
Date Study Added to alsconsortium.org:07/06/2018
Time since Symptom Onset:
Time since Diagnosis:
Can participants use Riluzole?Yes
Written or verbal informed consent (IC) for participation in the study
Diagnosis of laboratory supported probable, probable or definite ALS according to El Escorial revised criteria.
Able to swallow study treatment capsules, and in the opinion of the investigator, is expected to continue to do so during the study.
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 (up to 100mg/day, stable at least 4 weeks) and/or edaravone (at least one 28-day treatment cycle completed).
Other causes of neuromuscular weakness not excluded.
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 oral levosimenan trial.
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.
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.
Site Contact Information
Neuromuscular Research Center and Neuromuscular Clinic of Arizona
Phoenix, Arizona 85028
Colorado Springs Neurological Associates
Colorado Springs, Colorado 80907
Hospital of Special Care
New Britain, Connecticut 06053
The George Washington Medical Faculty Associates
Washington, District of Columbia 20037
University of Florida Health - Jacksonville
Jacksonville, Florida 32209
University of South Florida
Tampa, Florida 33612
Holy Cross Hospital
Fort Lauderdale, Florida 33308
Emory University School of Medicine
Atlanta, Georgia 30322
University of Kentucky Chandler Medical Center
Lexington, Kentucky 40536
Massachuesetts General Hospital
Boston, Massachuesetts 02114
Washington University School of Medicine
Saint Louis, Missouri 63110
Lincoln, Nebraska 68506
Providence Brain and Spine Institute
Portland, Oregon 97213
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania 15213
Nerve and Muscle Center of Texas
Houston, Texas 77030
Dallas, Texas 75214
University of Utah
Salt Lake City, Utah 84108
Milwaukee, Wisconsin 53226
Brain and Mind Centre
Perron Institute for Neurological and Translational Science
Calvary Health Care Bethlehem
Caulfield South, 3162
Flinders Medical Centre
Bedford Park, 5042
Universitaire Ziekenhuis Leuven
Algemeen Ziekenhuis St. Lucas Gent
Centre Hospitalier Régional de la Citadelle
Stan Cassidy Centre for Rehabilitation
Fredericton, E3B 0C7
Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame
Montreal, Quebec H2L 4M1
Alberta Health Services - Neuromuscular Clinic
Calgary, Alberta T3M1M4
Montreal Neurological Institute and Hospital
Montreal, Quebec H3A 2B4
University of Alberta
Edmondton, Alberta T6G 2G3
Moncton Hospital, Southeast Regional Health Authority
Moncton, E1C 2Z3
Turku University Hospital
Jena, Thuringen 07747
Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino
Universitair Medisch Centrum Utrecht - Rudolf Magnus Instituut voor Neurowetenschappen
Utrecht, 3584 CG
Academisch Medisch Centrum
Amsterdam, 1105 AZ
Hospital San Rafael - Madrid
Hospital Universitari de Bellvitge
Hospital Universitario y Politécnico de La Fe
Hospital Universitario Reina Sofia
Umeå, 901 85
The Walton Centre NHS Foundation Trust
Liverpool, England L9 7LJ