Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension (REFALS-ES)

Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS: Open-Label Extension for Patients Completing Study 3119002

This study provides an opportunity for subjects in the REFALS (3119002; NCT03505021) study to continue treatment with oral levosimendan. The study will also provide more information about long-term safety and effectiveness of oral levosimendan in patients with ALS.

This is an open-label study, so that all eligible subjects that complete the double-blind REFALS study (48-weeks of treatment) will have the opportunity to receive oral levosimendan treatment. The primary objective, in addition to continuing treatment for subjects enrolled in the REFALS study, is to evaluate long-term safety of oral levosimendan in ALS patients. Another important objective is to explore long-term effectiveness of oral levosimendan in the treatment of patients with ALS.

This study is open only to patients taking part in the REFALS study.

Study Overview

• Status: Terminated
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Levosimendan

• Study Type: Interventional
• Enrollment (Actual): 227
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Brain and Mind Centre
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women'S Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Victoria
    • Parkdale, Victoria, Australia, 3195
      • Calvary Health Care Bethlehem
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Perron Institute for Neurological and Translational Science
• Austria
  • Wein, Austria, 1090
    • Medizinische Universitat wein Universitatsklinik ffur Neurologie
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Medizinische Universität Innsbruck
  • Upper Austria
    • Vocklabruck, Upper Austria, Austria, 4840
      • Salzqammergut-klinikum Vocklabruck, Neurologie
• Belgium
  • Gent, Belgium, 9000
    • Algemeen Ziekenhuis St Lucas Gent
  • Leuven, Belgium, 3000
    • Universitair Ziekenhuis Leuven
  • Liège, Belgium, 4000
    • Centre Hospitalier Regional de la Vitadelle
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3M 1M4
      • Alberta Health Services-Neuromuscular Clinic
    • Edmonton, Alberta, Canada, T6G 2G3
      • University of Alberta, Division of Neurology
  • New Brunswick
    • Fredericton, New Brunswick, Canada, E3B 0C7
      • Stan Cassidy Centre for Rehabilitation
  • 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
    • Québec, Quebec, Canada, G1J 1Z4
      • Centre hospitalier affilié universitaire de Québec
• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Central Hospital, Neurology Outpatients Clinic
  • Turku, Finland, 20521
    • Turku University Hospital
• France
  • Limoges, France
    • Centre Hospitalier Universitaire de Limoges Service de Neurologie
  • Montpellier, France, 34295
    • Hopital Gui de Chauliac Service de Neurologie
  • Nice, France, 06202
    • Hopital Pasteur Centre de reference des Malades Neuromusculaires et SLA
• Germany
  • Berlin, Germany, 13353
    • Charite Universitatmedizin Berlin- Campus Virchow-Klinikum
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Jena, Germany, 07747
    • Universitätsklinikum Jena, Klinik für Neurologie
  • Münster, Germany, 48149
    • Universitatsklinikum Munster, Institut fur Schalfmedizin und Neuromuskalaire Erkrankungen
  • Rostock, Germany, 18147
    • Universitatsmedizin Rostock, Klinik und Poliklinik fuer Neurologie
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm, Poliklinik fur Neurologie
  • Wiesbaden, Germany, 65191
    • Deutsche Klinik fur Daignostik
• Ireland
  • Dublin, Ireland
    • Beaumont Hospital, Clinical Research Centre
• Italy
  • Genova, Italy, 16132
    • Azienda Policlinico San Martino
  • Milan, Italy, 20138
    • ICS Maugeri Spa S UO Riabilitazione Nurologica
  • Novara, Italy, 28100
    • Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara
  • Pisa, Italy, 56126
    • Azienda Ospedaliero Universitaria Pisana Ospedale Santa Chiara
  • Rome, Italy, 00161
    • Policlinico Umberto I di Roma Clinica Neurologica
  • Torino, Italy, 10126
    • Azienda Ospedaliera Universitaria Citta della Salute e della Scienza di Torino
• Netherlands
  • Utrecht, Netherlands, 3584
    • Univeritair Medisch Centrum Utrech
• Spain
  • Barcelona, Spain, 08207
    • Hospital Universitari de Bellvitge
  • Bilbao, Spain, 48013
    • Hospital Universitario de Basurto
  • Córdoba, Spain, 14011
    • Hospital Universitario Reina Sofia Servicio Neurologia
  • Madrid, Spain, 28016
    • Hospital San Rafael
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico de La Fe
• Sweden
  • Karlstad, Sweden
    • Karlstad Central Hospital Neurology and Rehabilitation
  • Stockholm, Sweden, 14186
    • Karolinska University Horpital Huddinge Neurology Clinic
  • Umeå, Sweden, 90185
    • Norrlanda University Hospital Neuro-huvud-hals-centrum Vasterbotten
• United Kingdom
  • Liverpool, United Kingdom, L9 7LJ
    • The Walton Centre NHs Foundation Trust, Neurology and Neurosurgery
  • London, United Kingdom, E1 1BB
    • Barts Health NHS Trust Royal London hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85028
      • Neuromuscular research Centre and Neuromuscular Clinic of Arizona
  • California
    • La Jolla, California, United States, 92037-0886
      • University of California San Diego
    • Orange, California, United States, 92868
      • University of California Irvine Medical Center
  • Connecticut
    • New Britain, Connecticut, United States, 06053
      • Hospital for Special Care
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • The George Washington Medical Faculty Associates
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital Neuroscience Institute
    • Gainesville, Florida, United States, 32611
      • University of Florida McKnight Brain Institute
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Tampa, Florida, United States, 33612
      • University of South Florida/USF Health
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University, Medical Centre
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan, Michigan Medicine University Hospital
  • Minnesota
    • Saint Paul, Minnesota, United States, 55130-5302
      • Health Partners Speciality 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
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Neurosciences Institute - Neurology Charlotte
    • Winston-Salem, North Carolina, United States, 27157-1023
      • Wake Forest University Baptist Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97201-3098
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97213
      • Providence Brain and Spine Institute
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
    • Pittsburgh, Pennsylvania, United States, 15212
      • Alleghenay General hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Nerve and Muscle Centre of Texas
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health-Imaging & Neurosciences Center in research Park
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 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
• Subjects who completed 48 weeks of treatment according to the REFALS study protocol
• Able to swallow study treatment capsules at the time of completing 48 weeks dosing in the REFALS study

Exclusion Criteria:

• Development (or significant worsening from baseline of the REFALS study) of serious cardiovascular disease (e.g.: myocardial infarction, heart failure, arrhythmia, stroke, or second or third degree atrioventricular (AV) block)
• Pulse/heart rate repeatedly >100 bpm after 5-minute rest at baseline. If the pulse/heart rate is >100 bpm in the first recording, then a second recording must be done after another 5 min rest to confirm pulse/heart rate >100 bpm
• Systolic blood pressure (SBP) <90 mmHg
• Severe renal impairment (creatinine clearance < 30ml/min or creatine >170 µmol/l at 48 week visit of the REFALS study, or on dialysis
• Severe hepatic impairment at the discretion of the investigator
• Women of reproductive age without a negative pregnancy test and without a commitment to using a highly effective method of contraception (e.g.: oral hormonal contraceptive associated with inhibition of ovulation, intrauterine devices and long acting progestin agent), 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
• Subject judged to be actively suicidal by the investigator
• Any other clinical 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: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Levosimendan; Oral Levosimendan; Levosimendan 1mg capsules for oral administration, once to twice a day, continued as long as clinically beneficial. The total study duration is up to 3 years.	Drug: Levosimendan; Levosimendan 1 mg capsule for oral administration; Other Names: ODM-109

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events Recording	Adverse Events as subject counts and proportions (%) of subject per Adverse Event	From signing informed consent until 14-25 days after the last study treatment for all patients, an average of 23.5 weeks.
Pulse/Heart Rate Assessment	Actual values and changes from baseline in supine pre-dose pulse/heart rate were summarised using descriptive statistics .	Change in pulse and heart rate(from ECG recording) from Baseline, week 2, week 4, week 6 (pulse rate only), Month 3, Month 6, end of study (subject's last visit, 2-48 weeks after study entry)
12-lead Electrocardiogram Assessments	Summarisation of any abnormal 12-lead ECG findings using descriptive statistics.	Baseline, week 2, week 4, month 3, month 6, end-of-study(subject's last visit, 2-48 weeks after study entry)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Progression	Count of study withdrawals due to disease progression	From Baseline through study completion(subject's last visit, 2-48 weeks after study entry)
Supine Slow Vital Capacity (SVC)	Change from baseline in supine and sitting SVC (all devices) through to the end of the study, expressed as a % of predicted normal	The change from Baseline, week 2, week 4, month 3, month 6, end-of-study (subject's last visit, 2-48 weeks after study entry)
Revised ALS Functional Rating Scale (ALSFRS-R)	ALSFRS-R scale contains 3 parameters related to respiratory function: Severity of dyspnea, occurrence of orthopnea (shortness of breath when in supine position i.e. lying flat), and the use of mechanical ventilation for respiratory in sufficiency. These 3 parameters are combined to create the respiratory domain with a score of 0-12(where 12 is 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 ro reduce the slope of decline.	Change from Baseline in respiratory function of ALSFRS-R at study completion (subject's last visit, 2-48 weeks after study entry)
Need for Respiratory Support Device	Time to respiratory device support (non invasive) or death	Time to event at study completion (subject's last visit, 2-48 weeks after study entry)
Borg Category Ratio 10 Scale (CR 10)	Patients rated their perception of the severity of their dyspnea using the Borg Category Ration 10 scale (CR 10). The scale ranges from 0(no dysponea) to 10 (maximal dyspnea). each category is numbered and most but 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 to the end of the study in both a supine and sitting position where a negative score indicates improvement and a positive score reflects worsening.	Baseline through study completion (week 2, week 4, month 3, month 6, end of study (subject's last visit, 2-48 weeks after study entry)
Number of Subjects Requiring Health and Home Care Resource Use	The number of study subjects requiring Health and home care resource use was aggregated over the course of the study for each subject and summarised using descriptive statistics.	Baseline through study completion (2- 48 weeks after study entry)
Subject's Status for Tracheostomy and Survival	Number of patients with the need for tracheostomy or who died whilst on treatment from baseline to the end of the study was summarised using descriptive statistics.	Baseline to end of study (average 2-48 weeks after study entry
Health Care Service Use During the Study(Stays in Hospital)	The number of night stays in hospital were recorded throughout the study using a diary given to the study subjects	From baseline to the end of the study(2-48 weeks after study entry)
Health Care Service Use During the Study(Visits to the Emergency Room)	The number of visits to the emergency room were recorded throughout the study using a diary given to the study subjects	From baseline to the end of the study(2-48 weeks after study entry)
Health Care Service Use During the Study (Days Spent in an Institutional Facility)	The number of days spent in an institutional facility were recorded throughout the study using a diary given to the study subjects	From baseline to the end of the study(2-48 weeks after study entry)

Collaborators and Investigators

• Sponsor: 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 26, 2019
• Primary Completion (Actual): November 18, 2020
• Study Completion (Actual): November 18, 2020

Study Registration Dates

• First Submitted: May 7, 2019
• First Submitted That Met QC Criteria: May 10, 2019
• First Posted (Actual): May 13, 2019

Study Record Updates

• Last Update Posted (Estimate): March 9, 2023
• Last Update Submitted That Met QC Criteria: February 9, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; 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: 3119003

Drug and device information, study documents

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