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

Amyotrophic Lateral Sclerosis Clinical Trial

— REFALS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03505021
• Other study ID #: 3119002
• Status: Completed
• Phase: Phase 3
• Start date: June 21, 2018
• Est. completion date: July 23, 2020

Study information

• Verified date: April 2022
• Source: Orion Corporation, Orion Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 496
• Est. completion date: July 23, 2020
• Est. primary completion date: July 23, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease

Intervention

Drug:
• Levosimendan
Levosimendan 1 mg capsule for oral administration
• Placebo for levosimendan
Placebo capsule for oral administration

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Royal Brisbane and Women's Hospital	Brisbane	Queensland
Australia	Brain and Mind Centre	Camperdown	New South Wales
Australia	Calvary Health Care Bethlehem	Caulfield South	Victoria
Australia	Perron Institute for Neurological and Translational Science	Murdoch	Western Australia
Austria	Universität Innsbruck	Innsbruck	Tyrol
Austria	Salzkammergut-Klinikum Vöcklabruck	Vöcklabruck	Upper Austria
Austria	Medizinische Universität Wien	Wien
Belgium	Algemeen Ziekenhuis St. Lucas Gent	Gent	Oost-Vlaanderen
Belgium	Universitaire Ziekenhuis Leuven	Leuven	Flemish Brabant
Belgium	Centre Hospitalier Régional de la Citadelle	Liège	Liege
Canada	Alberta Health Services - Neuromuscular Clinic	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	Stan Cassidy Centre for Rehabilitation	Fredericton	New Brunswick
Canada	McMaster University Medical Centre	Hamilton	Ontario
Canada	Moncton Hospital, Southeast Regional Health Authority	Moncton	New Brunswick
Canada	Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame	Montréal	Quebec
Canada	Montreal Neurological Institute and Hospital	Montréal	Quebec
Canada	Centre Hospitalier Affilie Universitaire de Quebec	Québec	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Finland	Neurologian Poliklinikka - Meilahden Tornisairaala 3	Helsinki
Finland	Etelä-Karjalan keskussairaala	Lappeenranta
Finland	Turku University Hospital	Turku
France	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
Germany	Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum	Berlin
Germany	Universitätsklinikum Carl Gustav Carus	Dresden	Sachsen
Germany	Alfried Krupp Krankenhaus Rüttenscheid	Essen	Nordrhein-westfalen
Germany	Medizinische Hochschule Hannover	Hannover	Niedersachsen
Germany	Universitätsklinikum Jena	Jena	Thuringen
Germany	Universitätsklinikum Münster	Münster	Nordrhein-Westfalen
Germany	Universitätsmedizin Rostock	Rostock	Mecklenburg-western-pommerania
Germany	Universitätsklinikum Ulm	Ulm	Baden-Württemberg
Germany	Deutsche Klinik für Diagnostik	Wiesbaden	Hessen
Ireland	Beaumont Hospital - Ireland	Dublin
Italy	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
Netherlands	Academisch Medisch Centrum	Amsterdam	Noord-Holland
Netherlands	Universitair Medisch Centrum Utrecht - Rudolf Magnus Instituut voor Neurowetenschappen	Utrecht
Spain	Hospital Universitari de Bellvitge	Barcelona
Spain	Hospital de Basurto	Bilbao	Vizcaya
Spain	Hospital Universitario Reina Sofia	Córdoba
Spain	Hospital San Rafael - Madrid	Madrid
Spain	Hospital Universitario y Politécnico de La Fe	Valencia
Sweden	Centralsjukhuset Karlstad	Karlstad
Sweden	Karolinska Universitetssjukhuset	Stockholm
Sweden	Norrlands Universitetssjukhus	Umeå	Vasterbotten
United Kingdom	The Walton Centre NHS Foundation Trust	Liverpool
United Kingdom	Barts Health NHS Trust	London	England
United Kingdom	King's College Hospital NHS Foundation Trust	London	England
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	The Johns Hopkins Hospital	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Neurosciences Institute - Neurology Charlotte	Charlotte	North Carolina
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	Colorado Springs Neurological Associates	Colorado Springs	Colorado
United States	The Ohio State University	Columbus	Ohio
United States	Texas Neurology	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Providence Holy Cross Medical Center	Fort Lauderdale	Florida
United States	University of Florida	Gainesville	Florida
United States	Nerve and Muscle Center of Texas	Houston	Texas
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	University of Florida Health - Jacksonville	Jacksonville	Florida
United States	University of California San Diego	La Jolla	California
United States	University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	Neurology Associates	Lincoln	Nebraska
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Kentucky Neuroscience Research	Louisville	Kentucky
United States	Froedtert Hospital	Milwaukee	Wisconsin
United States	Hospital for Special Care	New Britain	Connecticut
United States	Columbia Presbyterian Hospital	New York	New York
United States	Hospital for Special Surgery	New York	New York
United States	Mount Sinai Beth Israel	New York	New York
United States	University of California Irvine	Orange	California
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Temple University School of Medicine	Philadelphia	Pennsylvania
United States	Neuromuscular Research Center and Neuromuscular Clinic of Arizona	Phoenix	Arizona
United States	Phoenix Neurological Associates	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Brain and Spine Institute	Portland	Oregon
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	HealthPartners Specialty Center	Saint Paul	Minnesota
United States	University of Utah - Imaging & Neurosciences Center	Salt Lake City	Utah
United States	California Pacific Medical Center	San Francisco	California
United States	Swedish Neuroscience Institute	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	University of South Florida	Tampa	Florida
United States	Georgetown University	Washington	District of Columbia
United States	The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion	Washington	District of Columbia
United States	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Orion Corporation, Orion Pharma

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Supine Slow Vital Capacity (SVC)	Change from baseline to 12 weeks, expressed as % of predicted normal.	The change from baseline at 12 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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