Clinical trial NCT03505021: Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
Official title: Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Lead sponsor: Orion Corporation, Orion Pharma
Sponsor class: INDUSTRY
First posted: 2018-04-20
Enrollment: 496
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Supine Slow Vital Capacity (SVC)
timeFrame: The change from baseline at 12 weeks
Secondary outcomes:
measure: Combined Assessment of Function and Survival Through 48 Weeks
timeFrame: Mean rank at 48 weeks
measure: Time to Respiratory Event Through 48 Weeks
timeFrame: Time to event through 48 weeks
measure: Change From the Baseline in Clinical Global Impression CGI at 48 Weeks
timeFrame: The change from baseline at 48 weeks
measure: Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks
timeFrame: Slope of decline at 48 weeks
measure: Supine Borg Category Ratio 10 Scale at 12 Weeks
timeFrame: Change from baseline at 12 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Neurological Associates
state: Arizona
city: Phoenix
country: United States
facility: Neuromuscular Research Center and Neuromuscular Clinic of Arizona
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Orange
country: United States
facility: University of California Irvine
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Colorado Springs
country: United States
facility: Colorado Springs Neurological Associates
state: Colorado
city: New Britain
country: United States
facility: Hospital for Special Care
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Washington
country: United States
facility: The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Providence Holy Cross Medical Center
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: University of Florida Health - Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: Kentucky Neuroscience Research
state: Kentucky
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Paul
country: United States
facility: HealthPartners Specialty Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Lincoln
country: United States
facility: Neurology Associates
state: Nebraska
city: New York
country: United States
facility: Mount Sinai Beth Israel
state: New York
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Hospital
state: New York
city: Charlotte
country: United States
facility: Neurosciences Institute - Neurology Charlotte
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Portland
country: United States
facility: Providence Brain and Spine Institute
state: Oregon
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University School of Medicine
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: Texas Neurology
state: Texas
city: Houston
country: United States
facility: Nerve and Muscle Center of Texas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Imaging & Neurosciences Center
state: Utah
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Seattle
country: United States
facility: Swedish Neuroscience Institute
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Froedtert Hospital
state: Wisconsin
city: Camperdown
country: Australia
facility: Brain and Mind Centre
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Caulfield South
country: Australia
facility: Calvary Health Care Bethlehem
state: Victoria
city: Murdoch
country: Australia
facility: Perron Institute for Neurological and Translational Science
state: Western Australia
city: Innsbruck
country: Austria
facility: Universität Innsbruck
state: Tyrol
city: Vöcklabruck
country: Austria
facility: Salzkammergut-Klinikum Vöcklabruck
state: Upper Austria
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuis Leuven
state: Flemish Brabant
city: Liège
country: Belgium
facility: Centre Hospitalier Régional de la Citadelle
state: Liege
city: Gent
country: Belgium
facility: Algemeen Ziekenhuis St. Lucas Gent
state: Oost-Vlaanderen
city: Calgary
country: Canada
facility: Alberta Health Services - Neuromuscular Clinic
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Fredericton
country: Canada
facility: Stan Cassidy Centre for Rehabilitation
state: New Brunswick
city: Moncton
country: Canada
facility: Moncton Hospital, Southeast Regional Health Authority
state: New Brunswick
city: Hamilton
country: Canada
facility: McMaster University Medical Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Montréal
country: Canada
facility: Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame
state: Quebec
city: Montréal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Québec
country: Canada
facility: Centre Hospitalier Affilie Universitaire de Quebec
state: Quebec
city: Helsinki
country: Finland
facility: Neurologian Poliklinikka - Meilahden Tornisairaala 3
city: Lappeenranta
country: Finland
facility: Etelä-Karjalan keskussairaala
city: Turku
country: Finland
facility: Turku University Hospital
city: Limoges
country: France
facility: Centre Hospitalier Universitaire de Limoges
city: Montpellier
country: France
facility: Hôpital Gui de Chauliac
city: Nice
country: France
facility: Hôpital Pasteur
city: Tours
country: France
facility: Centre Hospitalier Régional et Universitaire de Tours Hôpital Bretonneau
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
state: Baden-Württemberg
city: Wiesbaden
country: Germany
facility: Deutsche Klinik für Diagnostik
state: Hessen
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock
state: Mecklenburg-western-pommerania
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Essen
country: Germany
facility: Alfried Krupp Krankenhaus Rüttenscheid
state: Nordrhein-westfalen
city: Münster
country: Germany
facility: Universitätsklinikum Münster
state: Nordrhein-Westfalen
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
state: Sachsen
city: Jena
country: Germany
facility: Universitätsklinikum Jena
state: Thuringen
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum
city: Dublin
country: Ireland
facility: Beaumont Hospital - Ireland
city: Genova
country: Italy
facility: Azienda Ospedaliera Universitaria San Martino
city: Novara
country: Italy
facility: Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara
city: Pavia
country: Italy
facility: ICS Maugeri Spa SB
city: Pisa
country: Italy
facility: Azienda Ospedaliero-Universitaria Pisana Ospedale Santa Chiara
city: Roma
country: Italy
facility: Policlinico Umberto I di Roma
city: Torino
country: Italy
facility: Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
state: Noord-Holland
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht - Rudolf Magnus Instituut voor Neurowetenschappen
city: Bilbao
country: Spain
facility: Hospital de Basurto
state: Vizcaya
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Madrid
country: Spain
facility: Hospital San Rafael - Madrid
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico de La Fe
city: Umeå
country: Sweden
facility: Norrlands Universitetssjukhus
state: Vasterbotten
city: Karlstad
country: Sweden
facility: Centralsjukhuset Karlstad
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset
city: London
country: United Kingdom
facility: Barts Health NHS Trust
state: England
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: England
city: Liverpool
country: United Kingdom
facility: The Walton Centre NHS Foundation Trust
Study officials:
affiliation: Orion Corporation, Orion Pharma
name: Merja Mäkitalo, CSD
role: STUDY_DIRECTOR
References:
citation: 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.