Study Purpose:
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 Status:
Not recruiting
Disease:
Amyotrophic Lateral Sclerosis
Study Type:
Interventional
Type of Intervention:
Drug
Intervention Name:
Levosimendan, Placebo for levosimendan
Placebo:
Yes
Phase:
Phase 3
Study Chair(s)/Principal Investigator(s):
Merja Mäkitalo, CSD, Orion Corporation, Orion Pharma
Clinicaltrials.gov ID:
Neals Affiliated?
Yes
Coordinating Center Contact Information
Massachusetts General Hospital
Boston, Massachusetts, 02114 United States
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
Participant Duration:
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 Enrollment:
496
Estimated Study Start Date:
06 / 21 / 2018
Estimated Study Completion Date:
07 / 23 / 2020
Posting Last Modified Date:
05 / 11 / 2022
Date Study Added to neals.org:
04 / 20 / 2018
Minimum Age:
18 Years
Maximum Age:
120 Years
Can participants use Riluzole?
Yes
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
Phoenix Neurological Associates
Phoenix, Arizona
85006
United States
Neuromuscular Research Center and Neuromuscular Clinic of Arizona
Phoenix, Arizona
85028
United States
University of California San Diego
La Jolla, California
92037-0886
United States
Cedars-Sinai Medical Center
Los Angeles, California
90048
United States
University of California Irvine
Orange, California
92868
United States
California Pacific Medical Center
San Francisco, California
94115
United States
Colorado Springs Neurological Associates
Colorado Springs, Colorado
80907
United States
Hospital for Special Care
New Britain, Connecticut
06053
United States
Georgetown University
Washington, District of Columbia
20007
United States
The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion
Washington, District of Columbia
20037
United States
University of South Florida
Tampa, Florida
33612
United States
Mayo Clinic - Jacksonville
Jacksonville, Florida
32224
United States
University of Florida Health - Jacksonville
Jacksonville, Florida
32209
United States
University of Florida
Gainesville, Florida
32611
United States
Providence Holy Cross Medical Center
Fort Lauderdale, Florida
33308
United States
Emory University School of Medicine
Atlanta, Georgia
30322
United States
Augusta University
Augusta, Georgia
30912
United States
Northwestern University Feinberg School of Medicine
Chicago, Illinois
60611
United States
University of Chicago
Chicago, Illinois
60637
United States
University of Kentucky Chandler Medical Center
Lexington, Kentucky
40536
United States
Kentucky Neuroscience Research
Louisville, Kentucky
40202
United States
The Johns Hopkins Hospital
Baltimore, Maryland
21205
United States
Massachusetts General Hospital
Boston, Massachusetts
02114
United States
University of Michigan
Ann Arbor, Michigan
49007
United States
Mayo Clinic - Rochester
Rochester, Minnesota
55905
United States
HealthPartners Specialty Center
Saint Paul, Minnesota
55130-5302
United States
Washington University School of Medicine
Saint Louis, Missouri
63110
United States
Neurology Associates
Lincoln, Nebraska
68506
United States
Mount Sinai Beth Israel
New York, New York
10003
United States
Hospital for Special Surgery
New York, New York
10021
United States
Columbia Presbyterian Hospital
New York, New York
10032
United States
Neurosciences Institute - Neurology Charlotte
Charlotte, North Carolina
28207
United States
Duke University Medical Center
Durham, North Carolina
27705
United States
Wake Forest University Baptist Medical Center
Winston-Salem, North Carolina
27157-1023
United States
The Ohio State University
Columbus, Ohio
43210
United States
Providence Brain and Spine Institute
Portland, Oregon
97213
United States
Oregon Health and Science University
Portland, Oregon
97201-3098
United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
19107
United States
Temple University School of Medicine
Philadelphia, Pennsylvania
19140
United States
Allegheny General Hospital
Pittsburgh, Pennsylvania
15212
United States
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania
15213
United States
Texas Neurology
Dallas, Texas
75214
United States
Nerve and Muscle Center of Texas
Houston, Texas
77030
United States
University of Utah - Imaging & Neurosciences Center
Salt Lake City, Utah
84108
United States
University of Vermont Medical Center
Burlington, Vermont
05401
United States
Swedish Neuroscience Institute
Seattle, Washington
98122
United States
University of Washington Medical Center
Seattle, Washington
98195
United States
Froedtert Hospital
Milwaukee, Wisconsin
53226
United States
Brain and Mind Centre
Camperdown, New South Wales
2050
Australia
Flinders Medical Centre
Bedford Park, South Australia
5042
Australia
Calvary Health Care Bethlehem
Caulfield South, Victoria
3162
Australia
Perron Institute for Neurological and Translational Science
Murdoch, Western Australia
6150
Australia
Royal Brisbane and Women's Hospital
Brisbane, Queensland
4029
Australia
Universität Innsbruck
Innsbruck, Tyrol
6020
Austria
Salzkammergut-Klinikum Vöcklabruck
Vöcklabruck, Upper Austria
4840
Austria
Medizinische Universität Wien
Wien 1090
Austria
Universitaire Ziekenhuis Leuven
Leuven, Flemish Brabant
3000
Belgium
Centre Hospitalier Régional de la Citadelle
Liège, Liege
4000
Belgium
Algemeen Ziekenhuis St. Lucas Gent
Gent, Oost-Vlaanderen
9000
Belgium
Sunnybrook Health Sciences Centre
Toronto, Ontario
M4N 3M5
Canada
Centre Hospitalier Affilie Universitaire de Quebec
Québec, Quebec
G1J 1Z4
Canada
Montreal Neurological Institute and Hospital
Montréal, Quebec
H3A 2B4
Canada
Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame
Montréal, Quebec
H2L 4M1
Canada
McMaster University Medical Centre
Hamilton, Ontario
L8N 3Z5
Canada
Moncton Hospital, Southeast Regional Health Authority
Moncton, New Brunswick
E1C 2Z3
Canada
Stan Cassidy Centre for Rehabilitation
Fredericton, New Brunswick
E3B 0C7
Canada
University of Alberta
Edmonton, Alberta
T6G 2G3
Canada
Alberta Health Services - Neuromuscular Clinic
Calgary, Alberta
T3M 1M4
Canada
Neurologian Poliklinikka - Meilahden Tornisairaala 3
Helsinki 00029
Finland
Etelä-Karjalan keskussairaala
Lappeenranta 53130
Finland
Turku University Hospital
Turku 20521
Finland
Centre Hospitalier Universitaire de Limoges
Limoges 87042
France
Hôpital Gui de Chauliac
Montpellier 34295
France
Hôpital Pasteur
Nice 06202
France
Centre Hospitalier Régional et Universitaire de Tours Hôpital Bretonneau
Tours 37044
France
Universitätsklinikum Münster
Münster, Nordrhein-Westfalen
48149
Germany
Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum
Berlin 13353
Germany
Universitätsklinikum Jena
Jena, Thuringen
07747
Germany
Universitätsklinikum Carl Gustav Carus
Dresden, Sachsen
01307
Germany
Deutsche Klinik für Diagnostik
Wiesbaden, Hessen
65191
Germany
Alfried Krupp Krankenhaus Rüttenscheid
Essen, Nordrhein-westfalen
45131
Germany
Medizinische Hochschule Hannover
Hannover, Niedersachsen
30625
Germany
Universitätsmedizin Rostock
Rostock, Mecklenburg-western-pommerania
18147
Germany
Universitätsklinikum Ulm
Ulm, Baden-Württemberg
89081
Germany
Beaumont Hospital - Ireland
Dublin 9
Ireland
Azienda Ospedaliera Universitaria San Martino
Genova 16132
Italy
Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara
Novara 28100
Italy
ICS Maugeri Spa SB
Pavia 27100
Italy
Azienda Ospedaliero-Universitaria Pisana Ospedale Santa Chiara
Pisa 56126
Italy
Policlinico Umberto I di Roma
Roma 0016
Italy
Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino
Torino 10126
Italy
Universitair Medisch Centrum Utrecht - Rudolf Magnus Instituut voor Neurowetenschappen
Utrecht 3584 CG
Netherlands
Academisch Medisch Centrum
Amsterdam, Noord-Holland
1105 AZ
Netherlands
Hospital de Basurto
Bilbao, Vizcaya
48013
Spain
Hospital Universitari de Bellvitge
Barcelona 08207
Spain
Hospital Universitario Reina Sofia
Córdoba 14011
Spain
Hospital San Rafael - Madrid
Madrid 28016
Spain
Hospital Universitario y Politécnico de La Fe
Valencia 46026
Spain
Norrlands Universitetssjukhus
Umeå, Vasterbotten
90737
Sweden
Centralsjukhuset Karlstad
Karlstad 651 85
Sweden
Karolinska Universitetssjukhuset
Stockholm 14186
Sweden
Barts Health NHS Trust
London, England
E1 1BB
United Kingdom
King's College Hospital NHS Foundation Trust
London, England
SE5 9RS
United Kingdom
The Walton Centre NHS Foundation Trust
Liverpool L9 7LJ
United Kingdom