Effect of Oral Levosimendan (ODM-109) on Respiratory Function in Patients with ALS (REFALS)

Study Purpose:

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 Status:

Enrolling

Phase:

Phase III

Study Chair(s)/Principal Investigator(s):

Merit Cudkowicz, MD, Massachusetts General Hospital

Clinicaltrials.gov ID (11 digit #):

NCT03505021

Neals Affiliated?

Yes

Coordinating Center Contact Information

Massachusetts General Hospital
Merit E Cudkowicz, MD / .(JavaScript must be enabled to view this email address) / 617-726-2383
Merja Mäkitalo / .(JavaScript must be enabled to view this email address) / +358 10 426 7737
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:

450

Estimated Study Start Date:

06/21/2018

Estimated Study Completion Date:

10/30/2020

Posting Last Modified Date:

09/19/2018

Date Study Added to alsconsortium.org:

07/06/2018

Eligibility Criteria

Gender:
Female, Male
Minimum Age:
18
Maximum Age:
N/A
Min Vital Capacity (% predicted normal):
60-90

Time since Symptom Onset:

Time since Diagnosis:

Can participants use Riluzole?
Yes

Inclusion criteria

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).

Exclusion criteria

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
United States

Phoenix Neurological Associates
Phoenix, Arizona 85006
United States

University of California San Diego
Rose Previte / .(JavaScript must be enabled to view this email address) / La Jolla, California 92037
United States

Colorado Springs Neurological Associates
Colorado Springs, Colorado 80907
United States

Hospital for Special Care
Honora Dalamagas / .(JavaScript must be enabled to view this email address) / 860-612-6356
Stephanie Beck / .(JavaScript must be enabled to view this email address) / 860-827-1958 ext 5753
New Britain, Connecticut 06053
United States

The George Washington Medical Faculty Associates
Lindsey Covington / .(JavaScript must be enabled to view this email address) / 202-741-2745
Washington, District of Columbia 20037
United States

University of Florida Health - Jacksonville
Jacksonville, Florida 32209
United States

University of South Florida
Tampa, Florida 33612
United States

Holy Cross Hospital
Fort Lauderdale, Florida 33308
United States

Mayo Clinic
Jacksonville, Florida 32224
United States

Emory University School of Medicine
Jane Bordeau / .(JavaScript must be enabled to view this email address) / Atlanta, Georgia 30322
United States

Northwestern University Feinberg School of Medicine
Benjamin Joslin / .(JavaScript must be enabled to view this email address) / Chicago, Illinois 60611
United States

University of Kentucky Chandler Medical Center
Lexington, Kentucky 40536
United States

Kentucky Neuroscience Research
Louisville, Kentucky 40202
United States

Johns Hopkins Hospital
Baltimore, Maryland 21205
United States

Massachuesetts General Hospital
Olivia Pijanowski / .(JavaScript must be enabled to view this email address) / 617-643-5376
Boston, Massachuesetts 02114
United States

Mayo Clinic - Rochester
Rochester, Minnesota 55905
United States

HealthPartners Specialty Center
Saint Paul, Minnesota 55130
United States

Washington University School of Medicine
Kelly Streckfuss / .(JavaScript must be enabled to view this email address) / Saint Louis, Missouri 63110
United States

Neurology Associates
Ashley Calhoun / .(JavaScript must be enabled to view this email address) / 402-770-7403
Lincoln, Nebraska 68506
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
United States

The Ohio State University
Adam Quick / .(JavaScript must be enabled to view this email address) / Rory Eustace / .(JavaScript must be enabled to view this email address) / Columbus, Ohio 43210
United States

Providence Brain and Spine Institute
Arlena Cummings / .(JavaScript must be enabled to view this email address) / 503-962-1171
Portland, Oregon 97213
United States

University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania 15213
United States

University of Pennsylvania
Philadelphia, Pennsylvania 19107
United States

Allegheny General Hospital
Pittsburgh, Pennsylvania 15212
United States

Nerve and Muscle Center of Texas
Zinah Rasheed / .(JavaScript must be enabled to view this email address) / 713-795-0033
Houston, Texas 77030
United States

Texas Neurology
Daragh Heitzman / 214-827-3610
Dallas, Texas 75214
United States

University of Utah
Salt Lake City, Utah 84108
United States

Swedish Neuroscience Institute
Seattle, Washington 98122
United States

Froedtert Hospital
Lynn Wheeler / .(JavaScript must be enabled to view this email address) / 414-805-9307
Milwaukee, Wisconsin 53226
United States

Brain and Mind Centre
Eleanor Ramsey / 02 9351 0976
Camperdown, New South Wales 2050
Australia

Perron Institute for Neurological and Translational Science
Joanne Borrelli / .(JavaScript must be enabled to view this email address) / Murdoch, Western Australia 6150
Australia

Calvary Health Care Bethlehem
Emma Windebank / .(JavaScript must be enabled to view this email address) / Caulfield South, Victoria 3162
Australia

Flinders Medical Centre
David Schultz / 61 8 8204 4187
Bedford Park, South Australia 5042
Australia

Royal Brisbane and Women's Hospital
Brisbane, Queensland 4029
Australia

Universität Innsbruck
Wolfgang Löscher / .(JavaScript must be enabled to view this email address) / Marina Peball / .(JavaScript must be enabled to view this email address) / Innsbruck, Tyrol 6020
Austria

Salzkammergut-Klinikum Vöcklabruck
Vöcklabruck, Upper Austria 4840
Austria

Universitaire Ziekenhuis Leuven
Philip Van Damme / 016 344280
Leuven, Flemish 3000
Belgium

Algemeen Ziekenhuis St. Lucas Gent
Jan De Bleeker / 32-9-2246530
Gent, Oost-Vlaanderen 9000
Belgium

Centre Hospitalier Régional de la Citadelle
Stephanie Delstanche / .(JavaScript must be enabled to view this email address) / 00 32 4 321 82 24
Liège, Liege 4000
Belgium

Stan Cassidy Centre for Rehabilitation
Fredericton, New Brunswick E3B 0C7
Canada

Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame
Montreal, Quebec H2L 4M1
Canada

Alberta Health Services - Neuromuscular Clinic
Calgary, Alberta T3M1M4
Canada

Montreal Neurological Institute and Hospital
Montreal, Quebec H3A 2B4
Canada

University of Alberta
Edmondton, Alberta T6G 2G3
Canada

Moncton Hospital, Southeast Regional Health Authority
Moncton, New Brunswick E1C 2Z3
Canada

Sunnybrook Health Sciences Centre
Toronto, Ontario M4N 3M5
Canada

Etelä-Karjalan keskussairaala
Lappeenranta, 53130
Finland

Turku University Hospital
Turku, 20521
Finland

Helsingin ja Uudenmaan sairaanhoitopiiri
Neurologian Poliklinikka - Meilahden Tornisairaala 3
Helsinki, 00029
Finland

Universitätsklinikum Jena
Jena, Thuringen 07747
Germany

Deutsche Klinik für Diagnostik
Wiesbaden, Hessen 65191
Germany

Universitätsklinikum Münster
Münster, Nordrhein-Westfalen 48149
Germany

Universitätsklinikum Carl Gustav Carus
Dresden, Sachsen 01307
Germany

Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum
Berlin, 13353
Germany

Beaumont Hospital - Ireland
Dublin,
Ireland

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, 1105 AZ
Netherlands

Hospital San Rafael - Madrid
Jesus S Mora Pardina / .(JavaScript must be enabled to view this email address) / Madrid, 28016
Spain

Hospital Universitari de Bellvitge
Berta Blanco Burguet / 34932607586
Barcelona, 08207
Spain

Hospital Universitario y Politécnico de La Fe
Juan Francisco Vázquez / .(JavaScript must be enabled to view this email address) / Paula Lizandra / .(JavaScript must be enabled to view this email address) / Valencia, 46026
Spain

Hospital Universitario Reina Sofia
Córdoba, 14011
Spain

Hospital de Basurto
Bilbao, Vizcaya 48013
Spain

Norrlands Universitetssjukhus
Peter M Andersen / .(JavaScript must be enabled to view this email address) / Umeå, 901 85
Sweden

Karolinska Universitetssjukhuset
Karolina Palmback / 08 51771231
Stockholm, 14186
Sweden

Centralsjukhuset Karlstad
Karlstad, 651 85
Sweden

The Walton Centre NHS Foundation Trust
Liverpool, England L9 7LJ
United Kingdom

Barts Health NHS Trust
London, England E1 1BB
United Kingdom

King's College Hospital NHS Foundation Trust
London , England SE5 9RS
United Kingdom