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

Orion Corporation/Orion Pharma
Merja Mäkitalo / .(JavaScript must be enabled to view this email address) / +358 10 426 7737
.(JavaScript must be enabled to view this email address) Tengströminkatu 8
Turku , Finland

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:

07/13/2018

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

    Colorado Springs Neurological Associates
    Colorado Springs, Colorado 80907
    United States

    Hospital of Special Care
    New Britain, Connecticut 06053
    United States

    The George Washington Medical Faculty Associates
    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

    Emory University School of Medicine
    Atlanta, Georgia 30322
    United States

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

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

    Washington University School of Medicine
    Saint Louis, Missouri 63110
    United States

    Neurology Associates
    Lincoln, Nebraska 68506
    United States

    Providence Brain and Spine Institute
    Portland, Oregon 97213
    United States

    University of Pittsburgh Medical Center
    Pittsburgh, Pennsylvania 15213
    United States

    Nerve and Muscle Center of Texas
    Houston, Texas 77030
    United States

    Texas Neurology
    Dallas, Texas 75214
    United States

    University of Utah
    Salt Lake City, Utah 84108
    United States

    Froedtert Hospital
    Milwaukee, Wisconsin 53226
    United States

    Brain and Mind Centre
    Camperdown, 2050
    Australia

    Perron Institute for Neurological and Translational Science
    Murdoch, 6150
    Australia

    Calvary Health Care Bethlehem
    Caulfield South, 3162
    Australia

    Flinders Medical Centre
    Bedford Park, 5042
    Australia

    Universität Innsbruck
    Innsbruck, 6020
    Austria

    Salzkammergut-Klinikum Vöcklabruck
    Vöcklabruck, 4840
    Austria

    Universitaire Ziekenhuis Leuven
    Leuven, 3000
    Belgium

    Algemeen Ziekenhuis St. Lucas Gent
    Gent, 9000
    Belgium

    Centre Hospitalier Régional de la Citadelle
    Liège, 4000
    Belgium

    Stan Cassidy Centre for Rehabilitation
    Fredericton, 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, E1C 2Z3
    Canada

    Etelä-Karjalan keskussairaala
    Lappeenranta, 53130
    Finland

    Turku University Hospital
    Turku, 20521
    Finland

    Universitätsklinikum Jena
    Jena, Thuringen 07747
    Germany

    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
    Madrid, 28016
    Spain

    Hospital Universitari de Bellvitge
    Barcelona, 08207
    Spain

    Hospital Universitario y Politécnico de La Fe
    Valencia, 46026
    Spain

    Hospital Universitario Reina Sofia
    Córdoba, 14011
    Spain

    Norrlands Universitetssjukhus
    Umeå, 901 85
    Sweden

    Karolinska Universitetssjukhuset
    Stockholm, 14186
    Sweden

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