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Amyotrophic Lateral SclerosisPhase 3REFALSNCT03505021

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

A Phase 3 study testing Levosimendan in people with Amyotrophic Lateral Sclerosis, run by Orion Corporation, Orion Pharma at 104 sites in 14 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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. Read more about this study

Who is it for?
Ages 18 to 120 years
Conditions the study is for
Amyotrophic Lateral Sclerosis
What is being tested?
Levosimendan
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
496 participants
Where
104 sitesin 14 countries
Study dates
21 Jun 2018to 23 Jul 2020
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 120 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 28Show fewer
  • 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

Trial locations and contacts

104 sites in 14 countries.

104 sites in 14 countries

United States48 sites

  • University of Michigan

    Ann Arbor, Michigan, 49007

  • Emory University School of Medicine

    Atlanta, Georgia, 30322

  • Augusta University

    Augusta, Georgia, 30912

  • The Johns Hopkins Hospital

    Baltimore, Maryland, 21205

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • University of Vermont Medical Center

    Burlington, Vermont, 05401

  • Neurosciences Institute - Neurology Charlotte

    Charlotte, North Carolina, 28207

  • Northwestern University Feinberg School of Medicine

    Chicago, Illinois, 60611

  • University of Chicago

    Chicago, Illinois, 60637

  • Colorado Springs Neurological Associates

    Colorado Springs, Colorado, 80907

  • The Ohio State University

    Columbus, Ohio, 43210

  • Texas Neurology

    Dallas, Texas, 75214

  • Duke University Medical Center

    Durham, North Carolina, 27705

  • Providence Holy Cross Medical Center

    Fort Lauderdale, Florida, 33308

  • University of Florida

    Gainesville, Florida, 32611

  • Nerve and Muscle Center of Texas

    Houston, Texas, 77030

  • University of Florida Health - Jacksonville

    Jacksonville, Florida, 32209

  • Mayo Clinic - Jacksonville

    Jacksonville, Florida, 32224

  • University of California San Diego

    La Jolla, California, 92037-0886

  • University of Kentucky Chandler Medical Center

    Lexington, Kentucky, 40536

  • Neurology Associates

    Lincoln, Nebraska, 68506

  • Cedars-Sinai Medical Center

    Los Angeles, California, 90048

  • Kentucky Neuroscience Research

    Louisville, Kentucky, 40202

  • Froedtert Hospital

    Milwaukee, Wisconsin, 53226

  • Hospital for Special Care

    New Britain, Connecticut, 06053

  • Mount Sinai Beth Israel

    New York, New York, 10003

  • Hospital for Special Surgery

    New York, New York, 10021

  • Columbia Presbyterian Hospital

    New York, New York, 10032

  • University of California Irvine

    Orange, California, 92868

  • Hospital of the University of Pennsylvania

    Philadelphia, Pennsylvania, 19107

  • Temple University School of Medicine

    Philadelphia, Pennsylvania, 19140

  • Phoenix Neurological Associates

    Phoenix, Arizona, 85006

  • Neuromuscular Research Center and Neuromuscular Clinic of Arizona

    Phoenix, Arizona, 85028

  • Allegheny General Hospital

    Pittsburgh, Pennsylvania, 15212

  • University of Pittsburgh Medical Center

    Pittsburgh, Pennsylvania, 15213

  • Oregon Health and Science University

    Portland, Oregon, 97201-3098

  • Providence Brain and Spine Institute

    Portland, Oregon, 97213

  • Mayo Clinic - Rochester

    Rochester, Minnesota, 55905

  • HealthPartners Specialty Center

    Saint Paul, Minnesota, 55130-5302

  • University of Utah - Imaging & Neurosciences Center

    Salt Lake City, Utah, 84108

  • California Pacific Medical Center

    San Francisco, California, 94115

  • Swedish Neuroscience Institute

    Seattle, Washington, 98122

  • University of Washington Medical Center

    Seattle, Washington, 98195

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • University of South Florida

    Tampa, Florida, 33612

  • Georgetown University

    Washington D.C., District of Columbia, 20007

  • The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion

    Washington D.C., District of Columbia, 20037

  • Wake Forest University Baptist Medical Center

    Winston-Salem, North Carolina, 27157-1023

Other trials in United States

Canada9 sites

  • Alberta Health Services - Neuromuscular Clinic

    Calgary, Alberta, T3M 1M4

  • University of Alberta

    Edmonton, Alberta, T6G 2G3

  • Stan Cassidy Centre for Rehabilitation

    Fredericton, New Brunswick, E3B 0C7

  • McMaster University Medical Centre

    Hamilton, Ontario, L8N 3Z5

  • Moncton Hospital, Southeast Regional Health Authority

    Moncton, New Brunswick, E1C 2Z3

  • Centre De Recherche Du Centre Hospitalier de l'Universite de Montreal - Hopital Notre-Dame

    Montreal, Quebec, H2L 4M1

  • Montreal Neurological Institute and Hospital

    Montreal, Quebec, H3A 2B4

  • Centre Hospitalier Affilie Universitaire de Quebec

    Québec, Quebec, G1J 1Z4

  • Sunnybrook Health Sciences Centre

    Toronto, Ontario, M4N 3M5

Other trials in Canada

Germany9 sites

  • Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum

    Berlin, 13353

  • Universitätsklinikum Carl Gustav Carus

    Dresden, Saxony, 01307

  • Alfried Krupp Krankenhaus Rüttenscheid

    Essen, North Rhine-Westphalia, 45131

  • Medizinische Hochschule Hannover

    Hanover, Lower Saxony, 30625

  • Universitätsklinikum Jena

    Jena, Thuringia, 07747

  • Universitätsklinikum Münster

    Münster, North Rhine-Westphalia, 48149

  • Universitätsmedizin Rostock

    Rostock, Mecklenburg-western-pommerania, 18147

  • Universitätsklinikum Ulm

    Ulm, Baden-Wurttemberg, 89081

  • Deutsche Klinik für Diagnostik

    Wiesbaden, Hesse, 65191

Other trials in Germany

Italy6 sites

  • Azienda Ospedaliera Universitaria San Martino

    Genova, 16132

  • Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara

    Novara, 28100

  • ICS Maugeri Spa SB

    Pavia, 27100

  • Azienda Ospedaliero-Universitaria Pisana Ospedale Santa Chiara

    Pisa, 56126

  • Policlinico Umberto I di Roma

    Roma, 0016

  • Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino

    Torino, 10126

Other trials in Italy

Australia5 sites

  • Flinders Medical Centre

    Bedford Park, South Australia, 5042

  • Royal Brisbane and Women's Hospital

    Brisbane, Queensland, 4029

  • Brain and Mind Centre

    Camperdown, New South Wales, 2050

  • Calvary Health Care Bethlehem

    Caulfield South, Victoria, 3162

  • Perron Institute for Neurological and Translational Science

    Murdoch, Western Australia, 6150

Other trials in Australia

Spain5 sites

  • Hospital Universitari de Bellvitge

    Barcelona, 08207

  • Hospital de Basurto

    Bilbao, Vizcaya, 48013

  • Hospital Universitario Reina Sofia

    Córdoba, 14011

  • Hospital San Rafael - Madrid

    Madrid, 28016

  • Hospital Universitario y Politécnico de La Fe

    Valencia, 46026

Other trials in Spain

France4 sites

  • Centre Hospitalier Universitaire de Limoges

    Limoges, 87042

  • Hôpital Gui de Chauliac

    Montpellier, 34295

  • Hôpital Pasteur

    Nice, 06202

  • Centre Hospitalier Régional et Universitaire de Tours Hôpital Bretonneau

    Tours, 37044

Other trials in France

Austria3 sites

  • Universität Innsbruck

    Innsbruck, Tyrol, 6020

  • Medizinische Universität Wien

    Vienna, 1090

  • Salzkammergut-Klinikum Vöcklabruck

    Vöcklabruck, Upper Austria, 4840

Other trials in Austria

Belgium3 sites

  • Algemeen Ziekenhuis St. Lucas Gent

    Ghent, Oost-Vlaanderen, 9000

  • Universitaire Ziekenhuis Leuven

    Leuven, Flemish Brabant, 3000

  • Centre Hospitalier Régional de la Citadelle

    Liège, Liege, 4000

Other trials in Belgium

Finland3 sites

  • Neurologian Poliklinikka - Meilahden Tornisairaala 3

    Helsinki, 00029

  • Etelä-Karjalan keskussairaala

    Lappeenranta, 53130

  • Turku University Hospital

    Turku, 20521

Other trials in Finland

Sweden3 sites

  • Centralsjukhuset Karlstad

    Karlstad, 651 85

  • Karolinska Universitetssjukhuset

    Stockholm, 14186

  • Norrlands Universitetssjukhus

    Umeå, Västerbotten County, 90737

Other trials in Sweden

United Kingdom3 sites

  • The Walton Centre NHS Foundation Trust

    Liverpool, L9 7LJ

  • Barts Health NHS Trust

    London, England, E1 1BB

  • King's College Hospital NHS Foundation Trust

    London, England, SE5 9RS

Other trials in United Kingdom

Netherlands2 sites

  • Academisch Medisch Centrum

    Amsterdam, North Holland, 1105 AZ

  • Universitair Medisch Centrum Utrecht - Rudolf Magnus Instituut voor Neurowetenschappen

    Utrecht, 3584 CG

Other trials in Netherlands

Ireland1 site

  • Beaumont Hospital - Ireland

    Dublin, 9

Other trials in Ireland

About this study

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.

Being tested
Levosimendan, Placebo for levosimendan
Medical subject headings
Amyotrophic Lateral Sclerosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LevosimendanDrug

    Also called ODM-109

    Levosimendan 1 mg capsule for oral administration

  • Placebo for levosimendanDrug

    Also called Placebo for ODM-109

    Placebo capsule for oral administration

Study groups in NCT03505021
Study groupRoleWhat they receive
LevosimendanExperimentalLevosimendan 1 mg capsules for oral administration, once to twice a day. The total duration of treatment 48 weeks
Receives: Drug: Levosimendan
Placebo for levosimendanPlacebo comparatorPlacebo capsule for oral administration, once to twice a day. The total duration of treatment 48 weeks.
Receives: Drug: Placebo for levosimendan

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Supine Slow Vital Capacity (SVC)

    Change from baseline to 12 weeks, expressed as % of predicted normal.

    Measured: The change from baseline at 12 weeks

Secondary outcomes (5)

  1. 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.

    Measured: Mean rank at 48 weeks

  2. 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.

    Measured: Time to event through 48 weeks

  3. 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.

    Measured: The change from baseline at 48 weeks

  4. 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.

    Measured: Slope of decline at 48 weeks

  5. 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.

    Measured: Change from baseline at 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Apr 2018
  2. Study start21 Jun 2018
  3. Primary completion23 Jul 2020
  4. Study completion23 Jul 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
496 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03505021
Sponsor's protocol ID
3119002
Acronym
REFALS
Status last verified
Apr 2022
First submitted
16 Apr 2018
Last updated
11 May 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 34536404

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Levosimendan in people with Amyotrophic Lateral Sclerosis, run by Orion Corporation, Orion Pharma at 104 sites in 14 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 104 sites in United States, Canada, Germany, Italy, Australia and 9 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 31 Aug 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Supine Slow Vital Capacity (SVC) (time frame: The change from baseline at 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03505021, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2022.

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