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Amyotrophic Lateral SclerosisPhase 3REFALS-ESNCT03948178

Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension

A Phase 3 study testing Levosimendan in people with Amyotrophic Lateral Sclerosis, run by Orion Corporation, Orion Pharma at 79 sites in 14 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This study provides an opportunity for subjects in the REFALS (3119002; NCT03505021) study to continue treatment with oral levosimendan. The study will also provide more information about long-term safety and effectiveness of oral levosimendan in patients with ALS. 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?
No, everyone receives an active treatment
How many people
227 participants
Where
79 sitesin 14 countries
Study dates
26 Jun 2019to 18 Nov 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
  • Subjects who completed 48 weeks of treatment according to the REFALS study protocol
  • Able to swallow study treatment capsules at the time of completing 48 weeks dosing in the REFALS study

Who cannot join

  • Development (or significant worsening from baseline of the REFALS study) of serious cardiovascular disease (e.g.: myocardial infarction, heart failure, arrhythmia, stroke, or second or third degree atrioventricular (AV) block)
  • Pulse/heart rate repeatedly >100 bpm after 5-minute rest at baseline. If the pulse/heart rate is >100 bpm in the first recording, then a second recording must be done after another 5 min rest to confirm pulse/heart rate >100 bpm
  • Systolic blood pressure (SBP) <90 mmHg
  • Severe renal impairment (creatinine clearance < 30ml/min or creatine >170 µmol/l at 48 week visit of the REFALS study, or on dialysis
  • Severe hepatic impairment at the discretion of the investigator
  • Women of reproductive age without a negative pregnancy test and without a commitment to using a highly effective method of contraception (e.g.: oral hormonal contraceptive associated with inhibition of ovulation, intrauterine devices and long acting progestin agent), 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
  • Subject judged to be actively suicidal by the investigator
  • Any other clinical 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

79 sites in 14 countries.

79 sites in 14 countries

United States31 sites

  • University of Michigan, Michigan Medicine University Hospital

    Ann Arbor, Michigan, 48109

  • Augusta University, Medical Centre

    Augusta, Georgia, 30912

  • Johns Hopkins Hospital

    Baltimore, Maryland, 21287

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Neurosciences Institute - Neurology Charlotte

    Charlotte, North Carolina, 28207

  • Northwestern University Feinberg School of Medicine

    Chicago, Illinois, 60611

  • University of Chicago

    Chicago, Illinois, 60637

  • The Ohio State University Wexner Medical center

    Columbus, Ohio, 43210

  • Holy Cross Hospital Neuroscience Institute

    Fort Lauderdale, Florida, 33308

  • University of Florida McKnight Brain Institute

    Gainesville, Florida, 32611

  • Nerve and Muscle Centre of Texas

    Houston, Texas, 77030

  • Mayo Clinic Jacksonville

    Jacksonville, Florida, 32224

  • University of California San Diego

    La Jolla, California, 92037-0886

  • Neurology Associates

    Lincoln, Nebraska, 68506

  • Hospital for Special Care

    New Britain, Connecticut, 06053

  • Hospital for Special Surgery

    New York, New York, 10021

  • Columbia Presbyterian Hospital

    New York, New York, 10032

  • University of California Irvine Medical Center

    Orange, California, 92868

  • Neuromuscular research Centre and Neuromuscular Clinic of Arizona

    Phoenix, Arizona, 85028

  • Alleghenay 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

  • Health Partners Speciality Center

    Saint Paul, Minnesota, 55130-5302

  • University of Utah Health-Imaging & Neurosciences Center in research Park

    Salt Lake City, Utah, 84132

  • University of Washington Medical Center

    Seattle, Washington, 98195

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • University of South Florida/USF Health

    Tampa, Florida, 33612

  • Georgetown University

    Washington D.C., District of Columbia, 20007

  • The George Washington Medical Faculty Associates

    Washington D.C., District of Columbia, 20037

  • Wake Forest University Baptist Medical Center

    Winston-Salem, North Carolina, 27157-1023

Other trials in United States

Canada7 sites

  • Alberta Health Services-Neuromuscular Clinic

    Calgary, Alberta, T3M 1M4

  • University of Alberta, Division of Neurology

    Edmonton, Alberta, T6G 2G3

  • Stan Cassidy Centre for Rehabilitation

    Fredericton, New Brunswick, E3B 0C7

  • McMaster University Medical Centre

    Hamilton, Ontario, L8N 3Z5

  • 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

Germany7 sites

  • Charite Universitatmedizin Berlin- Campus Virchow-Klinikum

    Berlin, 13353

  • Medizinische Hochschule Hannover

    Hanover, 30625

  • Universitatsklinikum Jena, Klinik fur Neurologie

    Jena, 07747

  • Universitatsklinikum Munster, Institut fur Schalfmedizin und Neuromuskalaire Erkrankungen

    Münster, 48149

  • Universitatsmedizin Rostock, Klinik und Poliklinik fuer Neurologie

    Rostock, 18147

  • Universitatsklinikum Ulm, Poliklinik fur Neurologie

    Ulm, 89081

  • Deutsche Klinik fur Daignostik

    Wiesbaden, 65191

Other trials in Germany

Italy6 sites

  • Azienda Policlinico San Martino

    Genova, 16132

  • ICS Maugeri Spa S UO Riabilitazione Nurologica

    Milan, 20138

  • Azienda Ospedaliera Universitaria-maggiore della Carita di Novara

    Novara, 28100

  • Azienda Ospedaliero Universitaria Pisana Ospedale Santa Chiara

    Pisa, 56126

  • Policlinico Umberto I di Roma Clinica Neurologica

    Rome, 00161

  • Azienda Ospedaliera Universitaria Citta della Salute e della Scienza di Torino

    Torino, 10126

Other trials in Italy

Australia5 sites

  • Flinders Medical Centre

    Bedford Park, South Australia, 5042

  • Brain and Mind Centre

    Camperdown, New South Wales, 2050

  • Royal Brisbane and Women's Hospital

    Herston, Queensland, 4029

  • Perron Institute for Neurological and Translational Science

    Nedlands, Western Australia, 6009

  • Calvary Health Care Bethlehem

    Parkdale, Victoria, 3195

Other trials in Australia

Spain5 sites

  • Hospital Universitari de Bellvitge

    Barcelona, 08207

  • Hospital Universitario de Basurto

    Bilbao, 48013

  • Hospital Universitario Reina Sofia Servicio Neurologia

    Córdoba, 14011

  • Hospital San Rafael

    Madrid, 28016

  • Hospital Universitario y Politecnico de La Fe

    Valencia, 46026

Other trials in Spain

Austria3 sites

  • Medizinische Universitat Innsbruck

    Innsbruck, Tyrol, 6020

  • Salzqammergut-klinikum Vocklabruck, Neurologie

    Vöcklabruck, Upper Austria, 4840

  • Medizinische Universitat wein Universitatsklinik ffur Neurologie

    Wein, 1090

Other trials in Austria

Belgium3 sites

  • Algemeen Ziekenhuis St Lucas Gent

    Ghent, 9000

  • Universitair Ziekenhuis Leuven

    Leuven, 3000

  • Centre Hospitalier Regional de la Vitadelle

    Liège, 4000

Other trials in Belgium

France3 sites

  • Centre Hospitalier Universitaire de Limoges Service de Neurologie

    Limoges

  • Hopital Gui de Chauliac Service de Neurologie

    Montpellier, 34295

  • Hopital Pasteur Centre de reference des Malades Neuromusculaires et SLA

    Nice, 06202

Other trials in France

Sweden3 sites

  • Karlstad Central Hospital Neurology and Rehabilitation

    Karlstad

  • Karolinska University Horpital Huddinge Neurology Clinic

    Stockholm, 14186

  • Norrlanda University Hospital Neuro-huvud-hals-centrum Vasterbotten

    Umeå, 90185

Other trials in Sweden

Finland2 sites

  • Helsinki University Central Hospital, Neurology Outpatients Clinic

    Helsinki, 00029

  • Turku University Hospital

    Turku, 20521

Other trials in Finland

United Kingdom2 sites

  • The Walton Centre NHs Foundation Trust, Neurology and Neurosurgery

    Liverpool, L9 7LJ

  • Barts Health NHS Trust Royal London hospital

    London, E1 1BB

Other trials in United Kingdom

Ireland1 site

  • Beaumont Hospital, Clinical Research Centre

    Dublin

Other trials in Ireland

Netherlands1 site

  • Univeritair Medisch Centrum Utrech

    Utrecht, 3584

Other trials in Netherlands

About this study

Official title: Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS: Open-Label Extension for Patients Completing Study 3119002

This study provides an opportunity for subjects in the REFALS (3119002; NCT03505021) study to continue treatment with oral levosimendan. The study will also provide more information about long-term safety and effectiveness of oral levosimendan in patients with ALS.

This is an open-label study, so that all eligible subjects that complete the double-blind REFALS study (48-weeks of treatment) will have the opportunity to receive oral levosimendan treatment. The primary objective, in addition to continuing treatment for subjects enrolled in the REFALS study, is to evaluate long-term safety of oral levosimendan in ALS patients. Another important objective is to explore long-term effectiveness of oral levosimendan in the treatment of patients with ALS.

This study is open only to patients taking part in the REFALS study.

Being tested
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

Study groups in NCT03948178
Study groupRoleWhat they receive
LevosimendanExperimentalOral Levosimendan; Levosimendan 1mg capsules for oral administration, once to twice a day, continued as long as clinically beneficial. The total study duration is up to 3 years.
Receives: Drug: Levosimendan

What is being measured

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

  1. Adverse Events Recording

    Adverse Events as subject counts and proportions (%) of subject per Adverse Event

    Measured: From signing informed consent until 14-25 days after the last study treatment for all patients, an average of 23.5 weeks.

  2. Pulse/Heart Rate Assessment

    Actual values and changes from baseline in supine pre-dose pulse/heart rate were summarised using descriptive statistics .

    Measured: Change in pulse and heart rate(from ECG recording) from Baseline, week 2, week 4, week 6 (pulse rate only), Month 3, Month 6, end of study (subject's last visit, 2-48 weeks after study entry)

  3. 12-lead Electrocardiogram Assessments

    Summarisation of any abnormal 12-lead ECG findings using descriptive statistics.

    Measured: Baseline, week 2, week 4, month 3, month 6, end-of-study(subject's last visit, 2-48 weeks after study entry)

Secondary outcomes (10)

  1. Disease Progression

    Count of study withdrawals due to disease progression

    Measured: From Baseline through study completion(subject's last visit, 2-48 weeks after study entry)

  2. Supine Slow Vital Capacity (SVC)

    Change from baseline in supine and sitting SVC (all devices) through to the end of the study, expressed as a % of predicted normal

    Measured: The change from Baseline, week 2, week 4, month 3, month 6, end-of-study (subject's last visit, 2-48 weeks after study entry)

  3. Revised ALS Functional Rating Scale (ALSFRS-R)

    ALSFRS-R scale contains 3 parameters related to respiratory function: Severity of dyspnea, occurrence of orthopnea (shortness of breath when in supine position i.e. lying flat), and the use of mechanical ventilation for respiratory in sufficiency. These 3 parameters are combined to create the respiratory domain with a score of 0-12(where 12 is 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 ro reduce the slope of decline.

    Measured: Change from Baseline in respiratory function of ALSFRS-R at study completion (subject's last visit, 2-48 weeks after study entry)

  4. Need for Respiratory Support Device

    Time to respiratory device support (non invasive) or death

    Measured: Time to event at study completion (subject's last visit, 2-48 weeks after study entry)

  5. Borg Category Ratio 10 Scale (CR 10)

    Patients rated their perception of the severity of their dyspnea using the Borg Category Ration 10 scale (CR 10). The scale ranges from 0(no dysponea) to 10 (maximal dyspnea). each category is numbered and most but 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 to the end of the study in both a supine and sitting position where a negative score indicates improvement and a positive score reflects worsening.

    Measured: Baseline through study completion (week 2, week 4, month 3, month 6, end of study (subject's last visit, 2-48 weeks after study entry)

  6. Number of Subjects Requiring Health and Home Care Resource Use

    The number of study subjects requiring Health and home care resource use was aggregated over the course of the study for each subject and summarised using descriptive statistics.

    Measured: Baseline through study completion (2- 48 weeks after study entry)

  7. Subject's Status for Tracheostomy and Survival

    Number of patients with the need for tracheostomy or who died whilst on treatment from baseline to the end of the study was summarised using descriptive statistics.

    Measured: Baseline to end of study (average 2-48 weeks after study entry

  8. Health Care Service Use During the Study(Stays in Hospital)

    The number of night stays in hospital were recorded throughout the study using a diary given to the study subjects

    Measured: From baseline to the end of the study(2-48 weeks after study entry)

  9. Health Care Service Use During the Study(Visits to the Emergency Room)

    The number of visits to the emergency room were recorded throughout the study using a diary given to the study subjects

    Measured: From baseline to the end of the study(2-48 weeks after study entry)

  10. Health Care Service Use During the Study (Days Spent in an Institutional Facility)

    The number of days spent in an institutional facility were recorded throughout the study using a diary given to the study subjects

    Measured: From baseline to the end of the study(2-48 weeks after study entry)

Timeline

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

  1. First posted13 May 2019
  2. Study start26 Jun 2019
  3. Primary completion18 Nov 2020
  4. Study completion18 Nov 2020

Why it stopped: This was an open label extension for patients completing the REFALS study (3119002; NCT03505021). Study 3119002 showed lack of efficacy of ODM109 so the sponsor decided to terminate this study

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
227 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03948178
Sponsor's protocol ID
3119003
Acronym
REFALS-ES
Status last verified
Feb 2023
First submitted
7 May 2019
Last updated
9 Mar 2023
Data monitoring committee
No
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 79 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 3 inclusion and 8 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: stopped early, as of the sponsor's last update on 9 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 79 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. 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 9 Mar 2023). 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?

Adverse Events Recording (time frame: From signing informed consent until 14-25 days after the last study treatment for all patients, an average of 23.5 weeks.). The study lists 3 primary outcomes in all. 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 NCT03948178, 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 9 Mar 2023.

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