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

Amyotrophic Lateral Sclerosis Clinical Trial

— REFALS-ES  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03948178
• Other study ID #: 3119003
• Status: Terminated
• Phase: Phase 3
• Start date: June 26, 2019
• Est. completion date: November 18, 2020

Study information

• Verified date: February 2023
• Source: Orion Corporation, Orion Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 227
• Est. completion date: November 18, 2020
• Est. primary completion date: November 18, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

Drug:
• Levosimendan
Levosimendan 1 mg capsule for oral administration

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Brain and Mind Centre	Camperdown	New South Wales
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Perron Institute for Neurological and Translational Science	Nedlands	Western Australia
Australia	Calvary Health Care Bethlehem	Parkdale	Victoria
Austria	Medizinische Universitat Innsbruck	Innsbruck	Tyrol
Austria	Salzqammergut-klinikum Vocklabruck, Neurologie	Vocklabruck	Upper Austria
Austria	Medizinische Universitat wein Universitatsklinik ffur Neurologie	Wein
Belgium	Algemeen Ziekenhuis St Lucas Gent	Gent
Belgium	Universitair Ziekenhuis Leuven	Leuven
Belgium	Centre Hospitalier Regional de la Vitadelle	Liège
Canada	Alberta Health Services-Neuromuscular Clinic	Calgary	Alberta
Canada	University of Alberta, Division of Neurology	Edmonton	Alberta
Canada	Stan Cassidy Centre for Rehabilitation	Fredericton	New Brunswick
Canada	McMaster University Medical Centre	Hamilton	Ontario
Canada	Montreal Neurological Institute and Hospital	Montréal	Quebec
Canada	Centre Hospitalier Affilie Universitaire de Quebec	Québec	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Finland	Helsinki University Central Hospital, Neurology Outpatients Clinic	Helsinki
Finland	Turku University Hospital	Turku
France	Centre Hospitalier Universitaire de Limoges Service de Neurologie	Limoges
France	Hopital Gui de Chauliac Service de Neurologie	Montpellier
France	Hopital Pasteur Centre de reference des Malades Neuromusculaires et SLA	Nice
Germany	Charite Universitatmedizin Berlin- Campus Virchow-Klinikum	Berlin
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitatsklinikum Jena, Klinik fur Neurologie	Jena
Germany	Universitatsklinikum Munster, Institut fur Schalfmedizin und Neuromuskalaire Erkrankungen	Münster
Germany	Universitatsmedizin Rostock, Klinik und Poliklinik fuer Neurologie	Rostock
Germany	Universitatsklinikum Ulm, Poliklinik fur Neurologie	Ulm
Germany	Deutsche Klinik fur Daignostik	Wiesbaden
Ireland	Beaumont Hospital, Clinical Research Centre	Dublin
Italy	Azienda Policlinico San Martino	Genova
Italy	ICS Maugeri Spa S UO Riabilitazione Nurologica	Milan
Italy	Azienda Ospedaliera Universitaria-maggiore della Carita di Novara	Novara
Italy	Azienda Ospedaliero Universitaria Pisana Ospedale Santa Chiara	Pisa
Italy	Policlinico Umberto I di Roma Clinica Neurologica	Rome
Italy	Azienda Ospedaliera Universitaria Citta della Salute e della Scienza di Torino	Torino
Netherlands	Univeritair Medisch Centrum Utrech	Utrecht
Spain	Hospital Universitari de Bellvitge	Barcelona
Spain	Hospital Universitario de Basurto	Bilbao
Spain	Hospital Universitario Reina Sofia Servicio Neurologia	Córdoba
Spain	Hospital San Rafael	Madrid
Spain	Hospital Universitario y Politecnico de La Fe	Valencia
Sweden	Karlstad Central Hospital Neurology and Rehabilitation	Karlstad
Sweden	Karolinska University Horpital Huddinge Neurology Clinic	Stockholm
Sweden	Norrlanda University Hospital Neuro-huvud-hals-centrum Vasterbotten	Umeå
United Kingdom	The Walton Centre NHs Foundation Trust, Neurology and Neurosurgery	Liverpool
United Kingdom	Barts Health NHS Trust Royal London hospital	London
United States	University of Michigan, Michigan Medicine University Hospital	Ann Arbor	Michigan
United States	Augusta University, Medical Centre	Augusta	Georgia
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Neurosciences Institute - Neurology Charlotte	Charlotte	North Carolina
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	The Ohio State University Wexner Medical center	Columbus	Ohio
United States	Holy Cross Hospital Neuroscience Institute	Fort Lauderdale	Florida
United States	University of Florida McKnight Brain Institute	Gainesville	Florida
United States	Nerve and Muscle Centre of Texas	Houston	Texas
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	University of California San Diego	La Jolla	California
United States	Neurology Associates	Lincoln	Nebraska
United States	Hospital for Special Care	New Britain	Connecticut
United States	Columbia Presbyterian Hospital	New York	New York
United States	Hospital for Special Surgery	New York	New York
United States	University of California Irvine Medical Center	Orange	California
United States	Neuromuscular research Centre and Neuromuscular Clinic of Arizona	Phoenix	Arizona
United States	Alleghenay General hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Brain and Spine Institute	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Health Partners Speciality Center	Saint Paul	Minnesota
United States	University of Utah Health-Imaging & Neurosciences Center in research Park	Salt Lake City	Utah
United States	University of Washington Medical Center	Seattle	Washington
United States	University of South Florida/USF Health	Tampa	Florida
United States	Georgetown University	Washington	District of Columbia
United States	The George Washington Medical Faculty Associates	Washington	District of Columbia
United States	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Orion Corporation, Orion Pharma

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Finland,  France,  Germany,  Ireland,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse Events Recording	Adverse Events as subject counts and proportions (%) of subject per Adverse Event	From signing informed consent until 14-25 days after the last study treatment for all patients, an average of 23.5 weeks.
Primary	Pulse/Heart Rate Assessment	Actual values and changes from baseline in supine pre-dose pulse/heart rate were summarised using descriptive statistics .	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)
Primary	12-lead Electrocardiogram Assessments	Summarisation of any abnormal 12-lead ECG findings using descriptive statistics.	Baseline, week 2, week 4, month 3, month 6, end-of-study(subject's last visit, 2-48 weeks after study entry)
Secondary	Disease Progression	Count of study withdrawals due to disease progression	From Baseline through study completion(subject's last visit, 2-48 weeks after study entry)
Secondary	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	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)
Secondary	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.	Change from Baseline in respiratory function of ALSFRS-R at study completion (subject's last visit, 2-48 weeks after study entry)
Secondary	Need for Respiratory Support Device	Time to respiratory device support (non invasive) or death	Time to event at study completion (subject's last visit, 2-48 weeks after study entry)
Secondary	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.	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)
Secondary	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.	Baseline through study completion (2- 48 weeks after study entry)
Secondary	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.	Baseline to end of study (average 2-48 weeks after study entry
Secondary	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	From baseline to the end of the study(2-48 weeks after study entry)
Secondary	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	From baseline to the end of the study(2-48 weeks after study entry)
Secondary	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	From baseline to the end of the study(2-48 weeks after study entry)