Effects of oral Levosimendan on breathing function in patients with the disease Amyotrophic Lateral Sclerosis (ALS)

• Register: EUCTR
• Last refreshed on: 8 October 2021
• Main ID: EUCTR2017-002754-36-ES
• Date of registration: 14/03/2018
• Prospective Registration: Yes
• Primary sponsor: Orion Corporation
• Public title: Effects of oral Levosimendan on breathing function in patients with the disease Amyotrophic Lateral Sclerosis (ALS)
• Scientific title: Effects of oral Levosimendan (ODM-109) on respiratory function in patients with ALS - REFALS
• Date of first enrolment: 29/04/2018
• Target sample size: 450
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002754-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Senior Regulatory Affairs Manager
• Affiliation: Orion Corporation

• Name: Senior Regulatory Affairs Manager
• Affiliation: Orion Corporation

Key inclusion & exclusion criteria

Inclusion criteria:
1. Written or verbal informed consent (IC) for participation in the study will be obtained from the subject. In case that the study subject him/herself cannot sign the IC due to severe muscle weakness, a witness may sign the consent form to indicate that the subject has given verbal consent.
2. Age at least 18 years.
3. Male or female subjects with diagnosis of laboratory supported probable, probable or definite ALS according to El Escorial revised criteria (Brooks BR et al., 2000). Full electromyogram (EMG) report available consistent with ALS (but not necessarily fulfilling the electrodiagnostic criteria for ALS) from an experienced neurophysiologist.
4. Able to swallow study treatment capsules, and in the opinion of the investigator, is expected to continue to do so during the study.
5. Sitting SVC between 60-90% of the predicted value for age, height and sex at screening visit.
6. Disease duration from symptom onset (defined by first muscle weakness or dysarthria) 12- 48 months at the time of visit 1 (baseline).
7. Able to perform supine SVC in an adequate and reliable way at screening and baseline visits as judged by the investigator.
8. Subjects with or without riluzole. 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 not on riluzole, the subjects should not start riluzole during the study.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 440
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion criteria:
1. Subject in whom other causes of neuromuscular weakness have not been excluded.
2. Subject with a diagnosis of another neurodegenerative disease (e.g. Parkinson’s or Alzheimer’s disease).
3. Assisted ventilation of any type within 3 months before the screening visit or at screening.
4. Any use of a diaphragm pacing system (DPS) within 3 months before the screening visit.
5. Any form of stem cell or gene therapy for the treatment of ALS.
6. Known hypersensitivity to levosimendan.
7. 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).
8. Any use of edaravone, tirasemtiv or CK-2127107 within 1 month before the screening visit.
9. 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.
10. Any botulinum toxin use within 3 months before the screening visit.
11. 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.
12. Pulmonary illness (e.g. asthma or COPD) requiring regular treatment.
13. Haemodynamically significant uncorrected valve disease or hypertrophic cardiomyopathy or restrictive cardiomyopathy.
14. Any cardiovascular event (e.g. myocardial infarction, HF, arrhythmia or stroke) requiring hospitalisation within 3 months before the screening visit.
15. History of Torsades de Pointes (TdP) or diagnosed long QT-syndrome.
16. 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).
17. History of second or third degree atrioventricular (AV) block or sinus node disease at screening, if not treated with pacemaker.
18. 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.
19. Systolic blood pressure (SBP) < 90 mmHg at screening.
20. Potassium < 3.7 mmol/l or > 5.5 mmol/l at screening.
21. Creatinine > 170 µmol/l at screening or on dialysis.
22. Blood haemoglobin < 10 g/dl at screening or blood donation or loss of significant amount of blood within 60 days before the screening visit.
23. Clinically significant hepatic impairment at the discretion of the investigator.
24. Body mass index (BMI) = 18.5kg/m2 (BMI = weight/height2).
25. Women of reproductive age without a negative pregnancy test and without a commitment to using an acceptable method of barrier or hormonal contraception (e.g. condoms, diaphragms, oral contraceptives 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.
26. Patient judged to be actively suicidal by the investigator during 3 months before the screening visit.
27. Patients with known history of human immunodeficiency virus (HIV) infection.
28. Any other clinically significant cardiovascular, gastrointestinal, hepatic, renal, neurological or psychiatr

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Amyotrophic lateral sclerosis (ALS)
MedDRA version: 20.0 Level: PT Classification code 10002026 Term: Amyotrophic lateral sclerosis System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Product Name: Oral LEVOSIMENDAN
Product Code: ODM-109
Pharmaceutical Form: Capsule
INN or Proposed INN: LEVOSIMENDAN
CAS Number: 141505-33-1
Current Sponsor code: ODM-109
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.0-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: The primary objective of this study is to confirm that levosimendan can significantly improve respiratory function measured by supine slow vital capacity (SVC) in amyotrophic lateral sclerosis (ALS) patients.

Secondary Objective: The secondary objective is to confirm that levosimendan improves the functionality of subjects, measured by Revised ALS Functional Rating Scale (ALSFRS-R), Clinical Global Impression (CGI), Epworth Sleepiness scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). The latter two are sleep scales assessing daytime somnolence and sleep quality, respectively.
In addition, the long-term tolerability and safety of levosimendan in ALS patients will be evaluated, assessing up to 48 weeks of exposure.

Timepoint(s) of evaluation of this end point: Primary evaluation will be performed at 12 weeks and contrasts will be used to obtain estimates for each of the visit from the primary model including all SVC measurements prior to 12 weeks. Additional evaluations will be performed including all data through 48 weeks.

Primary end point(s): Primary efficacy variable SVC % measured in supine position.

Secondary Outcome(s)

Secondary end point(s): Secondary efficacy endpoints will be tested in following hierarchy to preserve the overall alpha level:
1. Combined assessment of ALSFRS-R function and survival through 48 weeks
2. Time to respiratory event trough 48 weeks
3. CGI at 48 weeks
4. Change from baseline in respiratory function of ALSFRS-R at 48 weeks
The efficacy variables time to respiratory event, time to NIV or death, time to SVC (supine) decline of 20%, time
to ALSFRS-R total score decline of 20% and time to decline in ALSFRS-R respiratory domain will be evaluated

Timepoint(s) of evaluation of this end point: The total duration for double-blind comparison will be 48 weeks. Interim/futility analyses will be done when approximately 50% and 100% of the subjects have been treated for 12 weeks.

Secondary ID(s)

2017-002754-36-IE

3119002

Source(s) of Monetary Support

Orion Corporation

Ethics review

Status: Approved
Approval date: 10/04/2018
Contact:

Results

• Results available: Yes
• Date Posted: 27/05/2021
• Date Completed: 26/06/2020
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-002754-36/results