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    Summary
    EudraCT Number:2017-002754-36
    Sponsor's Protocol Code Number:3119002
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-11-27
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2017-002754-36
    A.3Full title of the trial
    Effects of oral levosimendan (ODM-109) on respiratory function in patients with ALS
    Effets du lévosimendan oral (ODM-109) sur la fonction respiratoire des patients atteints de SLA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects of oral levosimendan on breathing function in patients with the disease Amyotrophic Lateral Sclerosis (ALS)
    A.3.2Name or abbreviated title of the trial where available
    REFALS
    A.4.1Sponsor's protocol code number3119002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03505021
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOrion Corporation
    B.1.3.4CountryFinland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOrion Corporation
    B.4.2CountryFinland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOrion Corporation
    B.5.2Functional name of contact pointSenior Regulatory Affairs Manager
    B.5.3 Address:
    B.5.3.1Street AddressOrionintie 1A
    B.5.3.2Town/ cityEspoo
    B.5.3.3Post codeFI-02200
    B.5.3.4CountryFinland
    B.5.4Telephone number+358104263059
    B.5.6E-mailclinicaltrials@orionpharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/18/1980
    D.3 Description of the IMP
    D.3.1Product nameOral LEVOSIMENDAN
    D.3.2Product code ODM-109
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLEVOSIMENDAN
    D.3.9.1CAS number 141505-33-1
    D.3.9.2Current sponsor codeODM-109
    D.3.9.4EV Substance CodeSUB08493MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Amyotrophic lateral sclerosis (ALS)
    E.1.1.1Medical condition in easily understood language
    ALS is a disorder that affects the function of nerves and muscles,eventually taking away the ability to walk, dress, write, speak, swallow, and breathe and shortening the life span.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10002026
    E.1.2Term Amyotrophic lateral sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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), Borg Category Ratio 10
    (CR10) scale on dyspnea (shortness of breath), 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.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional Future Genetic Research, as part of the main protocol. The DNA of subjects who have given a separate Pharmacogenetic Informed Consent will be stored to allow possible exploratory PG research to assess whether genetic polymorphisms relate to the absorption, distribution, metabolism, excretion, pharmacodynamics or safety of levosimendan.
    E.3Principal 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 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.
    E.4Principal 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 tirasemtiv or reldesemtiv 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. Severe renal impairment (creatinine clearance < 30 ml/min at screening), creatinine > 170 μmol/l at screening or on dialysis.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 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.
    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 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.
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy variable SVC % measured in supine position.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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 through 48 weeks
    4. Supine Borg CR 10 scale at 12 weeks
    5. Slope of decline in respiratory function of ALSFRS-R through 48 weeks

    The efficacy variables time to respiratory event, time to NIV or death, time to SVC (supine) decline of 20%, time to SVC (supine) ≤ 50% of predicted, time to ALSFRS-R total score decline of 20% and time to decline in ALSFRS-R respiratory domain will be evaluated.
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA43
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    Finland
    France
    Germany
    Ireland
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS (Last visit last subject)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 440
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 290
    F.4.2.2In the whole clinical trial 450
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There is an option to continue levosimendan treatment once the study subject has completed 48
    weeks of treatment and the end-of-study visit of the current study in the form of an
    open-label extension study. Details will be included in a future protocol amendment before the first patient reaches end of study visit.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-01-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-06-25
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