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    Summary
    EudraCT Number:2018-004180-31
    Sponsor's Protocol Code Number:3119003
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-01-18
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-004180-31
    A.3Full title of the trial
    Effects of oral Levosimendan (ODM-109) on respiratory function in patients with ALS: open label extension for patients completing study 3119002
    Effetti di levosimendan orale (ODM-109) sulla funzionalità respiratoria nei pazienti con sclerosi laterale amiotrofica: estensione in aperto per i pazienti che completano lo studio 3119002
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open label extension for patients completing study 3119002 to study the effects of oral Levosimendan on breathing function in patients with the disease Amyotrophic Lateral Sclerosis (ALS)
    Uno studio di estensione in aperto per i pazienti che completano lo studio 3119002 per valutare gli effetti di levosimendan orale sulla funzionalità respiratoria nei pazienti con sclerosi laterale amiotrofica (SLA)
    A.3.2Name or abbreviated title of the trial where available
    REFALS-ES
    REFALS-ES
    A.4.1Sponsor's protocol code number3119003
    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 ORION PHARMA
    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 Organization
    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 number00358104263059
    B.5.5Fax number0000000000000
    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, hard
    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
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    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)
    Sclerosi Laterale Amiotrofica (SLA)
    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.
    SLA è un disordine che impatta sulla funzionalità di nervi e muscoli, togliendo progres la capacità di camminare, vestirsi, scrivere, parlare, deglutire e respirare e accorciando la durata della vita.
    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 21.1
    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, in addition to continuing treatment for subjects in this study, is to evaluate long-term safety of oral levosimendan in amyotrophic lateral sclerosis (ALS) patients.
    L'obiettivo primario, oltre a continuare il trattamento per i soggetti inclusi in questo studio, è valutare la sicurezza a lungo termine di levosimendan orale nei pazienti affetti da sclerosi laterale amiotrofica (SLA).
    E.2.2Secondary objectives of the trial
    The secondary objective is to explore long-term effectiveness of oral levosimendan in the treatment of patients with ALS, by continuing to observe rate of disease progression during the treatment.
    L'obiettivo secondario è valutare l'efficacia a lungo termine di levosimendan orale nel trattamento dei pazienti affetti da SLA, continuando a osservare il tasso di progressione della malattia durante il trattamento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet all of the following criteria to be included into the
    study:
    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, a witness may sign the consent form to
    indicate that the subject has given verbal consent.
    2. Subjects who completed 48 weeks of treatment according to the
    REFALS study protocol.
    3. Able to swallow study treatment capsules at the time of completing 48
    weeks dosing in the REFALS study
    I soggetti devono soddisfare tutti i criteri seguenti per essere inclusi nello studio:
    1. Il soggetto dovrà fornire il consenso informato (CI) scritto o orale alla partecipazione allo studio. Nel caso in cui il soggetto dello studio non sia in grado di firmare personalmente il CI, il modulo di consenso potrà essere firmato da un testimone per indicare che il soggetto ha fornito il consenso orale.
    2. Soggetti che hanno portato a termine le 48 settimane di trattamento secondo il protocollo dello studio REFALS.
    3. Capacità di deglutire le capsule del trattamento dello studio una volta portate a termine le 48 settimane di somministrazione nello studio REFALS.
    E.4Principal exclusion criteria
    Subjects will not be included into this study if they meet any of the
    following criteria:
    1. 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).
    2. 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.
    3. Systolic blood pressure (SBP) < 90 mmHg.
    4. Severe renal impairment (creatinine clearance < 30 ml/min or
    creatinine > 170 µmol/l at 48 week visit of the REFALS study, or on
    dialysis.
    5. Severe hepatic impairment at the discretion of the investigator.
    6. 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 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.
    7. Subject judged to be actively suicidal by the investigator.
    8. 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.
    I soggetti non saranno inclusi nello studio se soddisfano uno qualunque dei seguenti criteri:
    1. Sviluppo (o peggioramento significativo rispetto al basale dello studio REFALS) di malattia cardiovascolare grave (per es. infarto miocardico, insufficienza cardiaca, aritmia, ictus o blocco atrioventricolare [AV] di secondo o di terzo grado).
    2. Polso/frequenza cardiaca ripetutamente >100 battiti al minuto dopo 5 minuti di riposo al basale. Se il polso/frequenza cardiaca è >100 battiti al minuto alla prima misurazione, è necessario eseguire una seconda misurazione dopo altri 5 minuti di riposo per confermare che il valore sia >100 battiti al minuto.
    3. Pressione arteriosa sistolica (PAS) <90 mmHg.
    4. Compromissione renale severa (clearance della creatinina <30 ml/min o creatinina >170 µmol/l) alla visita a 48 settimane dello studio REFALS oppure necessità di dialisi.
    5. Compromissione epatica severa a discrezione dello sperimentatore.
    6. Le donne in età riproduttiva che non mostrino un risultato negativo del test di gravidanza e non si impegnino a utilizzare un metodo di contraccezione altamente efficace (per es. contraccettivi ormonali orali associati all'inibizione dell'ovulazione, dispositivi intrauterini e prodotti progestinici a lunga durata d'azione), se sessualmente attive, durante lo studio e per 1 mese dopo l'ultima dose di trattamento dello studio. Le donne post-menopausali (1 anno dall'ultimo ciclo mestruale), sterilizzate chirurgicamente o sottoposte a isterectomia non sono considerate fertili e possono essere incluse.
    7. Soggetto giudicato attivamente suicida dallo sperimentatore.
    8. Qualsiasi altro disturbo cardiovascolare, gastrointestinale, epatico, renale, neurologico o psichiatrico clinicamente significativo o qualsiasi altra malattia concomitante maggiore che secondo il parere dello sperimentatore potrebbe interferire con l'interpretazione dei risultati dello studio o costituire un rischio per la salute del soggetto qualora questi prenda parte allo studio.
    E.5 End points
    E.5.1Primary end point(s)
    This study is not endpoint driven. The primary and secondary objectives are summarized below. Safety will be assessed by adverse events (AEs), vital signs, 12-lead electrocardiogram (ECG) and by assessment of suicidality.
    Questo studio non è basato su endpoint. Gli obiettivi primari e secondari sono riassunti di seguito. La sicurezza sarà valutata mediante eventi avversi (AE), segni vitali, elettrocardiogramma a 12 derivazioni (ECG) e tramite valutazione di suicidalità.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The analysis will take place at end of the study, and be summarized with and without data from REFALS 3119002 study.
    L'analisi verrà eseguita al termine dello studio e sarà riassunta con e senza i dati dello studio REFALS 3119002.
    E.5.2Secondary end point(s)
    Secondary objectives is efficacy and include:
    Slope of decline in sitting and supine SVC and ALSFRS-R will be estimated using a random slope model.
    Median time to non-invasive mask ventilation (NIV) or death and to decline (by at least 1 point) in the ALSFRS-R
    respiratory domain will be evaluated using Kaplan-Meier estimates.
    Borg CR10 (sitting, supine and orthostatic changes) will be evaluated using mixed model for repeated measures.
    Health and home care resource use data will be summarized in the study report, but any further analysis for potential pharmacoeconomic purposes will be reported separately.
    L'obiettivo secondario è l'efficacia e comprende:
    La pendenza della diminuzione della capacità vitale lenta (SVC) e della scala di valutazione funzionale rivista della SLA (ALSFRS-R) tra seduti e supini sarà stimata utilizzando un modello casuale di pendenza.
    Il tempo mediano di ventilazione meccanica non invasiva (NIV) o morte e di diminuzione (di almeno 1 punto) nel dominio respiratorio dell’ALSFRS-R sarà valutato utilizzando le stime di Kaplan-Meier.
    La scala di Borg CR10 (passaggio da posizione seduta a posizione supina ed ortostatica) sarà valutata utilizzando il modello misto per misure ripetute. I dati relativi all’utilizzo dell’ausilio medico e dell’assistenza a domicilio saranno riassunti nella relazione dello studio, ma un’eventuale ulteriore analisi per potenziali scopi farmacoenomici sarà registrata separatamente.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The analysis will take place at end of the study, and be summarized with and without data from REFALS 3119002 study.
    L' analisi verrà eseguita al termine dello studio e sarà riassunta con e senza i dati dello studio REFALS 3119002.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    in aperto
    open
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned6
    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 Information not present in EudraCT
    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
    Canada
    United States
    Austria
    Belgium
    Finland
    France
    Germany
    Ireland
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    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
    LPLV
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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 state17
    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)
    This study provides an opportunity for subjects in the REFALS study to
    continue treatment with oral levosimendan. The study will continue
    until the time of marketing approval of oral levosimendan, cessation of
    development of oral levosimendan for ALS, or 3 years, whichever
    occurs first in each participating country. On termination of the study,
    an appropriate method of continued treatment supply will be sought for
    any subjects still requiring treatment with oral levosimendan.
    Questo studio fornisce l’opportunità di continuare il trattamento con levosimendan per via orale. Lo studio continuerà fino al momento dell’AIC di levosimendan per via orale, dell’eventuale sospensione dello sviluppo di levosimendan per via orale per la SLA o dopo 3 anni, a seconda di quale evento si verifichi prima in ciascun paese. Al termine dello studio, si cercherà un metodo di proseg della terapia per i soggetti che richiedano ancora il tratt con levosimendan per via orale [riassunto..]
    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 Decision2019-07-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-11
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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