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    Summary
    EudraCT Number:2017-002429-39
    Sponsor's Protocol Code Number:Leodor2017
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-12-06
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2017-002429-39
    A.3Full title of the trial
    REPETITIVE LEVOSIMENDAN INFUSIONS FOR PATIENTS WITH ADVANCED CHRONIC HEART FAILURE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    REPETITIVE LEVOSIMENDAN INFUSIONS FOR PATIENTS WITH ADVANCED CHRONIC HEART FAILURE
    A.3.2Name or abbreviated title of the trial where available
    LeoDOR
    A.4.1Sponsor's protocol code numberLeodor2017
    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 SponsorMedical University Innsbruck
    B.1.3.4CountryAustria
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOrion Pharma
    B.4.2CountryFinland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedical University Innsbruck
    B.5.2Functional name of contact pointDr. Gerhard Pölzl
    B.5.3 Address:
    B.5.3.1Street AddressAnichstraße 35
    B.5.3.2Town/ cityInnsbruck
    B.5.3.3Post code6020
    B.5.3.4CountryAustria
    B.5.4Telephone number00435050481318
    B.5.5Fax number00435050425622
    B.5.6E-mailgerhard.poelzl@i-med.ac.at
    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 Yes
    D.2.1.1.1Trade name Simdax 2,5mg/ml
    D.2.1.1.2Name of the Marketing Authorisation holderOrion
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSimdax
    D.3.4Pharmaceutical form Concentrate and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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 codeSimdax
    D.3.9.3Other descriptive nameLevosimendan
    D.3.9.4EV Substance CodeSUB08493MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 placeboConcentrate and solvent for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Advanced chronic heart failure
    E.1.1.1Medical condition in easily understood language
    Advanced chronic heart failure
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary efficacy objective of the study is to compare the effects of pulsed application of levosimendan versus placebo in patients with advanced chronic heart failure during a vulnerable period of 14 weeks following a recent hospitalisation on a global rank endpoint in which all participants are ranked across three hierarchical groups:
    • time to death or high-urgent heart transplantation or ventricular assist device (VAD),
    • time to non-fatal HF event requiring i.v. vasoactive therapy (i.v. diuretics, i.v. vasodilators or i.v. inotropes) and
    • time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to 14 weeks.
    E.2.2Secondary objectives of the trial
    The secondary efficacy objectives are to determine the effects of pulsed application of Levosimendan on:
    a. individual components of the primary endpoint at 14 weeks and 26 weeks (time-averaged proportional change in NT-proBNP from baseline to 14 weeks),
    b. changes in symptoms and functional status at 26 weeks,
    c. number of combined events at 14 and 26 weeks,
    d. cumulative number of AHF events at 14 weeks and 26 weeks,
    e. cumulative number of hospital admissions, and
    f. cumulative days alive and out of hospital
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written, signed and dated informed consent.
    2. Male and female patients over 18 years of age.
    3. Women of childbearing potential must have a monthly negative pregnancy test and must refrain from breastfeeding. Women who are postmenopausal (1 year since last menstrual cycle), surgically sterilised or who have undergone a hysterectomy are considered not to be of childbearing potential.
    4. CHF diagnosed at least 6 months before screening and treated with individually optimised long-term oral treatment for the last month, unless not tolerated (e.g., ACE-inhibitor or AT II blocker, beta-blocker, mineralocorticoid receptor antagonist, angiotensin II receptor blocker neprilysin inhibitor [ARNI] and with devices [e.g., CRT/ICD], as needed).
    5. Left ventricular ejection fraction less than or equal to 30% as assessed using echocardiography, radionuclide ventriculography or contrast angiography within the index hospitalisation.
    6. Currently hospitalised for decompensated HF requiring i.v. diuretics, or i.v. vasodilators, or i.v. inotropic therapy, or their combination.
    7. Previous hospitalisation or visit to outpatient clinic requiring i.v. diuretics, i.v. vasodilators, or i.v. inotropic therapy, or their combination for acute decompensated HF within 12 months before the current hospitalisation.
    8. NT-proBNP level (as measured by the local laboratory) after recompensation of 2500 ng/L and/or NYHA class III or IV at study entry
    E.4Principal exclusion criteria
    1. Severe obstruction of ventricular outflow tracts such as haemodynamically significant uncorrected primary valve disease or hypertrophic cardiomyopathy or impaired ventricular filling such as restrictive cardiomyopathy.
    2. Predominantly right heart failure and/or severe tricuspid regurgitation
    3. Cardiac surgery or coronary angioplasty within 30 days before study drug initiation.
    4. Acute coronary syndrome within 30 days before study drug initiation.
    5. Patients who are scheduled for cardiac surgery or angioplasty in the next 3 months.
    6. History of torsades de pointes.
    7. Stroke or transient ischaemic attack (TIA) within 3 months before study drug initiation.
    8. Systolic blood pressure less than 90 mmHg at baseline.
    9. Heart rate 120 bpm or greater at baseline.
    10. Serum potassium less than 3.5 mmol/l before study drug initiation.
    11. Severe renal insufficiency (estimated glomerular filtration rate [eGFR] less than 30 ml/min/1.73m2).
    12. Anaemia (haemoglobin less than 10 g/dl).
    13. Significant hepatic impairment at discretion of the investigator.
    14. Hypersensitivity to levosimendan.
    15. Other serious diseases limiting life expectancy considerably (e.g. end-stage cancer, end-stage renal disease, end-stage lung disease).
    16. Participation in a clinical trial with any experimental treatment within 30 days prior to screening or previous participation in the present study.
    17. Administration of levosimendan within 14 days prior the study drug initiation. (The first study drug application has to be postponed for at least 14 days after the end of this premedication)
    18. Suspected non-compliance
    19. Pregnant women and nursing mothers
    20. Failure to use highly effective (a Pearl Index lower than 1%) contraceptive methods.
    21. Persons with any kind of dependency on the investigator
    22. Persons held in an institution by legal or official order
    E.5 End points
    E.5.1Primary end point(s)
    The hypothesis will be tested based on a global rank endpoint in which all participants are ranked across three hierarchical groups that include deaths, non-fatal HF events and positive neurohormonal response on NT-proBNP (12). Each patient is given a global rank score based on the outcome during the follow-up. The components are analysed in a hierarchical manner so that deaths are the most important events, followed by non-fatal HF events and finally by the effect on NT-pro-BNP. This hierarchical approach increases the clinical validity of the endpoint:
    1. time to death or high-urgent heart transplantation or VAD,
    2. time to non-fatal HF event requiring i.v. vasoactive therapy (i.v. diuretics, i.v. vasodilators or i.v. inotropes) and
    3. time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to 14 weeks.
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 1 till week 26
    E.5.2Secondary end point(s)
    1. Individual components of the primary endpoint at short-term (14 weeks) and intermediate-term (26 weeks).
    • time to death / high-urgent heart transplantation / VAD implantation
    • time to non-fatal HF event defined as an episode requiring i.v. vasoactive therapy (i.v. diuretic, i.v. inotropic) at week 14 and 26
    • time-averaged proportional change in NT-proBNP from baseline to 14 weeks
    2. Change in functional status
    • 6-minute walk test at baseline and 14 weeks
    • New York Heart Association (NYHA) class at baseline and 14 weeks
    3. Change in symptoms
    • Kansas City Cardiomyopathy Questionnaire (KCCQ) – clinical summary score - from baseline to 14 weeks
    • Difference in the patient global assessment (PGA) between groups at 14 weeks
    4. Number of combined events
    • death / heart transplantation / VAD implantation / non-fatal HF event
    5. Cumulative number of non-fatal HF events
    6. Cumulative number of hospital admissions (non-fatal HF vs cardiovascular admissions vs. non-cardiovascular admissions)
    7. Cumulative days alive and out of hospital
    8. Cumulative number of death and total (first and recurrent) non-fatal HF events
    9. Safety assessment
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 1 till week 26
    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 Yes
    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 No
    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 No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Switzerland
    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
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    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: 52
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 212
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 254
    F.4.2.2In the whole clinical trial 264
    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)
    After the end of the 14 week study period patient are treated according to prevailing guidelines and to the discretion of the treating physician.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-02-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-12-31
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