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    Summary
    EudraCT Number:2013-000540-26
    Sponsor's Protocol Code Number:CVT-CV-002
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-03-14
    Trial 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 number2013-000540-26
    A.3Full title of the trial
    The clinical study of the safety and efficacy of Istaroxime in Treatment of Acute Decompensated Heart Failure - A multicenter, randomized, double-blind, placebo controlled, parallel group clinical study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study assessing safety and efficacy of Istaroxime in patients affected by acute cardiac insufficiency decompensated. Five centres will be involved. Each patient will receive, in a casual order, one of the two Istaroxime dosages or placebo and therefore there will be three different treatment groups. Nor the patients neither the doctors will know the treatment received/administered.
    A.4.1Sponsor's protocol code numberCVT-CV-002
    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 SponsorCVie Therapeutics Company Limited
    B.1.3.4CountryItaly
    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 supportCVie Therapeutics Company Limited
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCronos Ricerche Cliniche srl
    B.5.2Functional name of contact pointPaola Minguzzi
    B.5.3 Address:
    B.5.3.1Street AddressVia Tonale, 22
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20125
    B.5.3.4CountryItaly
    B.5.4Telephone number00390267382869
    B.5.5Fax number00390267382868
    B.5.6E-mailp.minguzzi@cronosrl.net
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameIstaroxime
    D.3.2Product code PST2744
    D.3.4Pharmaceutical form Powder 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 INNIstaroxime
    D.3.9.1CAS number 374559-48-5
    D.3.9.2Current sponsor codePST 2744
    D.3.9.3Other descriptive name(E,Z)-3-(2-Aminoethoxyimino)androstane-6,17-dione hydrochloride Androstane-3,6,17-trione (E,Z)-3-[O-(2-aminoethyl)]oxime hydrochloride
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 placeboPowder 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
    Acute heart failure decompensated
    E.1.1.1Medical condition in easily understood language
    Acute cardiac insufficiency decompensated
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10066332
    E.1.2Term Acute cardiac insufficiency
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To Assess the safety, tolerability and efficacy of two different doses of istaroxime (0.5 and 1.0 μg/kg/min), a new agent with lusitropic and inotropic activities that improves the cardiac contraction-relaxation cycle. The 2 doses of istaroxime (0.5 and 1.0 μg/kg/min) will be infused i. v. for 24 hours in comparison with placebo, in
    treatment of Chinese and Italian patients with Acute Decompensated Heart
    Failure.
    E.2.2Secondary objectives of the trial
    In all Italian patients and in a subset of Chinese patients pharmacokinetics and metabolism of istaroxime shall also be studied
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent; 2. Male or female patients ≥ 18 years; 3. Admission for a recurrent ADHF episode with dyspnea at rest or minimal exertion and need of intravenous diuretic therapy (>40 mg iv. furosemide); 4. Systolic blood pressure between 90 and 125 mmHg (limits included)
    without signs or symptoms of hypoperfusion including cardiogenic shock, cold extremities and peripheral vasoconstriction, oliguria/anuria, signs of cerebral hypo perfusion such as confusion;
    5. Left ventricular (LV) Ejection fraction (EF) ≤ 40 % measured by 2D-Echocardiography. 6. E/Ea ratio >10
    7. BNP ≥ 350pg/mL or NT-pro-BNP ≥1400 pg/mL 8. Adequate echocardiography window (defined as visualization of at least
    13/16 segment of the left ventricle);
    E.4Principal exclusion criteria
    1. Pregnant or breast-feeding women (women of child bearing potential must
    have the results of a negative pregnancy test recorded prior to study drug
    administration); 2. Current (within 12 hours prior to screening) or planned (through the completion of study drug infusion) treatment with any iv. therapies,
    including vasodilators (including nitrates or nesiritide), positive inotropic agents and vasopressors; 3. Current or need of mechanical support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device);
    4. Ongoing treatment with oral digoxin. Patient treated with digoxin within the last week, can be randomised if the plasma concentration of digoxin are tested before randomization and its value will be less than 0.5 ng/ml; 5. History of hypersensitivity to the study medication;
    6. Diagnosis of cardiogenic shock within the past month; 7. Acute coronary syndrome or stroke within the past 3 months; 8. Coronary artery bypass graft or percutaneous coronary intervention within the past month or planned in the next month; 9. Primary hypertrophic or restrictive cardiomyopathy or systemic illness known to be associated with infiltrative heart disease; 10. Cor pulmonale or other causes of right-sided HF not related to left ventricular dysfunction;
    11. Pericardial constriction or active pericarditis; 12. Atrial fibrillation with market irregularities of heart rhythm;
    13. Life threatening ventricular arrhythmia or ICD (implantable cardioverter
    defibrillator) shock within the past month;
    14. CRT (cardiac resynchronization therapy), ICD or pacemaker implantation
    within the past month; 15. Valvular disease as primary cause of HF; 16. Heart rate >120 bpm or < 50 bpm; 17. Acute respiratory distress syndrome or ongoing sepsis; 18. Fever >38°; 19. History of bronchial asthma or porphyria;
    20. Donation or loss of blood equal to or exceeding 500 mL, during the 8 weeks before administration of study medication;
    21. Positive testing for HIV, Hepatitis B and/or Hepatitis C; 22. Participation in another interventional study within the past 30 days; 23. The following laboratory exclusion criteria, verified based on results
    obtained within the last 24 hours of hospitalization: a. Serum creatinine > 3.0 mg/dl (> 265 μmol/L); b. Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 x upper limit of normal, c. Hemoglobin (Hb) < 10 g/dL,
    d. Platelet count < 100,000/μL, e. Serum potassium > 5.3 mmol/L or < 3.8 mmol/L.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline to 24 hours after infusion start (treatment period Day 1) in the E/Ea ratio assessed by tissue Doppler.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 day (24 hours)
    E.5.2Secondary end point(s)
    Efficacy:
    • Change from baseline to 24 hours in the treatment period Day1 (addressing the differences between the changes at 6 and 24 hours from baseline) of the following Echo-Doppler parameters:
    - LV Ejection fraction (EF)
    - LV end systolic and end diastolic volumes
    - Stroke volume index (SVI)
    - E, A and E/A ratio
    • Difference between the changes at 6 and 24 hours from baseline of the
    Tissue Doppler parameter E/Ea
    • Others Tissue Doppler parameters such as Sa, Da and Aa
    • Changes in dyspnoea assessed at 3, 6, 12, 24, 48 hours after infusion start by Visual Analog Scale (VAS) (including only patients presenting dyspnoea at baseline);
    • Area under the curve (AUC) on changes in dyspnoea assessed at 3, 6, 12, 24, 48 hours after infusion start by VAS (including only patients presenting dyspnea at baseline);
    • Changes in BNP from baseline at 24 hours;
    • Proportion of patients with hospital readmissions or emergency visits
    for cardiovascular reasons by Day 30;
    • Proportion of patients with episodes of worsening HF defined by the need to increase the dose or reinitiate i.v. therapy with diuretics and/ or other inotropic agents during the hospitalization;
    • Length of the hospitalization.
    Safety:
    • Incidence of adverse events;
    • Change in vital signs (including body temperature and dyspnoea);
    • Change in 12-lead ECG parameters;
    • Incidence of clinically or hemodynamically significant episodes of supraventricular or ventricular arrhythmias detected by continuous ECG dynamic monitoring;
    • Change in laboratory parameters (hematology, blood chemistry and
    urinalysis);
    • Change in renal function;
    • Change in in cTnT;
    • Incidence of cTnT elevation (>50% or > 20% relative increase over the basal cTnT levels at baseline, for patients with cTnT levels at baseline < or ≥ of the 99% URL (upper reference levels, as defined for the Roche hs test), respectively);
    • Mortality at Day 30.
    PK:
    The following PK metrics will be computed for E and Z isomers (when applicable) of istaroxime plasma concentrations using non-compartmental analysis: Cmax, tmax, AUC0-t, AUC0-∞, λz, t½, Cl, MRT, Vss, Vz;
    • the following PK metrics will be computed for E and Z isomers (when applicable) of istaroxime urine concentrations: Ae, Ae%, ClR;
    • In addition, the following PK metrics will be computed as above for plasma and urine concentrations of the E and Z isomers (when applicable) of istaroxime metabolites PST2915, PST2922, and
    PST3093: Cmax, tmax, AUC0-t, AUC0-∞, λz, t½ and, if possible, Ae and Ae%.


    E.5.2.1Timepoint(s) of evaluation of this end point
    30 days
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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
    China
    E.8.7Trial has a data monitoring committee No
    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
    LVLP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months13
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months13
    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: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 Yes
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 120
    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)
    None
    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 Decision2013-05-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-04-02
    P. End of Trial
    P.End of Trial StatusCompleted
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