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    Summary
    EudraCT Number:2020-000885-40
    Sponsor's Protocol Code Number:04-CL-1904
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-06-04
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2020-000885-40
    A.3Full title of the trial
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study on the Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock (SEISMiC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An international study at multiple sites testing the safety and effectiveness of an investigational drug called istaroxime, given through a vein in adults 18 – 85 years of age with severe heart failure who also have low blood pressure.
    A.4.1Sponsor's protocol code number04-CL-1904
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04325035
    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 SponsorWindtree Therapeutics, Inc.
    B.1.3.4CountryUnited States
    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 supportWindtree Therapeutics, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClinical Consulting Sp. z o.o.
    B.5.2Functional name of contact pointClinical Operation
    B.5.3 Address:
    B.5.3.1Street AddressDzwonkowa 104
    B.5.3.2Town/ cityTychy
    B.5.3.3Post code43-100
    B.5.3.4CountryPoland
    B.5.4Telephone number0048513344446
    B.5.6E-mailtadeusz.baron@clinicalconsulting.pl
    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 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.3.9.3Other descriptive nameAndrostane-3,6,17-trione(E,Z)-3-[O-(2- aminoethyl)]oxime hydrochloride
    D.3.9.4EV Substance CodeSUB125014
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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
    Pre-Cardiogenic Shock
    E.1.1.1Medical condition in easily understood language
    Pre-Cardiogenic Shock
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10007541
    E.1.2Term Cardiac disorders
    E.1.2System Organ Class 10007541 - Cardiac disorders
    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 objective of this study is to assess the ability of istaroxime to increase systolic blood pressure (SBP) in patients with cardiogenic shock (CS) or pre-shock (Society for Cardiovascular Angiography & Intervention (SCAI) Stage B), defined as hospitalization for ADHF with persistent hypotension who currently, and since admission to the hospital and throughout Screening, have not received IV vasopressors, inotropes, or digoxin, or not on cardiovascular, respiratory, or renal mechanical support.

    Subjects enrolled in Part A will have SBP of 75-90 mmHg and subjects enrolled in Part B will have SBP of 70-100 mmHg.
    E.2.2Secondary objectives of the trial
    To assess other measures of efficacy to ensure consistency of results across multiple endpoints.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Clinical presentation consistent with SCAI Stage B pre-cardiogenic shock caused by acute decompensation of chronic systolic heart failure (due to arterial hypertension, ischemic heart disease or dilated cardiomyopathy), without evidence for an acute coronary syndrome.
    2. Signed informed consent form (ICF);
    3. Males and females, 18 to 85 years of age (inclusive);
    4. An admission within 36 hours prior to randomization for ADHF episode, defined as:
    a. Dyspnea, at rest or with minimal exertion,
    b. Congestion on chest x-ray or lung US with BNP ≥ 400 pg/mL or NT-proBNP ≥ 1400 pg/mL.
    Elective admissions for medications tune up or procedures do not qualify as an ADHF admission.
    5. History of left ventricular ejection fraction (LVEF) ≤ 40%;
    6. Persistent hypotension defined as
    a. SBP of 75 to 90 mmHg (Part A) or 70 to 100 mmHg (Part B) for ≥ 2 hours prior to Screening;
    b. Stable SBP, defined as no decrease in SBP by > 7 mmHg on two separate measurements during the last 2 hours prior to randomization;
    7. Heart rate 75 to 150 bpm. If the subject is on a beta-blocker, the range is 60 to 150 bpm;
    8. Echocardiogram during index hospitalization confirming ejection fraction ≤ 40% and no evidence of other pathology to confound interpretation of cardiac physiology (eg, pericardial effusion).
    9. Subject is monitored by a PAC at the time of randomization (Part B only).
    E.4Principal exclusion criteria
    1. Cardiogenic shock of SCAI stage C or worse
    2. Cardiogenic shock due to any other condition besides acute decompensation of chronic heart failure.
    3. Any of the following in the past 60 days: acute coronary syndrome, coronary revascularization, MI, CABG, or percutaneous coronary intervention;
    4. Current (within 6 hours of Screening) or anticipated need for treatment with positive inotropic agents or vasopressors, renal support including ultrafiltration, or mechanical circulatory, ventilatory or renal support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device);
    5. Venous Lactate > 2 mmol/L;
    6. History of heart transplant or UNOS priority 1a heart transplant listing
    7. Ongoing treatment with digoxin (if digoxin was stopped before signing the ICF and the digoxin plasma level is < 0.5 ng/ml, the patient may be enrolled);
    8. Severe renal impairment (eGFR < 30 ml/min, calculated by the MDRD formula);
    9. Hypersensitivity to the study medication and its excipients (including known lactose hypersensitivity) or any related medication;
    10. Stroke or TIA within 3 months;
    11. Active coronary ischemia;
    12. Any significant valvular disease (including any moderate or severe valvular stenosis, moderate or severe aortic or pulmonary regurgitation, or severe tricuspid or mitral regurgitation);
    13. Primary hypertrophic or restrictive cardiomyopathy or systemic illness known to be associated with infiltrative heart disease;
    14. Admission for AHF triggered primarily by a correctable etiology such as significant arrhythmia (inclusive of atrial fibrillation as the main reason for admission), infection, severe anemia, acute coronary syndrome, pulmonary embolism, exacerbation of COPD, planned admission for device implantation, or over-diuresis as a cause of hypotension;
    15. Pericardial constriction or active pericarditis;
    16.Life-threatening ventricular arrhythmia, uncontrolled arrythmia, or implantable cardioverter defibrillator (ICD) shock or history of sudden death within 6 months;
    17.Cardiac resynchronization therapy (CRT), ICD, ablation, or pacemaker implantation (or planned implantation) within the past 3 months;
    18. Sustained ventricular tachycardia in the last 3 months with no defibrillator;
    19. Sustained hypotension (SBP < 70 mmHg) for at least 30 minutes from the time of arrival to the hospital;
    20. Severe pulmonary disease or cor pulmonale or other causes of isolated right-sided HF or not related to left ventricular dysfunction;
    21. Acute respiratory distress syndrome;
    22. Suspected sepsis; fever > 38° or active infection requiring IV antimicrobial treatment;
    23. Body weight < 40 kg or ≥ 150 kg;
    24. Laboratory exclusions:
    a. Hemoglobin < 9 g/dl,
    b. Platelet count < 100,000/μl,
    c. Serum potassium > 5.3 mmol/l or < 3.5 mmol/l;
    25. A life expectancy < 3 months based on the judgment of the investigator;
    26. Uncontrolled thyroid disease;
    27. Pregnant or breast-feeding;
    28. Ongoing drug or alcohol abuse;
    29. Participation in another interventional study within the past 30 days.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in systolic blood pressure (SBP) area under the curve (AUC) ) to 6 hours from start of infusion
    Change from baseline in AUC for systolic blood pressure measured via a sphygmomanometer or arterial line.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 hours after start of infusion.
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Variables:
    - SBP AUC to 12 hours from start of infusion for subjects in Part B
    - SBP AUC to 24 hours from start of infusion for subjects in Parts A and B.
    - SBP AUC to 48 hours from start of infusion for subjects in Part B.
    - SBP AUC to 60 hours from start of infusion for subjects in Part B.
    Other Secondary Efficacy Variables:
    • Treatment-failure score, based on death, circulatory, respiratory, or renal mechanical support or intravenous inotrope or vasopressor treatment, and changes in systolic blood pressure
    • Change from baseline in SBP at 6, 12 and 24 hours of treatment for both parts, and at 48 and 60 hours of treatment for Part B.
    • Number of subjects with increases from baseline in SBP ≥5% and ≥ 10 mmHg at a timepoint between 4-6 hours after dosing and at least one other measurement separated by ≥ 2 hours during the 24- or 60-hours infusion.
    • Number of subjects requiring treatment with intravenous vasopressors, inotropes, and/or mechanical cardiac or renal support or have died in the period from randomization to 24 or 48 hours (for subjects in Part A and B, respectively) and Day 5 (“treatment failure”).
    • Changes in quality of life measured by the EQ-5D from baseline to Day 5 (96 hours) from infusion start and at Day 30 (Part A only).
    • Change from baseline in Creatinine clearance at 24, 48, 72 and 96 hours from infusion start.
    • Change from baseline and observed heart rate measurements at 12, 24, 48, 72 and 96 hours from infusion start.
    • Change from baseline and observed mean arterial pressure (MAP) at 12, 24, 48, 72 and 96 hours from infusion start.
    • Change from baseline and observed brain natriuretic peptide (BNP), NT-pro-BNP, troponin (cTn; either T or I) and venous lactate at 12, 24, 48, 72 and 96 hours from infusion start.
    • Time to worsening heart failure through Day 5.
    • Time to HF re-admission or death through Day 30.
    • Length in ICU/length of initial hospitalization
    • Days alive and out of acute care (including all intensive acute care units).
    • Days alive and out of the hospital through Day 30
    • Number of subjects with hospital re-admissions through Day 30
    • Mortality and reasons for death through Day 30
    • Changes in invasive hemodynamic parameters (e.g. PCWP, RAP, CVP, PAP, CO)from pretreatment to 3, 6, 12, 18, 24, 48, 54, and 60 hours.
    • Number of subjects with CS SCAI stage progression through Day 30.
    • Changes in echocardiographic measurements at 24, 36,48, 60, and 72 hours, as applicable.
    Pharmacokinetics
    • PK assessments of istaroxime and its primary metabolites (PST 2915, PST 2922, and PST 3903). In addition, diastereoisomers of istaroxime, PST 2890 (E) and PST 2892 (Z), will be measured and assessed. For Part A: blood samples at 6, 12, and 24 hours after infusion start and 0.25, 0.5, 1, 6, 12, and 24 hours after infusion end. For Part B: blood samples at 6, 12, 24, 36, 48, 52, 56, 60 hours after infusion start and 12, 36, 48 hours after infusion end and
    at discharge.

    Safety Variables
    • Incidence of adverse events (AEs) and serious AEs (SAEs)
    • Clinically significant arrythmias (arrythmias requiring intervention) for a total of 72 hours from the start of infusion as determined by a Holter monitor (during the infusion and after the infusion has been stopped).
    E.5.2.1Timepoint(s) of evaluation of this end point
    3,6,12,18,24,30,36,48,54,60,72 and 96 hours and Day 30 from randomization.
    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 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) No
    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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    Argentina
    Italy
    Poland
    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
    last subject/last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 41
    F.4.2.2In the whole clinical trial 90
    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)
    Ongoing SAEs will be followed for at least 30 days following the end of the study. No other treatment or care is planned.
    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 Decision2020-08-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-04
    P. End of Trial
    P.End of Trial StatusOngoing
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