Clinical Trials Register

Summary
EudraCT Number:	2020-000885-40
Sponsor's Protocol Code Number:	04-CL-1904
National Competent Authority:	Romania - National Agency for Medicines and Medical Devices
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-08-24
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

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A. Protocol Information

A.1

Member State Concerned

Romania - National Agency for Medicines and Medical Devices

A.2

EudraCT number

2020-000885-40

A.3

Full 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.3.1

Title 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.4.1

Sponsor's protocol code number

04-CL-1904

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04325035

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Windtree Therapeutics, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Windtree Therapeutics, Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinical Consulting Sp. z o.o.
B.5.2	Functional name of contact point	Clinical Operation
B.5.3	Address:
B.5.3.1	Street Address	Dzwonkowa 104
B.5.3.2	Town/ city	Tychy
B.5.3.3	Post code	43-100
B.5.3.4	Country	Poland
B.5.4	Telephone number	0048322272005
B.5.5	Fax number	0048323298426
B.5.6	E-mail	tadeusz.baron@clinicalconsulting.pl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Istaroxime
D.3.2	Product code	PST2744
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Istaroxime
D.3.9.1	CAS number	374559-48-5
D.3.9.3	Other descriptive name	Androstane-3,6,17-trione(E,Z)-3-[O-(2- aminoethyl)]oxime hydrochloride
D.3.9.4	EV Substance Code	SUB125014
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pre-Cardiogenic Shock

E.1.1.1

Medical condition in easily understood language

Pre-Cardiogenic Shock

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10000803
E.1.2	Term	Acute heart failure
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to assess the ability of istaroxime to increase SBP in patients with cardiogenic shock or pre-shock, defined as hospitalization for acute decompensated heart failure (ADHF) with persistent hypotension (SBP 75-90 mmHg for two hours) who, for at least 6 hours prior to Screening, are not on cardiovascular, respiratory, or renal mechanical support, and have not received IV vasopressors or inotropes.

E.2.2

Secondary objectives of the trial

To assess other measures of efficacy to ensure consistency of results across multiple endpoints.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Clinical presentation consistent with SCAI Stage B precardiogenic 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 between 75 and 90 mmHg for at least 2 hours prior to
Screening;
b. SBP doesn’t decrease 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)

E.4

Principal 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 30 days: acute coronary
syndrome, coronary revascularization, MI, CABG, or
percutaneous coronary intervention;
4. Current (within 6 hours of Screening) or planned (within 6 hours
after randomization) 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. Incomplete revascularization (patients with ischemic heart
disease have to have had a catheterization in the last year
demonstrating that the main coronary arteries are well
revascularized);
12. Any significant valvular disease (including moderate or severe
valvular disease, such as severe aortic stenosis or regurgitation);
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 overdiuresis as a cause of hypotension;
15. Pericardial constriction or active pericarditis;
16. Life-threatening ventricular arrhythmia or implantable
cardioverter defibrillator (ICD) shock within the past month or
history of sudden death within 6 months;
17. Cardiac resynchronization therapy (CRT), ICD, or pacemaker
implantation within the past month;
18. Sustained ventricular tachycardia in the last 3 months with no
defibrillator;
19. Cor pulmonale or other causes of isolated right-sided HF or not
related to left ventricular dysfunction;
20. Acute respiratory distress syndrome;
21. Suspected sepsis; fever > 38° or active infection requiring IV
antimicrobial treatment;
22. Body weight < 40 kg or ≥ 150 kg;
23. 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;
24. A life expectancy < 3 months in the opinion of the investigator;
25. Severe pulmonary or thyroid disease;
26. Pregnant or breast-feeding;
27. Ongoing drug or alcohol abuse;
28. Participation in another interventional study within the past 30
days

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in SBP AUC at 6 hours measured via a sphygmomanometer or arterial line

E.5.1.1

Timepoint(s) of evaluation of this end point

6 hours after initiation of infusion.

E.5.2

Secondary end point(s)

• 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 and 24 hours of treatment,
measured via a sphygmomanometer or arterial line.
• SBP area under the curve (AUC) to 24 hours from infusion start.
• 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
hours infusion.
• Number of subjects requiring treatment with intravenous
vasopressors, inotropes, and/or mechanical cardiac or renal
support or have died from randomization to 24 hours 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.
• 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
• For patients who are invasively monitored with a pulmonary artery
catheter – changes in invasive hemodynamic parameters from pretreatment to 3, 6, 12, 24 and 30 hours
• Changes in echocardiographic measurements at 24 and 30 hours,
as applicable.

E.5.2.1

Timepoint(s) of evaluation of this end point

3,4,5,6,12,24,30,48,72 and 96 hours from randomization
Day 4 and Day 30 from randomization.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Israel

Russian Federation

United States

Italy

Poland

Romania

E.8.7

Trial has a data monitoring committee

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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-05-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-16

P. End of Trial
P.	End of Trial Status	Ongoing

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