Clinical Trials Register

Summary
EudraCT Number:	2008-003531-21
Sponsor's Protocol Code Number:	Debio 0614-202
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:	2008-08-18
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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2008-003531-21

A.3

Full title of the trial

A multicenter, randomized, double-blind, placebo-controlled parallel-group phase IIb study of the safety and efficacy of istaroxime over 24 hours at three doses in acute decompensated heart failure patients

A.3.2

Name or abbreviated title of the trial where available

IGNITE Trial

A.4.1

Sponsor's protocol code number

Debio 0614-202

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	DEBIOPHARM S.A.
B.1.3.4	Country	Switzerland
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Digoxin
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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 injection
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

acute decompensated heart failure

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10064653
E.1.2	Term	Acute decompensated heart failure

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

to assess the hemodynamic effects of istaroxime in patients with ADHF not requiring inotropic therapy at admission and receiving one of 3 doses (0.5, 1.0, and 1.5 µg/kg/min) of istaroxime i.v. infusion for 24 hours.

E.2.2

Secondary objectives of the trial

To assess clinical efficacy and safety including cardiovascular and renal tolerability as well as changes in biological markers such as brain natriuretic peptide (BNP) and troponin I (TNI), and the neurohormones renin and aldosterone;
To assess the PK of istaroxime and its metabolites (plasma concentration at infusion end in all patients and full PK profile in a subset of about 56 patients).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Screening Inclusion Criteria
1. Male or female patients ≥18 years;
2. Enrolled into the study during the first 48 hours of hospitalization;
3. Admission for ADHF defined as dyspnea at rest or orthopnea, with or without chest x-ray findings of pulmonary congestion;
4. Systolic blood pressure ≤ 120 mmHg;
5. Ejection fraction (EF) ≤ 35 % by any method (to be performed if not measured within the last 12 months);
6. Signed informed consent.
Randomization Inclusion Criteria
1. Persistence of ADHF signs (JVD, pulmonary rales, peripheral edema) despite initial treatment with i.v. diuretics and/or vasodilators;
2. Cardiac index ≤ 2.5 L/min/m²;
3. Pulmonary capillary wedge pressure  20 mmHg: 2 consecutive determinations at 30 minute intervals should not exceed a maximum of 10% variability; if the first 2 consecutive determinations fail to show the required stability, further determinations are allowed at the same interval within a maximum of 2 hours of evaluation. If stability is not demonstrated by 2 consecutive determinations within the 2-hour period, the patient will be excluded from the study.
4. Systolic BP comprised between 85 and 120 mmHg (limits included) without signs or symptoms of hypoperfusion including cardiogenic shock, cold extremities and peripheral vasoconstriction, oliguria/anuria, signs of cerebral hypoperfusion such as confusion.

E.4

Principal exclusion criteria

Screening Exclusion Criteria
1. Positive pregnancy test in females of childbearing potential;
2. Systolic blood pressure < 85 mmHg or > 120 mmHg;
3. Oral treatment with digoxin within one week before current hospitalization;
4. Any inotrope administered during the current hospitalization (e.g. dobutamine, dopamine, milrinone, levosimendan, digoxin, enoximone);
5. Presence of cardiogenic shock or its occurrence within the past month;
6. Acute coronary syndrome within the past 3 months;
7. Coronary artery bypass graft or percutaneous coronary intervention within the past month;
8. Stroke within the past 6 months;
9. Primary hypertrophic or restrictive cardiomyopathy or systemic illness known to be associated with infiltrative heart disease;
10. Presence of signs or symptoms of uncontrolled hyperthyroidism or hypothyroidism;
11. Cor pulmonale or other causes of right-sided HF not related to left ventricular dysfunction;
12. Pericardial constriction or active pericarditis;
13. Atrial fibrillation with uncontrolled HR (HR > 100 beats per minute bpm);
14. Life threatening ventricular arrhythmia or ICD (implantable cardioverter defibrillator) shock within the past month;
15. Presence of a CRT (cardiac resynchronization therapy), ICD or pacemaker devices implanted within the past month;
16. Second or third degree atrio-ventricular block without pacemaker;
17. Valvular disease as the primary cause of HF;
18. Hemodynamic support devices;
19. Need for mechanical ventilation;
20. Acute respiratory distress syndrome or ongoing sepsis;
21. Terminal illness other than HF with expected survival less than 1 year;
22. Participation in another interventional study within the past 30 days;
23. The following laboratory exclusion criteria must be verified based on results obtained within the last 24 hours of the screening period prior to pulmonary arterial catheter (PAC) insertion:
a. Serum creatinine > 2.5 mg/dL (> 221 µmol/L),
b. Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 x upper limit of normal,
c. Hemoglobin (Hb) < 10 g/dL,
d. International normalized ratio (INR) > 1.4 in patients not receiving anticoagulant therapy,
e. Platelet count < 100,000/µL,
f. Brain natriuretic peptide value < 500 pg/mL or NT-proBNP < 2000 pg/mL.
Randomization Exclusion Criteria
1. Any inotrope administered during the current hospitalization period (e.g. dobutamine, dopamine, milrinone, levosimendan, digoxin, enoximon);
2. Heart rate > 120 bpm or < 50 bpm.

E.5 End points

E.5.1

Primary end point(s)

Efficacy endpoints
Primary hemodynamic endpoint
PCWP change from baseline at 6 hours after infusion start.
Secondary hemodynamic endpoints
- PCWP change from baseline at 1, 3, 12, and 24 hours after infusion start, and at 1 and 3 hours after infusion end;
- MRAP and systolic, diastolic and mean PAP change from baseline at 1, 3, 6, 12, and 24 hours after infusion start, and at 1 and 3 hours after infusion end;
- SVR and PVR change from baseline at 6 and 24 hours after infusion start, and at 1 and 3 hours after infusion end (values will be calculated on the basis of vital sign recordings);
- Cardiac output and its indexed value (cardiac index) change from baseline at 1, 3, 6, 12, and 24 hours after infusion start, and at 1 and 3 hours after infusion end;
- SBP change from baseline at 1, 3, 6, 12 and 24 hours after infusion start, and at 1 and 3 hours after infusion end.

Safety endpoints
The following safety endpoints will be assessed during treatment and the post-treatment/follow-up periods:
- Incidence of AEs;
- Vital signs (HR, systolic, diastolic and mean BP, respiratory rate) change from baseline at 1, 3, 6, 12, and 24 hours after infusion start, and 1 and 3 hours after infusion end, and then in the morning on study Day 3 and Day 5 or at discharge(a), and on study Day 30 during the follow up visit;
- ECG (HR, RR and PR intervals, QRS duration, QTc, rhythm, ischemic changes) change from baseline at 6 and 24 hours after infusion start and at 6 hours after infusion end. Changes from screening to Day 3 and Day 5 on the same parameters will be assessed on the local ECGs;
- Number of episodes of sustained ventricular tachycardia (duration >30 seconds or requiring i.v intervention or cardioversion) and any clinically significant episode of supraventricular or ventricular arrhythmia detected by continuous ECG monitoring and documented by the Holter report, defined by the investigator as unexpected according to the patient’s history and/or previous screening observation period;
- Standard hematology and biochemistry parameter change from baseline at 24 hours after infusion end (on Day 3);
- Serum electrolytes change from baseline at 24 hours after infusion end (on Day 3);
- Serum creatinine and estimated glomerular filtration rate (eGFR - calculated according to the modification of diet in renal disease MDRD formula) change from baseline at 24 hours after infusion start, 24 hours after infusion end (on Day 3) and on Day 5 or at discharge(a);
- BNP and TNI change from baseline at 24 hours after infusion start and on Day 5 or at discharge(a);
- Renin, and aldosterone change from baseline at 24 hours after infusion start and on Day 5 or at discharge(a).
(a) If patient leaves hospital earlier than Day 5

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

Yes

E.8.1.7.1

Other trial design description

Stratificato

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

Yes

E.8.2.3.1

Comparator description

- same IMP used at different dosage

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

Information not present in EudraCT

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

E.8.7

Trial 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

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

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2008-08-18.	Yes
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	Yes
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	30
F.4.2	For a multinational trial
F.4.2.1	In the EEA	116
F.4.2.2	In the whole clinical trial	260

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

2009-05-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-08-05

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2009-09-03

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