Clinical Trials Register

Summary
EudraCT Number:	2019-002946-19
Sponsor's Protocol Code Number:	1245-0204
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-02-12
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2019-002946-19

A.3

Full title of the trial

A multicentre, randomised, double-blind, 90-day superiority trial to evaluate the effect on clinical benefit, safety and tolerability of once daily oral EMPagliflozin 10 mg compared to placebo, initiated in patients hospitalised for acUte heart faiLure (de novo or decompensated chronic HF) who have been StabilisEd (EMPULSE)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study to test the effect of empagliflozin in patients who are in hospital for acute heart failure

A.3.2

Name or abbreviated title of the trial where available

EMPULSE

A.4.1

Sponsor's protocol code number

1245-0204

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	Boehringer Ingelheim RCV GmgH & Co KG
B.1.3.4	Country	Austria
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	Boehringer Ingelheim RCV GmbH & Co KG
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	CT Disclosure and Data Transparency
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany

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	Yes
D.2.1.1.1	Trade name	JARDIANCE
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Empagliflozin
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	864070-44-0
D.3.9.3	Other descriptive name	EMPAGLIFLOZIN
D.3.9.4	EV Substance Code	SUB35915
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart Failure

E.1.1.1

Medical condition in easily understood language

Heart Faliure

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	10019279
E.1.2	Term	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

1. To assess whether in-hospital administration of empagliflozin results in improvements in HF-related clinical events and patient-reported outcomes (death, HFE and KCCQ-CSS as a measure of health status (symptoms and physical limitations)) in patients hospitalised for acute heart failure (de novo or decompensated chronic HF) and after initial stabilisation.

E.2.2

Secondary objectives of the trial

1. To further assess whether it is safe to start empagliflozin in patients admitted to hospital in this setting

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Currently hospitalised for the primary diagnosis of acute heart failure (de novo or decompensated chronic HF), regardless of ejection fraction (EF). Patients with a diagnosis of hospitalized heart failure must have HF symptoms at the time of hospital admission
2. Evidence of left ventricular ejection fraction (LVEF, either reduced or preserved EF) as per local reading preferably measured during current hospitalisation or in the 12 months prior to randomisation
3. Patients must be randomised after at least 24 hours and no later than 5 days after admission, as early as possible after stabilization and while still in hospital
4. Patients must fulfil the following stabilisation criteria (while in the hospital):
- SBP ≥100mm Hg and no symptoms of hypotension in the preceding 6 hours,
- no increase in i.v. diuretic dose for 6 hours prior to randomisation,
- no i.v. vasodilators including nitrates within the last 6 hours prior to randomisation
- no i.v. inotropic drugs for 24 hours prior to randomisation.
5. Elevated NT-proBNP ≥ 1600pg/mL or BNP ≥400 pg/mL according to the local lab, for patients without atrial fibrillation (AF); or elevated NT-proBNP ≥ 2400pg/mL or BNP ≥600 pg/mL for patients with AF, measured during the current hospitalization or in the 72 hours prior to hospital admission,. For patients treated with an angiotensin receptor neprilysin inhibitor (ARNI) in the previous 4 weeks prior to randomisation, only NT-proBNP values should be used
6. HF episode leading to hospitalisation must have been treated with a minimum dose of 40 mg of i.v. furosemide (or equivalent i.v. loop diuretic defined as 20 mg of torasemide or 1 mg of bumetanide)
7. Further Inclusion Criteria Apply

E.4

Principal exclusion criteria

1. Cardiogenic shock
2. Current hospitalisation for acute heart failure primarily triggered by pulmonary embolism, cerebrovascular accident, or acute myocardial infarction (AMI)
3.Current hospitalisation for acute heart failure not caused primarily by intravascular volume overload;
4. Below interventions in the past 30 days prior to randomisation or planned during the study:
- Major cardiac surgery, or TAVI (Transcatheter Aortic Valve Implantation), or PCI, or Mitraclip
- All other surgeries that are considered major according to investigator judgement
- Implantation of cardiac resynchronisation therapy (CRT) device
- cardiac mechanical support implantation
- Carotid artery disease revascularisation (stent or surgery)
5. Acute coronary syndrome / myocardial infarction, stroke or transient ischemic attack (TIA) in the past 90 days prior to randomisation
6. Heart transplant recipient, or listed for heart transplant with expectation to receive a transplant during the course of this trial (according to investigator judgement), or planned for palliative care for HF, or currently using left ventricular assist device (LVAD) or intra-aortic balloon pump (IABP) or any other type of mechanical circulatory support, or patients on mechanical ventilation, or patients with planned inotropic support in an outpatient setting
7. Haemodynamically significant (severe) uncorrected primary cardiac valvular disease planned for surgery or intervention during the course of the study (note: secondary mitral regurgitation or tricuspid regurgitation due to dilated cardiomyopathy is not excluded unless planned for surgery or intervention during the course of the study)
8. Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 as measured during hospitalization (latest local lab measurement before randomisation) or requiring dialysis
9. Type 1 Diabetes Mellitus (T1DM)
10. History of ketoacidosis, including diabetic ketoacidosis (DKA)
11. Further Exclusion Criteria Apply

E.5 End points

E.5.1

Primary end point(s)

1. The net clinical benefit, a composite of death, number of heart failure events (HFE) (including hospitalisations for heart failure (HHFs), urgent heart failure visits and unplanned outpatient visits), time to first HFE and change from baseline in KCCQ-CSS after 90 days of treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Baseline and after 90 days of treatment

E.5.2

Secondary end point(s)

1. Proportion of patients with an improvement in KCCQ-CSS of ≥ 10 points
2. Change from baseline in KCCQ-CSS after 90 days of treatment.
3. Change from baseline in log-transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) level over 30 days of treatment (area under the curve (AUC)).
4. Days alive and out of hospital from study drug initiation until 30 days after initial hospital discharge.
5. Days alive and out of hospital from study drug initiation until 90 days after randomisation.
6. Time to first occurrence of CV death or HFE until end of trial visit.
7. Occurrence of HHF until 30 days after initial hospital discharge.
8. Occurrence of chronic dialysis or renal transplant or sustained reduction of ≥40% eGFR Chronic Kidney Disease Epidemiology Collaboration Equation ((CKD-EPI)cr), or
-sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for patients with baseline eGFR ≥30 mL/min/1.73 m2
-sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2
9. Diuretic effect as assessed by weight loss per mean daily loop diuretic dose after 15 days of treatment.
10. Diuretic effect as assessed by weight loss per mean daily loop diuretic dose after 30 days of treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. After 90 days of treatment
2. Baseline and after 90 days of treatment
3. Baseline and after 30 days of treatment
4. 30 days after initial hospital discharge
5. 90 days after randomisation
6. End of Trial Visit (day 90 or 97 after randomisation)
7. 30 days after initial hospital discharge
8. End of Trial Visit (day 90 or 97 after randomisation)
9. After 15 days of treatment
10. After 30 days of treatment

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Belgium

Canada

China

Czech Republic

Denmark

Germany

Hungary

Italy

Japan

Netherlands

Norway

Poland

Spain

Sweden

United States

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

LVLS

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

E.8.9.2

In all countries concerned by the trial days

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:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

200

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

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

415

F.4.2.2

In the whole clinical trial

500

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)

Patients will continue with standard medical care. Patients receive SOC during study and will continue. Study medicaiton is on top.

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

2020-04-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-02-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-06-02

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