E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
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E.1.3 | Condition being studied is a rare disease | No |
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-TSS as a measure of health status (symptoms)) in patients hospitalised for acute heart failure (de novo or decompensated chronic HF) and after initial stabilisation. |
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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 |
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E.2.3 | Trial contains a sub-study | No |
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 |
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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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. 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-TSS after 90 days of treatment assessed by the win ratio. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline and after 90 days of treatment |
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E.5.2 | Secondary end point(s) |
1. Improvement in KCCQ-TSS of ≥ 10 points
2. Change from baseline in KCCQ-TSS 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. |
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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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
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 | No |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |