E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure (HF) with preserved ejection fraction (EF). |
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E.1.1.1 | Medical condition in easily understood language |
chronic (long-term) heart failure (HF) |
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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 | 10008908 |
E.1.2 | Term | Chronic 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 |
To demonstrate superiority of empagliflozin 10 mg versus placebo in patients with symptomatic, chronic HF and preserved ejection fraction (LVEF > 40%) under stable treatment of HF symptoms. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Drug concentration measurements and Pharmacokinetics (PK) substudy:
PK sampling will be done from a limited number of randomised patients (approx 1650) and at sites in pre-selected countries only. Pre-dose blood samples will be collected at Visit 4 and between 22 to 26 h after the most recent drug intake, to determine plasma empagliflozin trough concentrations. These samples will serve to determine steady state trough concentrations of empagliflozin.
Optional Biobanking sub-study requiring samples to be collected at Visit 2, 4 and 8 (plasma, serum, urine) and Visit 2 (DNA). |
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E.3 | Principal inclusion criteria |
- Patients with chronic HF diagnosed for at least 3 months before Visit 1 and currently in New York Heart Association (NYHA) HF class II-IV
- Chronic HF with preserved EF defined as LVEF > 40 % per local reading (obtained by echocardiography, radionuclide ventriculography, invasive angiography, MRI or CT), and no prior measurement of LVEF ≤ 40% under stable conditions. A historical LVEF may be used if it was measured within 6 months prior to visit 1, and more than 90 days after any myocardial infarction (as defined in exclusion criterion No.1) or the LVEF may be measured after study consent has been obtained. The LVEF must be documented in an official report prior to randomization.
- Elevated N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) > 300 pg/ml for patients without AF, OR > 900 pg/ml for patients with AF, analysed at the Central laboratory at Visit 1
- Patients must have at least one of the following evidence of HF:
a) Structural heart disease (left atrial enlargement and/or left ventricular hypertrophy) documented by echocardiogram at Visit 1,
OR
b) Documented hospitalisation for HF (HHF) within 12 months prior to Visit 1
- Oral diuretics, if prescribed to patient according to local guideline and discretion of the Investigator, should be stable for at least 1 week prior to Visit 2 (Randomisation)
- eGFR (CKD-EPI)cr ≥ 20 mL/min/1.73m2 at Visit 1 |
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E.4 | Principal exclusion criteria |
1. Myocardial infarction, coronary artery bypass graft surgery or other major cardiovascular surgery, stroke or TIA in past 90 days prior to Visit 1
2. Heart transplant recipient or listed for heart transplant
3. Implantation of cardioverter defibrillator within 3 months prior to Visit 1
4. Implanted cardiac resynchronisation therapy (CRT)
5. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases, muscular dystrophies, cardiomyopathy with reversible causes, hypertrophic
obstructive cardiomyopathy or known pericardial constriction
6. Any severe valvular heart disease expected to lead to
surgery during the trial in the Investigator’s opinion
7. Acute decompensated HF requiring intravenous (i.v.) diuretics, i.v. inotropes or i.v. vasodilators, or left ventricular assist device within 1 week from discharge to Visit 1, and during screening period until Visit 2 (Randomisation)
8. Atrial fibrillation or atrial flutter with a resting heart rate > 110 bpm documented by ECG at Screening
9. Systolic blood pressure (SBP) ≥ 180 mmHg at Visit 2. If SBP >150 mmHg and <180 mmHg at Visit 2, the patient should be receiving at least 3 antihypertensive drugs
10. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 or Visit 2 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to first event of adjudicated CV death or adjudicated HHF in patients with Heart Failure with preserved Ejection Fraction (HFpEF). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Occurrence of adjudicated HHF (first and recurrent),
2. eGFR (CKD-EPI)cr slope of change from baseline
Other secondary endpoints:
- Time to first occurrence of chronic dialysis or renal transplant or sustained* reduction of ≥40% eGFR (CKD-EPI)cr or
A: sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for patients with baseline eGFR ≥30 mL/min/1.73 m2
B: sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2
*An eGFR (CDK-EPI)cr reduction is considered sustained, if it is determined by two or more consecutive post-baseline central laboratory measurements separated by at least 30 days (first to last of the consecutive eGFR values).
Chronic dialysis is defined as dialysis with a frequency of twice per week or more often for at least 90 days.
- Time to first adjudicated HHF
- Time to adjudicated CV death
- Time to all-cause mortality
- Time to onset of DM (defined as HbA1c ≥6.5% or as diagnosed by the Investigator) in patients with pre-DM defined as no history of DM and no HbA1c ≥6.5 before treatment, and a pre-treatment HbA1c value of ≥ 5.7 and <6.5
- Change from baseline in clinical summary score (HF symptoms and physical limitations domains) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) at week 52
- Occurrence of all-cause hospitalisation (first and recurrent) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 251 |
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 |
Argentina |
Australia |
Brazil |
Canada |
China |
Colombia |
European Union |
India |
Japan |
Korea, Republic of |
Mexico |
Singapore |
South Africa |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 8 |