E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure (HF) with reduced ejection fraction (EF). |
|
E.1.1.1 | Medical condition in easily understood language |
chronic (long-term) heart failure (HF) |
|
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 |
|
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 on top of guideline-directed medical therapy in patients with symptomatic, chronic HF and reduced ejection fraction (LVEF ≤ 40%). |
|
E.2.2 | Secondary objectives of the trial |
|
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 1140) and at sites in pre-selected countries. 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). |
|
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 reduced EF defined as LVEF ≤ 40% per local reading (obtained under stable condition by echocardiography, radionuclide ventriculography, invasive angiography, MRI or CT). A historical LVEF may be used if it was measured within 6 months prior to visit 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.
- In addition to LVEF ≤ 40%, patients must have at least one of the following evidence of HF:
a) If EF ≥36% to ≤40%: Elevated NT-proBNP at Visit 1 ≥2500 pg/ml for patients without AF, OR ≥5000 pg/ml for patients with AF, analysed at the Central Laboratory,
b) If EF ≥31% to ≤35%: Elevated NT-proBNP at Visit 1 ≥1000 pg/ml for patients without AF, OR ≥2000 pg/ml for patients with AF, analysed at the Central Laboratory,
c) If EF≤30%: Elevated NT-proBNP at Visit 1 ≥600 pg/ml for patients without AF, OR ≥1200 pg/ml for patients with AF, analysed at the Central Laboratory
d) For EF ≤ 40% and documented HHFc within 12 months prior to visit 1, elevated NT-proBNP at Visit 1 ≥ 600 pg/ml for patients without AF and ≥ 1200 pg/ml for patients with AF, analysed at the Central Laboratory.
- Appropriate dose of medical therapy for HF (such as ACEi, ARB, β-blocker, oral diuretics, MRA, ARNI, ivabradine) consistent with prevailing local and international CV guidelines, stable for at least 1 week prior to Visit 1 and during screening period until Visit 2 with exception of diuretics stable for only one week prior to Visit 2 to control symptoms.
- Appropriate use of medical devices such as cardioverter defibrillator (ICD) or a cardiac resynchronization therapy (CRT) consistent with prevailing local or international CV guidelines
8. Body Mass Index < 45 kg/m2 at Visit 1.
|
|
E.4 | Principal exclusion criteria |
1. Myocardial infarction (increase in cardiac enzymes in combination with symptoms of ischaemia or newly developed ischaemic ECG changes), 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. Currently implanted left ventricular assist device (LVAD)
4. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy or known pericardial constriction
5. Any severe (obstructive or regurgitant) valvular heart disease, expected to lead to surgery during the trial in the investigator’s opinion
6. Acute decompensated HF (exacerbation of chronic HF) requiring i.v. diuretics, i.v. inotropes, or i.v. vasodilators, or LVAD within 1 week from discharge to Visit 1 (Screening) and during screening period until Visit 2 (Randomisation).
7. Atrial fibrillation or atrial flutter with a resting heart rate >110 bpm documented by ECG at Visit 2 (Randomisation)
8. Untreated ventricular arrhythmia with syncope in patients without ICD documented within the 3 months prior to Visit 1
9. Diagnosis of cardiomyopathy induced by chemotherapy or peripartum within the 12 months prior to Visit 1
10. Symptomatic bradycardia or second or third degree heart block without a pacemaker after adjusting beta-blocker therapy, if appropriate
|
|
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 reduced Ejection Fraction (HFrEF). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
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) 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
Chronic dialysis is regarded as chronic if the frequency of dialysis is twice or more per week 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)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 193 |
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 |
European Union |
India |
Japan |
Korea, Republic of |
Mexico |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
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 |