EMPEROR-HF: A phase III randomised, double-blind trial to evaluate efficacy and safety of once daily empagliflozin 10 mg compared to placebo, in patients with chronic Heart Failure with reduced Ejection Fraction (HFrEF)

Chronic heart failure (HF) is a progressive syndrome characterized by the inability of the heart to provide adequate blood supply to meet the metabolic demand of different tissues or to be able to do so only at the expense of elevated left ventricle filling pressure. HF is a prevalent disease affecting an estimated 26 million people worldwide. About 25 to 45% of patients with HF have concomitant type 2 diabetes mellitus (T2DM), and nearly 15-25% has borderline diabetes (pre-diabetes), indicating a potential link between the HF syndromes and glucometabolic disturbances.

Despite the current standard of care for treatment of HFrEF such as medical therapy [angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta blockers, mineralocorticoid receptor antagonists (MRA), ivabradine and angiotensin receptor blocker-neprilysin inhibitor (ARNI)] or device therapy the mortality and morbidity remains high in HF patients.

Empagliflozin is an orally available inhibitor of the renal dependent glucose co-transporter 2 (SGLT-2) indicated for, reduction of blood glucose in patients with T2DM by promoting urinary glucose excretion. It also reduces blood pressure, arterial stiffness and measures of the myocardial workload, likely through various mechanisms, as well as improving other CV risk factors (uric acid, visceral fat mass, albuminuria).

The objective of this event-driven trial is 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%). 

Inclusion criteria
1. Age ≥ 18 years at screening. For Japan only: Age ≥ 20 years at screening
2. Male or female patients. WOCBP must be ready and able to use highly effective methods of birth control per ICH M3 (R2) [R09-1400] that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information
3. Patients with chronic HF diagnosed for at least 3 months before Visit 1, and currently in HF NYHA class II-IV
4. 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.
5. 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 HHF 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.
6. 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 (Randomisation) with the exception of diuretics stable for only one week  prior to Visit 2 to control symptoms. The investigator must document in the source documents the reason why patient not on target dose per local guidelines
7. Appropriate use of medical devices such as cardioverter defibrillator (ICD) or a cardiac resynchronization therapy (CRT) consistent with prevailing local or international CV guidelines (refer also to exclusion #29)
8. Body Mass Index (BMI) < 45 kg/m2 at Visit 1 (Screening)
9. Signed and dated written ICF in accordance with Good Clinical Practice (GCP) and local legislation prior to admission to the trial

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 1(Screening)
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
11. Systolic blood pressure (SBP) ≥ 180 mmHg at Visit 2. If SBP >150mmHg and <180mmHg at Visit 2, the patient should be receiving at least 3 antihypertensive drugs
12. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 or Visit 2
13. Chronic pulmonary disease requiring home oxygen, oral steroid therapy or hospitalisation for exacerbation within 12 months, or significant chronic pulmonary disease in the opinion of the investigator, or primary pulmonary arterial hypertension
14. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at Visit 1
15. Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 (CKD-EPI) or requiring dialysis, as determined at Visit 1
16. Haemoglobin (HgB) <9 g/dl at Visit 1
17. History of ketoacidosis
18. Major surgery (major according to the investigator’s assessment) performed within 90 days prior to Visit 1, or scheduled major elective surgery (e.g. hip replacement) within  90 days after Visit 1
19. Gastrointestinal surgery or gastrointestinal disorder that could interfere with trial medication absorption in the investigator’s opinion
20. Any documented active or suspected malignancy or history of malignancy within 2 years prior to screening, except appropriately treated basal cell carcinoma of the skin, in situ carcinoma of uterine cervix, or low risk prostate cancer (patients with pretreatment PSA < 10 ng/mL, and biopsy Gleason score of ≤ 6 and clinical stage T1c or
T2a)
21. Presence of any other disease than heart failure with a life expectancy of <1 years in the opinion of the investigator
22. Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial
23. Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor within 12 weeks prior to Visit 1 or during screening period until Visit 2 (Randomisation). Discontinuation of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor for the purposes of study enrolment is not permitted.
24. Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational treatment(s). Patients participating in a purely observational trial will not be excluded
25. Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors
26. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion,makes them an unreliable trial subject or unlikely to complete the trial
27. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
28. Any other clinical condition that would jeopardise patients safety while participating in this trial, or may prevent the subject from adhering to the trial protocol
29. Implanted cardioverter defibrillator (ICD) or a cardiac resynchronization therapy (CRT) within 3 months prior to Visit 1, or if there is an intent to implant ICD or CRT within 3 months of visit 1

Conditions:
• Chronic Heart Failure with Reduced Ejection Fraction