Effects of Empagliflozin on Diuresis and Renal Function in Patients With Acute Decompensated Heart Failure

Study Overview
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Brief Summary
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Heart failure is the most common hospital admission diagnosis and shows increasing incidence and prevalence in Germany, the United States and worldwide. Improvements in the primary treatment conditions for e.g. myocardial infarction and reduced primary mortality has resulted in an increasing group of patients with secondary cardiac abnormalities including chronic heart failure. Progressive cardiac dysfunction and failure are associated with exercise intolerance, volume retention, nocturia, dyspnoea among others. The most severe progression of heart failure is cardiac decompensation (also called: acute heart failure) and cardiogenic shock. Volume retention, abnormal renal function and diuretic resistance are hallmarks of this clinical phenotype. Currently, the only available treatment is diuresis through various combinations of diuretics and the addition of cardiac inotropes when cardiac hypoperfusion is documented. Patients with acute decompensated heart failure (ADHF) often develop a state of diuretic resistance characterized by a need of rising dosages of diuretics for adequate diuresis and urine production. ADHF patients also show metabolic abnormalities including insulin resistance or type 2 diabetes mellitus. Empagliflozin is a potent and selective inhibitor of the sodium glucose cotransporter 2 (SGLT2) used in the treatment of type 2 diabetes. By inhibiting SGLT2, empagliflozin reduces renal glucose reabsorption and increases urinary glucose excretion. In addition to reducing hyperglycaemia, empagliflozin is associated with osmotic diuresis, reductions in weight and blood pressure without increases in heart rate, and has favourable effects on markers of arterial stiffness and vascular resistance. The investigators propose a single center exploratory study to test the hypothesis that the application of empagliflozin in addition to standard diuretic regimens increases urine output, decreases the need for further acceleration of diuretic regimens, and positively influences renal function as well as metabolism including insulin resistance in ADHF patients. Thereby, empagliflozin may be effective in the prevention of complex cardio metabolic alterations involved in ADHF.

Detailed Description
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If feasible (run-in of patients into the hospital from 08:00 a.m. to 06:00 p.m.) screening/baseline, enrolment, randomization and first dose of empagliflozin should be performed on the same day. In general, but especially in case of other run-in times (e.g. late evening, night and early morning hours) screening/baseline time period should not exceed 12 hours. In case a patient has to spend the night in hospital before randomization can be executed, a time period of up to 16 hours will not be counted as protocol deviation.

Official Title
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Effects of Empagliflozin on Diuresis and Renal Function in Patients With Acute Decompensated Heart Failure

Conditions
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Acute Decompensated Heart Failure

Intervention / Treatment
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* Drug: Empagliflozin 25 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients (age between 18-85 years) with acute decompensated heart failure (HF). Brain Natriuretic Peptide (BNP) >100 pg/ml, or N-terminal pro-BNP (NT-proBNP)>300 pg/ml as defined by current clinical guidelines for the diagnosis of acute decompensated HF (European Society of Cardiology 2016 HF guideline) Patients with diabetes mellitus type 2 or impaired glucose tolerance as defined by current clinical guidelines (German and International Diabetes Society 2016: HbA1c>6.5 % (upper limit for this clinical trial 12 %) or fasting glucose >7.0 mmol/l or any incidental glucose level >11.1 mmol/l or abnormal oral glucose tolerance test with 2h plasma glucose >7.8 mmol/l) or on antidiabetic medication or antidiabetic diet or patients with normal Glucose tolerance Patients without cognitive impairment, i.e. they must be capable of understanding the nature, significance and implications of the clinical trial and to form a rational intention in the light of the facts Written informed consent obtained For women with childbearing potential (until 2 years after menopause): Negative pregnancy test regular and correct use of a highly effective contraceptive method with an error rate of <1% per year (e.g. combined (estrogen and progesteron) hormonal contraception (oral, intravaginal, transdermal), progesteron-only hormonal contraception (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS) tubal ligation (female sterilization), hormon donating intrauterine device (hormonal spiral), double barrier methods, sexual abstinence, vasectomy of the partner) Exclusion Criteria: Type 1 diabetes mellitus Chronic Kidney Disease (CKD) with eGFR< 30 ml/min, or end-stage renal failure with the need for chronic dialysis treatment Acute kidney injury (AKI) ≥ Acute Kidney Injury Network (AKIN) stage 2 or requiring dialysis treatment Current medication with SGLT-2 inhibitors Known intolerance or hypersensitivity to the active substance empagliflozin, lactose or any other of the excipients listed in section 6.1. of the summary of product characteristics (SmPC). A contraindication or intolerance to furosemide Acute heart failure without signs of congestion (dry patient) Indication for urgent coronary angiography or any planned administration of a iodine based contrast agent within the next 6 days Need for hemofiltration or any other form of extracorporeal therapy Planned surgery Previous participation in this trial or recent participation in another clinical trial (within the last 3 months before inclusion, so that medical product/s from previous trial participation/s have been fully washed out )Identification of any causes of heart failure leading to decompensation that needs urgent management (like acute coronary syndrome, severe unstable arrhythmias, mechanical causes, acute pulmonary embolism) Incapacity to understand and / or to provide written informed consent Ongoing reported alcohol abuse (daily alcohol intake of more than 2 drinks (liquor, beer or wine) in men and 1 drink in women, corresponding to 12/24 g of pure alcohol per day women / men and/ or obvious alcoholisation of the patient during screening )

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single-center, prospective, double-blind, placebo-controlled, randomized and interventional exploratory study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Verum arm<br>25 mg tablet of empagliflozin once daily for five days | Drug: Empagliflozin 25 mg<br>* Empagliflozin 25 mg film-coated tablets, for oral use administered once daily for 5 days in addition to routinely administered (weight adjusted) intravenous furosemide<br>|
| Placebo Comparator: Placebo arm<br>one tablet of the matching Placebo once daily for five days | Drug: Placebo<br>* matching Placebo, film-coated tablets, for oral use, matching to investigational product Jardiance® administered once daily for 5 days in addition to routinely administered (weight adjusted) intravenous furosemide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total urinary output (UOP) as measured by daily volume summed up over 5 days | Total UOP as summed over 5 days | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal function under treatment | Change of creatinine values: increase in creatinine of > 0.3 mg/dl, doubling of serum creatinine, need for renal replacement therapy | 5 days | 
| Net fluid output | UOP - fluid intake | 5 days | 
| Worsening or persistent heart failure | NYHA class (New York Heart Association functional heart failure classification) | 30 days | 
| Intermediate Care (IMC) / Intensive Care Unit (ICU) and hospital length of stay | Duration in days | 30 days | 
| Liver function | bilirubin, serum aminotransferases, relevant change in coagulation status | 30 days | 
| Pulmonary function | oxygen saturation without oxygen therapy/ need for oxygen in l/min, presence of rales, changes in chest x-ray (worsening/ improvement/ new infiltration) | 30 days | 
| Number of patients alive and out of hospital -after 30 days | number of patients | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute decompensated heart failure, empagliflozin, diuresis, renal function