| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| acute decompensated heart failure |
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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 | 10010684 |
| E.1.2 | Term | Congestive 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 investigate the impact of SGLT-2 inhibitors (Empagliflozin and Dapagliflozin) on clinical endpoints in patients with acute/decompensated HF regardless of ejection fraction (HFrEF, HFmEF, HFpEF) or diabetes status within 9 months after the event |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
1. to investigate and compare the impact of SGLT-2 inhibitors on cardiac function based on echocardiography and biomarkers, including non-coding RNA (ncRNA) and microbiome metabolites in patients acute/decompensated HF
2. to evaluate the utility of specific circulating ncRNAs along with microbiome metabolites, biomarkers related with fibrosis, inflammation and cardiac remodeling processes and classic biomarkers for monitoring therapy with SGLT-2 inhibitors and its potential impact on expression of ncRNAs related to pathogenesis of acute/decompensated HF
3. to propose a risk score prediction tool for the course of acute/decompensated HF and therapy monitoring with SGLT-2 inhibitors based on concomitant usage of both selected ncRNA and biomarkers related to molecular pathways associated with disease progression.
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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 |
Biomarker substudies (EMPATHY-ncRNA, EMPATHY-microbiome, EMPATHY-multiomics, EMPATHY-redox)
The main objective of biomarker substudies is to characterize the peripheral blood non coding RNAs along with multiomics approach including microbiome metabolites, transcriptome, metabolome and proteome profiling in patients with acute decompensated HF in order to analyze their diagnostic and prognostic utility in long term follow-up in different time points under the treatment with SGLT-2 inhibitors. Moreover, the aim of this study is to investigate the impact of EMPA and DAPA on cardiac function and biomarkers for acute decompensated HF. All steps of the biomarker substudy (EMPATHY-ncRNA, EMPATHY-microbiome, EMPATHY-multiomic, EMPATHY-redox) will be performed at the Department of Experimental and Clinical Pharmacology, Medical University of Warsaw with CePT Infrastructure financed by the European Union – the European Regional Development Fund within the Operational Programme ‘Innovative economy for 2007–2013’ in cooperation with scientific partners from national and international institutions. Briefly, blood samples for selected biomarkers, ncRNAs analysis, targeted and untargeted microbiome metabolites and selected biomarkers associated with fibrosis/inflammation/cardiac function and oxidative stress will be taken from patients participating in the biomarker EMPATHY- study (between 0 day and 3 and 9 months from the index event i.e. day 0 – hospital stay, before randomization to EMPA/DAPA or placebo group. The following biomarkers associated to fibrosis, inflammation, hypertrophy will be measured using ELISA kits according to manufacturer recommendation: FGF-23 (fibroblast-growth-factor-23), IL-2 (interleukin-2), IL-6 (interleukin-6), CRP (c-reactive-protein), PCT (procalcitonin), ANP (atrial natriuretic peptide), NT-proBNP, Cystatin C, GDF-15 (growth differentiation factor 15), Galectin-3 according to manufacture instruction. Based on the biomarker substudies, a risk prediction score will be proposed (EMPATHY score).
EMPATHY-RF: The substudy will investigate the changes in renal function: eGFR (Estimated Glomerular Filtration Rate) (CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Equation)) CR slope of change from baseline: up to 18 months.
EMPATHY-gender: The substudy will investigate the differences in the efficacy and safety of SGLT2 inhibitors according to gender and sex.
EMPATHY-CEA: The substudy will investigate the cost-effectiveness of SGLT-2 in the setting of acute decompensated heart failure.
EMPATHY-AF: The substudy will investigate the incidence of new-onset atrial fibrillation (AF) and AF burden in patients with SGLT-2 inhibitors vs placebo.
EMPATHY-Fibrosis: The substudy will investigate the impact of SGLT-2 inhibitors on myocardial fibrosis using imaging (MRI) and biomarkers.
EMPATHY-QOL: The substudy will investigate a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire.
EMPATHY-age: The substudy will investigate the impact of SGLT-2 inhibitors among different age categories. |
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| E.3 | Principal inclusion criteria |
- Patients 18 years of age with the capacity to provide written informed consent
- Currently hospitalized for a primary diagnosis of acute/decompensated HF (HFrEF, HFmrEF,HFpEF), including symptoms and signs of fluid overload regardless of ejection fraction or diabetes status
- In patients with HFpEF the diagnosis has to be confirmed according to the current HFpEF definition (by non-invasive testing: evidence of structural or functional changes in the heart as
evidenced on echocardiography or by invasive testing as LVEDP assessment or right heart catheterisation).
- Randomized no earlier than 24 hours and up to 10 days after initial presentation while still hospitalized
- Stable as defined by: systolic blood pressure (SBP>100 mmHg for the preceding 6 hours)
- No intensification of IV diuretics within the last 6 hours,
- No use of IV vasodilators within the last 6 hours,
- No use of IV inotropes or levosimendan within the last 24 hours prior to randomization
- Elevated NT-proBNP >600 pg/mL during the current hospitalization in patients with HFrEF and >300 pg/mL in patients with HFmrEF or HFpEF (or above 900 pg/ml if atrial fibrillation is present at admission independently from EF).
- eGFR >20 ml/min/1,73m2
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| E.4 | Principal exclusion criteria |
- History of ketoacidosis
- Type 1 diabetes
- SGLT-2 Inhibitor at baseline or known allergy to SGLT-2 Inhibitors
- Current active cancer with less than 2 years of life expectancy
- Pulmonary embolism, cerebrovascular accident as the primary trigger for the current hospitalization
- 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
- Any severe (obstructive or regurgitant) valvular heart disease, expected to lead to surgery during the trial period
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant
- Blood pH<7.32
- >1 episode of severe hypoglycaemia within the last 6 months under treatment with insulin or sulfonylurea
- Acute symptomatic urinary tract infection or genital infection
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Composite primary endpoint - time to first event of all-cause death or worsening HF (defined as worsening signs or symptoms of HF that require an intensification of diuretic therapy or any other intravenous therapy for HF or mechanical ventilatory, renal or circulatory support) or HF readmission (unplanned ambulatory visit or hospitalization due to symptoms of HF through 3 months).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time of first event of all-cause death or worsening HF (defined as worsening signs or symptoms of HF that require an intensification of diuretic therapy or any other intravenous therapy for HF or mechanical ventilatory, renal or circulatory support) or HF readmission; (unplanned ambulatory visit or hospitalization due to symptoms of HF through 3 months). |
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| E.5.2 | Secondary end point(s) |
1. Composite secondary endpoint - time to first event of all-cause death or worsening HF (defined as worsening signs or symptoms of HF that require an intensification of diuretic therapy or any other intravenous therapy for HF or mechanical ventilatory, renal or circulatory support) or HF readmission (unplanned ambulatory visit or hospitalization due to symptoms of HF through 9 months
2. Difference in the number of recurrent hospitalizations due to heart failure between the treatment groups: at 3 and 9 months..
3. Difference in the number of hospitalizations for CV causes between the treatment groups: - time frame: at 3 and 9 months.
4. Difference in the number of hospitalizations for other than CV causes between the treatment groups: - time frame: at 3 and 9 months.
5. Time to adjudicate CV death- time frame: at 3 and 9 months.
6. Time to adjudicate all causes of death- time frame: at 3 and 9 months.
7. Time to adjudicate myocardial infarction- time frame: at 3 and 9 months.
8. eGFR (Estimated Glomerular Filtration Rate) (CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Equation)) CR slope of change from baseline: at 3 and 9 months.
9. Difference in the number of hospital readmissions due to heart failure between the treatment groups- time frame: at 3 and 9 months.
10. Difference in the number of hospital readmissions for any cause between the treatment groups- time frame: at 3 and 9 months.
11. Difference in the duration of hospital stay between the treatment groups after initiation of the study treatment- time frame: at 3 and 9 months.
12. Difference in the number of incidences of new onset AF and re-occurrence of AF between treatment groups- time frame: at 3 and 9 months.
13. Difference in the change of ejection fraction in echocardiography between treatment groups from randomization to 3 and 9 months.
14. Difference in the change of left ventricular diastolic function in echocardiography from randomization to 3 and 9 months.
15. Difference in the change of LV strain analysis in echocardiography from randomization to 3 and 9 months.
16. The time-averaged proportional change in NT-proBNP from baseline through 3 and 9 months.
17. Personalized medicine based on biomarker approach- the time-averaged proportional change in selected ncRNA expression linked to hypertrophy, inflammation, fibrosis, apoptosis, electric stability between treatment groups and placebo group from baseline through months 3 and 9.
18. Personalized medicine based on biomarker approach- the time-averaged proportional change in PCT- procalcitonin, ANP - atrial natriuretic peptide, FGF-23 - fibroblast growth factor-23, GDF-15 - growth differentiation factor-15, IL-2 - interleukin 2, IL-6 - interleukin 6 between treatment groups and placebo group from baseline through months 3 and 9.
19. Personalized medicine based on biomarker approach- association between primary and secondary clinical endpoints and microbiome metabolites at baseline in both treatment groups and placebo in long term follow-up (3 and 9 months).
20. Personalized medicine based on biomarker approach- association between primary and secondary clinical endpoints and metabolome at baseline in both treatment groups and placebo in long term follow-up (3 and 9 months).
21. Cost-effectiveness substudy.
22. Effect of SGLT-2 inhibitors according to clinical characteristics as age, gender.
23. Symptoms, Function, and Quality of Life substudy.
24. Polypharmacy substudy.
25. Effect of SGLT-2 inhibitors on cardiac muscle fibrosis based on magnetic resonance (MR) substudy.
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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 | 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 | 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 | 3 |
| 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 | 21 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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