Empagliflozin and dapagliflozin for improvement of outcome in patients with acute heart failure

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical University Of Warsaw

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

22 Mar 2022 → ongoing

Decision date (initial)

2024-12-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518685-27-00

EudraCT number

2020-003497-48

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective is to investigate and compare the impact of SGLT-2 inhibitors (Empagliflozin and Dapagliflozin) on primary and secondary clinical endpoints in patients hospitalized due to acute/decompensated HF regardless of ejection fraction (HFrEF, HFmEF, HFpEF) or diabetes status.

Secondary objectives 3

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.

Conditions and MedDRA coding

acute/decompensated heart failure

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Patients 18 years of age with the capacity to provide written informed consent
2. 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
3. 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).
4. Randomized no earlier than 24 hours and up to 10 days after initial presentation while still hospitalized
5. Stable as defined by: systolic blood pressure (SBP>100 mmHg for the preceding 6 hours)
6. No intensification of IV diuretics within the last 6 hours
7. No use of IV vasodilators within the last 6 hours
8. No use of IV inotropes or levosimendan within the last 24 hours prior to randomization
9. 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).
10. eGFR >20 ml/min/1,73m2

Exclusion criteria 11

1. History of ketoacidosis
2. Type 1 diabetes
3. SGLT-2 Inhibitor at baseline or known allergy to SGLT-2 Inhibitors
4. Current active cancer with less than 2 years of life expectancy
5. Pulmonary embolism, cerebrovascular accident as the primary trigger for the current hospitalization
6. 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
7. Any severe (obstructive or regurgitant) valvular heart disease, expected to lead to surgery during the trial period
8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant
9. Blood pH<7.32
10. >1 episode of severe hypoglycaemia within the last 6 months under treatment with insulin or sulfonylurea
11. Acute symptomatic urinary tract infection or genital infection

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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).

Secondary endpoints 25

1. Composite 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical University Of Warsaw

Sponsor organisation

Medical University Of Warsaw

Address

Ul. Zwirki I Wigury 61

City

Warsaw

Postcode

02-091

Country

Poland

Scientific contact point

Organisation

Medical University Of Warsaw

Contact name

Marek

Public contact point

Organisation

Medical University Of Warsaw

Contact name

Marek

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications