Evaluation of Empagliflozin Continuation Versus Placebo in Patients with Acute Decompensated Heart Failure on SGLT2 Inhibitor Therapy

The primary objective of this study is to assess the **non-inferiority** of continued administration of empagliflozin 10 mg compared to placebo plus standard medical care in patients admitted with **acute decompensated heart failure** (ADHF) who have been previously treated with an SGLT2 inhibitor. The evaluation focuses on a combined endpoint of all-cause mortality, heart failure hospitalization, and worsening renal function at 90 days post-admission. This is clinically relevant as it aims to determine whether empagliflozin can maintain its therapeutic benefits without increasing adverse outcomes in a vulnerable patient population.

Secondary objectives include evaluating the effects of continued administration of empagliflozin versus placebo plus standard medical care on:

• Urine output
• Diuretic efficiency
• Quality-of-life
• The need for further administration of diuretics

The clinical trial involves participants diagnosed with **acute decompensated heart failure** (ADHF) who are currently receiving treatment with a sodium-glucose co-transporter-2 (SGLT2) inhibitor. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a Brain Natriuretic Peptide (BNP) level greater than 100 pg/ml or an N-terminal pro-BNP (NT-proBNP) level exceeding 300 pg/ml. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations such as diet, physical activity, or habits are not specified. The selection criteria include obtaining written informed consent and a negative pregnancy test for women of childbearing potential. The trial aims to evaluate the non-inferiority of continued administration of empagliflozin 10 mg compared to placebo plus standard medical care in this patient group.

The clinical trial is designed to evaluate the **non-inferiority** of continued administration of **empagliflozin** 10 mg compared to placebo, in conjunction with standard medical care, in patients admitted with **acute decompensated heart failure** (ADHF) who have been previously treated with an SGLT2 inhibitor. This is a randomized, double-blind, controlled trial with a primary objective to assess the combined endpoint of all-cause mortality, heart failure hospitalization, and worsening renal function at 90 days post-admission. The trial is categorized as a Phase III clinical trial and is not considered low intervention.

The trial will commence with a screening visit to confirm eligibility based on criteria such as age (≥18 years), clinical assessment of ADHF, active SGLT2 inhibitor therapy, and specific **biomarker** levels (BNP >100 pg/ml or NT-proBNP >300 pg/ml). Informed consent and a negative pregnancy test for women of childbearing potential are also required. Participants will be randomly assigned to receive either empagliflozin or placebo, administered orally as film-coated tablets.

Participants will be involved in the study for a maximum of 90 days, with study visits scheduled at baseline, day 3, day 6, day 30, and day 90. These visits will include assessments of renal function, liver function, and changes in body weight, as well as measurements of urine output and diuretic efficiency. Quality of life and heart failure severity will be evaluated using the EQ-5D-3L and KCCQ-12 questionnaires, respectively, at specified intervals. The primary endpoint will be assessed through a hierarchical composite of time to all-cause death, number of heart failure events, time to first heart failure event, and eGFR decrease from baseline to day 90.

Secondary endpoints include cardiovascular and total mortality on day 90, re-hospitalization rates, and changes in renal and liver function. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The estimated recruitment start date is September 15, 2025, with an anticipated end date of June 14, 2027.

The clinical trial involves the administration of **Jardiance** (empagliflozin) 10 mg film-coated tablets. Jardiance is an oral medication formulated as film-coated tablets, containing the active substance **empagliflozin**, a chemical compound. The medication is administered orally at a dosage of 10 mg once daily. The maximum treatment period for participants is 90 days, with a total maximum dose of 900 mg. Jardiance is produced by Boehringer Ingelheim International GmbH and is authorized under the marketing authorization number EU/1/14/930/018. The trial aims to assess the non-inferiority of continued administration of empagliflozin in patients with acute decompensated heart failure (ADHF) who have been previously treated with an SGLT2 inhibitor.

The study also includes a **placebo** group, where participants receive placebo tablets that are visually identical to the Jardiance film-coated tablets. These placebo tablets are administered orally, matching the frequency and form of the experimental medication. The placebo serves as a comparator to evaluate the efficacy and safety of empagliflozin in the study population. Participants in both the experimental and placebo groups will receive standard medical care for heart failure as part of the trial protocol. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.

Efficacy in this clinical trial will be assessed using a four-step hierarchical composite primary endpoint. The primary endpoints include: 1) time to all-cause death by day 90, 2) number of heart failure events per patient by day 90, 3) time to first heart failure event by day 90, and 4) decrease in estimated glomerular filtration rate (**eGFR**) from baseline to day 90, with a threshold of ≥5 ml/min/1.73 m² between patients. Secondary endpoints will further evaluate efficacy through various parameters, including cardiovascular and total mortality on day 90, the number of patients alive and without re-hospitalization on day 90, and the number of re-hospitalizations after initial discharge. Additional secondary endpoints include changes in renal function, liver function, and biomarkers such as NT-proBNP from baseline to specified timepoints, as well as quality of life assessments using the EQ-5D-3L and KCCQ-12 questionnaires.

Data collection will occur at multiple timepoints, including baseline, day 1, day 3, day 6, discharge, day 30, and day 90. Renal function will be assessed through measurements of eGFR, serum creatinine, and the need for renal replacement therapy. Liver function will be evaluated by measuring bilirubin, serum aminotransferases, and coagulation status. Urine output and diuretic efficiency will be monitored from day 1 to day 6. The quality of life and severity of heart failure will be assessed using validated questionnaires at baseline, hospital discharge, and day 30. The analysis will involve comparing the outcomes between the empagliflozin and placebo groups to determine the non-inferiority of continued empagliflozin administration in patients with acute decompensated heart failure.