Evaluation of the Efficacy and Safety of BI 690517 and Empagliflozin in Patients with Symptomatic Heart Failure and LVEF ≥40%: A Phase III Randomized Controlled Trial

The primary objective of this study is to demonstrate the **superiority** of the combination of BI 690517 and empagliflozin compared with placebo and empagliflozin for the time to first cardiovascular (CV) death or hospitalization for heart failure (HHF) in participants with symptomatic heart failure (HF) and left ventricular ejection fraction (LVEF) ≥40%. This is clinically relevant as it aims to improve outcomes in patients with HF, a condition associated with high morbidity and mortality.

Secondary objectives include: - Demonstrating the superiority of the combination of BI 690517 and empagliflozin over placebo and empagliflozin for the time to first event of CV death, HHF, or urgent heart failure visit. - Evaluating the total number of HHF events (first and recurrent) and the absolute change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) at Week 32. - Assessing the time to CV death and the time to all-cause mortality. These objectives are crucial for understanding the broader impact of the treatment on patient health and quality of life.

The clinical trial involves a total of **3,498 participants** diagnosed with **heart failure (HF)**. The study population includes both male and female subjects, aged 18 years and older, with a focus on those who have a left ventricular ejection fraction (LVEF) of 40% or greater. Participants were selected based on specific inclusion criteria, such as having chronic HF diagnosed at least three months prior to the trial and being in New York Heart Association (NYHA) class II-IV. The trial also considers lifestyle factors, requiring participants to be on a stable dose of diuretic therapy or have a documented hospitalization for HF within six months prior to the trial. The population includes individuals with structural heart abnormalities and elevated NT-proBNP levels, analyzed at a central laboratory. Both genders are represented, and the trial includes a vulnerable population, ensuring comprehensive representation of the HF demographic. Participants are required to be treated according to the best possible standard of care in line with applicable local or international HF guidelines.

The clinical trial is designed as a **randomized**, **double-blind**, parallel-group superiority study to evaluate the efficacy and safety of the combined use of oral BI 690517 and **empagliflozin** compared with placebo and empagliflozin in participants with symptomatic **heart failure** and left ventricular ejection fraction (LVEF) ≥40%. The trial aims to demonstrate the superiority of the combination therapy for the time to first cardiovascular (CV) death or hospitalization for heart failure (HHF). The trial is expected to commence recruitment on October 7, 2024, and conclude by November 5, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, informed consent, and specific heart failure parameters. Following the screening, participants will be randomized to receive either the combination therapy or placebo. The trial will include multiple follow-up visits to monitor safety, efficacy, and adherence to the treatment regimen. These visits will assess primary and secondary endpoints, including time to first CV death, HHF, or urgent heart failure visit, and changes in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) at Week 32. The end-of-study visit will mark the completion of the participant's involvement, which is anticipated to last up to 42 weeks.

Participants may be withdrawn from the study early if they experience adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial will ensure that all participants are treated according to the best possible standard of care in line with applicable heart failure guidelines. The study will maintain rigorous standards of data collection and analysis to ensure the reliability and validity of the results.

The clinical trial involves the administration of **EMPAGLIFLOZIN**, a chemical compound formulated as a film-coated tablet. This medication is administered orally. The specific dosage and frequency of administration are not detailed in the provided data. The maximum treatment period for EMPAGLIFLOZIN is 42 days. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

Another experimental medication used in the trial is **BI 690517**, also a chemical compound in the form of a film-coated tablet. Similar to EMPAGLIFLOZIN, BI 690517 is administered orally. The trial does not specify the exact dosage or frequency of administration for BI 690517. The maximum treatment period is also 42 days, and participant compliance will be closely monitored to maintain the integrity of the study results.

The trial includes a **placebo** that matches BI 690517, serving as a comparator treatment. The placebo is designed to mimic the appearance of the BI 690517 film-coated tablet but does not contain any active pharmaceutical ingredients. The placebo is used to assess the efficacy and safety of the experimental treatments by providing a baseline for comparison. The administration route and frequency for the placebo are consistent with those of the active treatments, ensuring blinding and minimizing bias in the trial outcomes.

Efficacy in this clinical trial will be assessed using a composite primary endpoint, which is the time to first event of **cardiovascular (CV) death** or hospitalization for heart failure (HHF). CV death includes death of undetermined cause. Secondary endpoints include the time to first event of CV death, HHF, or urgent heart failure visit, the occurrence of HHFs (first and recurrent), and the absolute change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) at Week 32.

The trial will evaluate the efficacy of the combination of BI 690517 and empagliflozin compared with placebo and empagliflozin in participants with symptomatic heart failure and left ventricular ejection fraction (LVEF) ≥40%. The primary objective is to demonstrate the superiority of the combination therapy for the time to first CV death or HHF. The efficacy parameters will be measured and collected at specified timepoints, with the KCCQ-TSS being assessed at baseline and Week 32. The analysis will focus on the time to event data for the primary and secondary endpoints, providing a comprehensive evaluation of the treatment's impact on heart failure outcomes.