Evaluation of Balcinrenone and Dapagliflozin on Cardiovascular Outcomes in Heart Failure Patients with Renal Impairment: A Phase III Randomized, Double-Blind Study

The primary objective of this study is to evaluate whether the combination of **balcinrenone** and **dapagliflozin** is superior to dapagliflozin alone in reducing the risk of cardiovascular (CV) death and heart failure (HF) events, both with and without hospitalization, in patients with chronic heart failure and impaired kidney function. This is clinically relevant as it addresses the need for more effective treatments in reducing mortality and morbidity associated with heart failure, particularly in patients with comorbid conditions.

Secondary objectives include:

• Determining if balcinrenone/dapagliflozin is superior to dapagliflozin in reducing the rate of total occurrences of CV death and HF events with and without hospitalization.
• Assessing whether balcinrenone/dapagliflozin is superior in reducing the rate of total HF hospitalizations.
• Evaluating the superiority of balcinrenone/dapagliflozin in reducing the risk of CV death.
• Determining if balcinrenone/dapagliflozin is superior in reducing the risk of death from any cause, HF events, and improving patient-reported symptoms of HF.
• Assessing whether balcinrenone/dapagliflozin is superior in reducing the risk of death from any cause.

The clinical trial involves a total of **3579 participants** who are adults aged 18 years and older, diagnosed with **chronic heart failure (HF)** and comorbid impairment of kidney function. The study population includes both male and female subjects, and it is noted that a vulnerable population is selected. Participants have experienced a recent HF event within the past six months and are managed with standard care therapy for HF and renal impairment according to local guidelines. The trial population was selected based on specific criteria, including a documented diagnosis of symptomatic HF (NYHA functional class II-IV), a left ventricular ejection fraction (LVEF) assessment within the last 12 months, and an NT-proBNP level greater than 300 pg/mL, or greater than 600 pg/mL if there is concomitant atrial fibrillation or atrial flutter. Additionally, participants must not be taking a mineralocorticoid receptor antagonist (MRA) and must have an estimated glomerular filtration rate (eGFR) between 20 and less than 60 mL/min/1.73 m², with serum/plasma potassium levels between 3.5 mmol/L and 5.0 mmol/L. The trial aims to evaluate the effect of balcinrenone/dapagliflozin versus dapagliflozin alone on HF events and cardiovascular death.

The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the efficacy of **balcinrenone/dapagliflozin** compared to **dapagliflozin** alone in reducing the risk of heart failure (HF) events and cardiovascular (CV) death in patients with chronic heart failure and impaired kidney function. The trial aims to determine whether the combination therapy is superior in reducing CV death and HF events, both with and without hospitalization. The study is set to commence recruitment on April 12, 2024, and is expected to conclude by June 11, 2027, with a maximum treatment period of 38 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), documented diagnosis of symptomatic HF (NYHA class II-IV), recent HF event, and specific laboratory values. Following randomization, participants will attend regular follow-up visits to monitor health status, adherence to the study protocol, and any adverse events. The end-of-study visit will evaluate the primary endpoint, which is the time to the first occurrence of any component of the composite of CV death, HF hospitalization, or HF event without hospitalization. Secondary endpoints include total occurrences of these events, time to CV death, and other composite measures.

Participant involvement is expected to last up to 38 weeks, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will utilize **oral administration** of the investigational products, with the clinical product differing from the commercial product only in colorant and engraving. The study is not classified as a low-intervention trial and is conducted under the sponsorship of AstraZeneca AB, with the investigational products being synthetic small molecules. The trial is conducted in compliance with local guidelines for the management of HF and renal impairment.

The clinical trial involves the administration of **Forxiga** 10 mg film-coated tablets, which contain the active substance **dapagliflozin**. These tablets are manufactured by AstraZeneca AB and are designed for **oral use**. The pharmaceutical form is a film-coated tablet, and the tablets are administered once daily. The clinical product differs from the commercial product only in color and engraving. The maximum treatment period for this medication is 38 weeks. Participant compliance is monitored through regular follow-ups and pill counts.

Another treatment used in the trial is a combination of **Balcinrenone** and **Dapagliflozin**, provided in the form of hard capsules. This combination is also manufactured by AstraZeneca AB and is intended for oral administration. The capsules contain both active substances, balcinrenone and dapagliflozin, which are synthetic small molecules. The maximum treatment period for this combination is also 38 weeks. Compliance is ensured through similar monitoring methods as the Forxiga tablets.

In addition to the experimental treatments, a placebo is used as a comparator in the study. The placebo is designed to match the appearance of the active treatments but does not contain any active pharmaceutical ingredients. It is administered orally with the same frequency and duration as the active treatments to maintain blinding in the study. Compliance with placebo administration is monitored in the same manner as the active treatments.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the time to the first occurrence of any components of the composite of cardiovascular (CV) death, heart failure (HF) hospitalization, or HF event without hospitalization. Secondary endpoints include the total occurrences (first and recurrent) of the components of the composite of CV death, HF hospitalization, and HF event without hospitalization; total occurrences of HF hospitalizations; time to CV death; the hierarchical composite endpoint of death from any cause, total HF events, and change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score to 24 weeks post-randomization; and time to death from any cause.

These endpoints will be measured and collected at specified time points throughout the trial, with particular attention to the 24-week post-randomization period for the KCCQ total symptom score. The analysis will involve comparing the effects of the combination of **balcinrenone** and **dapagliflozin** against **dapagliflozin** alone in reducing the risk of CV death and HF events in patients with heart failure and impaired kidney function. The trial is designed as a Phase III, randomized, double-blind study, ensuring rigorous assessment of the efficacy parameters.