Evaluation of Eplerenone, Altizide, and Micronised Spironolactone in Heart Failure with Reduced Ejection Fraction and Severe Chronic Kidney Disease

The primary objective of the Swedish Cardiac And Renal Failure study-1 (SCARF-1) is to evaluate the **feasibility** and **safety** of eplerenone in patients with heart failure with reduced ejection fraction (HFrEF) and severe chronic kidney disease (CKD). This pilot trial aims to determine whether eplerenone can be safely administered to this patient population, which is clinically relevant as these patients often have limited treatment options due to their complex condition. An exploratory analysis of **efficacy** will also be performed to assess the potential therapeutic benefits of eplerenone in this context.

The clinical trial involves participants diagnosed with **heart failure with reduced ejection fraction** (HFrEF) in combination with severe chronic kidney disease (CKD). The study population includes both male and female subjects aged 18 years and older. Participants are required to have a diagnosis of HFrEF according to current criteria for at least three months prior to the screening visit, with an echocardiography showing an ejection fraction of 40% or less within 24 months of the screening. The trial includes individuals classified as New York Heart Association class II-III, who are optimally treated and stable on heart failure medications such as beta-blockers, SGLT2 inhibitors, ACE inhibitors, or ARBs, provided their estimated glomerular filtration rate (eGFR) is 20 ml/min/1.73m² or higher. Additionally, participants should have an eGFR of less than 30 ml/min/1.73m² at least once during the 12 months prior to the screening visit and less than 45 ml/min/1.73m² at the time of inclusion. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the **feasibility**, safety, and efficacy of **eplerenone** in patients with heart failure with reduced ejection fraction (HFrEF) and severe chronic kidney disease (CKD). This is a Phase 4, open-label pilot trial, categorized as Category 2, indicating minimal additional risk compared to routine clinical care. The trial will be conducted over an estimated duration from October 1, 2025, to December 31, 2026. Participants will be randomly assigned to receive the investigational product, administered orally, with a maximum daily dose of 25 mg and a total dose not exceeding 2100 mg over a 12-month period.

The study will include several key visits: an initial **screening visit** to confirm eligibility based on criteria such as age, diagnosis of HFrEF, and specific echocardiography and eGFR parameters. Following the screening, participants will undergo regular follow-up visits to monitor safety and efficacy endpoints, including changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score, six-minute walk distance (6MWD), and N-terminal pro b-type natriuretic peptide (NTpro-BNP) levels. Safety endpoints will also be assessed, such as plasma potassium levels, hospitalization for hyperkalemia or hypokalemia, and changes in eGFR.

The **end-of-study visit** will conclude the participant's involvement, summarizing the treatment outcomes and any adverse events. The expected length of participant involvement is up to 12 months, with conditions for early termination including significant adverse events or withdrawal of consent. The primary endpoint is the proportion of subjects completing the treatment period with or without the need for a potassium binder. Secondary endpoints include various safety and efficacy measures, ensuring comprehensive evaluation of the investigational product's impact on the target population.

The clinical trial involves the administration of **Eplerenone**, an experimental medication, to evaluate its feasibility, safety, and efficacy in patients with heart failure with reduced ejection fraction and severe chronic kidney disease. **Eplerenone** is formulated as a pharmaceutical product with the code PHF00245MIG. The active substances in this medication are **Altizide** and **Micronised Spironolactone**. **Altizide**, also known as Althiazide, is a chemical substance, while **Micronised Spironolactone**, also referred to as Microfine Spironolactone, belongs to the specified substance group 1. The medication is administered orally, with a maximum daily dose of 25 mg and a total maximum dose of 2100 mg over a treatment period of up to 12 months.

In addition to the experimental treatment, the study may include the use of standard-of-care therapy as a non-experimental treatment. This may involve the administration of an authorised synthetic compound, which serves as a comparator treatment to evaluate the effects of **Eplerenone**. The trial does not involve the use of a placebo. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The trial is designed to assess the potential benefits and risks associated with the use of **Eplerenone** in the specified patient population.

The efficacy of eplerenone in patients with heart failure with reduced ejection fraction (HFrEF) and severe chronic kidney disease (CKD) will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the proportion of subjects who complete the entire treatment period with and without the need to use a potassium binder. This will provide insight into the treatment's feasibility and its impact on potassium management.

Secondary endpoints will include changes in several parameters: the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score, six-minute walk distance (6MWD), N-terminal pro b-type natriuretic peptide (NTpro-BNP) levels, estimated glomerular filtration rate (eGFR), and urine-albumin-creatinine-ratio (UACR). These measures will help evaluate the treatment's impact on cardiac function, physical capacity, and renal function. Safety endpoints will also be monitored, including occurrences of plasma potassium levels (P-K) ≥ 5.5 and ≥ 6.0, hospitalizations for hyperkalemia or hypokalemia, decreases in eGFR of ≥ 30% and ≥ 50%, hospitalizations for renal failure, initiation of dialysis, and subject-reported symptoms such as syncope and lightheadedness due to orthostatic hypotension. Additionally, hospitalizations for heart failure, all-cause hospitalizations, cardiovascular death, and all-cause death will be recorded.