Efficacy and Safety Assessment of Finerenone and Empagliflozin Combination Versus Monotherapy in Chronic Kidney Disease with Type 2 Diabetes

The primary objective of this study is to demonstrate that **combination therapy** using finerenone and empagliflozin is superior in reducing the **Urinary Albumin-to-Creatinine Ratio (UACR)** compared to either empagliflozin or finerenone alone in participants with chronic kidney disease and type 2 diabetes mellitus. This is clinically relevant as reducing UACR is associated with improved renal outcomes and reduced progression of kidney disease in this patient population.

Secondary objectives include:

• To further investigate the efficacy of combination therapy using finerenone and empagliflozin versus either finerenone or empagliflozin alone.
• To evaluate the safety of combination therapy using finerenone and empagliflozin versus either finerenone or empagliflozin alone.

The clinical trial involves a total of **587 participants** diagnosed with **chronic kidney disease** in the context of **type 2 diabetes mellitus**. The study population includes both male and female subjects, with an age range spanning from 18 to 64 years. Participants were selected based on specific inclusion criteria, including a clinical diagnosis of chronic kidney disease with an estimated glomerular filtration rate (eGFR) between 30-90 ml/min/1.73m², and a history of albuminuria or proteinuria. Additionally, participants must have type 2 diabetes as defined by the American Diabetes Association, with glycated hemoglobin levels below 11% at screening. All participants are required to be on the maximum tolerated dose of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker for more than one month prior to the screening visit. The trial does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is a **Phase 2**, double-blind, three-arm study designed to evaluate the efficacy and safety of a combination therapy using **finerenone** and **empagliflozin** compared to each drug alone in participants with **chronic kidney disease** and **type 2 diabetes mellitus**. The trial employs a randomized, controlled design to ensure unbiased results. The estimated duration of the trial is from June 23, 2022, to February 28, 2025, with a maximum treatment period of 185 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as an eGFR range and UACR levels. Following successful screening, participants will be randomly assigned to one of the three treatment arms. The primary endpoint is the mean ratio of change from baseline to Day 180 in UACR for the combination therapy group compared to each monotherapy. Secondary endpoints include various measures of renal function and safety, such as changes in eGFR and the incidence of adverse events like hyperkalemia and hypoglycemia.

Study visits will include regular follow-up assessments to monitor the participants' health status and treatment efficacy. These visits will occur at predetermined intervals throughout the treatment period. The end-of-study visit will conclude the trial for each participant, where final assessments will be conducted to gather comprehensive data on the treatment outcomes.

Participant involvement is expected to last up to 185 days, with conditions for early termination including significant adverse events or withdrawal of consent. The trial aims to provide robust data on the potential benefits of the combination therapy in reducing UACR and improving renal outcomes in the target population.

The clinical trial involves the administration of **Kerendia** 10 mg film-coated tablets, which contain the active substance **finerenone**. This medication is a non-steroidal, potent, and selective mineralocorticoid receptor antagonist (MRA). The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose is 10 mg, with a total maximum dose of 1850 mg over a treatment period of 185 days. The tablets are commercially available with different colors and embossing per dose strength.

Another experimental treatment in the trial is **Kerendia** 20 mg film-coated tablets, also containing **finerenone**. Similar to the 10 mg formulation, these tablets are administered orally. The maximum daily dose for this formulation is 20 mg, with a total maximum dose of 3700 mg over the same treatment period of 185 days. The tablets are distinguished by their color and embossing, which differ from the 10 mg tablets.

The trial also includes the administration of **Jardiance** 10 mg film-coated tablets, which contain the active substance **empagliflozin**. This medication acts as a reversible, highly potent, and selective competitive inhibitor of sodium-glucose co-transporter 2 (SGLT2). The pharmaceutical form is a film-coated tablet, administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 1850 mg over 185 days. The tablets are encapsulated for administration.

In addition to the active treatments, the study utilizes a placebo control. The placebo for **Kerendia** 10 mg and 20 mg is designed to be identical to the test product in appearance but lacks the active substance. Similarly, a placebo for **Jardiance** 10 mg is used, matching the test product in appearance without containing the active substance. These placebos are used to maintain the double-blind nature of the trial.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to the treatment of chronic kidney disease and type 2 diabetes. The primary endpoints focus on the mean ratio of change from baseline to Day 180 in the **Urinary Albumin to Creatinine Ratio (UACR)** for the combination therapy group compared to empagliflozin alone and finerenone alone. This will determine the superiority of the combination therapy in reducing UACR.

Secondary endpoints include various measures of UACR and estimated Glomerular Filtration Rate (eGFR). These include the relative change in UACR between the end of treatment and 30 days after, as well as changes in UACR categories at 180 days. Additionally, the ratio of change from baseline in eGFR at 30 days, and the decline in eGFR greater than 30% at 30 days from baseline will be assessed. Other secondary endpoints involve the proportion and total number of participants experiencing adverse events such as acute kidney injury (AKI), hyperkalemia, severe hypoglycemia, symptomatic hypotension, genital mycotic events, ketoacidosis, necrotizing fasciitis of the perineum, and urosepsis and pyelonephritis.

The efficacy parameters will be measured and collected at specified timepoints, including baseline, Day 180, and 30 days post-treatment. The analysis will involve comparing the changes in these parameters across the different treatment groups to determine the efficacy of the combination therapy relative to the monotherapies. The trial is designed as a double-blind, three-arm study, ensuring that the assessments are conducted without bias.