Evaluation of Finerenone and SGLT2 Inhibitors on Cardio-Renal Outcomes in Type 2 Diabetes and Chronic Kidney Disease: A Randomized Controlled Trial

The primary objective of this study is to examine the effect of combination therapy with **finerenone** and sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with **type 2 diabetes** and chronic kidney disease. The hypothesis is that the combination therapy will have either a synergistic or additive effect on various cardio-renal endpoints. This is clinically relevant as it may offer a novel therapeutic approach to mitigate cardio-renal target organ damage in this patient population, potentially improving outcomes and quality of life.

The clinical trial involves participants diagnosed with **type 2 diabetes** and chronic kidney disease. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants are required to be currently undergoing treatment with a sodium-glucose cotransporter-2 (SGLT2) inhibitor and either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) at maximally tolerated doses. Additionally, they must have a serum potassium level of 4.8 mmol/L or less at the time of screening and be fluent in Danish. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants have a specific health profile, including an estimated glomerular filtration rate (eGFR) of 25 ml/min/1.73 m² or higher and elevated albuminuria, defined by a urinary albumin-to-creatinine ratio of 30-5000 mg/g. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the effect of **finerenone** on cardio-renal target organ damage in patients with **type 2 diabetes** and **chronic kidney disease**. This study is a randomized, double-blind, controlled trial, which will include a placebo group to ensure the reliability of the results. The trial is categorized as a low-intervention study, as the procedures pose minimal risk compared to standard clinical practice. The trial is expected to commence recruitment on September 2, 2024, and conclude by October 31, 2027, with a maximum treatment period of 26 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of type 2 diabetes, chronic kidney disease with specific eGFR and albuminuria levels, and current treatment with SGLT2 inhibitors and ACE inhibitors or ARBs. The screening will also ensure serum potassium levels are 4.8 mmol/L or less. Follow-up visits will be scheduled to monitor changes in primary endpoints, including left ventricular mass and albuminuria, as well as secondary endpoints like myocardial fibrosis, blood pressure, and renal function. The end-of-study visit will assess the overall impact of the treatment on the participants' health outcomes.

Participant involvement is expected to last for the duration of the treatment period, with regular monitoring to ensure safety and efficacy. Conditions that may lead to early termination from the study include adverse reactions to the treatment, non-compliance with study protocols, or withdrawal of consent. The trial aims to provide valuable insights into the potential synergistic or additive effects of finerenone in combination with SGLT2 inhibitors on cardio-renal endpoints.

The clinical trial involves the administration of **Kerendia** 10 mg film-coated tablets, which contain the active substance **finerenone**. Finerenone is a chemical compound, also known by the synonym BAY 94-8862, and is classified under the ATC code C03DA05. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. The maximum daily dose of finerenone is 20 mg, with a total maximum dose of 3640 mg over the course of the treatment period. The treatment duration is set for a maximum of 26 weeks. The medication is manufactured by Bayer AG and is authorized for use in the European Union under the marketing authorization number EU/1/21/1616/002. Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** control, referred to as "Placebo til finerenon kapsel 10 mg." This placebo is designed to match the finerenone capsules in appearance but does not contain any active pharmaceutical ingredients. The placebo is utilized to ensure the integrity of the trial by providing a comparator to the experimental treatment. The placebo is not associated with any specific pharmaceutical form or active substance, and it is not authorized for marketing. The use of a placebo allows for the assessment of the true efficacy and safety of finerenone by providing a baseline for comparison.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of **finerenone** on cardio-renal target organ damage in patients with type 2 diabetes. The primary endpoints include changes in left ventricular mass, measured by non-contrast cardiac MRI, and changes in albuminuria, assessed by the urinary albumin-to-creatinine ratio (UACR) in morning spot urine samples. Secondary endpoints encompass a range of cardiovascular and renal parameters, such as changes in myocardial fibrosis rates, left ventricular ejection fraction, arterial stiffness, and various biomarkers related to cardiovascular and chronic kidney disease. These will be measured using advanced imaging techniques like MRI, as well as blood and urine tests.

The trial will employ non-contrast MRI to measure changes in myocardial fibrosis, left ventricular and atrial volumes, and pulse wave velocity in the aorta. Additionally, arterial stiffness will be assessed through carotid-femoral pulse wave velocity, and 24-hour blood pressure changes will be monitored. Biomarkers related to cardiovascular and renal health will be measured in blood and urine samples. Renal assessments will include changes in glomerular filtration rate (GFR), kidney microstructure, fibrosis, and oxygenation, using techniques such as T1-mapping, diffusion-weighted MRI, and BOLD MRI. The trial will also evaluate changes in kidney size and thoracic aortic wall volume using MRI.

Data collection will occur at specified intervals throughout the trial, with the analysis focusing on both the immediate and long-term effects of the treatment. The trial is designed to determine whether the combination therapy of finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors provides synergistic or additive benefits on the specified endpoints. The study is categorized as a low-intervention clinical trial, with procedures posing minimal risk or burden to participants compared to standard clinical practice.