Evaluation of Finerenone in the Management of Early Diabetic Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of the FibroCAN study is to evaluate the **disease modifying effect** of finerenone on early diabetic cardiovascular autonomic neuropathy (CAN) in individuals with type 2 diabetes. This is a 78-week, double-blind, randomized, placebo-controlled, multi-centre trial. The clinical relevance of this study lies in its potential to provide insights into the therapeutic impact of finerenone on neuropathy measures, fibrosis, inflammation, and heart function in patients with early-stage CAN. Understanding these effects is crucial for developing effective treatment strategies for diabetic patients suffering from cardiovascular autonomic neuropathy.

The clinical trial focuses on individuals diagnosed with **type 2 diabetes** and early-stage **diabetic cardiovascular autonomic neuropathy**. The study population includes both male and female participants aged 40 years and older. Participants are required to have a pathological E/I ratio, which is a measure of autonomic function. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their ability to provide informed consent and meet the World Health Organization's criteria for type 2 diabetes. Lifestyle factors such as diet and physical activity are not specified in the available data. The trial aims to explore the effects of finerenone on neuropathy measures, fibrosis, inflammation, and heart function over a 78-week period.

The clinical trial is designed to evaluate the **disease-modifying** effect of **finerenone** on early-stage diabetic cardiovascular autonomic neuropathy (CAN) in individuals with type 2 diabetes. This is a Phase 4, double-blind, randomized, placebo-controlled, multi-center trial. The trial will span a total duration of 78 weeks, with the estimated recruitment start date set for January 1, 2025, and an estimated end date of March 31, 2027. Participants will be randomly assigned to receive either finerenone or a matching placebo, both administered orally in the form of film-coated tablets. The maximum daily dose of finerenone is 40 mg, and the treatment period is capped at 78 weeks.

The study will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be assessed based on criteria such as informed consent, a diagnosis of type 2 diabetes as per WHO criteria, age of 40 years or older, and a pathological E/I ratio. Follow-up visits will occur at specified intervals to monitor treatment effects on neuropathy measures, fibrosis and inflammation levels, and heart function. The primary endpoint is the CART E/I ratio, measured using the Vagustm device. Secondary endpoints include cardiovascular reflex tests, heart rate variability indices, and fibrosis markers assessed through serum and skin biopsies at weeks 0, 36, and 78.

Participant involvement is expected to last for the entire 78-week duration unless early termination is warranted. Conditions for early termination may include adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide insights into the potential benefits of finerenone as a treatment for early-stage CAN in the specified patient population.

The clinical trial involves the administration of **Finerenone**, a **film-coated tablet** provided by Bayer AG. Finerenone is an **aldosterone antagonist** with the active substance name **FINERENONE**. The pharmaceutical form is a film-coated tablet, and the route of administration is **oral**. The maximum daily dose is 40 mg, with a total maximum dose of 40 mg per day. The treatment period extends up to 78 weeks. Participants will receive the medication in a double-blind manner, ensuring neither the participants nor the investigators know who receives the active treatment or placebo. Compliance with the dosing schedule will be monitored throughout the study.

In addition to the experimental treatment, a **matching film-coated placebo tablet** will be provided by Bayer. The placebo is designed to be indistinguishable from the active medication in appearance and administration. This placebo will serve as a comparator to evaluate the efficacy and safety of Finerenone in the study population. The placebo will be administered orally, following the same dosing schedule as the active treatment, to maintain the integrity of the double-blind study design.

Efficacy in the clinical trial titled "The FibroCAN study. Mineralocorticoid receptor antagonist treatment for diabetic cardiovascular autonomic neuropathy" will be assessed through a series of primary and secondary endpoints. The primary endpoint is the **CART E/I ratio**, which will be measured using the Vagustm device. This endpoint is crucial for evaluating the effect of the treatment on early cardiovascular autonomic neuropathy (CAN) in participants with type 2 diabetes.

Secondary endpoints include a range of cardiovascular reflex tests such as the R/S ratio and the Valsalva manoeuvre, collectively referred to as CARTs. Additionally, heart rate variability (HRV) indices, including SDNN, RMSSD, and low and high-frequency power, will be assessed using the Vagustm device. Biomarkers of fibrosis, specifically serum PRO-C6 and C3M, will be measured through ELISA, and fibrosis markers in skin biopsies (Pro-C6 and C3M) will be evaluated by immunostaining at specific timepoints: week 0, week 36, and week 78.

The trial is designed as a 78-week double-blinded, randomized, placebo-controlled multi-centre study. The efficacy assessments will be conducted at various intervals throughout the trial to monitor the treatment effects on neuropathy measures, fibrosis and inflammation levels, and heart function. The use of validated tools and methods ensures the reliability and accuracy of the collected data, contributing to the overall assessment of the disease-modifying effects of **finerenone** in this patient population.