Evaluation of Antifibrotic Effects of Spironolactone and Dihydralazine on Myocardial Fibrosis Post-TAVI in Aortic Stenosis with High Fibrotic Burden

The primary objective of this study is to evaluate the effect of **antifibrotic therapy** on the regression of myocardial fibrosis in patients with aortic stenosis who have a high fibrotic burden, following transcatheter aortic valve implantation (TAVI). This is clinically relevant as myocardial fibrosis is a significant factor in the progression of heart failure and can impact patient outcomes post-TAVI. The study will compare the effects of standard care alone versus standard care combined with Spironolactone, and Spironolactone plus Dihydralazine. The assessment of myocardial fibrosis will be conducted using cardiac magnetic resonance imaging (CMR) both before TAVI and one year after, with quantification of irreversible replacement fibrosis via late gadolinium enhancement (LGE) and potentially reversible diffuse interstitial fibrosis through extracellular volume fraction (ECV) measurements.

The clinical trial involves participants diagnosed with **severe symptomatic aortic stenosis** who exhibit a high fibrotic burden. The study population includes both male and female subjects aged 60 years and older. Participants are required to have a scheduled transcatheter aortic valve implantation (TAVI) therapy and must provide written informed consent. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants involved in the study. The selection of participants is based on specific inclusion criteria, ensuring that only those with the necessary medical condition and treatment schedule are considered. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the effect of **antifibrotic therapy** on the regression of myocardial fibrosis in patients with severe symptomatic **aortic stenosis** who have undergone transcatheter aortic valve implantation (TAVI). This is a Phase 4, randomized, double-blind, controlled trial. Participants will be randomly assigned to receive either spironolactone in addition to standard care, spironolactone combined with dihydralazine in addition to standard care, or standard care alone without any study medication. The primary endpoint is the difference in the reduction of extracellular volume (ECV)-derived matrix volume, measured by cardiac magnetic resonance imaging (CMR), after 12 months.

The trial is expected to last approximately 12 months, with participant involvement beginning from the screening visit and continuing through the end-of-study visit. The inclusion visit will involve screening for eligibility criteria, which include being male or female aged 60 or older, having a diagnosis of severe symptomatic aortic stenosis, and having TAVI scheduled. Written informed consent is required. Follow-up visits will be conducted to monitor the participants' health status and adherence to the treatment regimen. The end-of-study visit will assess the primary and any secondary endpoints.

Participants are expected to be involved in the study for the full 12-month duration unless conditions arise that necessitate early termination. Such conditions may include adverse reactions to the study medication, withdrawal of consent, or any significant protocol deviations. The trial aims to provide insights into the potential benefits of antifibrotic therapy in reducing myocardial fibrosis in this patient population.

The clinical trial involves the administration of **Nepresol®**, a pharmaceutical product containing the active ingredient **dihydralazine**. Nepresol® is formulated as a 25 mg **tablet** and is administered orally. The maximum daily dose for this medication is 50 mg, with a total maximum dose of 18,250 mg over a treatment period of up to 12 months. The medication is produced by TEOFARMA S.R.L. and is classified under the ATC code C02DB01. Participants receiving Nepresol® will be monitored for compliance with the dosing schedule to ensure accurate assessment of its effects.

Another experimental medication used in the trial is **Aldactone® 25**, which contains the active substance **spironolactone**. This medication is provided as a 25 mg **coated tablet** and is also administered orally. The maximum daily dose for Aldactone® 25 is 25 mg, with a total maximum dose of 9,125 mg over a 12-month treatment period. Esteve Pharmaceuticals GmbH manufactures this product, and it is categorized under the ATC code C03DA01. Compliance with the dosing regimen will be closely monitored to evaluate the therapeutic outcomes accurately.

In addition to the experimental treatments, the study includes a control group receiving standard-of-care therapy without any study medication. This allows for a comparative analysis of the effects of the antifibrotic therapy on myocardial fibrosis regression in patients with aortic stenosis. The trial aims to determine the efficacy of spironolactone alone and in combination with dihydralazine in enhancing antifibrotic effects. Participants' adherence to the treatment protocol will be assessed to ensure the reliability of the study results.

Efficacy in this clinical trial will be assessed by evaluating the effect of antifibrotic therapy on the regression of **myocardial fibrosis** in patients with severe symptomatic aortic stenosis undergoing transcatheter aortic valve implantation (TAVI). The primary endpoint for efficacy evaluation is the difference between treatment groups in the reduction of extracellular volume (ECV)-derived matrix volume, which will be measured using cardiac magnetic resonance imaging (CMR) after 12 months. This assessment will focus on quantifying potentially irreversible replacement fibrosis through late gadolinium enhancement (LGE) and potentially reversible diffuse interstitial fibrosis by measuring the extracellular volume fraction (ECV), thereby deriving matrix volume and cell volume.