Evaluation of Angiotensin-Converting Enzyme Inhibitor Perindopril and Valsartan on Cardiac Remodeling in Women with Asymptomatic Subclinical Heart Failure

The primary objective of this study is to evaluate the effect of an **angiotensin-converting enzyme (ACE) inhibitor** compared to standard care, which involves no medication, over a two-year open-labeled treatment period in women with asymptomatic **heart failure**. The focus is on assessing the reversibility of aberrant cardiac remodeling in asymptomatic heart failure towards healthy values. This is clinically relevant as it may provide insights into the potential of ACE inhibitors to reverse cardiac changes before symptomatic heart failure develops, potentially improving long-term cardiac outcomes.

The secondary objectives of this trial are to evaluate the effect of the ACE inhibitor on: (i) **Cardiovascular performance**, including volume and pressure load, cardio-metabolic risk factors such as glucose metabolism, lipid status, and kidney function, as well as quality of life through questionnaires; and (ii) Novel biomarkers indicative of hypertrophy, fibrosis, inflammation, and ischemia. These secondary objectives aim to provide a comprehensive understanding of the broader impacts of ACE inhibitors on cardiovascular health and related metabolic processes.

The clinical trial focuses on evaluating the effect of an **angiotensin-converting enzyme (ACE) inhibitor** in women with **subclinical heart failure**. The study population consists exclusively of female participants, aged 18 years and older, who are either premenopausal or have a history of preeclamptic pregnancy. Participants are required to be at least six months post their last delivery and within 30 years of their first complicated pregnancy. The trial does not include male subjects or vulnerable populations. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize women with heart failure stage-B or diastolic dysfunction, ensuring a specific focus on this demographic. 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 an **angiotensin-converting enzyme (ACE) inhibitor** compared to standard care in women with asymptomatic **heart failure**. This study is a randomized, open-label, controlled trial with a duration of two years. Participants will be randomly assigned to receive either the ACE inhibitor or no medication, with the primary objective of assessing the reversibility of aberrant cardiac remodeling towards healthy values. The trial will include women aged 18 years and older, with heart failure stage-B or diastolic dysfunction, who are premenopausal and have a history of preeclamptic pregnancy, with the last delivery occurring at least six months prior to enrollment.

The trial will commence with a screening visit to confirm eligibility based on the inclusion criteria. Following randomization, participants will attend regular follow-up visits to monitor their health status and the effects of the treatment. These visits will include assessments of primary endpoints such as left ventricular hypertrophy, concentric remodeling, impaired systolic function, significant valve dysfunction, and signs of myocardial infarction. Secondary endpoints will include measurements of blood pressure, plasma volume, quality of life, metabolic syndrome, and biomarkers related to the renin-angiotensin-aldosterone system.

The expected length of participant involvement is up to 24 months, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The end-of-study visit will involve a comprehensive evaluation to assess the overall impact of the treatment. The trial is categorized as a low-intervention study, ensuring minimal additional risk to participants while maintaining the integrity and safety of the study. The estimated recruitment start date is September 2023, with an anticipated completion date in September 2027.

The clinical trial involves the administration of **Valsartan**, a medication provided in the form of hard capsules. Each capsule contains 40 mg of the active substance, valsartan, and is manufactured by Aurobindo Pharma (Malta) Limited. The medication is administered orally, with a maximum daily dose of 80 mg and a total maximum dose of 320 mg over the treatment period. The treatment duration is set for a maximum of 24 months. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another experimental medication used in the trial is **Perindopril Tert-Butylamine**, available as 2 mg tablets. These tablets are produced by Tillomed Laboratories Ltd and are also administered orally. The maximum daily dose is 2 mg, with a total maximum dose of 10 mg over the course of the study. The treatment period is similarly capped at 24 months. Adherence to the prescribed dosing regimen will be closely observed.

Additionally, the trial includes the use of **Glyceryl Trinitrate** in the form of a sublingual spray solution, marketed as Nitrospray. Each spray delivers 0.4 mg of glyceryl trinitrate, and the product is provided by VIP Pharma Eesti OU. The maximum allowable daily dose is 3 mg, with a total maximum dose of 3 mg during the treatment period, which is also limited to 24 months. The administration route is sublingual, and participant compliance will be tracked.

**Albumin** is utilized as an auxiliary treatment in the trial, provided as a solution for infusion. The active substance, albumin, is classified as a protein of other origin. The maximum daily dose is 1 mCi, with a total maximum dose of 5 mCi over the 24-month treatment period. The administration route is via injection. Monitoring of participant adherence to the infusion schedule will be conducted throughout the study.

Efficacy in this clinical trial will be assessed by evaluating the effect of an angiotensin-converting enzyme (ACE) inhibitor on the reversibility of aberrant cardiac remodeling in women with asymptomatic **heart failure**. The primary endpoints for efficacy evaluation include left ventricular hypertrophy, concentric remodeling, impaired systolic function, significant valve dysfunction, and signs of myocardial infarction. These parameters will be measured using established guidelines, such as the American Society of Echocardiography guidelines for valve dysfunction.

Secondary endpoints will include assessments of blood pressure, plasma volume, quality of life, behavior and symptoms, metabolic syndrome, the renin-angiotensin-aldosterone system, and novel biomarkers. The trial is designed to be conducted over a two-year open-labeled treatment period, with efficacy parameters collected and analyzed at specified intervals throughout the study duration. The trial aims to provide insights into the potential benefits of ACE inhibitors in reversing cardiac remodeling towards healthy values in the target population.