Evaluation of Hemodynamic Effects of Sacubitril/Valsartan in Patients with Heart Failure with Preserved Ejection Fraction and Secondary Mitral Valve Regurgitation

The primary objective of the study titled "Sacubitril-Valsartan in Heart Failure with Preserved Ejection Fraction and Secondary Mitral Valve Regurgitation (PRAISE-MR)" is to evaluate the **hemodynamic** effects of sacubitril-valsartan in patients diagnosed with heart failure with preserved ejection fraction (HFpEF) and secondary or atrial functional mitral regurgitation (AFMR). This assessment is conducted using a combination of cardiopulmonary exercise testing and stress echocardiography, referred to as CPETecho. The clinical relevance of this objective lies in its potential to improve understanding of the therapeutic impact of sacubitril-valsartan on cardiac function in this specific patient population, which may inform treatment strategies and improve patient outcomes.

The clinical trial involves participants diagnosed with **heart failure with preserved ejection fraction** and secondary mitral valve regurgitation. The study population includes both male and female subjects, aged 18 years and older, with a New York Heart Association (NYHA) classification of II to IV. Participants are required to have a left ventricular ejection fraction of 50% or greater and must provide written informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are selected based on objective evidence of cardiac structural and/or functional abnormalities consistent with left ventricular diastolic dysfunction or raised left ventricular filling pressures, including elevated natriuretic peptides, and moderate or greater functional mitral regurgitation assessed by transthoracic echocardiography within the previous year. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **hemodynamic** effects of sacubitril-valsartan in patients with heart failure with preserved ejection fraction and secondary mitral valve regurgitation. This study employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial is expected to span a duration of approximately two years, with an estimated recruitment start date of September 1, 2023, and an anticipated end date of September 1, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, NYHA class II to IV, and a left ventricular ejection fraction of 50% or greater. Following successful screening, participants will be randomized to receive either the investigational product or a control. The investigational product, Entresto, is administered orally in the form of film-coated tablets containing the active substances **valsartan** and sacubitril.

Throughout the trial, participants will attend regular follow-up visits to monitor their response to treatment and assess primary and secondary endpoints. The primary endpoint is the change in the mPAP/CO slope between randomization and six months thereafter. Secondary endpoints include changes in peak VO2, mitral effective regurgitant orifice area, natriuretic peptide levels, left atrial volume, left atrial function, VE/VCO2 slope, and patient-reported outcomes. The end-of-study visit will conclude the trial, during which final assessments will be conducted.

The expected length of participant involvement is up to six months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or any other reason deemed necessary by the investigator. The trial is categorized as a Phase IV study, indicating it is conducted post-marketing to gather additional information on the drug's effect in a broader patient population.

The clinical trial involves the administration of **Entresto** in three different dosages, each formulated as film-coated tablets. The primary active substances in these tablets are **valsartan** and **sacubitril**, both of which are of chemical origin. The tablets are manufactured by Novartis Europharm Limited and are authorized for use in the European Union. The pharmaceutical form for all dosages is a film-coated tablet, and the route of administration is oral. The maximum daily dose for each formulation is 194 mg, and the treatment period is capped at six months.

**Entresto 97 mg/103 mg film-coated tablets** contain valsartan and sacubitril in the specified dosages. The tablets are designed for oral administration and are to be taken as per the dosing schedule outlined in the study protocol. The frequency of administration is determined by the clinical trial design, ensuring that the maximum daily dose does not exceed 194 mg.

**Entresto 24 mg/26 mg film-coated tablets** also contain valsartan and sacubitril. These tablets are administered orally, with the dosing schedule tailored to maintain participant compliance and achieve the desired therapeutic outcomes. The administration frequency is structured to align with the study's objectives, ensuring adherence to the maximum daily dose limit.

**Entresto 49 mg/51 mg film-coated tablets** are similarly composed of valsartan and sacubitril. The oral administration of these tablets follows a specific dosing regimen, as detailed in the clinical trial protocol. The frequency and timing of doses are managed to optimize the therapeutic effects while adhering to the maximum daily dose of 194 mg.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure the integrity of the study data. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided. The focus remains on evaluating the hemodynamic effects of sacubitril-valsartan in patients with heart failure with preserved ejection fraction and secondary mitral valve regurgitation.

The efficacy of sacubitril-valsartan in patients with Heart Failure with Preserved Ejection Fraction (HFpEF) and secondary/atrial functional mitral regurgitation (AFMR) will be assessed through a combination of cardiopulmonary exercise testing and stress echocardiography (CPETecho). The primary endpoint for evaluating efficacy is the change in the **mPAP/CO slope** between randomization and six months thereafter. Secondary endpoints include changes in several parameters: Peak VO2, Mitral effective regurgitant orifice area (EROA), natriuretic peptide levels (NTproBNP), Left Atrial Volume Index (LAVI), Peak Atrial Longitudinal Strain (PALS), VE/VCO2 slope, and patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire (KCCQ-12).