Evaluation of Sacubitril/Valsartan on Systolic Function in Transthyretin Cardiac Amyloidosis and Heart Failure with Reduced Ejection Fraction

The primary objective of this study is to evaluate the impact of treatment with **Sacubitril/Valsartan** on systolic function in patients diagnosed with **transthyretin cardiac amyloidosis** and heart failure with reduced ejection fraction. This will be assessed by measuring the change in left ventricular ejection fraction via echocardiogram over a 12-month period. The clinical relevance of this objective lies in its potential to improve cardiac function and outcomes in this patient population, which is characterized by progressive heart failure and limited treatment options.

The clinical trial involves participants diagnosed with **transthyretin cardiac amyloidosis**, specifically those with transthyretin amyloid cardiomyopathy and heart failure with reduced ejection fraction. The study population includes adults aged 18 years and older, encompassing both male and female subjects. Participants are required to have a left ventricular ejection fraction of 40% or less and be classified within functional class I, II, or III according to the New York Heart Association (NYHA). The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include patients with either hereditary (ATTRv) or wild-type (ATTRwt) forms of the condition, confirmed through histological or non-invasive methods, and for ATTRv, genetic testing is required. Participants are initially evaluated or under follow-up in specialized Cardiomyopathy, Heart Failure, or Amyloidosis Units at participating centers. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the impact of **Sacubitril/Valsartan** on systolic function in patients with **transthyretin cardiac amyloidosis** and heart failure with reduced ejection fraction. This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thereby minimizing bias. The trial is expected to commence on February 27, 2025, and conclude by January 15, 2027, with an estimated recruitment start date of September 16, 2024. The primary endpoint is the change in left ventricular ejection fraction, assessed by echocardiogram, after 12 months of treatment compared to baseline values.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), diagnosis of transthyretin amyloid cardiomyopathy, and heart failure with reduced ejection fraction (LVEF ≤40%). Follow-up visits will be scheduled periodically to monitor the participants' health status and treatment efficacy. The end-of-study visit will occur at the 12-month mark, where the final assessment of the primary endpoint will be conducted. The expected length of participant involvement is approximately 12 months, aligning with the treatment period.

Participants may be subject to early termination from the study if they experience adverse effects that compromise their safety, if they withdraw consent, or if they fail to comply with the study protocol. The trial will utilize **Entresto 24 mg/26 mg film-coated tablets**, administered orally, with a maximum daily dose of 194 mg. The study is classified as a low-intervention trial, with a detailed justification provided in the trial documentation. The trial phase is categorized as phase 6, indicating a focus on post-marketing surveillance and long-term effects of the treatment.

The clinical trial involves the administration of **Entresto**, a combination medication consisting of **valsartan** and **sacubitril**. This experimental medication is provided in the form of film-coated tablets, with each tablet containing 24 mg of sacubitril and 26 mg of valsartan. The tablets are administered orally. The maximum daily dose is 194 mg, and the total maximum dose over the treatment period is 70,810 mg. The treatment period is set for a maximum of 12 months. The medication is manufactured by Novartis Europharm Limited and is authorized for use in the European Union under the marketing authorization number EU/1/15/1058/001. The active substances, valsartan and sacubitril, are of chemical origin.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the effects of Entresto on patients with transthyretin cardiac amyloidosis and heart failure with reduced ejection fraction. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. Participants will be assessed for changes in left ventricular ejection fraction via echocardiogram at the end of the 12-month treatment period to determine the impact of the medication on systolic function.

Efficacy in the clinical trial titled "Effect of pharmacological treatment with angiotensin receptor/neprilysin inhibitors on transthyretin cardiac amyloidosis and heart failure with reduced ejection fraction (SAVA-TTR trial)" will be assessed by evaluating the change in left ventricular ejection fraction (LVEF) in patients with transthyretin amyloid cardiomyopathy and heart failure with reduced ejection fraction. The primary endpoint is the change in LVEF, measured by echocardiogram, after a 12-month treatment period with Sacubitril/Valsartan compared to management without Sacubitril/Valsartan. An improvement in LVEF will be defined as an increase of at least 5% between the baseline echocardiogram and the 12-month echocardiogram.