Efficacy and Safety of LY3540378 in Adults with Worsening Chronic Heart Failure with Preserved Ejection Fraction: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to demonstrate that **LY3540378** administered subcutaneously is superior to placebo in improving atrial myopathy in participants with worsening chronic **Heart Failure with Preserved Ejection Fraction (HFpEF)**. This is clinically relevant as atrial myopathy is a significant contributor to the morbidity associated with HFpEF, and effective treatment could improve patient outcomes and quality of life.

The clinical trial involves a total of **265 participants** diagnosed with **Heart Failure with Preserved Ejection Fraction**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their diagnosis of chronic heart failure, ensuring a focus on individuals experiencing worsening symptoms. The trial does not specifically target a vulnerable population, and no particular lifestyle considerations such as diet or physical activity are highlighted. The selection criteria emphasize the presence of chronic heart failure, aligning with the study's objective to assess the efficacy of LY3540378 in improving atrial myopathy compared to a placebo.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of LY3540378 in adults with worsening **chronic heart failure with preserved ejection fraction (HFpEF)**. The trial aims to demonstrate that LY3540378, administered subcutaneously, is superior to placebo in improving atrial myopathy. The primary endpoint is the change from baseline in left atrial reservoir strain (LARS). The trial is expected to commence recruitment on April 13, 2023, and conclude by January 8, 2025, with an estimated duration of participant involvement of up to one year.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on the principal inclusion criterion of having chronic heart failure. Following randomization, participants will receive either LY3540378 or a placebo, both administered as a solution for injection via cutaneous use. The study will include multiple follow-up visits to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will evaluate the primary endpoint and gather final safety data.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with the study protocol, or withdraw consent. The trial is categorized as a Phase II study, assessing a non-authorized investigational medicinal product to investigate safety and efficacy. The investigational product, LY3540378, is a protein-based formulation, specifically an **IgG against serum albumin fused with relaxin 2, chain B (2-29) and relaxin 2 (chain A)**. The placebo is designed to match LY3540378 in appearance and administration method. The trial is not classified as a low-intervention study, and it adheres to the guidelines set forth by the European Medicines Agency (EMA) for disclosure and trial categorization.

The clinical trial involves the administration of **LY3540378**, an experimental medication formulated as a **solution for injection**. The active substance in LY3540378 is **IgG against serum albumin fused with relaxin 2, chain B (2-29) and relaxin 2 (chain A)**. This investigational drug is provided by Eli Lilly and Company Limited. The route of administration is **cutaneous use**, and the dosing schedule is determined by the study protocol, with a maximum treatment period of one time unit. The trial aims to assess the efficacy and safety of LY3540378 in adults with worsening chronic heart failure with preserved ejection fraction (HFpEF). Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes a **placebo** designed to match LY3540378, ensuring the double-blind nature of the trial. The placebo is administered in the same pharmaceutical form and route as the experimental medication, which is a solution for injection via cutaneous use. The placebo serves as a comparator treatment to evaluate the efficacy of LY3540378 in improving atrial myopathy in participants with HFpEF. The placebo is utilized to maintain the integrity of the study design and to provide a baseline for assessing the therapeutic effects of the investigational drug.

The efficacy of LY3540378 in the clinical trial will be assessed by evaluating the primary endpoint, which is the change from baseline in **Left Atrial Reservoir Strain (LARS)**. This parameter is used to measure the improvement in atrial myopathy in participants with worsening chronic Heart Failure with Preserved Ejection Fraction (HFpEF). The trial is designed as a Phase 2, randomized, double-blind, placebo-controlled study, ensuring rigorous assessment of the investigational product's efficacy compared to placebo.