Efficacy, Safety, and Tolerability of JTT-861 in Heart Failure with Reduced Ejection Fraction: A Phase 2a Randomized, Double-blind, Placebo-controlled Study

The primary objective of this Phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group study is to evaluate the **efficacy** of JTT-861 administered over a 12-week period in subjects with **Heart Failure with Reduced Ejection Fraction (HFrEF)**. This is clinically relevant as HFrEF is a condition characterized by the heart's inability to pump blood efficiently, leading to significant morbidity and mortality. Assessing the efficacy of JTT-861 could provide insights into potential therapeutic benefits for patients suffering from this condition.

Additional primary objectives include evaluating the **safety** and **tolerability** of JTT-861, as well as its **pharmacokinetics** (PK) in the same patient population. Understanding the safety profile and tolerability is crucial for determining the risk-benefit ratio of the treatment, while pharmacokinetic data will inform on the drug's absorption, distribution, metabolism, and excretion, which are essential for optimizing dosing regimens.

The clinical trial involves a total of **231 participants** diagnosed with **heart failure with reduced ejection fraction (HFrEF)**. The study population includes both male and female subjects, aged between 30 and 85 years. Participants were selected based on their clinical diagnosis of symptomatic heart failure, with a requirement of being in New York Heart Association (NYHA) functional class II or III. All subjects are on stable, guideline-directed therapy for heart failure, consistent with recommendations from major cardiology associations. The trial population is characterized by a left ventricular ejection fraction of 35% or less and elevated serum N-terminal pro b-type natriuretic peptide (NT-pro-BNP) levels. The selection process considered individuals who are part of a vulnerable population, ensuring comprehensive representation. Lifestyle factors such as diet and physical activity were not specified by the sponsor.

The clinical trial is a **Phase 2a**, multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy, safety, and tolerability of JTT-861 administered over a 12-week period in subjects with **heart failure with reduced ejection fraction** (HFrEF). The trial involves the administration of JTT-861 in capsule form, with a maximum daily dose of 100 mg and a total dose not exceeding 8400 mg over the treatment period. The study is expected to commence recruitment on January 1, 2024, and conclude by June 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, clinical diagnosis of symptomatic heart failure, and specific laboratory values. Following successful screening, participants will be randomized to receive either JTT-861 or a placebo. The trial design ensures that neither the participants nor the investigators know which treatment is being administered, maintaining the double-blind nature of the study.

Throughout the trial, participants will attend follow-up visits at Weeks 2, 4, 8, and 12. These visits will involve assessments of efficacy parameters, including changes in left ventricular ejection fraction (LVEF), left ventricular volumes, and NT-pro-BNP levels, as well as safety evaluations through adverse event monitoring, laboratory tests, and electrocardiograms. Pharmacokinetic parameters will also be assessed at specified intervals to determine JTT-861 plasma concentrations.

The end-of-study visit will occur at the conclusion of the 12-week treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints. Participant involvement is expected to last approximately 12 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial aims to provide comprehensive data on the potential benefits and risks of JTT-861 in the target population.

The clinical trial involves the administration of **JTT-861**, an investigational medication, to evaluate its efficacy, safety, and tolerability in subjects with **heart failure with reduced ejection fraction (HFrEF)**. **JTT-861** is formulated as a capsule containing the active substance **JTT-861 monohydrochloride dihydrate**. The pharmaceutical form is a capsule, and the medication is administered orally. The dosing regimen involves a maximum daily dose of 100 mg, with a total maximum dose of 8400 mg over a treatment period of 12 weeks (84 days). The trial is designed to monitor participant compliance with the dosing schedule and assess pharmacokinetics over the course of the study.

In addition to the experimental treatment, a **placebo tablet** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the appearance of the **JTT-861** capsule but does not contain the active substance. The placebo is administered orally with the same frequency and duration as the experimental medication to maintain the study's blinding integrity. The use of a placebo allows for the assessment of the true efficacy and safety profile of **JTT-861** by providing a baseline for comparison.

The efficacy of JTT-861 in subjects with **Heart Failure with Reduced Ejection Fraction (HFrEF)** will be assessed through a series of primary and exploratory endpoints. The primary efficacy parameters include changes from baseline to the end of treatment in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV) index, and left ventricular end-diastolic volume (LVEDV) index, all assessed by two-dimensional echocardiography (2D-echo). Additionally, changes in left atrial volume (LAV), N-terminal pro b-type natriuretic peptide (NT-pro-BNP) levels, and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores will be evaluated.

Exploratory efficacy parameters will include changes from baseline to the end of treatment in estimated glomerular filtration rate (eGFR), Cystatin C, urine albumin-to-creatinine ratio (ACR), hemoglobin A1c (HbA1c), plasma glucose, tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), right ventricular (RV) longitudinal strain, and tricuspid regurgitation peak gradient (TRPG), all assessed by 2D-echo. The pharmacodynamic parameters will also be explored, focusing on changes in branched-chain amino acids (BCAAs: isoleucine, leucine, and valine) and alanine plasma concentrations.

Measurements will be collected at various time points, with pharmacokinetic parameters including JTT-861 trough plasma concentrations at Weeks 4, 8, and 12, and post-dose plasma concentrations at Weeks 2, 4, and 8. The study is designed as a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, with a treatment duration of 12 weeks. The efficacy assessments will be conducted using validated tools and methodologies to ensure the reliability and accuracy of the data collected.