Dose-Ranging Study of AZD5462 in Stable Chronic Heart Failure: A Phase IIb Randomized, Double-Blind, Placebo-Controlled, Multi-Center Trial

The primary objective of this study is to evaluate the effect and dose response of **AZD5462** after 24 weeks of treatment in participants with **Chronic Heart Failure** (HF). This is clinically relevant as it aims to determine the therapeutic potential and optimal dosing of AZD5462, which could lead to improved management of HF, a condition characterized by the heart's inability to pump sufficient blood to meet the body's needs.

Secondary objectives include:

• Evaluating the effect of AZD5462 on echocardiographic markers related to structural, systolic, and diastolic function after 12 and 24 weeks of treatment in participants with HF.
• Assessing the effect of AZD5462 on HF health status in participants with HF.
• Evaluating the effect of AZD5462 on biomarkers of cardiac function in treatment participants with HF.
• Assessing the pharmacokinetics (PK) of AZD5462 after repeat once-daily oral dosing in participants with HF.
• Evaluating the safety and tolerability of AZD5462 as compared to placebo in participants with HF.

The clinical trial involves a total of **137 participants** diagnosed with **Chronic Heart Failure**. The study population includes both male and female subjects, aged between 18 and 85 years. Participants are required to have a pre-existing diagnosis of heart failure classified as NYHA Functional Class II to IV and must be on stable heart failure standard of care medications for at least four weeks prior to consent. The trial does not include a vulnerable population. Participants must have a minimum BMI of 18 kg/m² at screening, and their left ventricular ejection fraction (LVEF) and NT-pro-BNP levels must be centrally confirmed. Female participants must be of non-childbearing potential, and all participants must be capable of giving and willing to give signed informed consent. The selection process ensures that participants are in a stable health condition, with specific lifestyle considerations such as stable medication use being a key factor in eligibility.

The clinical trial is a **Phase IIb** randomized, double-blind, placebo-controlled, multi-center study designed to evaluate the efficacy, safety, and pharmacokinetics of **AZD5462** in patients with **chronic heart failure**. The trial will involve two cohorts and aims to assess the effect and dose response of AZD5462 over a 24-week treatment period. Participants will be randomly assigned to receive either the active drug or a placebo, both administered as film-coated tablets via the oral route. The trial is expected to commence recruitment on June 10, 2024, and conclude by September 19, 2026.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis of heart failure, and stability of standard care medications. The inclusion criteria specify that participants must be between 18 and 85 years old, have a pre-existing diagnosis of heart failure classified as NYHA FC II to IV, and meet specific biomarker thresholds. The screening visit will also ensure that female participants are not pregnant or lactating and are of non-childbearing potential.

Following the screening, participants will attend regular follow-up visits at specified intervals, including weeks 3, 5, 13, and 25, to monitor changes in echocardiographic measurements, health status, NYHA functional class, and cardiac biomarkers. The primary endpoint is the change in echocardiographic measurements from baseline to week 25, with secondary endpoints including additional time points and pharmacokinetic assessments of AZD5462 plasma concentrations.

The expected duration of participant involvement is approximately 25 weeks, encompassing the treatment period and follow-up assessments. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or failure to adhere to the study protocol. The trial is not classified as low intervention, and all procedures will be conducted in accordance with regulatory and ethical standards.

The clinical trial involves the administration of **AZD5462**, an investigational medication developed by AstraZeneca AB. **AZD5462** is provided in the form of a **film-coated tablet**. The active substance, **AZD5462**, is of chemical origin. The medication is administered orally. The trial is designed to evaluate the effect and dose response of **AZD5462** over a treatment period of 24 weeks in participants with chronic heart failure. The dosage and frequency of administration are determined based on the study protocol, with a focus on maintaining participant compliance through regular monitoring.

In addition to the experimental treatment, a placebo is utilized in the study to serve as a comparator. The placebo is formulated to match the **AZD5462** film-coated tablet in appearance and is composed of microcrystalline cellulose, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol (polyethylene glycol), and talc. It is supplied in the same packaging as the active medication and must be stored according to the instructions provided on the label. The use of a placebo allows for a double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias in the assessment of the investigational drug's efficacy and safety.

The efficacy of AZD5462 in the treatment of **Chronic Heart Failure** will be assessed through a series of primary and secondary endpoints. The primary endpoint involves evaluating the change in echocardiographic measurements from baseline to Week 25. Secondary endpoints include changes in echocardiographic measurements at Week 13 and Week 25, changes in health status from baseline to Weeks 3, 5, 13, and 25, changes in NYHA Functional Class from baseline to Week 25, changes in cardiac biomarkers from baseline to Weeks 5, 13, and 25, and the measurement of AZD5462 plasma pharmacokinetic concentrations.

These efficacy parameters will be collected and analyzed at specified timepoints throughout the study duration, which extends up to 24 weeks. The study is designed as a Phase IIb, randomized, placebo-controlled, double-blind, multi-center, dose-ranging trial. The assessments will be conducted using validated scales and laboratory tests to ensure the accuracy and reliability of the data collected. The trial aims to evaluate the effect and dose response of AZD5462 in participants with heart failure, with a focus on both efficacy and safety outcomes.