Study to Evaluate the Efficacy and Safety of AZD4831 in Participants with Heart Failure with Left Ventricular Ejection Fraction > 40% - ENDEAVOR

Inclusion Criteria

• Part A
• 1. ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent.
• 2. Documented stable symptomatic HF (New York Heart Association Class II-IV) for at least 1 month at Screening (Visit 1) (transient HF in the setting of an MI does not qualify), with a medical history of typical symptoms of HF and receiving optimal therapy for HF as determined by the health-care physician.
• 3. LVEF > 40% at Screening (Visit 1). All participants will undergo a local echocardiogram at the Screening (Visit 1) with central reading to confirm the LVEF > 40% eligibility criteria before randomisation.
• 4. 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 3). Difference in 6MWD between Screening and Randomisation must be < 50 meters.
• 5. KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 3)
• 6.NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI ≤30 kg/m2.
• NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI > 30 kg/m2.
• The ECG performed at Screening should be used for heart rhythm evaluation.
• 7.At least one of the following:
• (a) Structural heart disease, ie, LA enlargement and/or left ventricular hypertrophy at the echocardiogram performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI > 34 mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or LVMI > 95 g/m2 in women and > 115 g/m2 in men.
• (b) Spectral tissue Doppler echocardiography - E/e’ ratio (average of septal and lateral) ≥ 13 at rest at the echocardiogram performed at Screening (Visit 1).
• (c) Indirectly estimated elevation of PASP by TRmax velocity > 2.8 m/s (280 cm/s) (PASP > 35 mmHg) at the echocardiogram performed at Screening (Visit 1) OR directly measured pulmonary capillary wedge pressure > 15 mmHg at rest within the past 12 months or > 25 mmHg at exercise documented by right heart catheterisation within 12 months prior to Screening (Visit 1).
• (d) HF decompensation within 6 months before Randomisation (Visit 3), defined as hospitalisation for HF or IV diuretic treatment for HF during an urgent, unscheduled visit without hospitalisation.
• 8.Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2
• 9.Male or female of non-childbearing potential.
• Part B
• 1. Participant must be ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent.
• 2. Documented diagnosis of symptomatic HF (NYHA class II-IV) at Screening (Visit 1), and a medical history of typical symptoms/signs of heart failure ≥ 6 weeks before Screening (Visit 1), and receiving optimal therapy for HF as determined by the health-care physician, with at least intermittent need for diuretic treatment.
• 3. LVEF >40% and evidence of structural heart disease (ie, left ventricular hypertrophy or
• left atrial enlargement [defined by at least one of the following:LA enlargement and/or left ventricular hypertrophy at the echocardiogram
• performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width
• (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI > 34
• mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or
• LVMI > 95 g/m2 in women and > 115 g/m2 in men.]) documented by the most recent echocardiogram, or cardiac
• magnetic resonance imaging within the last 12 months prior to Screening (Visit 1). If no
• echocardiogram is available, it can be performed at Screening (Visit 1).
• 4. 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 2). Difference in 6MWD between Screening and Randomisation must be < 50 meters
• 5. KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 2).
• 6. NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI ≤ 30 kg/m2. NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI > 30 kg/m2. The ECG performed at Screening should be used for heart rhythm evaluation
• 7. Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2
• 8. Male or female of non-childbearing potential.