Safety and Tolerability Study of AZD4831 in Patients With Heart Failure.

Inclusion Criteria:

Informed consent

Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this CSP

Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses

Age

Patient must be 45 to 85 years of age inclusive, at the time of signing the informed consent form

Type of patient and disease characteristics

Signs and symptoms of HF in judgement of Investigator AND

Stable NYHA II-IV and
Ejection fraction (EF) ≥ 40 % and

Elevated NT-proBNP or BNP in the last 1 year defined as:

o Measured as out-patient: NT-proBNP ≥125 ng/L or BNP≥35 ng/L with sinus rhythm, NT-proBNP ≥750 ng/L or BNP ≥200 ng/L with atrial fibrillation (AF),

or

o Measured when hospitalized acutely: NT-proBNP ≥500 (ng/L) or BNP ≥125 ng/L with sinus rhythm, NT-proBNP ≥1250 (ng/L) or BNP ≥350 ng/L with AF

And at least one of the following:

Hospitalization with HF as primary cause in last 12 months
Structural heart disease on echo according to ESC guidelines i.e. either enlarged Left atrial volume index (LAVI > 34 ml/m2) or increased LVM (LVM index > 95 g/m2 in women and > 115 g/m2 in men)
Pulmonary capillary wedge pressure (PCWP) at rest >15 mmHg or >25 mmHg at exercise
Spectral tissue Doppler echocardiography - E/e' ratio ≥13 at rest

Weight

Body Mass Index (BMI) range 18-40kg/m2

Sex

Male or female of nonchildbearing potential

Reproduction

Female patients must be 1 year post-menopausal or surgically sterile

Male patients must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of AZD4831/matching placebo to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period

Genetic sampling

For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described above and provide informed consent for the genetic sampling and analysis

Exclusion Criteria:

Creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR <30 ml/min/1.73m2 or dialysis

Life expectancy < 3 years due to other reasons than cardiovascular disease

Any ongoing skin disorder, history of or ongoing clinically significant allergy/hypersensitivity.

Current decompensated HF

Primary cardiomyopathy (e.g. constrictive, restrictive, infiltrative, toxic, hypertrophic, congenital or any primary cardiomyopathy) in judgment of investigator

Current hemodynamically significant valve disease in opinion of investigator

EF ever documented < 40%

Any current life-threatening dysrhythmia

Probable alternative primary reason for patient's symptoms in judgment of investigator, including but not limited to:

Isolated pulmonary arterial hypertension or right ventricular (RV) failure; in the absence of left-sided HF
Anaemia: Hb <100 mg/L (10g/dL)
Severe chronic obstructive pulmonary disease (COPD) or lung disease (chronic O2, nebulizer or oral steroid therapy)

Cardiac surgery, acute coronary syndrome (ACS), or non-elective percutaneous coronary intervention (PCI) < 3 months

Known or clinically judged significant macrovascular coronary artery disease (CAD) that has not been revascularized

Heart transplantation or left ventricular assist device ever

Patients with uncontrolled or clinically significant thyroid disease as judged by the investigator.

Alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥2 x upper limit of normal (ULN). Resampling will not be allowed during the same screening period if detected abnormal values do not have reasonable explanation and are not expected to return to normal level within few days.

Known positive HIV, hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening