Safety and Tolerability Study of AZD4831 in Patients With Heart Failure.
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: AZD4831; Placebo
Intervention description: AZD4831 tablet taken orally for 90 days.; Placebo tablet taken orally for 90 days.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 41.0
Sex: All
Minimum age: 45 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Heart Failure with Ejection Fraction

Summary:

      A randomized, double-blind, placebo-controlled, parallel group, multicentre study in patients
      with Heart Failure with preserved Ejection Fraction (HFpEF). The study will be conducted at
      approximately 15 sites in 5 countries. Approximately 96 patients will be randomized to
      AZD4831 or placebo (treatment duration 90 days).
    

Eligibility criteria:

        Inclusion Criteria:

        Informed consent

          1. 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

          2. Provision of signed and dated, written informed consent form prior to any mandatory
             study specific procedures, sampling, and analyses

             Age

          3. 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

          4. Signs and symptoms of HF in judgement of Investigator AND

               1. Stable NYHA II-IV and

               2. Ejection fraction (EF) ≥ 40 % and

               3. 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

               4. 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

          5. Body Mass Index (BMI) range 18-40kg/m2

             Sex

          6. Male or female of nonchildbearing potential

             Reproduction

          7. Female patients must be 1 year post-menopausal or surgically sterile

          8. 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

          9. 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:

          1. Isolated pulmonary arterial hypertension or right ventricular (RV) failure; in the
             absence of left-sided HF

          2. Anaemia: Hb <100 mg/L (10g/dL)

          3. 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