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

Study Overview
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Brief Summary
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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).

Detailed Description
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This is a randomized, double-blind, placebo controlled, parallel group, multicentre study in patients with Heart Failure with preserved Ejection Fraction (HFpEF) and mid-range Ejection Fraction (HRmrEF). The study will be conducted at approximately 15 sites in 5 countries (USA, Sweden, Denmark, Finland, Netherlands). Patients suitable for the study will be checked for eligibility, signing the informed consent and enrolled to the study at visit 1. The study will be divided into two parts, Part A and Part B. In part A 37 patients will be randomized at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or matching placebo for approximately 90 days. After approximately 30 days of treatment, an interim analysis will be done to analyse the safety, tolerability and target engagement. After the evaluation, the randomization to Part B may proceed. In Part B the approximate 59 remaining patients will be randomized and treated for approximately 90 days.

Official Title
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A Randomized, Double Blind, Placebo-controlled, Parallel Group, Multicentre, Phase 2a Study to Assess Target Engagement, Safety and Tolerability of AZD4831 in Patients With Heart Failure With Preserved Ejection Fraction (HFpEF)

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: AZD4831
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD4831<br>AZD4831 tablets taken orally for for 90 days. | Drug: AZD4831<br>* AZD4831 tablet taken orally for 90 days.<br>|
| Placebo Comparator: Placebo<br>Placebo tablets taken orally for 90 days. | Drug: Placebo<br>* Placebo tablet taken orally for 90 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in MPO Specific Activity | To compare the effect of AZD4831 to placebo on Target engagement, defined as ex vivo zymozan stimulated Myeloperoxidase (MPO) specific activity | Measurements on day 0, 10, 30 and 90. Change reported from day 0 to day 90. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in CFVR Measured in the Mid-distal Segment of the Left Anterior Descending (LAD) Coronary Artery Under Adenosine Infusion Measured by Transthoracic Doppler Echocardiography (TDE). | To compare the effect of AZD4831 to placebo on coronary flow velocity reserve (CFVR) measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE). | Measurement on day 0 and 90. | 
| Change From Baseline in Walking Distance | To compare the effect of AZD4831 to placebo on 6 minutes walking test (6MWT) | Measurement on day 0, 30 and 90. Change reported from day 0 to day 90. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure with Ejection Fraction