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

• Status: Recruiting
• Trial end date: 2024-09-30
• Target enrollment: 0
• Participant gender: All

Summary

This is a randomised, double-blind, placebo-controlled, multi-center sequential phase 2b and Phase 3 study to evaluate the efficacy and safety of AZD4831 administered for up to 48 Weeks in participants with heart failure with left ventricular ejection fraction > 40%. The study will consist of 2 separate parts, Part A and Part B, approximately 660 participants will be randomised in Part A, 825 in Part B.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: AstraZeneca

Criteria

Inclusion Criteria:

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), and typical symptoms and signs of HF since at least 1 month (transient HF in the setting of an MI does not qualify) prior to screening (Visit 1). Participants must be receiving a stable dose of an oral diuretic agent for at least 1 month prior to Visit 1 with no more than 50% dose adjustment in the last month.

3. LVEF > 40%, documented by the most recent echocardiogram, or cardiac magnetic resonance imaging within the last 12 months prior to Screening (Visit 1).

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 ≤ 80 points at Screening (Visit 1) and Randomisation (Visit 3)

6. NT-proBNP ≥ 300 pg/mL (sinus rhythm) or ≥ 600 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1).

7. At least one of the following:

1. 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.

2. Spectral tissue Doppler echocardiography - E/e' ratio (average of septal and lateral) ≥ 13 at rest at the echocardiogram performed at Screening (Visit 1).

3. Indirectly estimated elevation of PASP by TRmax velocity > 2.8 m/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).

4. 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.

Exclusion Criteria:

1 eGFR < 30 mL/min/1.73m2 (Chronic Kidney Disease-Epidemiology Collaboration formula) at Screening (Visit 1).

2. Systolic blood pressure < 90 mmHg or ≥ 160 mmHg if not on treatment with ≥ 3 blood pressure lowering medications or ≥ 180 mmHg irrespective of treatments at Randomisation 3. Heart rate > 110 bpm or < 50 bpm at Randomisation 4. Life expectancy < 3 years due to other reasons than cardiovascular disease. 5. History or ongoing allergy/hypersensitivity reactions to drugs (including but not limited to rash, angioedema, acute urticaria).

6. Presence of any disease or condition rather than HF constituting the main reason for limiting the ability to exercise/reduced exercise capacity.

7. Current decompensated HF and/or NT-proBNP > 5000 pg/mL at Screening (Visit 1) 8. Documented history of ejection fraction ≤ 40%. 9. Any planned cardiac procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter, and/or valve repair/replacement).

10. Any cardiac event (eg, myocardial infarction, unstable angina), coronary revascularisation (percutaneous coronary intervention or coronary artery bypass grafting), ablation of atrial fibrillation/flutter, valve repair/replacement, implantation of a cardiac resynchronisation therapy device within 12 weeks prior to Screening (Visit 1) or between Screening and Randomisation (Visit 3).

11. Medical history of aborted sudden cardiac death or sustained ventricular tachycardia with haemodynamic compromise.

12. Any primary cardiomyopathy (eg, genetic hypertrophic cardiomyopathy, obstructive hypertrophic, arrhythmogenic right ventricular cardiomyopathy/dysplasia), cardiomyopathies related to current toxic or infective conditions (eg, ongoing chemotherapy, myocarditis, septic cardiomyopathy), cardiomyopathies due to infiltrative diseases (eg, amyloidosis, sarcoidosis), peripartum cardiomyopathy, as well as HF due to pericardial disease, congenital heart disease or clinically significant uncorrected primary cardiac valvular disease 13. Any past or planned organ transplantation (including cardiac). 14. Hb < 110 g/L (male) and < 100 g/L (female) or iron-deficiency with/without anaemia requiring ongoing or planned IV iron treatment.

15. Participants with hyperthyroidism, uncontrolled hypothyroidism, or any clinically significant thyroid disease as judged by the investigator.