Efficacy, Safety and Tolerability of AZD9977 and Dapagliflozin in Participants With Heart Failure and Chronic Kidney Disease (MIRACLE)

Inclusion Criteria:

Participants are included in the study if any of the following criteria apply:

• Documented diagnosis of stable symptomatic HF (New York Heart Association class II-III) at screening, and a medical history of typical symptoms and signs of HF in those who are currently receiving loop diuretic treatment
• Left ventricular ejection fraction <60% documented by the most recent echocardiogram or cardiac magnetic resonance imaging within the last 12 months prior to screening
• Stable background treatment for HF, hypertension, diabetes mellitus or renal disease according to guidelines
• N-terminal-pro-brain natriuretic peptide (NT proBNP) ≥300 pg/mL for participants with sinus rhythm at screening; and NT proBNP ≥600 pg/mL for participants with atrial fibrillation/flutter at screening
• The eGFR ≥30 and ≤60 mL/min/1.73^2 (by CKD- EPI formula) and UACR ≥30 mg/g (3 mg/mmol) and <3000 mg/g (300 mg/mmol)
• Body mass index less than 40 kg/m^2
• Serum/plasma K+ level ≥ 3.5 and < 5.0 mmol/L within 10 days prior to randomization
• Serum/ plasma Na+ level within normal reference values within 10 days prior to randomization
• Systolic blood pressure should be at protocol defined range at randomization (Visit 3), with no change to antihypertensive treatments in previous 3 weeks
• Male or female of non-childbearing potential
• All participants must follow protocol defined contraceptives procedures

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Primary glomerulopathy, vasculitic renal disease, prior dialysis or unstable rapidly progressing renal disease, autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasm antibody-associated vasculitis
• Participants with currently decompensated HF requiring hospitalization for optimization of HF treatment and are not on stable HF therapy at the time of enrollment
• HF due to cardiomyopathies
• High output HF (e.g., due to hyperthyroidism or Paget's disease)
• HF due to pericardial disease, congenital heart disease or clinically significant uncorrected primary cardiac valvular disease or planned cardiac valve repair/replacement
• Participants with uncontrolled diabetes mellitus (Glycated hemoglobin >10%)
• Participants with Type 1 diabetes mellitus
• Intermittent or persistent 2nd or 3rd degree atrioventricular block, sinus node dysfunction with clinically significant bradycardia or sinus pauses, not treated with a pacemaker
• History of any life-threatening cardiac dysrhythmia or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter
• Acute coronary syndrome and/or elective/non-elective percutaneous cardiac interventions (within 3 months) prior to randomisation or is planned to undergo any of these procedures during the study
• Any major cardiovascular (eg, open chest, coronary artery bypass grafting or valvular repair/replacement) or major non-cardiovascular surgery within 3 months prior to randomisation or is planned to undergo any cardiovascular surgery during the study
• Heart transplantation or left ventricular assist device at any time or if these are planned
• Kidney or any organ transplantation or if these are planned
• Medical conditions associated with development of hyperkalaemia (Addison's disease )
• History or ongoing allergy/hypersensitivity, to sodium-glucose co-transporter-2 inhibitor (SGLT2i e.g., dapagliflozin, empagliflozin)
• Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within previous 3 months prior to randomisation
• Hepatic disease, including hepatitis and/or hepatic impairment (Child-Pugh class A-C), and aspartate aminotransferase or alanine transaminase or total bilirubin should be in protocol defined range at time of screening and/ or within 7 days prior to randomization
• Participants with newly detected pathological laboratory values or an ongoing disease condition
• If the participants clinical signs and symptoms consistent with COVID-19, and has been previously hospitalized with COVID-19 infection and did not fully recover their previous health status
• Previous randomization in the present study
• Prior medical treatment with an mineralocorticoid receptor antagonist where the medication was taken within 90 days prior to screening
• Current or prior treatment within 6 months prior to screening with cytotoxic therapy, immunosuppressive therapy, or other immunotherapy