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

The purpose of the study is to evaluate the efficacy and safety of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone and to assess the dose-response relationship, dapagliflozin alone and 3 doses of AZD9977 combined with dapagliflozin on urinary albumin to creatinine ratio (UACR). The study will be conducted in participants with heart failure (HF) with left ventricular ejection fraction (LVEF \[below 60%\]) and chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR \[between ≥ 20 and ≤ 60 mL/min/1.73 m\^2, with at least 20% of participants with eGFR ≥ 20 to \<30 mL/min/1.73\^2 and a maximum of 35% of participants with eGFR ≥ 45 mL/min/1.73 m\^2\]).

After screening, eligible participants will undergo a run-in period where all participants receive dapagliflozin for up to 7 weeks depending on pre-study use of SGLT2i or not. At the end of the run-in period, eligible participants will be randomly assigned with a 1:1:1:1 ratio to receive once daily administration of one of the following 4 study treatments group for 12 weeks. To ensure blinding, the study treatment will be administered in the form of 3 oral capsules of AZD9977 or placebo and 1 oral tablet or dapagliflozin.

1. AZD9977 Dose A + dapagliflozin 10 mg
2. AZD9977 Dose B + dapagliflozin 10 mg
3. AZD9977 Dose C + dapagliflozin 10 mg
4. Dapagliflozin 10 mg

Participants will be randomized to one of the above treatment group, according to type 2 diabetes mellitus \[T2DM (yes/no)\] and eGFR (≥ 20 to \<30 mL/min/1.73\^2; or ≥ 30 to \< 45 mL/min/1.73\^2; or ≥45 mL/min/1.73\^2).

The total duration of participation will be approximately 22 to 24weeks.

Eligibility Criteria:
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