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

• Status: Recruiting
• Trial end date: 2022-07-22
• Target enrollment: 0
• Participant gender: All

Summary

The purpose of the study is to evaluate the efficacy and safety of AZD9977 alone and AZD9977 in combination with dapagliflozin and to assess the dose-response relationship of placebo, AZD9977 alone, 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 55%]) and chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR [between 20 and 60 mL/min/1.73 m^2, with at least 30% of participants with eGFR ≥ 20 to <30 mL/min/1.73^2 and a maximum of 25% of participants with eGFR >45 mL/min/1.73 m^2]), including at least 40% of participants with type 2 diabetes mellitus (T2DM).

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

Details

• Lead Sponsor: AstraZeneca
• Treatments: 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol; Dapagliflozin

Criteria

Inclusion Criteria:

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

• Documented diagnosis of stable symptomatic HF (New York Heart Association class II-III) at screening (Visit 1), and a medical history of typical symptoms and signs of HF in those who are currently receiving loop diuretic treatment

• Left ventricular ejection fraction <55% documented by the most recent echocardiogram or cardiac magnetic resonance imaging within the last 12 months prior to screening (Visit 1)

• Stable background treatment for HF, hypertension, diabetes mellitus or renal disease for at least 3 weeks prior to randomization (Visit 3)/ or within the 3 weeks run-in period; i.e., therapy should have been stable for 3 weeks before randomization (Visit 3)

• N-terminal-pro-brain natriuretic peptide (NT proBNP) ≥600 pg/mL for participants with sinus rhythm at screening; and NT proBNP ≥900 pg/mL for participants with atrial fibrillation/flutter at screening or in medical history

• The eGFR ≥30 and ≤60 mL/min/1.73^2 and UACR >30 mg/g (3 mg/mmol) and <3000 mg/g (300 mg/mmol)

• Serum/plasma potassium level ≥3.5 and <5.0 mmol/L within 7 days prior to randomization (Visit 3)

• Serum/ plasma sodium level within normal reference values within 7 days prior to randomization (Visit 3)

• Systolic blood pressure should be at protocol defined range at randomization (Visit 3), with no change to antihypertensive treatments in previous 3 weeks

• Body mass index less than 40 kg/m^2

• 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 (Visit 3) 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 (Visit 3).

• 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 (Visit 1) and/ or within 7 days prior to randomization (Visit 3)

• 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 either an MRA or an SGLT2i where the medication was taken within 90 days prior to screening

• Current or prior treatment within 6 months prior to screening (Visit 1) with cytotoxic therapy, immunosuppressive therapy, or other immunotherapy