Efficacy, safety and tolerability of AZD9977 and dapagliflozin in patients with heart failure and chronic kidney disease

Phase 1

• Conditions: Heart Failure with Left Ventricular Ejection Fraction (LVEF) Below 55% and Chronic Kidney Disease; MedDRA version: 20.0Level: LLTClassification code 10019279Term: Heart failureSystem Organ Class: 100000004849; MedDRA version: 23.1Level: PTClassification code 10064848Term: Chronic kidney diseaseSystem Organ Class: 10038359 - Renal and urinary disorders; Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

• Registration Number: EUCTR2020-003126-23-IT
• Lead Sponsor: ASTRAZENECA AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-05-24
• Last Update Posted: 8 January 2024

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 540

Inclusion Criteria

1. Participant must be 21 years of age or older, at the time of signing the
informed consent.
2. Documented diagnosis of stable symptomatic HF (NYHA class II-III) at screening (Visit 1), and a medical history of typical symptoms and signs of HF who are currently receiving loop diuretic treatment.
3. Left ventricular ejection fraction <55% documented by the most recent echocardiogram 2D or 3D or cardiac magnetic resonance imaging within the last 12 months prior to screening (Visit 1).
4. Stable background treatment for heart failure, hypertension, diabetes mellitus or renal disease for at least 3 weeks prior to randomisation (Visit 3)/ within the 3 weeks run-in period.
5. NT-proBNP >=600 pg/mL for patients with sinus rhythm or >=900 pg/mL for patients with atrial fibrillation at screening.
6. eGFR >=30 and <=60 mL/min (by CKD-EPI formula) and UACR >30 mg/g (3 mg/mmol) and <3000 mg/g (300 mg/mmol).
7. Serum K+ level >=3.5 and <5.0 mmol/L within 5 days prior to randomisation (Visit 3) from local laboratory.
8. Serum Na+ level within normal reference values within 5 days prior to
randomisation (Visit 3) from local laboratory.
9. Systolic BP >=100 and <150 mmHg at randomisation (Visit 3), with no change to antihypertensive treatments in previous 3 weeks.
10. Diastolic BP >=60 and <90 mmHg at randomisation (Visit 3), with no change to antihypertensive treatments in previous 3 weeks.
11. No prior medical treatment with an MRA or SGLT2i taken for 3 months or longer during the 12 months prior to screening (Visit 1).
12. No current or prior (within the 3 weeks run-in period prior to randomisation [Visit 3]) treatment with MRA or SGLT2i and other prohibited concomitant medications.
13. No current or prior treatment within 6 months prior to screening (Visit 1) with cytotoxic therapy, immunosuppressive therapy or other immunotherapy.
14. Body mass index less than 40 kg/m2 .
15. Male or female of non-childbearing potential.
16. Female patients must have a negative pregnancy test at screening, must not be lactating and must be of nonchild-bearing potential, confirmed at screening by fulfilling one of the following criteria:
(a) Postmenopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and LH and FSH levels in the postmenopausal range.
(b) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
17. Male patients must be surgically sterile or using, in conjunction with their female partner, a highly effective method of contraception for the duration of the study (from the time they sign consent) and for 3 months after the last dose of study drug to prevent pregnancy in a partner. Male study participants must not donate or bank sperm during this same time period.
18. Capable of giving signed informed consent as described in Appendix A
which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.

FOR FURTHER INCLUSION CRITERIA, PLEASE REFER TO THE PROTOCOL
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 350
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 190

Exclusion Criteria

1. Primary glomerulopathy, vasculitic renal disease, prior dialysis or unstable rapidly progressing renal disease, Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or ANCA-associated vasculitis.
2. Patients with unstable HF requiring hospitalisation for optimisation of HF treatment and are not on stable HF therapy at the time of enrolment.
3. HF due to cardiomyopathies that would primarily require specific other treatment such as cardiomyopathy due to amyloidosis or infiltrative diseases, primary hypertrophic cardiomyopathy, cardiomyopathy related to current toxic or infective conditions.
4. High output HF.
5. HF due to pericardial disease, congenital heart disease or clinically significant uncorrected primary cardiac valvular disease, or planned cardiac valve repair/replacement.
6. Patients with uncontrolled diabetes mellitus (HbA1c >12%).
7. Patients with T1DM.
8. Intermittent or persistent 2nd or 3rd degree atrioventricular block, sinus node dysfunction with clinically significant bradycardia or sinus pauses, not treated with a pacemaker.
9. Prolonged QT interval (QTcF >470ms) on ECG at screening (Visit 1), known congenital long QT syndrome or history of QT prolongation associated with other medications.
10. History of any life-threatening cardiac dysrhythmia or uncontrolled ventricular rate in patients with atrial fibrillation or atrial flutter.
11. Acute coronary syndrome and/or elective/non-elective percutaneous cardiac interventions (within 3 months) or open chest cardiovascular surgery (within 12
months) prior to screening is planned to undergo any of these procedures during the study.
12. Heart transplantation or left ventricular assist device at any time or if these are planned.
13. Kidney or any organ transplantation or if these are planned.
14. Addison's disease.
15. History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i (eg, dapagliflozin, empagliflozin).
16. Any clinically significant disease or disorder which, as judged by the investigator, might put the patient at risk because of participation in the study, or probable alternative primary reason for patient's symptoms in judgement of investigator, including but not limited to:
(a) Isolated pulmonary arterial hypertension (PAP >=25 mmHg at rest) or right ventricular failure; in the absence of left-sided HF.
(b) Anaemia defined as haemoglobin level <100g/l or 10g/dl within 5 days prior to randomisation.
(c) Severe chronic obstructive pulmonary disease or other lung disease including but not limited to pulmonary fibrosis requiring chronic O2 therapy, regular nebuliser use or oral steroid therapy.
17. Stroke, transient ischaemic attack, carotid surgery or carotid angioplasty within previous 3 months prior to screening.
18. Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas of the skin).
19. Hepatic disease, including hepatitis and/or hepatic impairment (Child-Pugh class A-C), AST or ALT >2×ULN; or TBL >2×ULN at time of screening (Visit 1) and/or within 5 days prior to randomisation (Visit 3). An isolated increase in bilirubin in patients with known Gilbert's syndrome is not a reason for exclusion.

FOR FURTHER EXCLUSION CRITERIA, PLEASE REFER TO THE PROTOCOL

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on UACR;Secondary Objective: To assess the dose-response relationship of placebo, AZD9977 (150 mg) alone, dapagliflozin (10 mg) alone and 3 doses of AZD9977 (15, 50, or 150 mg) combined with dapagliflozin (10 mg) on UACR.;Primary end point(s): The primary efficacy endpoint for this study is the percent change from baseline in UACR at 12 weeks.;Timepoint(s) of evaluation of this end point: From baseline at 12 weeks.<br>Baseline for UACR will be defined as the value obtained at Visit 3 before the first dose of study treatment.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): The dose-response relationship of percent change from baseline in UACR at 12 weeks will be assessed using data from placebo, AZD9977 (150 mg) alone, dapagliflozin (10 mg) alone and 3 doses of AZD9977 (15, 50, or 150 mg) combined with dapagliflozin (10 mg).;Timepoint(s) of evaluation of this end point: From baseline at 12 weeks.