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

Phase 1

• Conditions: Heart Failure 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-SE
• Lead Sponsor: AstraZeneca AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-12-08
• Last Update Posted: 8 January 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 500

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 1a), and a medical history of typical symptoms and signs of HF in those who are currently receiving loop diuretic treatment.
3 Left ventricular ejection fraction <60% documented by the most recent echocardiogram 2D or 3D or cardiac magnetic resonance imaging within the last 12 months prior to screening.
4 Patients should be treated for HF, hypertension, T2DM, or renal disease according to guidelines.
5 NT-proBNP =300 pg/mL for patients with sinus rhythm at screening ; and NT-proBNP =600 pg/mL for patients with atrial fibrillation/flutter at screening or using local laboratory sample.
6 eGFR =30 and =60 mL/min/1.73m2 (by CKD-EPI formula) based on local laboratory sample.
7 UACR at screening: spot urine sample analysed at local laboratory = 30 mg/g (3 mg/mmol) and < 3000 mg/g (300 mg/mmol) for participants
on SGLT2i; spot urine sample analysed at local laboratory = 50 mg/g (5 mg/mmol) and < 3000 mg/g (300 mg/mmol) for participants not on
SGLT2i.
8 Body mass index less than 40 kg/m2 .
9 Male or female of non-childbearing potential.
10 Female patients must be of non-childbearing potential.
Women of non-childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause. The following age-specific requirements apply:
(a) Women <50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and FSH levels in the postmenopausal range.
(b) Women =50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
11 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.
12 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
13 Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses. NOTE: For the optional pre-
screening visit there is a separate informed consent. Refer to Section 4.1.1
14 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative.
Participants are eligible to be randomised in the study only if all of the
following criteria apply at randomisation (Visit 3):
15 eGFR = 30 mL/min/1.73 m2 (by CKD-EPI formula at central
laboratory) based on results from pre-randomisation Visit 2.
16 UACR = 30 mg/g (3 mg/mmol) and < 3000 mg/g (300 mg/mmol)
based on central laboratory samples collected at pre-randomisation Visit 2. Refer to
Section 8.1.1.
17 Serum/plasma K+ level = 3.5 and < 5.0 mmol/L within 10 da

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 currently decompensated unstable HF requiring hospitalisation for optimisation of HF treatment and 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 >10%).
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 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) prior to randomisation or is planned to undergo any of these procedures during the study.
12 Any major cardiovascular or major non-cardiovascular surgery within 3 months prior to randomisation or is planned to undergo any of these procedures during the study.
13 Heart transplantation or left ventricular assist device at any time or if these are planned.
14 Kidney or any organ transplantation or if these are planned.
15Addison’s disease.
16 History or ongoing allergy/hypersensitivity to SGLT2i.
17 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 at time of screening (Visit 1a).
(c) Severe chronic obstructive pulmonary disease or other lung disease including but not limited to pulmonary fibrosis requiring chronic oxygen therapy, regular nebuliser use or oral steroid therapy.
18 Stroke, transient ischaemic attack, carotid surgery or carotid angioplasty within previous 3 months prior to randomisation.
19 Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas of the skin).
20 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 1a) and/or within 7 days prior to randomisation (Visit 3). An isolated increase in bilirubin in patients with known Gilbert’s syndrome is not a reason for exclusion.
21 Prior or ongoing drug or alcohol abuse.
22 Patients treated with strong or moderate CYP3A4 inhibitor or inducer.
23 Patients with newly detected pathological laboratory values or an ongoing disease condition requiring investigation and/or initiation or adjustment of current treatment.

Study & Design

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