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-LT
• Lead Sponsor: AstraZeneca AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-11-24
• 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 days

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).
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.
24 Any condition outside the renal and cardiovascular

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 in combination with dapagliflozin compared with dapagliflozin alone on UACR<br>;Secondary Objective: To assess the dose-response relationship of dapagliflozin (10 mg) alone and 3 doses of AZD9977 (15, 50, or 150 mg) combined with dapagliflozin<br>(10 mg) on UACR<br>;Primary end point(s): The primary efficacy endpoint for this study is the percent change from<br>baseline in UACR at the end of 12 weeks of study treatment.<br>;Timepoint(s) of evaluation of this end point: From baseline at the end of 12 weeks of study treatment.<br><br>

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Percent change from baseline in UACR at the end of 12 weeks of study<br>treatment.<br><br>;Timepoint(s) of evaluation of this end point: From baseline at the end of 12 weeks of study treatment<br>