Clinical trial NCT04595370: Efficacy, Safety and Tolerability of AZD9977 and Dapagliflozin in Participants With Heart Failure and Chronic Kidney Disease
Official title: A Phase 2b, Randomised, Double-Blind, Active Controlled, Multi Centre Study to Evaluate the Efficacy, Safety and Tolerability of Oral AZD9977 and Dapagliflozin Treatment in Patients With Heart Failure and Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Chronic Kidney Disease
Keywords: Heart Failure
Type 2 diabetes mellitus
Diabetic kidney disease
Chronic kidney disease
Mineralocorticoid receptor modulator
Sodium-glucose co-transporter-2 inhibitor
AZD9977
Dapagliflozin
Urinary albumin creatinine ratio
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-10-20
Enrollment: 153
Sex: ALL
Minimum age (years): 21
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants who meet the eligibility criteria will be randomized to one of the following treatment group:

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
Primary purpose: TREATMENT

Brief summary: 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 \[between ≥ 20 and ≤ 60 mL/min/1.73 m\^2, with at least 20% of participants with eGFR ≥ 20 to \<30 mL/min/1.73\^2 and a maximum of 35% of participants with eGFR ≥ 45 mL/min/1.73 m\^2\]).

Detailed description: 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

Primary outcomes:
measure: Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12
timeFrame: Baseline (Day 1) to Week 12
Secondary outcomes:
measure: Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship
timeFrame: Baseline (Day 1) to Week 12
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From baseline (Day 1) until Day 113
measure: Change From Baseline in Serum Potassium (K+)
timeFrame: Baseline (Day 1) and Week 12
measure: Absolute Value of Serum Potassium Over Time
timeFrame: Baseline (Day 1) and Week 12
measure: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
timeFrame: Baseline (Day 1) and Week 12
measure: Absolute Value of eGFR Over Time
timeFrame: Baseline (Day 1) to Week 12
Other outcomes:
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country: Poland
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city: Łódź
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country: Russian Federation
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city: Kazan
country: Russian Federation
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city: Kemerovo
country: Russian Federation
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city: Moscow
country: Russian Federation
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city: Moscow
country: Russian Federation
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city: Moscow
country: Russian Federation
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city: Moscow
country: Russian Federation
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city: Saint-Petersburg
country: Russian Federation
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city: St Petersburg
country: Russian Federation
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city: St. Petersburg
country: Russian Federation
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city: St. Petersburg
country: Russian Federation
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city: Banska Bystrica
country: Slovakia
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city: Brezno
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city: Lucenec
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city: Presov
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city: Svidnik
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city: Trencin
country: Slovakia
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city: Barcelona
country: Spain
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city: Coruña
country: Spain
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city: El Palmar
country: Spain
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city: Madrid
country: Spain
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country: Spain
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country: Spain
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city: Sevilla
country: Spain
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country: Spain
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country: Spain
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city: Goeteborg
country: Sweden
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country: Sweden
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city: Stockholm
country: Sweden
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city: Uppsala
country: Sweden
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country: Taiwan
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country: Taiwan
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city: Taipei City
country: Taiwan
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city: Taipei
country: Taiwan
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city: Taipei
country: Taiwan
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city: Bangkok
country: Thailand
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city: Bangkok
country: Thailand
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city: Chaingmai
country: Thailand
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city: Khon Kaen
country: Thailand
facility: Research Site
city: Adana
country: Turkey
facility: Research Site
city: Kocaeli
country: Turkey
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kharkiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
Study officials:
affiliation: University of Glasgow, United Kingdom
name: John McMurray
role: PRINCIPAL_INVESTIGATOR
References: