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

Heart Failure Clinical Trial

— MIRACLE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04595370
• Other study ID #: D6402C00001
• Secondary ID: 2020-003126-23
• Status: Completed
• Phase: Phase 2
• Start date: January 26, 2021
• Est. completion date: September 22, 2023

Study information

• Verified date: October 2023
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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]).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 153
• Est. completion date: September 22, 2023
• Est. primary completion date: September 22, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 130 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Heart Failure
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• AZD9977
Participants will receive AZD9977 as per the arms they are randomized.
• Dapagliflozin
Participants will receive dapagliflozin as per the arms they are randomized.

Locations

Country	Name	City	State
Belgium	Research Site	Roeselare
Bulgaria	Research Site	Pleven
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Veliko Turnovo
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Peterborough	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Toronto	Ontario
Czechia	Research Site	Pardubice
Czechia	Research Site	Praha 2
Czechia	Research Site	Praha 5
Czechia	Research Site	Uherske Hradiste
Denmark	Research Site	Aarhus
Denmark	Research Site	Herlev
Denmark	Research Site	Svendborg
Germany	Research Site	Dresden
Germany	Research Site	Frankfurt
Germany	Research Site	Homburg
Germany	Research Site	Jena
Germany	Research Site	Leipzig
Hungary	Research Site	Balatonfüred
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Miskolc
Hungary	Research Site	Oroshaza
India	Research Site	Ahmedabad
India	Research Site	Chennai
India	Research Site	Kolkata
India	Research Site	Pune
Italy	Research Site	Roma
Japan	Research Site	Chuo-ku
Japan	Research Site	Hamada-shi
Japan	Research Site	Hamamatsu-shi
Japan	Research Site	Hanyu-shi
Japan	Research Site	Itabashi-ku
Japan	Research Site	Kasugai-shi
Japan	Research Site	Kawaguchi
Japan	Research Site	Kishiwada-shi
Japan	Research Site	Kobe
Japan	Research Site	Kobe-shi
Japan	Research Site	Matsudo-Shi
Japan	Research Site	Matsumoto-shi
Japan	Research Site	Ono
Japan	Research Site	Osaka-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Sayama
Japan	Research Site	Takasago-shi
Japan	Research Site	Takasaki-shi
Japan	Research Site	Ueda-shi
Japan	Research Site	Yokohama-shi
Japan	Research Site	Yokohama-shi
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Gangwon-do
Korea, Republic of	Research Site	Seongnam-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Lithuania	Research Site	Kaunas
Lithuania	Research Site	Klaipeda
Lithuania	Research Site	Siauliai
Lithuania	Research Site	Vilnius
Poland	Research Site	Gdansk
Poland	Research Site	Gdansk
Poland	Research Site	Katowice
Poland	Research Site	Lódz
Poland	Research Site	Lódz
Poland	Research Site	Lódz
Poland	Research Site	Lublin
Poland	Research Site	Olawa
Poland	Research Site	Ostrowiec Swietokrzyski
Poland	Research Site	Oswiecim
Poland	Research Site	Pabianice
Poland	Research Site	Poznan
Poland	Research Site	Skorzewo
Poland	Research Site	Sopot
Poland	Research Site	Szczecin
Poland	Research Site	Torun
Poland	Research Site	Warszawa
Russian Federation	Research Site	Kazan
Russian Federation	Research Site	Kazan, Tatarstan
Russian Federation	Research Site	Kemerovo
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	St Petersburg
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	Yaroslavl
Slovakia	Research Site	Banska Bystrica
Slovakia	Research Site	Brezno
Slovakia	Research Site	Lucenec
Slovakia	Research Site	Presov
Slovakia	Research Site	Svidnik
Slovakia	Research Site	Trencin
Spain	Research Site	Barcelona
Spain	Research Site	Coruña
Spain	Research Site	El Palmar
Spain	Research Site	Madrid
Spain	Research Site	Málaga
Spain	Research Site	Santiago(A Coruña)
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
Spain	Research Site	Valencia
Sweden	Research Site	Goeteborg
Sweden	Research Site	Stockholm
Sweden	Research Site	Stockholm
Sweden	Research Site	Uppsala
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei City
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Thailand	Research Site	Chaingmai
Thailand	Research Site	Khon Kaen
Turkey	Research Site	Adana
Turkey	Research Site	Kocaeli
Ukraine	Research Site	Cherkasy
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Zaporizhzhia
United States	Research Site	Augusta	Georgia
United States	Research Site	Baltimore	Maryland
United States	Research Site	Beverly Hills	California
United States	Research Site	Bronx	New York
United States	Research Site	Columbus	Georgia
United States	Research Site	Fountain Valley	California
United States	Research Site	Hialeah	Florida
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Jacksonville	Florida
United States	Research Site	Kingwood	Texas
United States	Research Site	McKinney	Texas
United States	Research Site	Memphis	Tennessee
United States	Research Site	Methuen	Massachusetts
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	New Bern	North Carolina
United States	Research Site	Northridge	California
United States	Research Site	Ocala	Florida
United States	Research Site	Rapid City	South Dakota
United States	Research Site	S. Gate	California
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Antonio	Texas
United States	Research Site	Sherman	Texas
United States	Research Site	Tampa	Florida
United States	Research Site	Webster	Texas

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Canada,  Czechia,  Denmark,  Germany,  Hungary,  India,  Italy,  Japan,  Korea, Republic of,  Lithuania,  Poland,  Russian Federation,  Slovakia,  Spain,  Sweden,  Taiwan,  Thailand,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of participants with adverse events (AEs) and serious adverse events (SAEs)	Assessment of the general safety and tolerability of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone.	From baseline (Day 1) until Day 113 (Safety Follow-up)
Other	Absolute value of serum potassium over time	Assessment of the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on serum potassium.	Days 1, and 3 until Day 85
Other	Change from baseline in serum potassium over time	Assessment of the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on serum potassium.	From baseline (Day 1), Day 3 until Day 85
Other	Absolute value of eGFR over time	Assessment of the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on eGFR.	Days 1, and 3 until Day 85
Other	Change from baseline in eGFR over time	Assessment of the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on eGFR.	From baseline (Day 1), Day 3 until Day 85
Primary	Percent change from baseline in UACR at 12 weeks	Evaluating the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on UACR.	Baseline (Day 1) until Week 12 (Day 85)
Secondary	Percent change from baseline in UACR at 12 weeks to assess dose-response relationship	Assessment of the dose-response relationship of dapagliflozin (10 mg) alone and 3 doses of AZD9977 (A, B, or C) combined with dapagliflozin (10 mg) on UACR.	Baseline (Day 1) until Week 12 (Day 85)