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

Sponsor
AstraZeneca (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04595370
Collaborator
(none)
540
Enrollment
183
Locations
6
Arms
17.8
Anticipated Duration (Months)
3
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the efficacy and safety of AZD9977 alone and AZD9977 in combination with dapagliflozin and to assess the dose-response relationship of placebo, AZD9977 alone, 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 55%]) and chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR [between 20 and 60 mL/min/1.73 m2, with at least 30% of participants with eGFR ≥ 20 to <30 mL/min/1.732 and a maximum of 25% of participants with eGFR >45 mL/min/1.73 m^2]), including at least 40% of participants with type 2 diabetes mellitus (T2DM).

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

After screening, eligible participants will undergo a 3 to 4-week run-in period to ensure washout of prior medications. At the end of the run-in period, eligible participants will be randomly assigned with a 1:1:1:1:1:1 ratio to receive once daily administration of one of the following 6 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 of placebo or dapagliflozin.

  1. AZD9977 Dose A + dapagliflozin 10 mg

  2. AZD9977 Dose B + dapagliflozin 10 mg

  3. AZD9977 Dose C + dapagliflozin 10 mg

  4. AZD9977 Dose C

  5. Dapagliflozin 10 mg

  6. Placebo

Participants will be randomized to one of the above treatment group, according to T2DM (yes/no) and eGFR (≥ 20 to <30 mL/min/1.732; or ≥ 30 to < 45 mL/min/1.732; or ≥45 mL/min/1.73^2).

The total duration of participation will be approximately 19 to 21 weeks.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
540 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Participants who meet the eligibility criteria will be randomized to one of the following treatment group: AZD9977 Dose A + dapagliflozin 10 mg AZD9977 Dose B + dapagliflozin 10 mg AZD9977 Dose C + dapagliflozin 10 mg AZD9977 Dose C Dapagliflozin 10 mg PlaceboParticipants who meet the eligibility criteria will be randomized to one of the following treatment group:AZD9977 Dose A + dapagliflozin 10 mg AZD9977 Dose B + dapagliflozin 10 mg AZD9977 Dose C + dapagliflozin 10 mg AZD9977 Dose C Dapagliflozin 10 mg Placebo
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 2b, Randomised, Double-Blind, Placebo-Controlled, Multi-Centre Study to Evaluate the Efficacy, Safety and Tolerability of Oral AZD9977 and Dapagliflozin Treatment in Patients With Heart Failure With Left Ventricular Ejection Fraction (LVEF) Below 55% and Chronic Kidney Disease
Actual Study Start Date :
Jan 26, 2021
Anticipated Primary Completion Date :
Jul 22, 2022
Anticipated Study Completion Date :
Jul 22, 2022

Arms and Interventions

ArmIntervention/Treatment
Experimental: AZD9977 Dose A + dapagliflozin 10 mg

Participants will receive once daily oral dose A of AZD9977 and 10 mg dapagliflozin for 12 weeks.

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

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

Experimental: AZD9977 Dose B + dapagliflozin 10 mg

Participants will receive once daily oral dose B of AZD9977 and 10 mg dapagliflozin for 12 weeks.

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

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

Experimental: AZD9977 Dose C + dapagliflozin 10 mg

Participants will receive once daily oral dose C of AZD9977 and 10 mg dapagliflozin for 12 weeks.

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

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

Experimental: AZD9977 Dose C

Participants will receive once daily oral dose C of AZD9977 alone for 12 weeks.

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

Experimental: Dapagliflozin 10 mg

Participants will receive once daily oral dose of dapagliflozin 10 mg alone for 12 weeks.

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

Placebo Comparator: Placebo

Participants will receive once daily oral dose of placebo matched to AZD9977 or dapagliflozin for 12 weeks.

Drug: Placebo
Participants will receive placebo matched to AZD9977 or dapagliflozin.

Outcome Measures

Primary Outcome Measures

  1. Percent change from baseline in UACR at 12 weeks [Baseline (Day 1) until Week 12 (Day 85)]

    Evaluating the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on UACR.

Secondary Outcome Measures

  1. Percent change from baseline in UACR at 12 weeks to assess dose-response relationship [Baseline (Day 1) until Week 12 (Day 85)]

    Assessment of the dose-response relationship of placebo, AZD9977 (Dose C) alone, dapagliflozin (10 mg) alone and 3 doses of AZD9977 (A, B or C) combined with dapagliflozin (10 mg) on UACR.

  2. Number of participants with adverse events (AEs) and serious adverse events (SAEs) [From baseline (Day 1) until Day 113 (Safety Follow-up)]

    Assessment of the general safety and tolerability of AZD9977 and dapagliflozin in combination and alone compared with placebo.

  3. Absolute value of serum potassium over time [Days 1, and 3 until Day 85]

    Assessment of the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on serum potassium.

  4. Change from baseline in serum potassium over time [From baseline (Day 1), Day 3 until Day 85]

    Assessment of the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on serum potassium.

  5. Absolute value of eGFR over time [Days 1, and 3 until Day 85]

    Assessment of the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on eGFR.

  6. Change from baseline in eGFR over time [From baseline (Day 1), Day 3 until Day 85]

    Assessment of the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on eGFR.

Eligibility Criteria

Criteria

Ages Eligible for Study:
21 Years to 130 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
Participants are included from the study if any of the following criteria apply:
  • Documented diagnosis of stable symptomatic HF (New York Heart Association class II-III) at screening (Visit 1), and a medical history of typical symptoms and signs of HF in those who are currently receiving loop diuretic treatment

  • Left ventricular ejection fraction <55% documented by the most recent echocardiogram or cardiac magnetic resonance imaging within the last 12 months prior to screening (Visit 1)

  • Stable background treatment for HF, hypertension, diabetes mellitus or renal disease for at least 3 weeks prior to randomization (Visit 3)/ or within the 3 weeks run-in period; i.e., therapy should have been stable for 3 weeks before randomization (Visit

  • N-terminal-pro-brain natriuretic peptide (NT proBNP) ≥600 pg/mL for participants with sinus rhythm at screening; and NT proBNP ≥900 pg/mL for participants with atrial fibrillation/flutter at screening or in medical history

  • The eGFR ≥30 and ≤60 mL/min/1.73^2 and UACR >30 mg/g (3 mg/mmol) and <3000 mg/g (300 mg/mmol)

  • Serum/plasma potassium level ≥3.5 and <5.0 mmol/L within 7 days prior to randomization (Visit 3)

  • Serum/ plasma sodium level within normal reference values within 7 days prior to randomization (Visit 3)

  • Systolic blood pressure should be at protocol defined range at randomization (Visit 3), with no change to antihypertensive treatments in previous 3 weeks

  • Body mass index less than 40 kg/m^2

  • 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 (Visit 3) 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 (Visit 3).

  • 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 (Visit 1) and/ or within 7 days prior to randomization (Visit 3)

  • 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 either an MRA or an SGLT2i where the medication was taken within 90 days prior to screening

  • Current or prior treatment within 6 months prior to screening (Visit 1) with cytotoxic therapy, immunosuppressive therapy, or other immunotherapy

Contacts and Locations

Locations

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Sponsors and Collaborators

  • AstraZeneca

Investigators

  • Principal Investigator: John McMurray, University of Glasgow, United Kingdom

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT04595370
Other Study ID Numbers:
  • D6402C00001
  • 2020-003126-23
First Posted:
Oct 20, 2020
Last Update Posted:
Oct 6, 2021
Last Verified:
Sep 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by AstraZeneca
Additional relevant MeSH terms:

Study Results

No Results Posted as of Oct 6, 2021