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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04595370
Recruitment Status : Not yet recruiting
First Posted : October 20, 2020
Last Update Posted : November 20, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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, with at least 30% of participants with eGFR <30 mL/min and a maximum of 25% of participants with eGFR >45 mL/min]), including at least 40% of participants with type 2 diabetes mellitus (T2DM).

Condition or disease Intervention/treatment Phase
Heart Failure Chronic Kidney Disease Drug: AZD9977 Drug: Dapagliflozin Drug: Placebo Phase 2

Detailed Description:

The study will be conducted in approximately 140 sites in about 12 countries.

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 study treatments group for 12 weeks:

  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 (<30 mL/min / ≥ 30 to ≤ 45 mL/min / >45 mL/min).

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

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Study Type : Interventional  (Clinical Trial)
Estimated 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:

  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
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
Estimated Study Start Date : December 8, 2020
Estimated Primary Completion Date : April 12, 2022
Estimated Study Completion Date : April 12, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/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.




Primary Outcome Measures :
  1. Percent change from baseline in UACR at 12 weeks [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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 heart failure, hypertension, diabetes mellitus or renal disease for at least 3 weeks prior to randomization (Visit 3)/within the 3 weeks run-in period; i.e., therapy should have been stable for 3 weeks before randomization (Visit 3)
  • N-terminal-pro-brain natriuretic peptide ≥600 pg/mL for participants with sinus rhythm or ≥900 pg/mL for participants with atrial fibrillation at screening
  • The eGFR ≥30 and ≤60 mL/min and UACR >30 mg/g (3 mg/mmol) and <3000 mg/g (300 mg/mmol)
  • Serum potassium level ≥3.5 and <5.0 mmol/L within 5 days prior to randomization (Visit 3)
  • Serum sodium level within normal reference values within 5 days prior to randomization (Visit 3)
  • Systolic and diastolic BP should be at protocol defined range at randomization (Visit 3), with no change to antihypertensive treatments in previous 3 weeks
  • No prior medical treatment with a mineralocorticoid receptor antagonist (MRA) or sodium-glucose co-transporter-2 inhibitor (SGLT2i) taken for 3 months or longer during the 12 months prior to screening (Visit 1)
  • No current or prior (within the 3 weeks run-in period prior to randomization [Visit 3]) treatment with MRA or SGLT2i and other protocol defined prohibited concomitant medications
  • No current or prior treatment within 6 months prior to screening (Visit 1) with cytotoxic therapy, immunosuppressive therapy or other immunotherapy
  • Body mass index less than 40 kg/m^2
  • Male or female of non-childbearing potential
  • Female participants must have a negative pregnancy test at screening, and 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 unstable 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 >12%)
  • Participants with T1DM.
  • 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) or open chest cardiovascular surgery (within 12 months) prior to screening (Visit 1) 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
  • History or ongoing allergy/hypersensitivity, to SGLT2i (e.g., dapagliflozin, empagliflozin)
  • Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within previous 3 months prior to screening (Visit 1).
  • 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/ 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
  • Previous randomization in the present study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04595370


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: John McMurray University of Glasgow, United Kingdom
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04595370    
Other Study ID Numbers: D6402C00001
2020-003126-23 ( EudraCT Number )
First Posted: October 20, 2020    Key Record Dates
Last Update Posted: November 20, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
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
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Heart Failure
Heart Diseases
Cardiovascular Diseases
Urologic Diseases
Renal Insufficiency
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs