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

  • STATUS
    Recruiting
  • End date
    May 31, 2022
  • participants needed
    540
  • sponsor
    AstraZeneca
Updated on 14 February 2021

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).

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.

Details
Condition chronic renal insufficiency, Chronic renal failure, Heart failure, Heart disease, Congestive Heart Failure, Cardiac Disease, chronic kidney disease, chronic kidney disease (ckd), cardiac failure, congestive heart disease
Treatment Placebo, Dapagliflozin, AZD9977
Clinical Study IdentifierNCT04595370
SponsorAstraZeneca
Last Modified on14 February 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 21 yrs and 130 yrs?
Gender: Male or Female
Do you have any of these conditions: Heart disease or Cardiac Disease or Heart failure or Chronic renal failure or chronic kidney disease (ckd) or Congestive Heart Failure or cardiac fail...?
Do you have any of these conditions: Heart disease or cardiac failure or Heart failure or Congestive Heart Failure or Chronic renal failure or Cardiac Disease or chronic renal insufficien...?
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
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