Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of dapagliflozin on the incidence of worsening heart failure or cardiovascular death in patients with chronic heart failure with reduced ejection fraction

Detailed Description
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This is an international, multicentre, parallel group, event-driven, randomized, double-blind, placebo-controlled study in patients with chronic heart failure with reduced ejection fraction (HFrEF), evaluating the effect of dapagliflozin versus placebo, given once daily in addition to background regional standard of care therapy, for the prevention of cardiovascular (CV) death or reduction of heart failure (HF) events.

Official Title
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Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure With Reduced Ejection Fraction

Conditions
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Chronic Heart Failure With Reduced Ejection Fraction (HFrEF)

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed informed consent prior to any study specific procedures Male or female, aged ≥18 years Established documented diagnosis of symptomatic HFrEF (NYHA functional class II-IV), which has been present for at least 2 months LVEF≤40% Elevated NT-proBNP levels Patients should receive background standard of care for HFrEF and be treated according to locally recognized guidelines eGFR ≥30 mL/min/1.73 m^2 (CKD-EPI formula) at enrolment (visit 1) Exclusion Criteria: Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor Type 1 diabetes mellitus Symptomatic hypotension or systolic BP <95 mmHg at 2 out of 3 measurements either at visit 1 or visit 2 Current acute decompensated HF or hospitalization due to decompensated HF <4 weeks prior to enrolment MI, unstable angina, stroke or transient ischemic attack within 12 weeks prior to enrolment Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or valvular repair/replacement within 12 weeks prior to enrolment or planned to undergo any of these operations after randomization Implantation of a CRT within 12 weeks prior to enrolment or intent to implant a CRT device Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or implantation expected after randomization HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease Symptomatic bradycardia or second or third degree heart block without a pacemaker Severe (eGFR <30 mL/min/1.73 m^2 by CKD-EPI), unstable or rapidly progressing renal disease at the time of randomization

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Patients will be randomized 1:1 to either dapagliflozin or placebo. | Drug: Dapagliflozin<br>* 10 mg or 5 mg tablets given once daily, per oral use.<br>* Other names: Farxiga TM;|
| Placebo Comparator: Placebo<br>Placebo matching dapagliflozin. | Drug: Placebo<br>* Placebo matching dapagliflozin 10 mg or 5 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure. | Primary efficacy | Up to 27.8 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects Included in the Composite Endpoint of CV Death or Hospitalization Due to Heart Failure. | Secondary | Up to 27.8 months. | 
| Events Included in the Composite Endpoint of Recurrent Hospitalizations Due to Heart Failure and CV Death. | Secondary | Up to 27.8 months. | 
| Change From Baseline in the KCCQ Total Symptom Score | KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ total symptom score incorporates the symptom domains into a single score. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. | Baseline and 8 months or death before 8 months | 
| Subjects Included in the Composite Endpoint of ≥50% Sustained Decline in eGFR, ESRD or Renal Death. | Secondary | Up to 27.8 months. | 
| Subjects Included in the Endpoint of All-cause Mortality. | Secondary | Up to 27.8 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HFrEF, Heart Failure (HF), Cardiovascular Events (CV), Phase III outcome trial