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

Phase 3

Completed

Brief Summary: 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: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo matching dapagliflozin.
Dapagliflozin	Dapagliflozin	Patients will be randomized 1:1 to either dapagliflozin or placebo.

Primary Outcome Measures

Name	Time	Method
Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure.	Up to 27.8 months.	Primary efficacy

Secondary Outcome Measures

Name	Time	Method
Subjects Included in the Composite Endpoint of CV Death or Hospitalization Due to Heart Failure.	Up to 27.8 months.	Secondary
Subjects Included in the Composite Endpoint of ≥50% Sustained Decline in eGFR, ESRD or Renal Death.	Up to 27.8 months.	Secondary
Subjects Included in the Endpoint of All-cause Mortality.	Up to 27.8 months.	Secondary
Change From Baseline in the KCCQ Total Symptom Score	Baseline and 8 months or death before 8 months	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.
Events Included in the Composite Endpoint of Recurrent Hospitalizations Due to Heart Failure and CV Death.	Up to 27.8 months.	Secondary