Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure.

Study Overview
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Brief Summary
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This is an international, multicentre, parallel-group, event-driven, randomised, double-blind, placebo-controlled study in HFpEF patients, evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in addition to background regional standard of care therapy, including treatments to control co-morbidities, in reducing the composite of CV death or heart failure events.

Detailed Description
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This is an international, multicentre, parallel-group, event-driven, randomised, double-blind study in patients with HFpEF, evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in addition to background regional standard of care therapy, including treatments to control co-morbidities, in reducing the composite of CV death and heart failure events (hospitalisations for HF or urgent HF visits). Adult patients aged ≥40 years with HFpEF (LVEF >40% and evidence of structural heart disease) and New York Heart Association (NYHA) class II-IV who are eligible according to the inclusion/exclusion criteria will be randomised in a 1:1 ratio to receive either dapagliflozin 10 mg or placebo. Both out-patients and in-patients hospitalised for heart failure and off intravenous heart failure-therapy for 24 hours can be randomised. It is estimated that approximately 11000 patients at approximately 400-500 sites in 20-25 countries will need to be enrolled to reach the target of approximately 6100 randomised patients.

Official Title
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An International, Double-blind, Randomised, Placebo-Controlled Phase III Study to Evaluate the Effect of Dapagliflozin on Reducing CV Death or Worsening Heart Failure in Patients With Heart Failure With Preserved Ejection Fraction (HFpEF)

Conditions
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Heart Failure With Preserved Ejection Fraction

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 patients age ≥40 years. Documented diagnosis of symptomatic heart failure (NYHA class II-IV) at enrolment, and a medical history of typical symptoms/signs of heart failure ≥6 weeks before enrolment with at least intermittent need for diuretic treatment. Left Ventricular Ejection Fraction (LVEF) >40% and evidence of structural heart disease (i.e. left ventricular hypertrophy or left atrial enlargement ) documented by the most recent echocardiogram, and/or cardiac MR within the last 12 months prior to enrolment. For patients with prior acute cardiac events or procedures that may reduce LVEF, e.g. as defined in exclusion criterion 6, qualifying cardiac imaging assessment at least 12 weeks following the procedure/event is required. Elevated NT-pro BNP levels. Both ambulatory and hospitalised patients may be enrolled and randomised. Patients currently hospitalised for HF, must be off intravenous HF medications for at least 24 before randomisation. Further details regarding inclusion criteria 4-6 may apply. Exclusion Criteria: Receiving therapy with an SGLT2 inhibitor within 4 weeks prior to randomisation or previous intolerance to an SGLT2 inhibitor. Type 1 diabetes mellitus (T1D). eGFR <25 mL/min/1.73 m2 (CKD-EPI formula) at Visit 1. Systolic blood pressure (BP) <95 mmHg on 2 consecutive measurements at 5-minute intervals, at Visit 1 or at Visit 2. Systolic BP≥160 mmHg if not on treatment with ≥3 blood pressure lowering medications or ≥180 mmHg irrespective of treatments, on 2 consecutive measurements at 5-minute intervals, at Visit 1 or at Visit 2. MI, unstable angina, coronary revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)), ablation of atrial flutter/fibrillation, valve repair/replacement within 12 weeks prior to enrolment. Before enrolment, these patients must have their qualifying echocardiography and/or cardiac MRI examination at least 12 weeks after the event. Planned coronary revascularization, ablation of atrial flutter/fibrillation and valve repair/replacement. Stroke or transient ischemic attack (TIA) within 12 weeks prior to enrolment. Probable alternative or concomitant diagnoses which in the opinion of the investigator could account for the patient's HF symptoms and signs (e.g. anaemia, hypothyroidism). Body mass index >50 kg/m2. Further exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 40 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
Interventional Model Description: International, Double-blind, Randomised, Placebo-Controlled
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 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<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. | Dual primary efficacy Primary endpoint analysed in all patients randomised (Full analysis set). The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date. | Up to 42.1 months | 
| Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure for LVEF <60% Subpopulation | Dual primary efficacy Primary endpoint analysed in all patients randomised with LVEF < 60% at baseline. The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date. | Up to 42.1 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) | Secondary efficacy Total number of heart failure events (first and recurrent) and cardiovascular death, analysed in all randomized patients. The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date. | Up to 42.1 months | 
| Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) for LVEF <60% Subpopulation | Secondary efficacy Total number of heart failure events (first and recurrent) and cardiovascular death, analysed in all randomized patients with LVEF < 60% at baseline The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date. | Up to 42.1 months | 
| Change From Baseline in the KCCQ Total Symptom Score at 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. | Baseline and 8 months or death before 8 months | 
| Subjects Included in the Endpoint of Cardiovascular Death | Secondary efficacy The analysis was assessed on Full Analysis Set, including deaths occurring on or prior to Primary Analysis Censoring Date. | Up to 42.1 months | 
| Subjects Included in the Endpoint of All-cause Mortality | Secondary efficacy The analysis was assessed on Full Analysis Set, including deaths occurring on or prior to Primary Analysis Censoring Date. | Up to 42.1 months |