DELIVER - 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)

The study is designed to determine whether dapagliflozin is superior to placebo, when added to standard of care, in reducing the composite of CV death and HF events (hospitalisation for HF or urgent HF visit) in patients with HF and preserved systolic function.

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 8000 patients at approximately 400-500 sites in 20-25 countries will need to be enrolled to reach the target of approximately 4700 randomised patients.

Inclusion Criteria

Subjects are eligible to be randomised in the study only if all of the following inclusion criteria and none of the exclusion criteria apply:
1. Provision of signed informed consent prior to any study specific procedures.
2. Male or female patients age ≥40 years.
3. Documented diagnosis of symptomatic heart failure (NYHA class II-IV) at enrollment, and a medical history of typical symptoms/signs of heart failure ≥6 weeks before enrollment with at least intermittent need for diuretic treatment.
4. 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 enrollment. 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.
5. NT-pro BNP ≥300 pg/ml at Visit 1 for patients without ongoing atrial fibrillation/flutter. If ongoing atrial fibrillation/flutter at Visit 1, NT-pro BNP must be ≥600 pg/mL.
6. Patients may be ambulatory, or hospitalized; patients must be off intravenous heart failure therapy (including diuretics) for at least 12 hours prior to enrollment and 24 hours prior to randomisation.

Exclusion Criteria

1. Receiving therapy with an SGLT2 inhibitor within 4 weeks prior to randomisation or previous intolerance to an SGLT2 inhibitor
2. Type 1 diabetes mellitus (T1D)
3. eGFR <25 mL/min/1.73 m2 (CKD-EPI formula) at Visit 1
4. Systolic blood pressure (BP) <95 mmHg on 2 consecutive measurements at 5-minute intervals, at Visit 1 or at Visit 2
5. 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.
6. 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 enrollment. Before enrollment, these patients must have their qualifying echocardiography and/or cardiac MRI examination at least 12 weeks after the event.
7. Planned coronary revascularization, ablation of atrial flutter/fibrillation and valve repair/replacement.
8. Stroke or transient ischemic attack (TIA) within 12 weeks prior to enrollment
9. 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)
10. Body mass index >50 kg/m2
11. Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD (i.e., requiring home oxygen, chronic nebulizer therapy or chronic oral steroid therapy, or hospitalisation for exacerbation of COPD requiring ventilatory assist within 12 months prior to enrollment)
12. Previous cardiac transplantation, or complex congenital heart disease. Planned cardiac resynchronisation therapy.
13. HF due to any of the following: known infiltrative cardiomyopathy (e.g. amyloid, sarcoid, lymphoma, endomyocardial fibrosis), active myocarditis, constrictive pericarditis, cardiac tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), or uncorrected primary valvular disease
14. A life expectancy of less than 2 years due to any non-cardiovascular condition, based on investigator's clinical judgement.
15. Inability of the patient, in the opinion of the investigator, to understand and/or comply with study medications, procedures and/or follow-up OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study
16. Active malignancy requiring treatment (with the exception of basal cell or squamous cell carcinomas of the skin).
17. Acute or chronic liver disease with severe impairment of liver function (e.g., ascites, oesophageal varices, coagulopathy)
18. Women of child-bearing potential (i.e. those who are not chemically or surgically sterilised or post-menopausal) not willing to use a medically accepted method of contraception considered reliable in the judgment of the investigator OR who have a positive pregnancy test at randomisation OR who are breast-feeding
19. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca personnel and/or personnel at the study site)
20. Previous randomisation in the present study
21. Participation in another clinical study with an IP or device during the last month prior to enrollment

Conditions:
• Cardiology