Dapagliflozin in PRESERVED Ejection Fraction Heart Failure

A 12-week randomized, double-blind, placebo-controlled trial to evaluate the effects of
once-daily dapagliflozin 10 mg on heart failure disease-specific biomarkers (NTproBNP and
BNP), symptoms, health status, and quality of life in patients with chronic heart failure
with preserved systolic function. An imaging substudy will also be conducted to explore the
effects of dapagliflozin vs. placebo on various echocardiographic parameters.

Inclusion Criteria:

1. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic
explanation for dyspnea

2. Ejection fraction (EF) ≥ 45% as determined on imaging study within 24 months of
enrolment with no change in clinical status suggesting potential for deterioration in
systolic function

3. Elevated NT-proBNP (≥ 225 pg/ml) or BNP (≥ 75 pg/ml). For patients with permanent
atrial fibrillation inclusion thresholds will be BNP ≥ 100 pg/mL or NTproBNP ≥ 375
pg/mL

4. Stable medical therapy for heart failure for 15 days as defined by: i. No addition or
removal of ACE, angiotensin receptor blockers (ARBs), valsartan/sacubitril,
beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists; ii.No
substantial change in dosage (100% or greater increase or decrease from baseline dose)
of ACE, ARBs, beta-blockers, CCBs or aldosterone antagonists

5. On a diuretic ≥15 days prior to screening visit and a stable diuretic therapy for 7
days

6. At least one of the following: i. Hospitalization for decompensated HF in the last 12
months; ii. Acute treatment for HF with intravenous loop diuretic or hemofiltration in
the last 12 months; iii. Mean pulmonary capillary wedge pressure ≥15 mmHg or LV end
diastolic pressure (LVEDP) ≥15 mmHg documented during catheterization at rest, or
pulmonary capillary wedge pressure or LVEDP ≥25 mmHg documented during catheterization
with exercise; iv. Structural heart disease evidenced by at least one of the following
echo findings (any local measurement made within the 24 months prior to screening
visit): a) left atrial (LA) enlargement defined by at least one of the following: LA
width ≥3.8cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 mL or LA volume
index ≥29 mL/m2 b) or left ventricular hypertrophy (LVH) defined by septal thickness
or posterior wall thickness ≥1.1 cm.

Exclusion Criteria:

1. Decompensated heart failure (hospitalization for heart failure within 7 days prior to
screening)

2. History of type 1 diabetes

3. History of diabetic ketoacidosis

4. Estimated glomerular filtration rate (eGFR) < 30 at the screening visit by modified
MDRD equation GFR (mL/min/1.73 m2 ) = 175 x (Scr) -1.154 x (Age)-0.203 x (0.742 if
female) x (1.210 if African American)

5. Admission for an acute coronary syndrome (ST-elevation MI, non-ST-elevation MI, or
unstable angina), percutaneous coronary intervention, or cardiac surgery within 30
days prior to the screening visit.

6. Admission for cardiac resynchronization therapy (CRT) within 90 days prior to the
screening visit.

7. Planned cardiovascular revascularization (percutaneous intervention or surgical) or
major cardiac surgery (coronary artery bypass grafting, valve replacement, ventricular
assist device, cardiac transplantation, or any other surgery requiring thoracotomy, or
transcatheter aortic valve replacement) or CRT within the 90 days after the screening
visit.

8. Participation in any interventional clinical trial (with an investigational drug or
device) that is not an observational registry within 15 days of the screening visit.

9. History of hypersensitivity to dapagliflozin

10. For women of child-bearing potential: Current or planned pregnancy or currently
lactating.

11. Life expectancy <1 year at the screening visit

12. Patients who are volume depleted based upon physical examination at the time of the
screening or randomization visit

13. BNP <75 pg/mL and NTproBNP<225 pg/mL at the screening visit. For patients with
permanent atrial fibrillation exclusion thresholds will be BNP<100 pg/mL and
NTproBNP<375pg/mL.

14. Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin,
canagliflozin, empagliflozin) or having received treatment with any SGLT-2 inhibitor
within the 12 weeks prior to the screening visit.

15. Average supine systolic BP <100 mmHg at the screening or randomization visit

16. Past or current history of bladder cancer

17. Donation of blood or bone marrow 12 weeks prior to the screening visit and no planned
donations during the study period

18. Heart failure due to restrictive/infiltrative cardiomyopathy, active myocarditis,
constrictive pericarditis, severe stenotic valve disease, and HOCM (hypertrophic
obstructive cardiomyopathy).

19. Heart failure due to severe aortic or mitral regurgitation

20. Severe COPD thought to be a primary contributor to dyspnea

21. Isolated right heart failure due to pulmonary disease

22. Active and significant ischemia thought to contribute to dyspnea

23. Documentation of previous EF < 45%, under stable conditions, within the past 36 months

24. Complex congenital heart disease

25. Uncontrolled hypertension, defined as systolic blood pressure ≥200 mmHg during the
screening visit (average value of three blood pressure measurements obtained in supine
position)

26. Any other condition that in the judgment of the investigator would jeopardize the
patient's participation in the study or that may interfere with the interpretation of
study data or if the patient is considered unlikely to comply with study procedures,
restrictions and requirements

27. Bariatric surgery within the past 6 months or planned bariatric surgery within the
study time course.

28. CardioMems device implantation within previous 4 weeks or planned CardioMems
implantation during study period

29. For echo substudy only: patients with ventricular paced rhythm or left bundle branch
block on the most recent clinically available 12-lead electrocardiogram.

30. For echo substudy only: permanent atrial fibrillation