Principal Investigator: John  Ryan
Keywords: HfPef , Diabetes , Heart Failure , Pre-Diabetes Department: Cardiovascular Medicine
IRB Number: 00100200
Specialty: Cardiology, Cardiology, Cardiology, Pulmonary, Pulmonary
Sub Specialties: General Cardiology, Heart Failure, General Pulmonary, Pulmonary
Recruitment Status: Recruiting

Contact Information

Brittany Penn
brittany.penn@hsc.utah.edu
8015852469

Brief Summary

2 STUDY OBJECTIVE 

To evaluate the impact of dapagliflozin, as compared with placebo, on heart failure disease-specific biomarkers, symptoms, health status, and quality of life in patients with chronic heart failure with preserved systolic function. 

2.1 Primary Outcome 

To evaluate the effects of dapagliflozin, as compared with placebo, on heart failure disease-specific health status (symptoms and physical limitations) in patients with chronic heart failure with preserved systolic function. PRESERVED-HF Protocol v3.0 Page 17 of 67 

 

2.2 Secondary Outcomes 

1. Change from baseline in heart failure related health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 weeks 

2. Change from baseline in NTproBNP at 6 and 12 weeks 

3. Change from baseline in BNP at 6 and 12 weeks 

4. Change from baseline in 6 minute walk test at 12 weeks 

5. Change from baseline in BNP at 6 and 12 weeks 

6. Change from baseline in HbA1c over the treatment period 

7. Proportion of patients with a ≥ 5pts increase in KCCQ clinical summary score and KCCQ overall summary score at 12 weeks 

8. Proportion of patients with a ≥ 20% decrease in NTproBNP at 6 and 12 weeks 

9. Proportion of patients with a ≥ 5pts increase in KCCQ and a ≥ 20% decrease in NTproBNP at 6 and 12 weeks 

10. Change in weight at 6 and 12 weeks 

11. Change in systolic blood pressure at 6 and 12 weeks 

 

2.3 Exploratory Outcomes 

1. Composite mean hierarchical-rank clinical score between dapagliflozin vs. placebo. All patients will receive a global rank endpoint based on time to death (tier 1) time to HF hospitalization or urgent HF visit (tier 2) or change KCCQ clinical summary score from baseline to 12 weeks 

2. Number of heart failure hospitalizations 

3. Number of urgent heart failure visits 

4. Number of heart failure hospitalizations and urgent heart failure visits 

5. Proportion of patients that progress to diabetes during the treatment period (within the subgroup of patients without diabetes at baseline only) 

6. Change from baseline in average weekly loop diuretic dose (furosemide equivalent) 

7. Change in NYHA Class at 6 and 12 weeks. 

8. 

9. Change from baseline in left atrial volume index and other measures of left ventricular diastolic function 

 

2.4 Safety Outcomes 

1. All cause death 

PRESERVED-HF Protocol v3.0 Page 18 of 67 

 

 

2. Cardiovascular death 

3. Non-fatal myocardial infarction (MI) 

4. Stroke 

5. Acute kidney injury (defined as doubling of serum creatinine based on modified RIFLE criteria) 

6. Adverse events (AEs) and serious adverse events (SAEs). AEs of special interest will include DKA, volume depletion (defined as hypotension, syncope, orthostatic hypotension or dehydration), severe hypoglycemic events and lower limb amputations. 

Inclusion Criteria

4 STUDY POPULATION
Voluntary participation will be sought from patients with chronic heart failure with preserved systolic function at outpatient general cardiology and specialized heart failure clinics. Informed consent will be obtained from potentially eligible participants prior to initiating screening visit procedures.
It is expected that approximately 60% (174 patients) of the study cohort will have pre-diabetes or normal glucose metabolism (no diabetes), and therefore, the proportion of patients with established Type 2 diabetes may be capped at 45% (146 patients).
The proportion of patients with permanent atrial fibrillation may be capped at 33% of the study cohort (105 patients).
Randomization will be stratified by diabetes status (diabetes vs. no-diabetes), permanent atrial fibrillation status (Yes vs. No), and by patients’ participation in the echocardiography sub-study.


4.1 Inclusion criteria
1. Age > 18 and < 120 at the screening visit
2. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
3. Ejection fraction (EF) ≥ 45% as determined on imaging study within 24 months of enrollment with no change in clinical status suggesting potential for deterioration in systolic function
4. Elevated NT-proBNP (≥ 225 pg/ml) or BNP (≥ 75 pg/ml) Ŧ
5.  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
6. On a diuretic ≥15 days prior to screening visit and a stable diuretic therapy for 7 days
7. 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):
1) 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
2) OR left ventricular hypertrophy (LVH) defined by septal thickness or
posterior wall thickness ≥1.1 cm.

Exclusion Criteria

 

4.2 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) < 20 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. 

 

Women of childbearing potential are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal. Post menopausal is defined as 12 consecutive months with no menses without an alternative medical cause. Women of child-bearing potential, who are sexually active, must agree to use a medically-accepted method of birth control for the duration of the study. Acceptable birth control methods include: (1) surgical sterilization (such as a hysterectomy or bilateral tubal ligation), (2) progesterone hormonal contraceptives (birth control pills or implants), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Women of child-bearing potential will have a urine pregnancy test at every clinic visit and it must be negative to continue study participation. 

11. Life expectancy <1 year at the screening visit 

PRESERVED-HF Protocol v3.0 Page 23 of 67 

 

 

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 £ 

14. Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, empagliflozin, ertugliflozin) 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. 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 be a primary contributor 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 

Ŧ For patients with permanent atrial fibrillation inclusion thresholds will be BNP ≥ 100 pg/mL or NTproBNP ≥ 375 pg/mL