Preserved-HF

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

Contact Information

Ashlee Rooks
ashlee.rooks@hsc.utah.edu
801-585-7295

Brief Summary

To evaluate the effects of dapagliflozin, as compared with placebo, on heart failure disease-specific biomarkers, symptoms, health status, and quality of life in patients with type 2 diabetes or prediabetes and chronic heart failure with preserved systolic function.

Inclusion Criteria

4 STUDY POPULATION
Voluntary participation will be sought from patients with type 2 diabetes or prediabetes and
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.
At least 45% (144 patients) of the study cohort will have pre-diabetes, and therefore, the
proportion of patients with established Type 2 diabetes will be capped at 55% (176 patients).
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The proportion of patients with permanent atrial fibrillation will be capped at 33% of the study
cohort (105 patients).
Randomization will be stratified by diabetes status (diabetes vs. pre-diabetes), NYHA class at
baseline (NYHA class II vs NYHA class III-IV), 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. Documented type 2 diabetes for at least 3 months, or prediabetes. Those with type 2
diabetes must be prescribed a lifestyle intervention alone (see below under inclusion
criterion 3) or in combination with a stable dose(s) of at least one glucose-lowering
medication during the 8 weeks prior to the screening visit, with no changes between the
screening and randomization visits. Changes in sliding scale insulin dose are not considered
to be a disqualifying change in insulin dose. Changes in total daily dose of insulin of ≤10% of
the baseline total daily dose are not considered to be a disqualifying change in insulin dose.
3. Hemoglobin A1c inclusion criteria as follows:
i. Hemoglobin A1c of 6-11% (inclusive) for patients with documented type 2
diabetes receiving metformin monotherapy
ii. Hemoglobin A1c of 6.5-11% (inclusive) for patients with documented type 2
diabetes receiving any type of glucose-lowering medication (except metformin
monotherapy)
iii. Hemoglobin A1c of 6.0-6.9% (inclusive) for patients with documented type 2
diabetes receiving lifestyle intervention alone
iv. Hemoglobin A1c of > 5.7% and < 6.5 % for patients with pre-diabetes
4. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic
explanation for dyspnea
5. Ejection fraction (EF) ≥ 45% as determined on imaging study within 18 months of enrolment
with no change in clinical status suggesting potential for deterioration in systolic function
6. Elevated NT-proBNP (≥ 300 pg/ml) or BNP (≥ 100 pg/ml) Ŧ
7. Stable medical therapy for heart failure for 30 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
8. On a diuretic ≥30 days prior to screening visit and a stable diuretic therapy for 14 days
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9. 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 18 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 the 30 days prior to
screening)
2. History of type 1 diabetes
3. History of diabetic ketoacidosis
4. Hemoglobin A1c <5.7 or >11% at the screening visit
5. 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)
6. Admission for an acute coronary syndrome (ST-elevation MI, non-ST-elevation MI, or
unstable angina), percutaneous coronary intervention, or cardiac surgery within 60 days
prior to the screening visit.
7. Admission for cardiac resynchronization therapy (CRT) within 90 days prior to the screening
visit.
8. 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.
9. Participation in any interventional clinical trial (with an investigational drug or device) that is
not an observational registry within 30 days of the screening visit.
10. History of hypersensitivity to dapagliflozin
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11. 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 childbearing
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.
12. Life expectancy <1 year at the screening visit
13. Patients who are volume depleted based upon physical examination at the time of the
screening or randomization visit
14. BNP <100 pg/mL and NTproBNP<300 pg/mL at the screening visit £
15. 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.
16. Average supine systolic BP <100 mmHg at the screening or randomization visit
17. Past or current history of bladder cancer
18. Active Hematuria
19. Donation of blood or bone marrow 12 weeks prior to the screening visit and no planned
donations during the study period
20. Heart failure due to restrictive/infiltrative cardiomyopathy, active myocarditis, constrictive
pericarditis, severe stenotic valve disease, and HOCM (hypertrophic obstructive
cardiomyopathy).
21. Heart failure due to severe aortic or mitral regurgitation
22. Severe COPD thought to contribute to dyspnea
23. Isolated right heart failure due to pulmonary disease
24. Active and significant ischemia thought to contribute to dyspnea
25. Documentation of previous EF < 40% at any time
26. Complex congenital heart disease
27. Uncontrolled hypertension, defined as systolic blood pressure ≥200 mmHg during the
screening visit (average value of three blood pressure measurements obtained in supine
position)
28. 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
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patient is considered unlikely to comply with study procedures, restrictions and
requirements
29. Bariatric surgery within the past 6 months or planned bariatric surgery within the study time
course.
30. CardioMems device implantation within previous 4 weeks or planned CardioMems
implantation during study period
31. For echo substudy only: history of poor echo windows as judged by the investigator
32. For echo substudy only: patients with ventricular paced rhythm or left bundle branch block
on the most recent clinically available 12-lead electrocardiogram.
33. For echo substudy only: permanent atrial fibrillation
Ŧ For patients with permanent atrial fibrillation inclusion thresholds will be BNP ≥ 125 pg/mL or
NTproBNP ≥ 500 pg/mL
£For patients with permanent atrial fibrillation exclusion thresholds will be BNP<125 pg/mL and
NTproBNP<500pg/mL