Dapagliflozin in PRESERVED Ejection Fraction Heart Failure

Phase 4

Completed

Conditions: Chronic Heart Failure With Preserved Systolic Function

Interventions: Drug: Dapagliflozin matching placebo
Drug: Dapagliflozin 10Mg Oral Tablet

Registration Number: NCT03030235

Lead Sponsor: Saint Luke's Health System

Brief Summary: The primary purpose of this study is 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 324

Inclusion Criteria

Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
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
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
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
On a diuretic ≥15 days prior to screening visit and a stable diuretic therapy for 7 days
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

Decompensated heart failure (hospitalization for heart failure within 7 days prior to screening)
History of type 1 diabetes
History of diabetic ketoacidosis
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)
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.
Admission for cardiac resynchronization therapy (CRT) within 90 days prior to the screening visit.
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.
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.
History of hypersensitivity to dapagliflozin
For women of child-bearing potential: Current or planned pregnancy or currently lactating.
Life expectancy <1 year at the screening visit
Patients who are volume depleted based upon physical examination at the time of the screening or randomization visit
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.
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.
Average supine systolic BP <100 mmHg at the screening or randomization visit
Current history of bladder cancer
Donation of blood or bone marrow 12 weeks prior to the screening visit and no planned donations during the study period
Heart failure due to restrictive/infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, severe stenotic valve disease, and HOCM (hypertrophic obstructive cardiomyopathy).
Heart failure due to severe aortic or mitral regurgitation
Severe COPD thought to be a primary contributor to dyspnea
Isolated right heart failure due to pulmonary disease
Active and significant ischemia thought to be a primary contributor to dyspnea
Documentation of previous EF < 45%, under stable conditions, within the past 36 months
Complex congenital heart disease
Uncontrolled hypertension, defined as systolic blood pressure ≥200 mmHg during the screening visit (average value of three blood pressure measurements obtained in supine position)
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
Bariatric surgery within the past 6 months or planned bariatric surgery within the study time course.
CardioMems device implantation within previous 4 weeks or planned CardioMems implantation during study period
For echo substudy only: patients with ventricular paced rhythm or left bundle branch block on the most recent clinically available 12-lead electrocardiogram.
For echo substudy only: permanent atrial fibrillation

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Dapagliflozin matching placebo	Dapagliflozin matching placebo oral tablet, once daily, for 12 weeks
Dapagliflozin	Dapagliflozin 10Mg Oral Tablet	Dapagliflozin 10 mg oral tablet, once daily, for 12 weeks

Primary Outcome Measures

Name	Time	Method
Effect of Dapagliflozin, as Compared With Placebo, on Heart Failure Related Health Status Using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Summary Score (KCCQ-CS)	Baseline to Week 12	Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS) at Week 12. The KCCQ is a disease-specific health status instrument composed of 23 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Scores range from 0-100, in which higher scores reflect better health status. For the KCCQ-CS, a small but clinically meaningful change is considered to be ≥ 5 points. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.

Secondary Outcome Measures

Name	Time	Method
Effect of Dapagliflozin, as Compared With Placebo, on 6 Minute Walk Test Distance	Baseline to Week 12	6 minute walk test distance at 12 weeks. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.
Effect of Dapagliflozin, as Compared With Placebo, on Brain Natriuretic Peptide (BNP)	Baseline to Week 12	BNP at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.
Effect of Dapagliflozin, as Compared With Placebo, on Proportion of Patients With ≥ 5 Point Increase in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS) and ≥ 20% Decrease in N-terminal Pro B-type Natriuretic Peptide(NTproBNP)	Baseline to Week 12	Proportion of patients with a ≥ 5 point increase in KCCQ-CS and a ≥ 20% decrease in NTproBNP at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.
Effect of Dapagliflozin, as Compared With Placebo, on Weight	Baseline to Week 12	Weight at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.
Effect of Dapagliflozin, as Compared With Placebo, on Hemoglobin A1c	Baseline to Week 12	Hemoglobin A1c at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.
Effect of Dapagliflozin, as Compared With Placebo, on the Proportion of Patients With a ≥ 5 Point Increase in KCCQ Clinical Summary Score (KCCQ-CS) and KCCQ Overall Summary Score (KCCQ-OS)	Baseline to Week 12	Proportion of patients with a ≥ 5 point increase in KCCQ-CS and KCCQ-OS at Week 12. The KCCQ is a disease-specific health status instrument composed of 23 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Scores range from 0-100, in which higher scores reflect better health status. For KCCQ-CS and KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.
Effect of Dapagliflozin, as Compared With Placebo, on Heart Failure Related Health Status Using the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS)	Baseline to Week 12	Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OS) at Week 12. The KCCQ is a disease-specific health status instrument composed of 23 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Scores range from 0-100, in which higher scores reflect better health status. For the KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.
Effect of Dapagliflozin, as Compared With Placebo, on N-terminal Pro B-type Natriuretic Peptide (NTproBNP)	Baseline to Week 12	NTproBNP at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.
Effect of Dapagliflozin, as Compared With Placebo, on the Proportion of Patients With a ≥ 20% Decrease in N-terminal Pro B-type Natriuretic Peptide (NTproBNP)	Baseline to Week 12	Proportion of patients with a ≥ 20% decrease in NTproBNP at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.
Effect of Dapagliflozin, as Compared With Placebo, on Systolic Blood Pressure	Baseline to Week 12	Systolic blood pressure at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.

Trial Locations

Locations (26): First Coast Cardiovascular Institute
🇺🇸
Jacksonville, Florida, United States
OSF HealthCare Cardiovascular Institute
🇺🇸
Peoria, Illinois, United States
Chicago Medical Research
🇺🇸
Hazel Crest, Illinois, United States
Washington University
🇺🇸
Saint Louis, Missouri, United States
Columbia University
🇺🇸
New York, New York, United States
St. Francis Hospital
🇺🇸
New York, New York, United States
Eastern Nephrology Associates
🇺🇸
New Bern, North Carolina, United States
Heart Group of the Eastern Shore
🇺🇸
Fairhope, Alabama, United States
Charlotte Heart Group Research Center
🇺🇸
Port Charlotte, Florida, United States
Emory University
🇺🇸
Atlanta, Georgia, United States
NorthShore University HealthSystem Research Insititute
🇺🇸
Evanston, Illinois, United States
Northwestern University
🇺🇸
Evanston, Illinois, United States
St. Vincent Cardiovascular Research Institute
🇺🇸
Indianapolis, Indiana, United States
Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
Massachusetts Hospital
🇺🇸
Boston, Massachusetts, United States
Allegheny Health Network Research Institute
🇺🇸
Pittsburgh, Pennsylvania, United States
Baylor Scott and White Research Institute
🇺🇸
Dallas, Texas, United States
Cotton O'Neil Clinical Research Center
🇺🇸
Topeka, Kansas, United States
University of Southern California
🇺🇸
Los Angeles, California, United States
Eastern Virginia Medical School
🇺🇸
Norfolk, Virginia, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Saint Luke's Mid America Heart Institute
🇺🇸
Kansas City, Missouri, United States
Wake Forest University
🇺🇸
Winston-Salem, North Carolina, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
University of Utah
🇺🇸
Salt Lake City, Utah, United States