Empagliflozin Impact on Hemodynamics in Patients With Heart Failure

Study Overview
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Brief Summary
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The primary purpose of this trial is to evaluate the impact of empagliflozin, as compared with placebo, on hemodynamic parameters (pulmonary artery diastolic pressure) in patients with heart failure (reduced or preserved ejection fraction, ischemic or non-ischemic etiology) who already have a CardioMEMs device (a wireless hemodynamic monitoring system) implanted for non-study related clinical reasons.

Detailed Description
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A 12-week randomized, double-blind, placebo-controlled trial to explore the effects of once-daily empagliflozin 10 mg on hemodynamic parameters (pulmonary artery pressures) in patients with heart failure (reduced or preserved ejection fraction, ischemic or non-ischemic etiology) who already have a CardioMEMs device implanted for non-study related clinical reasons.

Official Title
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Empagliflozin Evaluation by Measuring Impact on Hemodynamics in Patients With Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Empagliflozin 10 mg Tab
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Established diagnosis of heart failure (for at least 16 weeks prior to the screening visit) with either preserved (LVEF>40%) or reduced systolic function (LVEF≤40%), due to either ischemic or non-ischemic etiology, documented by an imaging modality (echocardiography, nuclear imaging, LV angiography, magnetic resonance imaging) within the past 24 months. No major change in diuretic management for 48 hours prior to screening visit or 48 hours prior to randomization visit (major change defined by doubling of diuretic dose or addition of another diuretic medication) New York Heart Association (NYHA) class II, III or IV heart failure symptoms at the screening and randomization visit Presence of previously (≥ 2 weeks prior to screening visit) implanted CardioMEMs pulmonary artery pressure monitor for a clinical indication unrelated to the study. Pulmonary artery diastolic pressure ≥ 12 mmHg at the time of the screening visit (last measurement available prior to the screening visit). Ability to provide informed consent prior to initiating screening visit procedures Exclusion Criteria: Decompensated heart failure (hospitalization for heart failure within the 2 weeks prior to screening) or between screening and randomization History of type 1 diabetes Major change in diuretic management during 48 hours prior to screening visit or 48 hours prior to randomization visit. (major change defined by doubling of diuretic dose or addition of another diuretic medications) Significant variability in baseline pulmonary artery diastolic pressures during screening period. Defined as changes greater than +/- 6 mmHg from average pulmonary artery diastolic pressure during week 1 of the screening phase and average pulmonary artery diastolic pressure during week 2 of the screening phase for those patients with an average baseline pulmonary artery diastolic pressure during week 1 of the screening phase of <30 mmHg. If the average baseline pulmonary artery diastolic pressure during week 1 of the screening phase is ≥30 mmHg, then ≥20% relative change in average pulmonary diastolic pressure between week 1 and week 2 of the screening phase will be used to define significant variability. Initiation of hydralazine, long-acting nitrates, beta blockers, angiotensin-converting enzyme inhibitors (ACEIs) , angiotensin II receptor blockers (ARBs) or valsartan/sacubitril in the prior 4 weeks prior to screening Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 at the screening visit Admission for an acute coronary syndrome (ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, or unstable angina), percutaneous coronary intervention, or cardiac surgery within 30 days prior to the screening visit. Implantation of cardiac resynchronization therapy (CRT) device within the previous 90 days. Implantation of the CardioMEMs device within the past 2 weeks. 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 planned implantation of cardiac resynchronization therapy (CRT) device 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 the 4 weeks prior to the screening visit. History of hypersensitivity to empagliflozin 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 Pulmonary artery diastolic pressure < 12 mmHg at the time of the screening visit (average of last four measurements available prior to the screening visit). Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, empagliflozin) or having received treatment with any SGLT-2 inhibitor within the 8 weeks prior to the screening visit Average supine systolic BP <90 mmHg at the screening or randomization visit Current documented history of bladder cancer Active Gross Hematuria Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, severe stenotic valve disease, and hypertrophic obstructive cardiomyopathy (HOCM). History of heart transplant. Patients on heart transplant list as 1a and 1b status

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 119 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Empagliflozin<br>Empagliflozin 10 mg tab, once daily, for 12 weeks | Drug: Empagliflozin 10 mg Tab<br>* Empagliflozin 10 mg Tab<br>* Other names: Jardiance;|
| Placebo Comparator: Placebo<br>Empagliflozin matching placebo oral tablet, once daily for 12 weeks | Drug: Placebo Oral Tablet<br>* Empagliflozin matching placebo<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pulmonary Artery Diastolic Pressure From Baseline to End of Treatment Period (Defined as Average of Pulmonary Artery Diastolic Pressure Measurements Between Weeks 8-12) Between Empagliflozin and Placebo | Change in pulmonary artery diastolic pressure from baseline to end of treatment period (defined as average of pulmonary artery diastolic pressure measurements between weeks 8-12) between empagliflozin and placebo | Baseline to average between Weeks 8-12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Pulmonary Artery Diastolic Pressure at Each Interim Timepoint (Wks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12) Between Empagliflozin and Placebo. | Change from baseline in pulmonary artery diastolic pressure at each interim timepoint (wks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12) between empagliflozin and placebo. | Baseline to Weeks 1-12 | 
| Change in Pulmonary Artery Systolic Pressure From Baseline to End of Treatment Period (Week 12) Between Empagliflozin and Placebo. | Change in pulmonary artery systolic pressure from baseline to end of treatment period (week 12) between empagliflozin and placebo. | Baseline to Week 12 | 
| Change From Baseline in Pulmonary Artery Systolic Pressure at Each Interim Time Point (Wks 1, 2, 3, 4, 5, 6, 7, 8, 9,10,11,12) Between Empagliflozin and Placebo. | Change from baseline in pulmonary artery systolic pressure at each interim time point (wks 1, 2, 3, 4, 5, 6, 7, 8, 9,10,11,12) between empagliflozin and placebo. | Baseline to Weeks 1-12 | 
| Change in Mean Pulmonary Artery Pressure From Baseline to End of Treatment Period (Week 12) Between Empagliflozin and Placebo. | Change in mean pulmonary artery pressure from baseline to end of treatment period (week 12) between empagliflozin and placebo. | Baseline to Week 12 | 
| Change From Baseline in Mean Pulmonary Artery Pressure at Each Interim Time Point (Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) Between Empagliflozin and Placebo. | Change from baseline in mean pulmonary artery pressure at each interim time point (weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) between empagliflozin and placebo. | Baseline to Weeks 1-12 | 
| Change in Heart Failure Related Quality of Life, Using the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS) From Baseline to Follow-up (Defines as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. | The Kansas City Cardiomyopathy Questionnaire (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 Kansas City Cardiomyopathy Questionnaire Overall Summary Score KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points. | Baseline to Week 6 and Week 12 | 
| Proportion of Patients With a ≥ 5 Point Increase From Baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS) at Either 6 Weeks or 12 Weeks of Follow-up Between Empagliflozin and Placebo. | The Kansas City Cardiomyopathy Questionnaire (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 Kansas City Cardiomyopathy Questionnaire Overall Summary Score KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points. | Baseline to Week 6 and Week 12 | 
| Change in 6 Minute Walk Test From Baseline to Follow-up (Defined as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. | Change in 6 minute walk test from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) between empagliflozin and placebo. | Baseline to Week 6 and Week 12 | 
| Change in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) From Baseline to Follow-up (Defined as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. | Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) between empagliflozin and placebo. | Baseline to Week 6 and Week 12 | 
| Change in Brain Natriuretic Peptide (BNP) From Baseline to Follow-up (Defined as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. | Change in brain natriuretic peptide (BNP) from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) between empagliflozin and placebo. | Baseline to Week 6 and Week 12 | 
| Proportion of Patients With a ≥ 20% Decrease From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Either 6 Weeks or 12 Weeks of Follow-up Between Empagliflozin and Placebo. | Proportion of patients with a ≥ 20% decrease from baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) at either 6 weeks or 12 weeks of follow-up between empagliflozin and placebo. | Baseline to Week 6 and Week 12 | 
| Proportion of Patients With a ≥ 20% Decrease From Baseline in Brain Natriuretic Peptide (BNP) at Either 6 Weeks or 12 Weeks of Follow-up Between Empagliflozin and Placebo. | Proportion of patients with a ≥ 20% decrease from baseline in brain natriuretic peptide (BNP) at either 6 weeks or 12 weeks of follow-up between empagliflozin and placebo. | Baseline to Week 6 and Week 12 | 
| Proportion of Patients With Both a ≥ 5 Point Increase From Baseline in KCCQ-OS and a ≥ 20% Decrease From Baseline in NT-proBNP at Either 6 Weeks or 12 Weeks of Follow-up Between Empagliflozin and Placebo. | Proportion of patients with both a ≥ 5 point increase from baseline in Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS) and a ≥ 20% decrease from baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) at either 6 weeks or 12 weeks of follow-up between empagliflozin and placebo. The Kansas City Cardiomyopathy Questionnaire (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 Kansas City Cardiomyopathy Questionnaire Overall Summary Score KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points. | Baseline to Week 6 and Week 12 | 
| Number of Participants With Diuretic Medication Adjustments During the Treatment Period Between Empagliflozin and Placebo | Number of Participants with Diuretic Medication Adjustments During the Treatment Period Between Empagliflozin and Placebo | Baseline to Week 12 | 
| Change in Hemoglobin A1c From Baseline to Follow-up (Defined as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. | Change in Hemoglobin A1c from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) between empagliflozin and placebo. | Baseline to Week 6 and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, empagliflozin, Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors