Circulating NEP and NEP Inhibition Study in Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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To determine biomarker responses to Entresto™in patients with Heart Failure with preserved Ejection Fraction (HFpEF) and who have high or low serum neprilysin (NEP) levels.

Detailed Description
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This is a proof of concept single arm study in which 40 subjects with HFpEF will be assigned to Entresto™ 49/51 mg (sacubitril/valsartan) twice-daily for a total duration of up to 5 weeks of treatment. Blood will be drawn prior to and at completion of treatment. The primary endpoint measured is change in biomarkers with Entresto™ administration that reflect NEP activity and myocardial stress (NT pro-ANP, -BNP, -CNP) and drug action (cGMP). This endpoint has been well validated as a measure of Entresto™ drug response.

Official Title
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A Proof of Concept Study to Determine the Efficacy of Entresto™ in HFpEF Based on Circulating Neprilysin Levels: The Circulating NEP and NEP Inhibition (CNEPi) Study

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: Entresto™ 49Mg-51 mg tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age ≥ 50 years LVEF ≥ 45% assessed by echocardiography, nuclear scan, MRI or left ventriculogram within the past 24 months Current New York Heart Association (NYHA) class 2-4 symptoms of heart failure (HF) Stable medical therapy for 30 days as defined by: No addition or removal of ACE, ARB, beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists No change in dosage of ACE, ARBs, beta-blockers, CCBs or aldosterone antagonists of more than 100% One of the following within the last 24 months Previous hospitalization for HF with radiographic evidence of pulmonary congestion (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) or Catheterization documented elevated filling pressures at rest (LVEDP≥15 or PCWP≥20) or with exercise (PCWP≥25) or Elevated NT-proBNP (> 400 pg/ml) or BNP (> 200 pg/ml) or Echo evidence of diastolic dysfunction / elevated filling pressures (at least two) i. E/A > 1.5 + decrease in E/A of > 0.5 with valsalva ii. Deceleration time ≤ 140 ms iii. Pulmonary vein velocity in systole < diastole (PVs<PVd) (sinus rhythm) iv. E/e'≥15 v. Left atrial enlargement (≥ moderate) vi. Pulmonary artery systolic pressure > 40 mmHg vii. Evidence of left ventricular hypertrophy LV mass/BSA ≥ 96 (♀) or ≥ 116 (♂) g/m2 Relative wall thickness ≥ 0.43 (♂ or ♀) [(IVS+PW)/LVEDD] Posterior wall thickness ≥ 0.9 (♀) or 1.0 (♂) cm Exclusion Criteria History of hypersensitivity or allergy to ACE inhibitors (ACEIs), ARBs, or NEP inhibitors Known history of angioedema Previous LVEF < 40% at any time Systolic blood pressure < 100 mmHg or > 180 mmHg Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy) Unstable angina, myocardial infarction, stroke, transient ischemic attack, or cardiovascular surgery or urgent percutaneous coronary intervention (PCI) within 3 months of screening or elective PCI within 30 days of entry Significant valvular stenosis or regurgitation (greater than moderate in severity), hypertrophic, restrictive or obstructive cardiomyopathy including amyloidosis, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis Severe congenital heart disease History of heart transplant or with LV assist device Evidence of severe hepatic disease as determined by any one of the following: history of hepatic encephalopathy, history of esophageal varices, or history of porto-caval shunt. Glomerular filtration rate < 20 ml/min/1.73 m2 on most recent clinical laboratories* Serum potassium of > 5.5 mEq/dL on most recent clinical laboratories* Concomitant use of aliskiren in patients with diabetes Currently receiving an investigational drug Inability to comply with planned study procedures Female subject who is pregnant or breastfeeding Performed within 90 days of enrollment

Ages Eligible for Study
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Minimum Age: 50 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: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Entresto™ will be administered to subjects with high and low circulating neprilysin (NEP) levels.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Serum Neprilysin (sNEP) levels<br>Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml | Drug: Entresto™ 49Mg-51 mg tablet<br>* Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks<br>|
| Experimental: High Serum Neprilysin (sNEP) levels<br>Subjects with baseline sNEP greater than or equal to 0.9 ng/ml | Drug: Entresto™ 49Mg-51 mg tablet<br>* Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP) | Change in plasma NT pro-ANP value levels as measured in pg/mL. NT-pro ANP means N-terminal polypeptide of ANP (atrial natriuretic peptide) precursor. Natriuretic peptides are substances made by the heart. Elevated levels can mean the heart isn't pumping as much blood the body needs. | baseline, 5 weeks | 
| Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | Change in plasma NT pro-ANP value levels as measured in pg/mL. Natriuretic peptides are substances made by the heart. Two main types of these substances are brain natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP). Elevated levels can mean the heart isn't pumping as much blood the body needs. | baseline, 5 weeks | 
| Change in Plasma N-terminal Brain Natriuretic Peptide (BNP) | Change in plasma BNP biomarker value levels as measured in pg/mL. Brain natriuretic peptide is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume. Elevated levels can mean the heart isn't pumping as much blood the body needs. | baseline, 5 weeks | 
| Change in Plasma Cyclic Guanine Monophosphate (cGMP) | Change in Plasma cGMP biomarker value levels as measured in nmol/L. Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate. cGMP acts as a second messenger to tissue and cellular responses. | baseline, 5 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, HFpEF, Entresto™, Neprilysin, Diastolic Heart Failure