Clinical trial NCT03506412: Circulating NEP and NEP Inhibition Study in Heart Failure With Preserved Ejection Fraction
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure With Preserved Ejection Fraction
Keywords: Heart Failure
HFpEF
Entresto™
Neprilysin
Diastolic Heart Failure
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2018-04-24
Enrollment: 40
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Entresto™ will be administered to subjects with high and low circulating neprilysin (NEP) levels.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria

1. Age ≥ 50 years
2. LVEF ≥ 45% assessed by echocardiography, nuclear scan, MRI or left ventriculogram within the past 24 months
3. Current New York Heart Association (NYHA) class 2-4 symptoms of heart failure (HF)
4. Stable medical therapy for 30 days as defined by:

   1. No addition or removal of ACE, ARB, beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists
   2. No change in dosage of ACE, ARBs, beta-blockers, CCBs or aldosterone antagonists of more than 100%
5. One of the following within the last 24 months

   1. Previous hospitalization for HF with radiographic evidence of pulmonary congestion (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) or
   2. Catheterization documented elevated filling pressures at rest (LVEDP≥15 or PCWP≥20) or with exercise (PCWP≥25) or
   3. Elevated NT-proBNP (\> 400 pg/ml) or BNP (\> 200 pg/ml) or
   4. 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

1. LV mass/BSA ≥ 96 (♀) or ≥ 116 (♂) g/m2
2. Relative wall thickness ≥ 0.43 (♂ or ♀) \[(IVS+PW)/LVEDD\]
3. Posterior wall thickness ≥ 0.9 (♀) or 1.0 (♂) cm

Exclusion Criteria

1. History of hypersensitivity or allergy to ACE inhibitors (ACEIs), ARBs, or NEP inhibitors
2. Known history of angioedema
3. Previous LVEF \< 40% at any time
4. Systolic blood pressure \< 100 mmHg or \> 180 mmHg
5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy)
6. 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
7. 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
8. Severe congenital heart disease
9. History of heart transplant or with LV assist device
10. 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.
11. Glomerular filtration rate \< 20 ml/min/1.73 m2 on most recent clinical laboratories\*
12. Serum potassium of \> 5.5 mEq/dL on most recent clinical laboratories\*
13. Concomitant use of aliskiren in patients with diabetes
14. Currently receiving an investigational drug
15. Inability to comply with planned study procedures
16. Female subject who is pregnant or breastfeeding

    * Performed within 90 days of enrollment

Primary outcomes:
measure: Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP)
timeFrame: baseline, 5 weeks
measure: Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
timeFrame: baseline, 5 weeks
measure: Change in Plasma N-terminal Brain Natriuretic Peptide (BNP)
timeFrame: baseline, 5 weeks
measure: Change in Plasma Cyclic Guanine Monophosphate (cGMP)
timeFrame: baseline, 5 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Naveen L Pereira, MD
role: PRINCIPAL_INVESTIGATOR
References: