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

NCT ID: NCT03506412

Last Updated: 2022-02-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-25
• Study Completion Date: 2021-03-23

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.

Conditions

Heart Failure With Preserved Ejection Fraction

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low Serum Neprilysin (sNEP) levels

Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml

Group Type: EXPERIMENTAL

Entresto™ 49Mg-51 mg tablet

Intervention Type: DRUG

Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks

High Serum Neprilysin (sNEP) levels

Subjects with baseline sNEP greater than or equal to 0.9 ng/ml

Group Type: EXPERIMENTAL

Entresto™ 49Mg-51 mg tablet

Intervention Type: DRUG

Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks

Interventions

Entresto™ 49Mg-51 mg tablet

Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks

Intervention Type: DRUG

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

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

Naveen L. Pereira

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Naveen L Pereira, MD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic in Rochester

Rochester, Minnesota, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.mayo.edu/research/clinical-trials

Mayo Clinic Clinical Trials

Other Identifiers

R21AG053512

Identifier Type: NIH

Identifier Source: secondary_id

View Link

18-000044

Identifier Type: -

Identifier Source: org_study_id