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

• ClinicalTrials.gov Identifier: NCT03506412
• Recruitment Status: Recruiting
• First Posted: April 24, 2018
• Last Update Posted: January 6, 2021
• Sponsor: Mayo Clinic
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Naveen L. Pereira, Mayo Clinic

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Heart Failure With Preserved Ejection Fraction	Drug: Entresto™ 49Mg-51 mg tablet	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Entresto™ will be administered to subjects with high and low circulating neprilysin (NEP) levels.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: June 25, 2018
• Estimated Primary Completion Date: March 2021
• Estimated Study Completion Date: March 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Entresto™; HFpEF patients will be given Entresto™	Drug: Entresto™ 49Mg-51 mg tablet; Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline of Biomarkers Based on NEP Levels with Entresto™ Administration [ Time Frame: 5 weeks ]
   The effect of administering Entresto™ to subjects with "high" or "low" NEP levels will be studied. Favorable response to Entresto™ therapy in these subjects will be assessed by evaluating a change in biomarkers that reflect NEP activity. Entresto™ is FDA approved for use in HFrEF and will be administered as recommended in the drug labeling information as an off label use in HFpEF as 49/51 mg twice-daily.

Secondary Outcome Measures :

1. Change From Baseline in NT-proANP, NT-proBNP and NT-proCNP [ Time Frame: 5 weeks ]
   Evaluation of NT-proANP, NT-proBNP and NT-proCNP was performed by laboratory testing.
2. Change From Baseline in Plasma Cyclic Guanine Monophosphate (cGMP) [ Time Frame: 5 weeks ]
   Evaluation of cGMP was performed by laboratory testing.

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Nancy G Acker, BSN; (507) 266-4058; acker.nancy@mayo.edu

Locations

United States, Minnesota

Mayo Clinic in Rochester; Recruiting

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Mayo Clinic

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Naveen L Pereira, MD; Mayo Clinic

More Information

Additional Information:

Mayo Clinic Clinical Trials 

• Responsible Party: Naveen L. Pereira, Professor of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03506412
• Other Study ID Numbers: 18-000044; R21AG053512 ( U.S. NIH Grant/Contract )
• First Posted: April 24, 2018
• Last Update Posted: January 6, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Naveen L. Pereira, Mayo Clinic:

Heart Failure; HFpEF; Entresto™; Neprilysin; Diastolic Heart Failure

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; LCZ 696; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action