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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03506412
Recruitment Status : Completed
First Posted : April 24, 2018
Results First Posted : February 4, 2022
Last Update Posted : February 4, 2022
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Naveen L. Pereira, Mayo Clinic

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Non-Randomized
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
Actual Primary Completion Date : March 23, 2021
Actual Study Completion Date : March 23, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: Low Serum Neprilysin (sNEP) levels
Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml
Drug: Entresto™ 49Mg-51 mg tablet
Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks

Experimental: High Serum Neprilysin (sNEP) levels
Subjects with baseline sNEP greater than or equal to 0.9 ng/ml
Drug: Entresto™ 49Mg-51 mg tablet
Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks




Primary Outcome Measures :
  1. Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP) [ Time Frame: baseline, 5 weeks ]
    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.

  2. Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) [ Time Frame: baseline, 5 weeks ]
    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.

  3. Change in Plasma N-terminal Brain Natriuretic Peptide (BNP) [ Time Frame: baseline, 5 weeks ]
    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.

  4. Change in Plasma Cyclic Guanine Monophosphate (cGMP) [ Time Frame: baseline, 5 weeks ]
    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.



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03506412


Locations
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United States, Minnesota
Mayo Clinic in Rochester
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Naveen L Pereira, MD Mayo Clinic
  Study Documents (Full-Text)

Documents provided by Naveen L. Pereira, Mayo Clinic:
Additional Information:
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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    Key Record Dates
Results First Posted: February 4, 2022
Last Update Posted: February 4, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Sacubitril and valsartan sodium hydrate drug combination
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action