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

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ClinicalTrials.gov Identifier: NCT03506412
Recruitment Status : Recruiting
First Posted : April 24, 2018
Last Update Posted : October 5, 2018
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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
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 30, 2019
Estimated Study Completion Date : April 30, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

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




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.



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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 12 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


Contacts
Contact: Sarah C Wolhart, BSN (507) 422-5310 wolhart.sarah@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

Responsible Party: Naveen L. Pereira, Professor of Medicine, Mayo Clinic
ClinicalTrials.gov Identifier: NCT03506412     History of Changes
Other Study ID Numbers: 18-000044
R21AG053512 ( U.S. NIH Grant/Contract )
First Posted: April 24, 2018    Key Record Dates
Last Update Posted: October 5, 2018
Last Verified: April 2018
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
Valsartan
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers