Heart Failure With Preserved Ejection FractionPhase 4CNEPiNCT03506412
Circulating NEP and NEP Inhibition Study in Heart Failure With Preserved Ejection Fraction
A Phase 4 study testing Entresto™ 49Mg-51 mg tablet in people with Heart Failure With Preserved Ejection Fraction, run by Mayo Clinic at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- Heart Failure With Preserved Ejection Fraction
- What is being tested?
- Entresto™ 49Mg-51 mg tablet
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Jun 2018to 23 Mar 2021
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 50 years
- LVEF ≥ 45% assessed by echocardiography, nuclear scan, MRI or left ventriculogram within the past 24 months
- Current New York Heart Association (NYHA) class 2-4 symptoms of heart failure (HF)
- Stable medical therapy for 30 days as defined by:
- No addition or removal of ACE, ARB, beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists
- No change in dosage of ACE, ARBs, beta-blockers, CCBs or aldosterone antagonists of more than 100%
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- One of the following within the last 24 months
- Previous hospitalization for HF with radiographic evidence of pulmonary congestion (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) or
- Catheterization documented elevated filling pressures at rest (LVEDP≥15 or PCWP≥20) or with exercise (PCWP≥25) or
- Elevated NT-proBNP (> 400 pg/ml) or BNP (> 200 pg/ml) or
- Echo evidence of diastolic dysfunction / elevated filling pressures (at least two)
- E/A > 1.5 + decrease in E/A of > 0.5 with valsalva
- Deceleration time ≤ 140 ms
- Pulmonary vein velocity in systole < diastole (PVs<PVd) (sinus rhythm)
- E/e'≥15
- Left atrial enlargement (≥ moderate)
- Pulmonary artery systolic pressure > 40 mmHg
- Evidence of left ventricular hypertrophy
- LV mass/BSA ≥ 96 (♀) or ≥ 116 (♂) g/m2
- Relative wall thickness ≥ 0.43 (♂ or ♀) [(IVS+PW)/LVEDD]
- Posterior wall thickness ≥ 0.9 (♀) or 1.0 (♂) cm
Who cannot join
- History of hypersensitivity or allergy to ACE inhibitors (ACEIs), ARBs, or NEP inhibitors
- Known history of angioedema
- Previous LVEF < 40% at any time
- Systolic blood pressure < 100 mmHg or > 180 mmHg
- Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy)
- 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
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- 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
- Severe congenital heart disease
- History of heart transplant or with LV assist device
- 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.
- Glomerular filtration rate < 20 ml/min/1.73 m2 on most recent clinical laboratories*
- Serum potassium of > 5.5 mEq/dL on most recent clinical laboratories*
- Concomitant use of aliskiren in patients with diabetes
- Currently receiving an investigational drug
- Inability to comply with planned study procedures
- Female subject who is pregnant or breastfeeding
- Performed within 90 days of enrollment
Trial locations and contacts
1 site in 1 country.
United States1 site
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
About this study
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
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.
Read the 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.
- Being tested
- Entresto™ 49Mg-51 mg tablet
- Keywords
- Heart Failure, HFpEF, Entresto™, Neprilysin, Diastolic Heart Failure
- Medical subject headings
- Heart Failure, Heart Failure, Diastolic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Entresto™ 49Mg-51 mg tabletDrug
Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks
| Study group | Role | What they receive |
|---|---|---|
| Low Serum Neprilysin (sNEP) levels | Experimental | Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml Receives: Drug: Entresto™ 49Mg-51 mg tablet |
| High Serum Neprilysin (sNEP) levels | Experimental | Subjects with baseline sNEP greater than or equal to 0.9 ng/ml Receives: Drug: Entresto™ 49Mg-51 mg tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP)
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.
Measured: baseline, 5 weeks
Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
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.
Measured: baseline, 5 weeks
Change in Plasma N-terminal Brain Natriuretic Peptide (BNP)
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.
Measured: baseline, 5 weeks
Change in Plasma Cyclic Guanine Monophosphate (cGMP)
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.
Measured: baseline, 5 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2018
- Study start25 Jun 2018
- Primary completion23 Mar 2021
- Study completion23 Mar 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Heart Failure With Preserved Ejection FractionStudies of the same condition, open and under way.
- More trials run by Mayo ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Model description
- Entresto™ will be administered to subjects with high and low circulating neprilysin (NEP) levels.
- Masking
- None (open label)
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mayo Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Principal investigator, Naveen L. Pereira, Mayo Clinic
- Investigators
- Naveen L Pereira, MD, Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03506412
- Sponsor's protocol ID
- 18-000044
- Other IDs
- R21AG053512
- Acronym
- CNEPi
- Status last verified
- Jan 2022
- First submitted
- 11 Apr 2018
- Last updated
- 4 Feb 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 4 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03506412
- Acronym / sponsor ID
- CNEPi / 18-000044
- Keywords
- Heart Failure, HFpEF, Entresto™, Neprilysin, Diastolic Heart Failure
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Mayo ClinicUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- 25 Jun 2018 (actual)
- Primary completion
- 23 Mar 2021 (actual)
- Study completion
- 23 Mar 2021 (actual)
- First posted
- 24 Apr 2018 (actual)
- Results
- Posted 4 Feb 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Entresto™ will be administered to subjects with high and low circulating neprilysin (NEP) levels.
| Arm | Type | Receives |
|---|---|---|
| Low Serum Neprilysin (sNEP) levels | Experimental | Drug: Entresto™ 49Mg-51 mg tabletSubjects with baseline sNEP levels less than or equal to 0.9 ng/ml |
| High Serum Neprilysin (sNEP) levels | Experimental | Drug: Entresto™ 49Mg-51 mg tabletSubjects with baseline sNEP greater than or equal to 0.9 ng/ml |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- Age ≥ 50 years
- LVEF ≥ 45% assessed by echocardiography, nuclear scan, MRI or left ventriculogram within the past 24 months
- Current New York Heart Association (NYHA) class 2-4 symptoms of heart failure (HF)
- Stable medical therapy for 30 days as defined by:
- One of the following within the last 24 months
Key exclusion criteria (17 listed)
- History of hypersensitivity or allergy to ACE inhibitors (ACEIs), ARBs, or NEP inhibitors
- Known history of angioedema
- Previous LVEF < 40% at any time
- Systolic blood pressure < 100 mmHg or > 180 mmHg
- Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Entresto™ 49Mg-51 mg tabletEntresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks | Drug | High Serum Neprilysin (sNEP) levels, Low Serum Neprilysin (sNEP) levels |
Primary outcome
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.
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.
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.
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Feb 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Mayo Clinic Clinical TrialsLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Naveen L Pereira, MD principal investigator
Mayo Clinic
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Entresto™ 49Mg-51 mg tablet in people with Heart Failure With Preserved Ejection Fraction, run by Mayo Clinic at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP) (time frame: baseline, 5 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Feb 2022.