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

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT03506412
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 40
• Location: 1
• Arms: 2
• Actual Duration (Months): 32.9
• Patients Per Site Per Month: 1.2

Study Details

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
• 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.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: Jun 25, 2018
• Actual Primary Completion Date: Mar 23, 2021
• Actual Study Completion Date: Mar 23, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP) [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) [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) [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) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

5. No addition or removal of ACE, ARB, beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists

6. No change in dosage of ACE, ARBs, beta-blockers, CCBs or aldosterone antagonists of more than 100%

7. One of the following within the last 24 months

8. Previous hospitalization for HF with radiographic evidence of pulmonary congestion (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) or

9. Catheterization documented elevated filling pressures at rest (LVEDP≥15 or PCWP≥20) or with exercise (PCWP≥25) or

10. Elevated NT-proBNP (> 400 pg/ml) or BNP (> 200 pg/ml) or

11. Echo evidence of diastolic dysfunction / elevated filling pressures (at least two)

1. E/A > 1.5 + decrease in E/A of > 0.5 with valsalva

1. Deceleration time ≤ 140 ms

2. Pulmonary vein velocity in systole < diastole (PVs<PVd) (sinus rhythm)

3. E/e'≥15

4. Left atrial enlargement (≥ moderate)

5. Pulmonary artery systolic pressure > 40 mmHg

6. 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

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Institute on Aging (NIA)

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 29, 2021

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Naveen L. Pereira, Professor of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03506412
• Other Study ID Numbers: 18-000044; R21AG053512
• First Posted: Apr 24, 2018
• Last Update Posted: Feb 4, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• 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, Professor of Medicine, Mayo Clinic: Heart Failure; HFpEF; Entresto™; Neprilysin; Diastolic Heart Failure
• Additional relevant MeSH terms: Heart Failure; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Pre-assignment Detail	Total of 40 subject enrolled. Enrolled subjects were assigned to an arm based on their Baseline serum Neprilysin (sNEP) levels. Baseline sNEP levels were only available for 37 subjects. Data not collected for 3 subjects.

Arm/Group Title	Low Serum Neprilysin (sNEP) Levels	High Serum Neprilysin (sNEP) Levels
Arm/Group Description	Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49 Mg-51 mg will be given twice daily orally for 5 weeks	Subjects with baseline sNEP greater than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49 Mg-51 mg will be given twice daily orally for 5 weeks
Period Title: Overall Study
STARTED	18	19
COMPLETED	18	19
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Low Serum Neprilysin (sNEP) Levels	High Serum Neprilysin (sNEP) Levels	Total
Arm/Group Description	Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks	Subjects with baseline sNEP greater than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks	Total of all reporting groups
Overall Participants	18	19	37
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	77.0	74.0	76
Sex: Female, Male (Count of Participants)
Female	10 55.6%	7 36.8%	17 45.9%
Male	8 44.4%	12 63.2%	20 54.1%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%	19 100%	37 100%

Outcome Measures

1. Primary Outcome

Title	Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP)
Description	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.
Time Frame	baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Serum Neprilysin (sNEP) Levels	High Serum Neprilysin (sNEP) Levels
Arm/Group Description	Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks	Subjects with baseline sNEP greater than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks
Measure Participants	18	19
Median (Inter-Quartile Range) [pg/mL]	47.4	46.4

2. Primary Outcome

Title	Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
Description	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.
Time Frame	baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Serum Neprilysin (sNEP) Levels	High Serum Neprilysin (sNEP) Levels
Arm/Group Description	Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks	Subjects with baseline sNEP greater than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks
Measure Participants	18	19
Median (Inter-Quartile Range) [pg/mL]	-11.5	45.0

3. Primary Outcome

Title	Change in Plasma N-terminal Brain Natriuretic Peptide (BNP)
Description	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.
Time Frame	baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Serum Neprilysin (sNEP) Levels	High Serum Neprilysin (sNEP) Levels
Arm/Group Description	Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks	Subjects with baseline sNEP greater than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks
Measure Participants	18	19
Median (Inter-Quartile Range) [pg/mL]	-301.5	-100.0

4. Primary Outcome

Title	Change in Plasma Cyclic Guanine Monophosphate (cGMP)
Description	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.
Time Frame	baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Serum Neprilysin (sNEP) Levels	High Serum Neprilysin (sNEP) Levels
Arm/Group Description	Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks	Subjects with baseline sNEP greater than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks
Measure Participants	18	19
Median (Inter-Quartile Range) [nmol/L]	4.2	1.0

Adverse Events

Time Frame	Adverse Events were collected from baseline to end of study, approximately 5 weeks
Arm/Group Title	Low Serum Neprilysin (sNEP) Levels		High Serum Neprilysin (sNEP) Levels
Arm/Group Description	Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks		Subjects with baseline sNEP greater than or equal to 0.9 ng/ml Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks
All Cause Mortality
	Low Serum Neprilysin (sNEP) Levels		High Serum Neprilysin (sNEP) Levels
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/19 (0%)
Serious Adverse Events
	Low Serum Neprilysin (sNEP) Levels		High Serum Neprilysin (sNEP) Levels
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Low Serum Neprilysin (sNEP) Levels		High Serum Neprilysin (sNEP) Levels
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.