Neprilysin Inhibition to Reduce Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction

NCT ID: NCT06536309

Last Updated: 2026-01-07

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-01-31
• Study Completion Date: 2029-09-30

Brief Summary

Cardiac magnetic resonance imaging (MRI) measures of myocardial interstitial fibrosis (MIF) are elevated in heart failure with preserved ejection fraction (HFpEF) patients and associated with poor prognosis. Extracellular volume (ECV) is the most reproducible and best validated cardiac MRI measure of MIF. Sacubitril/valsartan reduces histological MIF in mice and levels of some extracellular matrix regulatory proteins in humans with HFpEF. However, the effect of sacubitril/valsartan on robust measures of MIF in humans is unknown. Demonstrating reductions in ECV with sacubitril/valsartan would clarify the mechanism of this approved medication. Given the borderline reduction in heart failure hospitalizations with sacubitril/valsartan and the heterogeneity of HFpEF pathophysiology, this result would suggest that neprilysin inhibition may particularly benefit HFpEF patients with greater MIF. The investigators propose a proof-of-concept clinical trial to evaluate the effect of neprilysin inhibition (sacubitril/valsartan vs valsartan alone) on cardiac MRI measures of fibrosis (principally ECV) and circulating protein levels.

Conditions

Heart Failure With Preserved Ejection Fraction; Myocardial Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Sacubitril/valsartan

Patient randomized to the interventional arm will be treated with sacubitril/valsartan

Group Type: EXPERIMENTAL

Sacubitril-valsartan

Intervention Type: DRUG

Sacubitril-valsartan titrated to maximally targeted dose

Valsartan

Patient randomized to the active comparator arm will be treated with valsartan

Group Type: ACTIVE_COMPARATOR

Valsartan

Intervention Type: DRUG

Valsartan titrated to maximally targeted dose

Interventions

Sacubitril-valsartan

Sacubitril-valsartan titrated to maximally targeted dose

Intervention Type: DRUG

Valsartan

Valsartan titrated to maximally targeted dose

Intervention Type: DRUG

Other Intervention Names

Entresto; Diovan

Eligibility Criteria

Inclusion Criteria

• Adults aged 50 years or older
• Able to provide informed consent, as assessed by a physician investigator, and willing to comply with the study
• Clinically confirmed diagnosis of heart failure
• Left ventricular ejection fraction greater than or equal to 45% within 1 year by echocardiogram, cardiac MRI, or nuclear scan

Exclusion Criteria

• Contraindication to MRI (metal prosthesis, implantable cardiac device, or severe claustrophobia)
• Systolic blood pressure < 100mm Hg, or <110 mm Hg for patients not taking an ACE inhibitor or angiotensin receptor blocker
• symptomatic hypotension
• eGFR < 30 mL/min/1.73m2 within 60 days of enrollment
• Serum potassium >5.2mmol/L within 60 days of enrollment, or >5.0 mmol/L for patients not taking an ACE inhibitor or angiotensin receptor blocker
• Myocardial infarction within 6 months of enrollment
• Infiltrative or hypertrophic cardiomyopathy
• History of cirrhosis, biliary cirrhosis, or cholestasis
• History of angioedema
• Pregnancy, planning pregnancy, or breastfeeding
• Active treatment with lithium or a direct renin inhibitor

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Jonathan Cunningham MD MPH

Assistant Professor of Medicine, Cardiovascular Division

Responsibility Role: PRINCIPAL_INVESTIGATOR

Central Contacts

Jonathan Cunningham, MD

Role: CONTACT

jcunningham3@bwh.harvard.edu

671-732-5524

References

Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Dungen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP; PARAGON-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620. doi: 10.1056/NEJMoa1908655. Epub 2019 Sep 1.

Reference Type: BACKGROUND

PMID: 31475794 (View on PubMed)

Other Identifiers

1K23HL168163-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2024P001894

Identifier Type: -

Identifier Source: org_study_id