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

Phase 4

Not yet recruiting

• Conditions: Heart Failure With Preserved Ejection Fraction; Myocardial Fibrosis
• Interventions: Drug: Sacubitril-valsartan; Drug: Valsartan

• Registration Number: NCT06536309
• Lead Sponsor: Brigham and Women's Hospital

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-07-26
• Study First Submitted QC: 2024-07-30
• Study First Posted: 2024-08-02
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-06
• Last Update Posted: 2025-03-10
• Study Start: 2025-07
• Primary Completion: 2026-12
• Study Completion: 2029-09

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 36

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sacubitril/valsartan	Sacubitril-valsartan	Patient randomized to the interventional arm will be treated with sacubitril/valsartan
Valsartan	Valsartan	Patient randomized to the active comparator arm will be treated with valsartan

Primary Outcome Measures

Name	Time	Method
Change in extracellular volume by cardiac MRI	1 year	The primary outcome is to evaluate the change in extracellular volume (ECV), measured by cardiac MRI, from baseline to one year, in the sacubitril/valsartan arm compared to the valsartan arm

Secondary Outcome Measures

Name	Time	Method
Change in left ventricular native T1 time	1 year	Measured by cardiac MRI