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NCT Number: NCT06536309

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

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.

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Key information

Conditions

Heart Failure With Preserved Ejection Fraction Myocardial Fibrosis

Age range

50 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Sacubitril-valsartan

Drug

Sacubitril-valsartan titrated to maximally targeted dose

Other names: Entresto

valsartan

Drug

Valsartan titrated to maximally targeted dose

Other names: Diovan

Primary outcomes

  1. Change in extracellular volume by cardiac MRI

    Time frame: 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 outcomes

  1. Change in left ventricular native T1 time

    Time frame: 1 year

    Measured by cardiac MRI

Other outcomes

  1. Change in left ventricular mass

    Time frame: 1 year

    Measured by cardiac MRI

  2. Change in left atrial size

    Time frame: 1 year

Study contacts

Contact information is provided by the study sponsor or research team.

Jonathan Cunningham, MD

CONTACT

[email protected]

671-732-5524

Sponsors and collaborators

Lead sponsor

Brigham and Women's Hospital

Other

Registry information

Important dates

Study start
2026
Primary completion
2028
Study completion
2029
First posted
Aug 2, 2024
Registry last updated
Feb 25, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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