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

NCT06536309 | Not Yet Recruiting Phase 4 DMC FDA Drug

• 2 other identifiers: 2024P0018941K23HL168163-01A1
• Study Type: interventional
• Target: 36
• Locations: 0 countries
• Sites: N/A

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

Outcome Measures

Primary Outcomes (1)

• Change in extracellular volume by cardiac MRI

  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

  1 year

Secondary Outcomes (1)

• Change in left ventricular native T1 time

  1 year

Other Outcomes (2)

• Change in left ventricular mass

  1 year

• Change in left atrial size

  1 year

Study Arms (2)

Sacubitril/valsartan

EXPERIMENTAL

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

Drug: Sacubitril-valsartan

Valsartan

ACTIVE COMPARATOR

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

Drug: Valsartan

Interventions

Sacubitril-valsartan DRUG

Sacubitril-valsartan titrated to maximally targeted dose

Also known as: Entresto

Sacubitril/valsartan

Valsartan DRUG

Valsartan titrated to maximally targeted dose

Also known as: Diovan

Valsartan

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Related Publications (1)

• 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.

  PMID: 31475794 BACKGROUND

MeSH Terms

Interventions

sacubitril and valsartan sodium hydrate drug combination; Valsartan

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Central Study Contacts

Jonathan Cunningham, MD

CONTACT

671-732-5524; jcunningham3@bwh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine, Cardiovascular Division

Study Record Dates

• First Submitted: July 26, 2024
• First Posted: August 2, 2024
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): September 1, 2029
• Last Updated: February 25, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share