Recruiting
Phase 1

Vascular Function

Sponsor:

VA Office of Research and Development

Code:

NCT06312748

Conditions

Heart Failure With Preserved Ejection Fraction

Inflammation

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

L-Citrulline

Placebo for L-Citrulline

BH4

Placebo for BH4

Atorvastatin

Study Details

Brief summary:

This project will evaluate the impact of L-Citrulline, tetrahydrobiopterin (BH4), and atorvastatin administration on physical capacity and vascular function in Veterans with heart failure with preserved ejection fraction (HFpEF).

Conditions

Heart Failure With Preserved Ejection Fraction

Inflammation

Study ID

NCT06312748

Start date

May 19, 2021

Status verified date

Apr, 2026

Completion date

Sep 30, 2030

Anticipated

Primary completion date

Sep 30, 2028

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Age 18 years or older and able to give written informed consent.
  • New York Heart Association (NYHA) functional class I, II, or III.
  • Left Ventricular Ejection Fraction (LVEF) > 50%.
  • Plasma Brain Natriuretic Peptide (BNP) equal to or greater than 150 pg/mL or NT-proBNP equal to or greater than 600 pg/mL at Visit 1, or a BNP equal to or great than 100 pg/mL (or NT-proBNP equal to or greater than 400 pg/mL) and a hospitalization for heart failure within the last 12 months.

Exclusion Criteria:

  • History of hypersensitivity or allergy to any lipophilic statin.
  • Prior EF <50%.
  • NYHA Class IV.
  • Patients with HFpEF secondary to significant uncorrected primary valvular disease.
  • Active liver disease or unexplained persistent elevations in serum transaminase.
  • Women who are pregnant or may become pregnant.
  • Patients currently treated with antioxidants, nitrates, PDE-5 inhibitors, or statins.

Study Design

Enrollment

90 participants

Anticipated

Allocation

Randomized

Intervention Model

Crossover

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: L-Citrulline, Then Placebo

Participants will receive a 90-day supply of L-Citrulline and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Placebo and perform baseline and follow-up assessments as above.

experimental: BH4, Then Placebo

Participants will receive a 90-day supply of BH4 and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Placebo and perform baseline and follow-up assessments as above.

experimental: Atorvastatin, Then Placebo

Participants will receive a 90-day supply of Atorvastatin and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Placebo and perform baseline and follow-up assessments as above.

experimental: Placebo, Then L-Citrulline

Participants will receive a 90-day supply of Placebo and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of L-Citrulline and perform baseline and follow-up assessments as above.

experimental: Placebo, Then BH4

Participants will receive a 90-day supply of Placebo and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of BH4 and perform baseline and follow-up assessments as above.

experimental: Placebo, Then Atorvastatin

Participants will receive a 90-day supply of Placebo and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Atorvastatin and perform baseline and follow-up assessments as above.

Interventions

L-Citrulline

100 mg tablet

Placebo for L-Citrulline

L-Citrulline-matched Placebo tablet

BH4

10mg/kg

Placebo for BH4

BH4-matched Placebo

Atorvastatin

10 mg tablet

Placebo for Atorvastatin

Atorvastatin-matched Placebo

Primary outcome measure

  • Flow-mediated dilation (FMD) [ Time Frame: Baseline, Day 90 ]

Central Contacts and Locations

Central contacts

David W Wray, PhD

(801) 582-1565David.Wray2@va.gov

Misti R Seppi, MBA BS AAS

(801) 582-1565Misti.Seppi@va.gov

Locations

VA Salt Lake City Health Care System, Salt Lake City, UT

Recruiting

Salt Lake City, Utah, United States, 84148-0001

Contacts

David W Wray, PhD

801-582-1565David.Wray2@va.gov

Principal Investigator:

David W. Wray, PhD

More Information

Sponsor

VA Office of Research and Development

Last update posted

Apr 23, 2026

Last verified

Apr, 2026

Keywords

  • vascular health
  • exercise tolerance
  • HFpEF
  • nitric oxide

Trial information was received from ClinicalTrials.gov and was last updated on 2026-10-24. This information was provided to ClinicalTrials.gov by VA Office of Research and Development on 2026-04-23. Recruitment status is synced daily from ClinicalTrials.gov and may not reflect the sponsor's current status. Confirm during your call.