A Study of Oral Nitrate in Adults With Pulmonary Hypertension With Heart Failure and Preserved Ejection Fraction (PMED)

An Open Label Study of Oral Nitrate in Adults With Pulmonary Hypertension With Heart Failure and Preserved Ejection Fraction (PH-HFpEF) and Normal Healthy Adults

This is an open-label, single-center study to examine distinguishing features of the structure and function of the oral and gut microbiome in healthy adult normal volunteers compared to volunteers with PH-HFpEF in the breakdown of oral nitrate.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Preserved Ejection Fraction; Pulmonary; Hypertension
• Intervention / Treatment: Drug: 15N Nitrate; Drug: 14N Nitrate

Detailed Description

We will enroll 60 Group II PH (PH-HFpEF) or Group I PAH patients and 60 matched healthy controls over three years. The Subjects will receive a single dose of one of the two study drugs, determined by whether they will participate in one study visit or two: 15N nitrate (1,000 mg) or 14N Sodium Nitrate: standard sodium nitrate, and all will receive one dose of CLA 3g. Twenty of the PH or PAH subjects and 20 of the control subjects willing to return for a follow up visit 24 hours after drug administration will receive 15N nitrate. All others will receive standard sodium nitrate. CLA will be obtained from GNC (General Nutrition Corporation) and given once.

Throughout the experiment, we will measure blood pressure, heart rate, and respiratory rate as well as co-oximetry. Plasma samples are collected at approximate times 0, 2, and 6 hrs post-drug administration. Urine will be collected at approximate times 0 and 6 hrs. We will examine plasma and urine nitrate and nitrite. The 40 subjects who return for a second visit 24 hours post-drug administration will provide an additional plasma and urine sample.

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
    • Pittsburgh, Pennsylvania, United States, 15213
      • Nydia Chien

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

INCLUSION:

• Male or female, 18 years of age or older
• PH group: Pulmonary hypertension, hemodynamically defined by a mean PAP ≥ 25 mm Hg, and a TPG >= 12 at rest or during exercise as demonstrated on a right heart catheterization in the last 10 years
• RHC Control group: Normal hemodynamics (mean PAP < 25 mm Hg, PCWP ≤ 15 mm Hg) on clinical right heart catheterization
• Healthy Control group: Healthy patients with no evidence of pulmonary hypertension, respiratory or cardiac disease
• Ability to provide written informed consent

EXCLUSION:

• Use of systemic antibiotics and/or chlorhexidine mouthwash, within the previous three months
• Use of immune suppression (chemotherapy, oral prednisone greater than 20mg per day, etc) with in the previous three months
• Use of phosphodiesterase-5 inhibitors (tadalafil, sildenafil, etc) within 7 days before study drug administration
• Current pregnancy or lactation
• Uncontrolled systemic hypertension based on repeated measurement of sitting systolic blood pressure >185 mm Hg or sitting diastolic blood pressure >110 mm Hg at screening
• Has chronic renal insufficiency as defined by serum creatinine >3 mg/dL at screening or requires dialytic support
• Known history of left ventricular ejection fraction < 40% by multiple gated acquisition scan (MUGA), angiography, or echocardiography
• History of atrial septostomy
• Repaired or unrepaired congenital heart disease
• Pericardial constriction
• Restrictive or constrictive cardiomyopathy
• Symptomatic coronary disease with demonstrable ischemia
• Addition or change in dosing of hormonal contraception medications (OCP, IUD, Depo-Provera) in the past 4 weeks.
• Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study or would prevent completion of the study
• Active participation in other research studies with investigational drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 15N Nitrate; single 1,000mg dose of 15N nitrate with 3g of conjugated linoleic acid (CLA).	Drug: 15N Nitrate; 1,000 mg/11.8 mmol, oral, on day one, hour zero; Other Names: 15N Sodium Nitrate
Experimental: 14N Sodium Nitrate; single 1,000mg dose of 14N sodium nitrate with 3g of conjugated linoleic acid (CLA)	Drug: 14N Nitrate; 1,000 mg/11.18 mmol, oral, on day hour, hour zero; Other Names: 14N Sodium Nitrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in nitrate level in urine	The investigators will examine urine nitrate	Urine collected approx 0 & 6 hours after drug administration
Change in nitrate level in plasma	The investigators will examine plasma nitrate	Approx 50cc of blood drawn approx 0, 2, & 6 hours after drug administration
Bacterial content of gut microbiome	Stool will be analyzed for bacterial makeup	Stool collected before drug administration
Bacterial content of the oral microbiome	Saliva and tongue scraping will be analyzed for bacterial makeup	Saliva and tongue scraping will occur preceding administration of drug
Change in nitrite level in urine	The investigators will examine urine nitrite	Urine collected approx 0 & 6 hours after drug administration
Change in nitrite level in plasma	The investigators will examine plasma nitrite	Approx 50cc of blood drawn approx 0, 2, & 6 hours after drug administration

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in blood pressure	Frequently over 6 hour study visit
Change in heart rate	Continuous over 6 hour study visit
Change in respiratory rate	Continuous over 6 hour study visit
Change in hemoglobin concentration	Continuous over 6 hour study visit

Collaborators and Investigators

• Sponsor: Gladwin, Mark, MD
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2017
• Primary Completion (Actual): February 25, 2022
• Study Completion (Actual): February 25, 2022

Study Registration Dates

• First Submitted: November 17, 2016
• First Submitted That Met QC Criteria: December 1, 2016
• First Posted (Estimate): December 2, 2016

Study Record Updates

• Last Update Posted (Actual): March 22, 2022
• Last Update Submitted That Met QC Criteria: March 21, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Hypertension; Hypertension, Pulmonary
• Other Study ID Numbers: STUDY19120066; 5P01HL103455 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After de-identification, all participant data collected during the trial will be made available.
• IPD Sharing Time Frame: Data will be made following publication.
• IPD Sharing Access Criteria: Data will be available publicly.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No