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

• Sponsor: Gladwin, Mark, MD
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Alison Morris, University of Pittsburgh

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Pulmonary; Hypertension; Heart Failure; Preserved Ejection Fraction	Drug: 15N Nitrate; Drug: 14N Nitrate	Phase 1

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	120 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	August 28, 2017
Estimated Primary Completion Date :	July 2020
Estimated Study Completion Date :	July 2021

Arms and Interventions

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 Name: 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 Name: 14N Sodium Nitrate

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Change in blood pressure [ Time Frame: Frequently over 6 hour study visit ]
2. Change in heart rate [ Time Frame: Continuous over 6 hour study visit ]
3. Change in respiratory rate [ Time Frame: Continuous over 6 hour study visit ]
4. Change in hemoglobin concentration [ Time Frame: Continuous over 6 hour study visit ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

INCLUSION:

• Male or female, 18 years of age or older
• Undergoing clinical right heart catheterization (RHC) or RHC in the past 5 years
• PAH group: WHO Group I PAH hemodynamically defined by a mean PAP ≥ 25 mm Hg, a PCWP <= 15 mm Hg, and have a TPG >= 12
• PH-HFpEF group: WHO Group II PH secondary to heart failure with preserved ejection fraction (PH-HFpEF) hemodynamically defined by a mean PAP ≥ 25 mm Hg, a PCWP > 15 mm Hg, and have TPG >= 12 at rest or during exercise
• Control group: Normal hemodynamics (mean PAP < 25 mm Hg, PCWP ≤ 15 mm Hg) on clinical right heart catheterization
• 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

Contacts and Locations

Contacts

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Contact: Cathy Kessinger, RN	412-624-8330	kessingercj@pitt.edu
Contact: Cathy Kessinger, RN	412-624-8330	kessingercj@upmc.edu

Locations

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United States, Pennsylvania
University of Pittsburgh	Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Noel Britton, MPH 412-383-5289 brittonm@upmc.edu
Contact: Cathy Kessinger, RN 412-624-8330 kessingercj@upmc.edu
Principal Investigator: Alison Morris, MD, MS
University of Pittsburgh	Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Alison Morris, MD 412-624-8330 morrisa@upmc.edu
Contact: Cathy kessingercj, RN 4126248330 kessingercj@upmc.edu

Sponsors and Collaborators

Gladwin, Mark, MD

National Heart, Lung, and Blood Institute (NHLBI)

More Information

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Responsible Party:	Alison Morris, Professor, University of Pittsburgh
ClinicalTrials.gov Identifier:	NCT02980068 History of Changes
Other Study ID Numbers:	PRO16090149; 5P01HL103455 ( U.S. NIH Grant/Contract )
First Posted:	December 2, 2016
Last Update Posted:	December 27, 2018
Last Verified:	December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	After de-identification, all participant data collected during the trial will be made available.
Supporting Materials:	Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
Time Frame:	Data will be made following publication.
Access Criteria:	Data will be available publicly.

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

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Hypertension; Heart Failure; Hypertension, Pulmonary; Vascular Diseases	Cardiovascular Diseases; Heart Diseases; Lung Diseases; Respiratory Tract Diseases