Chlorhexidine Mouthwash and Oral Nitrate in Adults With Pulmonary Hypertension

A Randomized Trial of Chlorhexidine Mouthwash and Oral Nitrate in Adults With Pulmonary Hypertension

This is an open-label, single-center study to examine distinguishing features of the structure and function of the oral and gut microbiome in volunteers with PH in the breakdown of oral nitrate and effect on hemodynamics.

Study Overview

• Status: Withdrawn
• Conditions: Pulmonary Hypertension; Heart Failure With Normal Ejection Fraction; Pulmonary Heart Disease and Diseases of Pulmonary Circulation
• Intervention / Treatment: Drug: Nitrates; Drug: Chlorhexidine Gluconate Mouthwash; Drug: Placebo Mouthwash

Detailed Description

This is an open-label, single-center study to examine distinguishing features of the structure and function of the oral and gut microbiome in volunteers with PH in the breakdown of oral nitrate and effect on hemodynamics.

The investigators will enroll 40 PH patients over three years. 5 healthy participants will be enrolled as controls. Participants will receive a single dose of the study drug,:14N Sodium Nitrate(1000mg): standard sodium nitrate, and all will receive one dose of CLA 3g. CLA will be obtained from GNC (General Nutrition Corporation) and given once. Participants will be randomized to receive chlorhexidine gluconate 0.12% (15mL) or placebo to rinse their mouth with for 1 minute.

Oral samples will be collected pre- and post-chlorhexidine treatments and stool samples will be collected post-chlorhexidine treatment.

Right heart catheterization will be performed for clinical or research purposes.

The RHC done (in the last 5 years) that establishes inclusion is not the same RHC done as part of the study in most cases. If there is a strong suspicion of PH based on echocardiography in a patient who has not had a clinical RHC, the first hemodynamic measurements obtained in the clinical RHC will establish inclusion and the RHC study procedures will be performed following confirmation of inclusion.

Participants for whom the RHC done in the study is considered a clinical RHC will be participants who do have an additional follow up RHC scheduled.

Participants for whom the RHC done in the study is considered a research RHC will be those who do not have an additional follow RHC scheduled or who are considered healthy and have not had an RHC before.

Catheterization will generally be performed via the right internal jugular vein access with the assistance of fluoroscopy, if needed. Once the pulmonary arterial (PA) catheter has been placed in proper position, measured values will be obtained. The investigators often perform simultaneous measurement of right atrial pressure and distal pressure (PAP/PAWP) using two transducers in order to assess both pressures during vasodilator challenge, or other confrontational testing. An initial hemodynamic profile will be obtained.

With the right heart catheter still in place, participants will be randomized to either chlorhexidine mouthwash or placebo, then after 30 minutes, all will receive 14N oral nitrate and CLA. A repeat hemodynamic profile will be performed after two hours. Nitrate metabolites in plasma will be measured at time 0, 2, and 6 hrs after 14N nitrate dose. Urine nitrite and nitrate will be measured at 0 and 6 hours. Participants will be monitored with continuous pulse oximetry and EKG monitoring. Blood pressure measurements will be performed every 15 minutes during the catheterization. Pressure-volume loop and impedance analysis will be performed at the time of the right heart catheterization (RHC) using the micromanometer catheter technique to simultaneously measure RV pressure and pulmonary blood flow.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Cathy Kessinger

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, 18 years of age or older
• Undergoing clinical right heart catheterization or had a RHC in past 5 years if in PH group
• Pulmonary Hypertension: hemodynamically defined by a mean PAP ≥ 25 mm Hg and have a PVR > 3 Woods units and normal cardiac index (>2.0 L/min/m2)
• Healthy Control group: no history of or active cardiac or pulmonary disease
• Ability to provide written informed consent

Exclusion Criteria:

• 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
• Has chronic renal insufficiency as defined by serum creatinine >3 mg/dL in the last 6 months or requiring dialytic support as reported in the medical record
• 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: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chlorhexidine Gluconate Mouthwash; rinse with chlorhexidine gluconate 0.12% (15mL) mouthwash before administration of 14N Sodium Nitrate 1,000 mg/11.18 mmol, oral	Drug: Nitrates; 1,000 mg/11.18 mmol, oral; Other Names: 14N Sodium Nitrate; Drug: Chlorhexidine Gluconate Mouthwash; chlorhexidine gluconate 0.12% (15mL) mouth rinse for 1 minute; Other Names: Chlorhexidine mouthwash
Placebo Comparator: Placebo Mouthwash; rinse with placebo mouthwash (15mL) before administration of 14N Sodium Nitrate 1,000 mg/11.18 mmol, oral	Drug: Nitrates; 1,000 mg/11.18 mmol, oral; Other Names: 14N Sodium Nitrate; Drug: Placebo Mouthwash; sterile water (15mL) mouth rinse for 1 minute; Other Names: Sterile Water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Plasma Nitrate	At baseline and 2 hours post drug administration
Change in Urine Nitrate	At baseline and 2 hours post drug administration
Change in Plasma Nitrate	At baseline and 6 hours post drug administration
Change in Urine Nitrate	At baseline and 6 hours post drug administration
Change in Plasma Nitrate	At 2 hours post drug administration and 6 hours post drug administration
Change in Urine Nitrate	At 2 hours post drug administration and 6 hours post drug administration

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in Pulmonary Vascular Resistance (PVR)	At baseline and 2 hours post drug administration

Collaborators and Investigators

• Sponsor: Gladwin, Mark, MD
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Pittsburgh; National Institutes of Health (NIH)

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2022
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: December 24, 2018
• First Submitted That Met QC Criteria: December 24, 2018
• First Posted (Actual): December 26, 2018

Study Record Updates

• Last Update Posted (Actual): July 7, 2022
• Last Update Submitted That Met QC Criteria: July 5, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Diseases; Hypertension; Hypertension, Pulmonary; Pulmonary Heart Disease; Anti-Infective Agents, Local; Anti-Infective Agents; Dermatologic Agents; Disinfectants; Chlorhexidine; Chlorhexidine gluconate
• Other Study ID Numbers: STUDY19120104; 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; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

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