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TranspulmonarY Estrogen Gradient and Estrogen Receptors (TYEGER) in PAH (TYEGER)

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ClinicalTrials.gov Identifier: NCT04280523
Recruitment Status : Recruiting
First Posted : February 21, 2020
Last Update Posted : January 20, 2021
Sponsor:
Information provided by (Responsible Party):
Eric Austin, Vanderbilt University Medical Center

Brief Summary:

Pulmonary arterial hypertension (PAH) is a disease characterized by elevated pressures in the blood vessels of the lungs that is not caused by another disease processes. More specifically, it is defined by a mean pulmonary artery pressure > 25 mm Hg, a pulmonary vascular resistance > 3 Wood Units (WU), and a normal pulmonary capillary wedge pressure in the absence of other etiology of pulmonary hypertension. The underlying mechanism of the disease in still unknown, but marked changes to the small arteries in the lungs have been observed. These changes include thickening of vessel walls and clot formation -- making the vessels less capable of gas exchange. Currently, PAH therapies focus on dilating the "good" remaining vessels that haven't been altered by this disease process; however, this therapy does not cure the disease. Survival remains low despite progress.

There is growing human and experimental evidence supporting the concept that estrogens and estrogen receptors in the lungs are involved in the process that leads to PAH.

As mentioned above, no current therapies attack the cause of PAH; they only act to dilate remaining "good" vessels which can reduce the burden of the disease, but not cure it. Thus, there is a critical need for novel therapeutics, as recently highlighted by a National Institute of Health workshop on pulmonary vascular diseases which called for the exploration of novel therapeutic approaches. None of the current FDA-approved treatments for PAH target estrogen or estrogen receptors.

Despite the evidence supporting the concept that estrogens and estrogen receptors in the lungs contribute to PAH, no human studies investigate the estrogen level and the amount of estrogen receptors within the lungs of patients with PAH and their potential associations with current disease severity or 1 year outcomes including survival after 1 year, functional status, etc. Investigators hypothesize that a subset of PAH patients will have higher levels of estrogen and estrogen receptors in their lungs which would make them good candidates for novel therapies that block estrogen in hopes of halting the disease process.


Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: ESR-specific PET scan Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: TranspulmonarY Estrogen Gradient and Estrogen Receptors (TYEGER) in PAH
Actual Study Start Date : January 5, 2021
Estimated Primary Completion Date : October 2024
Estimated Study Completion Date : October 2024


Arm Intervention/treatment
Experimental: ESR-specific PET Scan

Specific Aim: To test the hypothesis that among PAH patients, higher lung ESR density associates with a more severe hemodynamic profile and worse 1 year outcomes.

Study Design: Enroll 20 randomly selected subjects from each group (PAH vs. control)

Drug: ESR-specific PET scan
Lung ESR Density by PET: Investigators will use 18F-FES as an estrogen receptor (ESR)-specific PET tracer to determine lung ESR density. 18F-FES will be prepared according to published methods. Briefly, all subjects will be evaluated by PET imaging, using standardized protocols. Blood will be obtained just before FES injection to measure the endogenous estrogen level [estradiol (E2)], to rule out pregnancy in female patients, and some reserved for future studies of mechanism. Approximately 6 mCi (222 MBq) of 18F-FES will be administered intravenously over 1~2 minutes, with scanning initiated 1 hour after administration of the tracer. Emission scans will be performed of the chest. A multimodality computer platform (Syngo; Siemens) will be used for image review and manipulation.
Other Name: [18F]FES




Primary Outcome Measures :
  1. To correlate lung ESR density with pulmonary vascular resistance (PVR) [ Time Frame: Day 1 ]
    Positron emission tomography (PET) with ESR-targeting radiopharmaceuticals is a noninvasive method for assessing regional ESR expression in vivo. For example, multiple studies have shown that the detection of ESR positive tissue by 18F-FES PET is reliable and that 18F-FES uptake correlates well with immunohistochemical scoring for ESR density. We will determine the relationship, if any, between the density of ESR in the lungs of subjects, and pulmonary vascular resistance (PVR), measured in Woods Units, acquired at time of recent cardiac catheterization.


Secondary Outcome Measures :
  1. Survival at one year [ Time Frame: 1 year ]
    We will determine the association of lung ESR density with survival within one year of the PET scan study.



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Ages Eligible for Study:   13 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 13 years or older
  • Group 1: PH Patients, who have precapillary PH (PAH). Patients with and without a known PAH-associated gene mutation (e.g., a BMPR2 mutation) (i.e. those with HPAH and those with IPAH) will be identified based on previous genotyping. Investigators define pulmonary hypertension diagnostically by accepted clinical and cardiac catheterization criteria, including mean pulmonary arterial pressure of more than 25 mmHg. Precapillary PH (PAH) cases have pulmonary capillary or left atrial pressure of ≤15 mm Hg, and exclusion of other causes of pulmonary hypertension in accordance with accepted international standards of diagnostic criteria.
  • Group 2: PVH Patients, who have pulmonary hypertension secondary to left heart disease. PVH cases have left ventricular (LV) filling pressure >15 mmHg (measured by the pulmonary artery occlusion pressure or left ventricular end-diastolic pressure) and a diastolic pressure gradient <7mmHg, indicating the absence of pulmonary vascular disease. Inclusion in this group will require a clinical diagnosis of systolic or diastolic heart failure and right heart catheterization on at least one occasion demonstrating elevated pulmonary wedge pressure and a normal (< 16mmHg) trans-pulmonary gradient
  • Group 3: Healthy Control Patients, who have no known history of cardiopulmonary disease recruited from the Vanderbilt Research Notification Distribution List and the population at large.

Exclusion Criteria:

  1. Subjects with the following concurrent diagnoses

    • Type 1 Diabetes Mellitus
    • Polycystic ovarian disease
    • Breast/uterine/endometrial cancer
  2. Subjects with the following concurrent exposures

    • Use of hormone modifying therapy
    • Use of hormone-containing pharmaceuticals including hormone replacement therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04280523


Contacts
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Contact: Eric D Austin, MD, MSCI (615) 343-7396 eric.austin@vumc.org
Contact: Jeff Cunningham, RN (615) 322-2653 jeffrey.d.cunningham@vumc.org

Locations
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United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37203
Contact: Eric D Austin, MD, MSCI    615-343-7396    eric.austin@vumc.org   
Sponsors and Collaborators
Vanderbilt University Medical Center
Investigators
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Principal Investigator: Eric D Austin, MD, MSCI Vanderbilt University Medical Center
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Responsible Party: Eric Austin, Associate Professor of Pediatrics, Director Vanderbilt Pediatric PH Program, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT04280523    
Other Study ID Numbers: 191946
First Posted: February 21, 2020    Key Record Dates
Last Update Posted: January 20, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Vanderbilt may share subject information, without identifiers, to others or use it for other research projects not listed in the consent form. Vanderbilt, Dr. Eric Austin, and his staff will comply with any and all laws regarding the privacy of such information. There are no plans to pay subjects for the use or transfer of this de-identified information.

All efforts, within reason, will be made to keep subjects protected health information (PHI) private. All federal privacy laws will be followed.

As part of the study, Dr. Austin and his study team may share the results of subject's study blood work, PET CT, and catheterization data as well as parts of their medical record in de-identified manner. The Federal Government Office for Human Research Protections and the Vanderbilt University Institutional Review Board might review this study to ensure investigators are following all local and Federal guidelines for patient protection.


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases