PET Image in PAH Patients

Utilizing 18F-fluoroglutamine PET Imaging in Patients With Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is mortal disease affecting the blood vessels of the lung. Despite its morbid prognosis, PAH is often misdiagnosed or ignored, with an average time of 44 months between onset of symptoms to diagnosis and substantial progression of disease severity. Therefore, a pressing need exists to develop non-invasive diagnostic imaging tools, particularly that can detect early disease stages.

Efforts have been made to develop such imaging capabilities through platform development of echocardiography, cardiac MRI, chest computed tomography (CT), and positron emission tomography (PET), among others. While some have demonstrated promise, few have shown a precise ability to offer disease quantifications of the diseased lung and vasculature itself, to detect early stages of disease, and to reflect alterations of the lung, vasculature, and right ventricle that reflect the molecular origins of this disease.

[F-18]FGln has been previously utilized in oncology studies as a non-invasive in vivo imaging biomarker of tumor glutamine flux and metabolism. Our preliminary in vivo pre-clinical rodent studies demonstrated that [F-18]FGln demonstrated increased uptake in diseased pulmonary vessels and the right ventricle in a rodent model of PAH. The proposed research study will provide preliminary evidence of the potential to utilize [F-18]FGln as a non-invasive imaging biomarker of glutamine flux and metabolism across a range of PAH subjects.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Diagnostic test: 18F-FGLN PET Imaging; Drug: (18F)FPGLU

Detailed Description

Objective: Investigators will conduct in-human PET imaging of 18F-fluoroglutamine (18F-FGln) in patients with PAH to compare glutamine uptake to that of controls.

Specific Aim: Utilizing18F-FGln PET imaging to measure pathogenic glutamine uptake in patients with PAH or eiPAH and controls.

Significance: Investigator multi-disciplinary team, comprised of Drs. Chan, Tavakoli, and Mason are already actively collaborating together, and are uniquely positioned to image and quantify glutamine uptake in this special patient population. In doing so, investigators will determine the potential of this [F-18]FGln to serve as a non-invasive imaging biomarker of in vivo glutamine flux and metabolism associated with PAH

Investigators are proposing a pilot experiment, in which they will enroll 10 subjects from the following five groups:

10 subjects with Idiopathic PAH (IPAH) 10 subjects with Scleroderma-PAH (SSc-PAH) 10 subjects with Scleroderma exercise induced PAH (SSc-eiPAH) 10 subjects with scleroderma but no PAH 10 healthy controls will be recruited as a comparison group; The cases will matched for age and gender with 10 healthy controls for comparison 18F-FGLN PET Imaging will be performed at The University of Pittsburgh's PET Research Facility directed by S. Mason who has experience in human PET/CT . S. Tavakoli (Radiology) will provide expertise in vascular glutamine uptake.

Human Subjects: Given the already approved investigational new drug (IND) application for this tracer for human use (Memorial Sloan Kettering, J. Lewis), the regulatory process to commence human testing should occur in an expeditious manner. Per Dr. Lewis' team, 66 research PET imaging studies of human subjects with 18F-FGln have been performed at their institution, without detectable pharmacologic effects; no immediate or delayed side effects have otherwise been observed (see Dr. Dunphy's letter). Given our track record for high volume patient recruitment for PAH clinical studies, investigators do not anticipate challenges with recruiting idiopathic PAH patients, anchored by Dr. Chan's experience in such work.

18F-FGLN Synthesis: [18F]-(2S,4R)-4-Fluoroglutamine (18F-FGln) will be synthesized in accordance with previously described methods and is readily available from the Organic Synthesis Core Facility (OSCF, see letter and quote). Final tracer will be synthesized by the U. Pitt PET Center (S. Mason), working in conjunction with S. Tavakoli, as described. The final 18F-FGln product will be required to meet all product release criteria, which include specifications for radiochemical and chemical purity, appearance, residual solvent content, pH, and endotoxin content consistent with USP.

PET/CT Imaging: The duration of PET will be around 90 minutes. Women of child-bearing potential (WCBP) will need to complete a urine pregnancy test (conducted by PET Facility staff) on the day of the scan procedure, prior to any PET scan procedures. the test should be negative in order to participate in the study.

An arterial line will be placed in the radial artery for arterial blood sampling and this will be performed by an experienced anesthesiologist who is a collaborator with the PET imaging department. An intravenous catheter will be placed in the subject's opposite arm, which will be used for radiotracer administration. All PET scans will be performed for a single bed position on a Siemens Biograph mCT Flow. Patients will be positioned in the scanner in a head-first-supine orientation. A scout CT scan will be performed to fix the PET bed position such that the superior axial image planes are located approximately 1 cm above the lung apex, which will cover the axial extent of the heart and the majority of lung tissue. A low-dose helical CT scan will be performed during a ~15 sec inspiratory breath hold and used for CT-based attenuation correction of PET emission data and as an anatomical reference for image analyses. Following the CT acquisition, 10.0 mCi of 18F-FGln will be injected intravenously as a slow bolus (20 sec) and 90 minutes of PET emission data will be collected in list-mode. List-mode PET emission data will be binned into an ungated dynamic series of 28 frames for initial tracer kinetic analyses. Additional reconstructions will be performed with cardiac gating to isolate the end-diastole phase, respiratory gating to isolate the inspiratory respiratory phase, and dual-gating (cardiac and respiratory gating) to achieve virtually motion-free PET images. These data will also be used to optimize reconstruction and gating parameters for future 18F-FGln studies.

Blood Sampling: For the PET scan, hand-drawn arterial blood samples (0.5 ml) will be collected throughout the scan with no more than 20 collected during the first 2 min and no more than 15 collected at intervals of increasing duration minutes (no more than 35 total samples). Also, larger blood samples (3-5 ml) will be obtained at no more than 8 times during each PET scan for the determination of radiolabeled metabolites and protein binding. This would let the amount to be no more than 43 arterial samples and a blood volume loss of no more than 60 ml (4-5 tablespoonfuls).

Participants will be retained in the PET facility following the PET scan to evaluate for bleeding from the arterial puncture site and/or to promote urination to increase elimination of the radiotracer.

If for reasons of participant discomfort or technical difficulty (problems with PET camera, cyclotron breakdown etc.), the full PET scanning procedure cannot be completed in 1 day investigators may be given the option to ask the participant to return within 30 days to complete the study. On this "completion" day, preparation will again consist of intravenous and arterial catheterization. The scanning protocol will be identical to that described above. Participant will not receive more than 2-3 CT scans and, no more than two [F-18] FGln PET scans with maximum effective dose exposure of 1.777 rads, as a result in participation in this research study. If participant had to be scheduled for a "completion" day for this study, he/she will receive an additional IV and arterial line and will also have to undergo urine pregnancy testing (if applicable).

Follow-up Procedures: A follow-up telephone call will be made to subjects by the research team approximately 1 to 7 days after the PET/CT scan to inquire about any adverse events the participant may have encountered related to the scans.

Medical Record Information: Investigators will request subjects authorization to access medical record information from their past, current and future medical record information related to their health condition to be recorded into the Research study. This information will be collected from Heart and Vascular Institute (HVI) records, hospital records and, if applicable, private physician records. Since heart failure symptoms/progression may change over time, and these changes may be important to this study result, future medical records will be collected indefinitely. The medical record information contained within the study database will be used for research related purposes for an indefinite time. Subjects medical record information may be reviewed to see if they were eligible for any ongoing or future research studies; if they were eligible, then investigators may contact them

• Study Type: Interventional
• Enrollment (Estimated): 71
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Yassmin Al Aaraj; Phone Number: 14126479227; Email: yaa29@pitt.edu
• Study Contact Backup: Name: Stephen Chan; Email: chansy@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • Montefiore Hospital Clinical and Translational Research Center
      • Contact: Yassmin Al Aaraj

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Cases:

1. Age between 18-75 years old
2. Confirmed diagnosis of SSc-PAH / SSc-eiPAH/IPAH/Scleroderma with no PAH by right heart catheterization.

Controls:

1. Age between 18-75 years old
2. Individuals who are at low risk for current or future cardiovascular or pulmonary symptoms or diseases

Exclusion Criteria:

Cases:

1. Smoking
2. Pregnant/ breast feeding women
3. Children under 18
4. Inability to read and understand the informed consent
5. History of CT contrast allergy
6. Inability to lie down for long period of time
7. Having claustrophobic
8. History of radiation exposure at workplace
9. Consuming more than 2-3 alcoholic drinks a week
10. Answering yes to any of occupations listed in 'Occupation Exposure History
11. Answering Yes to any of the "Medical conditions involving the heart or lungs or that would make participation in the study unsafe in the opinion of the PI.

Controls:

1. Smoking
2. Pregnant/ breast feeding women
3. Children under 18
4. Inability to read and understand the informed consent
5. History of CT contrast allergy;
6. Inability to lie down for long period of time
7. Having claustrophobic
8. History of radiation exposure at workplace
9. Consuming more than 2-3 alcoholic drinks a week
10. Answering yes to any of occupations listed in 'Occupation Exposure History'
11. Answering Yes to any of the "Medical conditions involving the heart or lungs or that would make participation in the study unsafe in the opinion of the PI.
12. Family history of Pulmonary Hypertension or Scleroderma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 18F-FGLN PET Imaging; 10.0 mCi of 18F-FGln will be injected intravenously as a slow bolus (20 sec)

Diagnostic test: 18F-FGLN PET Imaging; PET/CT Imaging: The duration of PET will be around 90 minutes. Women should have negative pregnancy test prior to the study. An arterial line will be placed in the radial artery for arterial blood sampling and this will be performed by an experienced anesthesiologist. An intravenous catheter will be placed in the subject's opposite arm, which will be used for radiotracer administration. A low-dose helical CT scan will be performed during a ~15 sec inspiratory breath hold and used for CT-based attenuation correction of PET emission data and as an anatomical reference for image analyses. Blood Sampling: For the PET scan, the amount of blood will not be more than 43 arterial samples and a blood volume loss of no more than 60 ml (4-5 tablespoonfuls). Participants will be retained in the PET facility following the PET scan to evaluate for bleeding from the arterial puncture site and/or to promote urination to increase elimination of the radiotracer.; Drug: (18F)FPGLU; [F-18]FGln is a natural glutamine derivative was synthesized to explore its potential application of imaging glutamine uptake for cancer diagnosis. The proposed research study will provide preliminary evidence of the potential to utilize [F-18]FGln as a non-invasive imaging biomarker of glutamine flux and metabolism across a range of PAH subjects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SUV or image-based threshold of 18F-FGNnon-diseased controls	Regional [F-18] fluoroglutamine (18F-FGN) utilization will be measured as standardized uptake values (SUV) of 18F-FGN in right ventricle wall, left ventricle wall, and perivascular tissue within the lung parenchyma.	90 minutes

Collaborators and Investigators

• Sponsor: Stephen Y. Chan
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Bayer
• Investigators: Principal Investigator: Stephen Chan, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: June 9, 2022
• First Submitted That Met QC Criteria: July 7, 2022
• First Posted (Actual): July 11, 2022

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Pulmonary hypertension; Non invasive; Early diagnoses
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: STUDY21050035; PHAB Level 4 award 2021 (Other Grant/Funding Number: Bayer Healthcare Pharmaceuticals Inc.); R01HL124021 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data may be shared with other individuals for future research and if shared will be shared without identifiers.

Participant's medical record information contained within the Research study may be provided to secondary research investigators (i.e., research investigators who are not affiliated with the Comprehensive Pulmonary Hypertension Program at University of Pittsburgh).The type of data shared would include demographic information, past medical history, medications, lab results, right heart Cath hemodynamics and cardiac imaging studies. However, prior to its provision to any secondary investigators, the information shall be de-identified. The Comprehensive Pulmonary Hypertension Program and Comprehensive lung center shall require secondary investigators to obtain regulatory approval prior its provision of de-identified information to the secondary investigators.

• IPD Sharing Time Frame: Data will available starting 6 months after publication
• IPD Sharing Access Criteria: The Comprehensive Pulmonary Hypertension Program and Comprehensive lung center shall require secondary investigators to obtain regulatory approval prior its provision of de-identified information to the secondary investigators
• 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