Clinical trial NCT03367312
Conditions: Pulmonary Vascular Disease
Sponsor: Bastiaan Driehuys
Start date: 2018-03-29; Completion date: 2022-11-01
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study seeks to deploy several forms of 129Xe MRI contrast as well as emerging conventional proton MRI techniques for imaging lung structure and perfusion. Specifically, the 129Xe MRI scans will provide 3D images of ventilation and gas exchange, and spectroscopic indices will be evaluated too test gas exchange dynamics with high temporal resolution. The conventional 1H MRi scans will include a free-breathing ultra-short echo time scan that provides images similar to that of a CT scan. This will be done pre, immediately post, and 2-4 hours post inhaled prostacyclin therapy.

Detailed description:
This study seeks to determine whether hyperpolarized 129Xenon MRI can detect improvements in pulmonary gas exchange in patients with Group 1 and 3 PH treated with iTRE. We will associate this with changes in serum concentrations of treprostinil and levels of peripheral vasodilation. This work seeks to apply and test a novel non-invasive methodology, hyperpolarized (HP) 129Xenon (Xe) magnetic resonance imaging (MRI), for the diagnosis of Pulmonary Vascular Disease. Hyperpolarized 129Xe MRI has been under active development and used in clinical research at Duke for over 7 years. If successful, 129Xe MRI could overcome the current limitations of PVD diagnosis while conferring a number of potential benefits. First, imaging the abnormalities in the lungs allows the diagnosis of PVD in the setting of concomitant heart or lung disease. With HP 129Xe MRI, abnormalities in gas exchange secondary to PVD can be directly visualized. Second, non-invasive diagnosis of PVD could remove the need for an invasive RHC. While RHC is a relatively safe procedure, there are a number of limitations to the interpretation of RHC, including arbitrary cutoffs for mPAP, PCWP, and PVR. Third, the abnormalities on HP 129Xe MRI could be used to non-invasively monitor response to therapy. If we are successful in demonstrating the applicability of HP 129Xe MRI, this technology holds the promise of greatly improving the diagnosis and management of PVD.

This study will enroll ten patients with pulmonary hypertension (PH). The ten patients will be World Health Organization (WHO) PH classification Group 1 or out-of-proportion Group 3, with lung disease. These patient have been inhaled treprostinil (iTRE) as standard of care for their PH. Inhaled treprostinil (iTRE) is an FDA approved medication under the brand name of Tyvaso. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. The medication is delivered noninvasively, directly to the lungs using the approved ultrasonic nebulizer delivery system. Patients will take the inhaled treatment four times a day, about every four hours.

The iTRE will be used to characterize their 129Xe MRI imaging, peripheral vasodilation and serum treprostinil concentration before and after treatment with iTRE. As iTRE has a plasma concentration half-life of \~ 45 minutes and time-to-peak concentration of 15 minutes, imaging done immediately before, 15 minutes after and 2-4 hours after drug treatment would potentially allow the visualization of changes in gas diffusion and peripheral vasodilation associated with iTRE. This is similar to changes seen in changes in ventilation in asthma after treatment with bronchodilators. Monitoring a later time point would also allow us to test whether vasodilation persists in the lung vasculature compared to the peripheral circulation. This study seeks to deploy several forms of 129Xe MRI contrast as well as emerging conventional proton MRI techniques for imaging lung structure and perfusion. Specifically, the 129Xe MRI scans will provide 3D images of ventilation and gas exchange, and spectroscopic indices will be evaluated to test gas exchange dynamics with high temporal resolution. The conventional 1H MRI scans will include a free-breathing ultra-short echo time (UTE) scan that provides images similar to that of a CT scan.

Arms: arm 1: 10 subjects will Pulmonary Hypertension on a stable dose of Inhaled Prostacyclin for treatment of PH.
Interventions: intervention 1: Hyperpolarized 129Xenon gas
Intervention descriptions: intervention 1: Hyperpolarized 129Xenon gas XeMRI scans will provide 3D images of ventilation and gas exchange pre, post, and 2-4 hours post inhaled prostacyclin treatment. Subjects will inhale HP 129Xe from the dose delivery bags with each scan and then move into the scanner and undergo basic 1H localizer and anatomical scans. Once localization is complete, subjects will undergo several MRI scans after inhalation of HPXe. This will occur as three scans at the three different time points (pre, post, and 2-4 hours post) of inhaled prostacyclin treatment.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
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Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI 
 
NCT03367312 
 
18Jun2020 
 


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Protocol Title: 
Assessing Response to Inhaled Prostacyclin with Hyperpolarized 129Xe MRI 
Purpose of the Study:  
 
To determine whether hyperpolarized 129Xenon MRI can detect improvements in pulmonary gas 
exchange in patients with PH treated with iTRE. We will associate this with changes in serum 
concentrations of treprostinil and levels of peripheral vasodilation. 
Background & Significance: 
 
Pulmonary hypertension (PAH) carries a significant economic burden, with average annual health care 
costs of ~ $100,000/yr. The diagnosis of PAH can be challenging, as it requires fulfillment of specific 
clinical and hemodynamic criteria. However, these are limited because they do not allow the diagnosis of 
PAH in the setting of concomitant left heart disease or lung disease. Patients with mild to moderate 
idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD), which are 
common in older patients, technically cannot be diagnosed with true PAH, but are diagnosed with 
Pulmonary Hypertension (PH).  Similarly, hemodynamic criteria are limited by arbitrary cutoffs for mean 
pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), and pulmonary 
vascular resistance (PVR) obtained at right heart catheterization (RHC) (PH is defined as mPAP ≥ 25 
mmHg; PAH is defined as mPAP ≥ 25-mmHg and a PCWP ≤ 15 mmHg, with some criteria 
recommending an additional cutoff of PVR ≥ 3 Woods units. Moreover, it is currently unclear what 
constitutes abnormal hemodynamics in the setting of in lung disease, which can increase the PVR. These 
hemodynamic criteria also frequently exclude patients who may have a borderline elevation in mPAP or 
abnormalities primarily associated with exercise that are not captured with a resting heart catheterization. 
As the majority of patients who are now evaluated for PAH are older with common cardiac and 
pulmonary comorbidities, the clinical and hemodynamic criteria are frequently inadequate for diagnosing 
patients who actually have PVD.  
This work seeks to apply and test a novel non-invasive methodology, hyperpolarized (HP) 129Xenon 
(Xe) magnetic resonance imaging (MRI), for the diagnosis of PVD. Hyperpolarized 129Xe MRI has been 
under active development and used in clinical research at Duke for over 7 years. Over 250 patients and 
volunteers have undergone 129Xe MRI. The technology permits 3D quantitative imaging of both 
pulmonary ventilation and gas exchange during a breath-hold exam. It has been used at Duke and around 
the world to study COPD, asthma, and interstitial lung disease. However, until recently it has not been 
applied to PVD. In preliminary studies under an existing protocol, two patients in whom PVD was 
suspected, but who did not meet strict PAH criteria, underwent 129Xe-MRI research studies. These 
patients had no other evidence of significant lung disease, despite undergoing a thorough evaluation that 
included pulmonary function tests, CT scan, and RHC. In both patients, the 129Xe study demonstrated 
spectroscopic and imaging indices consistent with a barrier to diffusion of 129Xe to red blood cells 
(RBCs). These patients subsequently had lung tissue obtained (one at time of lung transplant, the other 
with a surgical lung biopsy). Strikingly, both biopsies demonstrated PVD. We believe that the 
abnormalities seen on 129Xe MRI scans in these patients represent areas of PVD that are associated with 
a barrier to gas diffusion. Moreover, these changes appear to be different to those seen in other lung 
diseases associated with barriers to gas diffusion, such as idiopathic fibrosis. Among the objectives of this 
proposal is to clarify and strengthen these distinguishing features.  


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If successful, 129Xe MRI could overcome the current limitations of PVD diagnosis while conferring a 
number of potential benefits. First, imaging the abnormalities in the lungs allows the diagnosis of PVD in 
the setting of concomitant heart or lung disease.  With HP 129Xe MRI, abnormalities in gas exchange 
secondary to PVD can be directly visualized. Second, non-invasive diagnosis of PVD could remove the 
need for an invasive RHC. While RHC is a relatively safe procedure, there are a number of limitations to 
the interpretation of RHC, including arbitrary cutoffs for mPAP, PCWP, and PVR. Third, the 
abnormalities on HP 129Xe MRI could be used to non-invasively monitor response to therapy. If we are 
successful in demonstrating the applicability of HP 129Xe MRI, this technology holds the promise of 
greatly improving the diagnosis and management of PVD. 
Design & Procedures: 
This study will consent 15 patients (accrued 12 subjects total) with pulmonary hypertension (PH).   
Patients will be on inhaled treprostinil (iTRE) as standard of care for their PH.  Inhaled treprostinil (iTRE) 
is an FDA approved medication under the brand name of Tyvaso.  The major pharmacologic actions of 
treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of 
platelet aggregation.  The medication is delivered noninvasively, directly to the lungs using the approved 
ultrasonic nebulizer delivery system.  Patients will take the inhaled treatment four times a day, about 
every four hours.    
Patients will be characterized by their 129Xe MRI imaging, peripheral vasodilation and serum treprostinil 
concentration before and after treatment with iTRE. As iTRE has a plasma concentration half-life of ~ 45 
minutes and time-to-peak concentration of 15 minutes, imaging will be conducted immediately before, 15 
minutes after and 2-4 hours after drug treatment. This would potentially allow the visualization of 
changes in gas diffusion and peripheral vasodilation associated with iTRE.  This is similar to changes 
seen in ventilation in asthma after treatment with bronchodilators. A follow-up scan at the 2-4hr time 
point would also allow us to test whether vasodilation persists in the lung vasculature compared to the 
peripheral circulation.   This study seeks to deploy several forms of 129Xe MRI contrast. Specifically, the 
129Xe MRI scans will provide 3D images of ventilation and gas exchange, and spectroscopic indices will 
be evaluated to test gas exchange dynamics with high temporal resolution. This will be augmented with 
several conventional 1H MRI scans to delineate the subject’s thoracic cavity. 
Once the subjects has signed consent, the study session will begin with a collection of relevant patient 
history and symptoms, measurement of hemoglobin levels (finger sensor), and urine pregnancy testing (if 
applicable). Study team will use the PFTs that are available from the medical record. Subjects will receive 
an IV catheter to be used for blood draws. The following activities will take place for the MRI procedure: 
1. Patient receives first scan before scheduled dose of iTRE (trough study) Baseline timepoint: 129Xe 
calibration and dissolved-phase spectroscopy - to obtain global RBC:barrier ratios, RBC 
oxygenation shifts, and spectral linewidths; Isotropic 3D 129Xe gas exchange MRI – to detect 
focal defects in gas transfer from airspaces to RBCs in capillary bed; Other 1H scans to obtain 
anatomic data on the lung. 
2. Assessment of peripheral vasodilation in the arm and hands with noninvasive laser speckle 
imaging 
3. Blood sample for serum treprostinil concentration 
4. Subject takes iTRE treatment as with standard of care. Timepoint 1: Wait ~ 15 minutes to peak 
effect (peak study). Patient receives second scan: 129Xe calibration and dissolved-phase 
spectroscopy - to obtain global RBC:barrier ratios, RBC oxygenation shifts, and spectral 
linewidths; Isotropic 3D 129Xe gas exchange MRI – to detect focal defects in gas transfer from 
airspaces to RBCs in capillary bed; Other 1H scans to obtain anatomic data on the lung. 


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5. Assessment of peripheral vasodilation  in the arm and hands with noninvasive laser speckle 
imaging 
6. Blood sample for serum treprostinil concentration 
7. Timepoint 2: 2-4 hrs after initial treatment with iTRE; Patient receives third scan: 129Xe calibration 
and dissolved-phase spectroscopy - to obtain global RBC:barrier ratios, RBC oxygenation shifts, 
and spectral linewidths; Isotropic 3D 129Xe gas exchange MRI – to detect focal defects in gas 
transfer from airspaces to RBCs in capillary bed; Other 1H scans to obtain anatomic data on the 
lung. 
8. Assessment of peripheral vasodilation  in the arm and hands with noninvasive laser speckle 
imaging 
9. Blood sample for serum treprostinil concentration 
 
With each time point (baseline/trough scan, timepoint 1 scan, timepoint 2 scan) the patient will undergo 
several scans after inhalation of HP 129Xe gas. Each dose will be limited to a volume less than 25% of 
subject lung capacity (TLC) as is the case for all protocols currently carried out under IND 109,490. After 
each 129Xe dose, the table will be moved out of the magnet bore and the subject queried for any 
symptoms. The next 129Xe dose and scan will be administered when the subject and study personnel are 
ready. Subjects will undergo a 129Xe MR spectroscopy calibration scan, 129Xe ventilation MRI, and 
129Xe gas exchange MRI. Any given 129Xe MRI scan may be repeated, if necessary. There is no limit to 
the number of 129Xe scans allowed during the session, although current 129Xe production capabilities 
generally limit this to 5 129Xe doses.  
 
Selection of Subjects: 
We propose to recruit and consent 15 subjects (accrued 12 subjects total) with known PH on treatment 
with iTRE that are followed in the Duke Pulmonary Vascular Disease Clinic. Inclusion criteria includes: 
PH (mPAP ≥ 25 mmHg, PCWP ≤ 15 mmHg in the absence of significant concomitant left heart disease 
or lung disease), , maintenance on a stable, well-tolerated treatment dose of iTRE (ideally ≥ 8 breaths 
QID).  Pregnant women will be excluded from this study.  Women of childbearing potential must have a 
negative urine pregnancy test in order to participate on this study.  
 
Definition of Women of CBP: The median age of menopause in the US, defined as 12 months of 
amenorrhea, is 51 years; by age 48, approximately 15% of women will be postmenopausal, while 
virtually 100% will be post-menopausal by age 55.  Women are considered past the age of “child-bearing 
potential” if  they are greater than 55 years of age, OR  they are at least 50 years of age AND o have not 
menstruated for at least 12 months, OR  have a documented Follicule Stimulating Hormone (FSH) level 
of greater than 40 mIU/mL. they are at least 45 years of age AND o have not menstruated for at least 18 
months, OR  o have a documented Follicule Stimulating Hormone (FSH) level of greater than 40 
mIU/mL. For drugs classified, or likely to be classified, as FDA Category X, the duration of amenorrhea 
for women of all ages must be 24 months, consistent with FDA labeling of these drugs.   
 
 
 
 
 
 


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Subject Recruitment and Compensation: 
 
Patients will be recruited based on predetermined inclusion criteria. They will be recruited in the Pulmonary 
Vascular disease clinics and inpatient services at Duke by their care providers. The patient’s provider will 
initiate conversation with the subject about the research trial and assess their interest in participation.  The 
screening of subjects will be conducted by the study coordinator and will include the informed consent 
process.  
 
Before entry into the protocol, the nature and risks of the study will be reviewed with each subject. Each 
subject will be given the opportunity to read the consent form and ask questions. After all questions by the 
study subject are answered, and before any protocol specified procedures are initiated, each subject will 
sign and date the consent form. A copy of the signed consent will be provided to the subject.  
 
Dr. Driehuys is founder and chief technology officer of Polarean, Inc. a start-up company that seeks to 
commercialize hyperpolarized 129Xe gas MRI technology. He is a shareholder in the company and 
provides it with technical consulting. In addition, Polarean has licensed from Duke, a patent on which Dr. 
Driehuys is an inventor, and is currently evaluating several others. For these reasons he has had a conflict 
management plan, administered by the Duke Office of Research Integrity. The study proposed here uses 
Polarean technology, but is not sponsored by the company nor is it being used for regulatory advancement 
with FDA. However, if the findings are positive, Polarean may have an interest in commercializing these 
aspects of the technology as well. Therefore, consistent with his management plan, Dr. Driehuys will not 
serve as principal investigator on this study, nor will he obtain consent from subjects. He will oversee the 
technical aspects of hyperpolarized gas production and MR image acquisition. However, data analysis will 
be overseen by Dr. Rajagopal, who also serves as overall principal investigator on this protocol.  Duke is 
being paid to conduct the study by United Therapeutics.  Subjects will take their standard of care iTRE 
medications during the necessary timepoints in the study.  Subjects will receive $150 for their time and 
travel expenses.   
 
Consent Process: 
 
See Section 14 of the e-IRB submission form and complete the questions in that section.   
 
Subject’s Capacity to Give Legally Effective Consent: 
 
Subjects without capacity to give consent will not be recruited into this study. 
 
Risk/Benefit Assessment: 
 
Potential Risks 
The risks of participating in this study are considered greater than minimal risk. MRI is a non-invasive 
imaging modality that involves no ionizing radiation. All subjects will have already completed a standard 
questionnaire to screen for contraindications to MRI imaging since the parent trial also employs MR 
imaging.  
 
Risks of Xenon Inhalation 
Inhalation of hyperpolarized 129Xe may carry some minor risks. Xenon is a general anesthetic when 
breathed continuously at concentrations greater than 70% for extended periods of time. In the proposed 
study, xenon will be delivered in a single breath, with alveolar concentrations below 25%. At these 
concentrations, subjects may experience transient effects including dizziness, slight tingling or numbness 
of the extremities, nausea, smelling of flowers, or a feeling of well-being and euphoria. These effects will 
wane within 1-2 minutes of exhaling the xenon and are documented in the consent forms.  


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A second risk comes from administering HP 129Xe without oxygen. This is necessary to preserve good 
image quality, because O2 is paramagnetic and depolarizes the HP 129Xe. Administration of a single anoxic 
1-liter breath has been well tolerated by subjects undergoing both 3He and 129Xe MRI because for a single 
breath, the residual oxygen in the subject’s lungs is sufficient to maintain blood O2 saturation during the 
breath-hold. If a subject has an oxygen saturation below 90% at baseline, the attending medical professional 
may provide supplemental oxygen via nasal cannula as needed. Numerous studies have now been published 
demonstrating the safety and tolerability of hyperpolarized 129Xe MRI. 
 
Hyperpolarized 129Xe is treated as a drug by the FDA and is covered by our existing Investigational New 
Drug Filing (IND# 109,490), which has been active for 7 years and has reported no SAEs, and no early 
withdrawals from the study. The proposed studies will use hyperpolarized 129Xe prepared in exact 
accordance with the Drug Master File that is part of the IND held by Polarean, Inc. Our center has been 
granted the rights by Polarean to cross-reference this IND for their own filings. We will continue to follow 
a 129Xe administration protocol that is well established in our hands.  
 
Risks of Incidental Findings 
Since the MRI methods being tested are experimental, the MRI images will not be formally reviewed for 
incidental findings. However, if there is something that is of concern to the PI, then the PI will approach 
the IRB for guidance on how to proceed on a case-by-case basis. The consent will clearly state that the MRI 
images will not be evaluated for incidental imaging findings.  
 
Protection Against Risk:  Study visits and informed consent will be performed in private rooms, to prevent 
potential loss of confidentiality. This individual will be present in the MRI suite during 129Xe 
administration and will monitor all aspects of the subject’s wellbeing and record any transient CNS effects 
and adverse events should they occur. The subject will be monitored continuously by an MRI-compatible 
pulse oximeter, recording both heart rate and oxygen saturation. Subjects may discontinue the study at any 
time. The MRI suite is also equipped with a safe source of supplemental oxygen that can be provided if 
needed for patients with pulmonary disease to maintain O2 saturation. All subjects will receive a 24-hour 
follow-up phone call to check for any symptoms or adverse effects. Any symptoms or effects will be 
recorded, regardless of their suspected association with 129Xe MRI. 
 
  
Extraordinary care will be taken to ensure that all patient data remains confidential and any information is 
deidentified prior to publication or presentation. All study personnel will have completed their institution’s 
mandatory training in human subjects’ research and protecting PHI. 
 
 
Potential Benefits to Subjects: 
 
We anticipate no direct benefit to subjects as a result of participating in the study, since our primary 
emphasis is to collect a range of MR images and develop interpretation of these results over time. 
However, it is conceivable that either the anatomical 1H scans or 129Xe MR scans may reveal an 
incidental pathology that requires medical attention. Such a finding could benefit the subject because it 
will be found earlier than would likely be the case during the subject’s normal medical care. Any such 
findings will be immediately communicated to the subject and his/her physician and all associated records 
of the study will be made available to them for any further work-ups. The potential benefit of this 
research is in the noninvasive diagnosis of PAH, which would obviate the need for invasive RHC in these 
patients. 
 


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Costs to the Subject: 
 
There are no additional costs to the subject for the MRI examination. Subjects will be compensated $150.00 
for the study visit.  
 
Data Analysis & Statistical Considerations: 
 
We will perform pairwise comparisons for all endpoints before and after treatment with iTRE with 
correction for multiple comparisons. We will also compare the baseline and post-treatment values to a group 
of normal subjects so we can assess the degree of normalization of gas transfer associated with drug 
treatment. 
 
Data & Safety Monitoring: 
 
All of the protocols in this proposal trial will be approved by Institutional Review Boards and reviewed 
periodically (every 12 months). Any adverse event will be reported to the appropriate IRB, the NIH Office 
of Biotechnology Activities (OBA), and if deemed related to xenon, will also be reported to FDA. Per 
Institutional and FDA policy, any serious adverse events (SAEs) will be reported within 24 hours. An 
annual progress report (or more frequently, if requested) will be submitted to the IRB, OBA and FDA. 
 
The clinical investigator(s) will terminate the study immediately if the occurrence of serious adverse events 
that suggests unacceptable risk to the health of the subjects. All observed or volunteered adverse events, 
regardless of suspected causal relationship to the study procedure(s), will be recorded on the adverse events 
page(s) of the CRFs or worksheets. Events involving adverse experiences occurring during the study 
procedure(s) will be recorded. 
 
Subjects will be monitored before, during, and after each dose of xenon to assess for adverse events and 
changes in vital signs. The parameters monitored include the following: subject assessment of 
anesthetic/analgesic effects, heart rate, and SpO2. The subjective sense of analgesia is assessed by in 
inquiring about how the subject feels after administration of the Xenon dose. The subject will be asked to 
describe how they feel as well as about specific symptoms including: dizziness, light-headedness, 
numbness, euphoria, sleepiness, and tingling in extremities. SPO2 is measured at baseline and after each 
Xenon dose. A decrease of SpO2 by greater than 5% is considered significant. If the subject is to receive 
another dose, the next dose will not be administered until the SpO2 is within 5 % of its baseline value. If 
the subject has received their last dose, they will be observed until the SpO2 is within 5% of its baseline 
value or until the end of the observation period, whichever is longer. The subject will be monitored for the 
duration of the Xenon dose and post-procedural period, as well as the MRI with contrast by a qualified 
medical professional. 
 
Privacy, Data Storage & Confidentiality:  
 
All consent and case report forms will be stored in a locked filing cabinet in the office of the study 
coordinator or principal investigator. Any other digital data (images, image analysis) will be associated 
only with the subject identification number and the date and time of the MRI. Image data will be retrieved 
and analyzed only by study personnel. Data will be captured in a RedCap database. After all manuscripts 
have been published the key to the code will be destroyed. 
 
 
 


Statistical Plan 
We will perform pairwise comparisons for all endpoints before and after treatment with Tyvaso 
with correction for multiple comparisons. We will also compare the baseline and post-treatment 
values to a group of normal subjects so we can assess the degree of normalization of gas 
transfer associated with drug treatment. 
 


Consent to Participate in a Research Study
Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
Page 1 of 8
Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
You are being asked to take part in this research study because you are a patient with pulmonary 
hypertension (PH) being treated with a medication called treprostinil.  Research studies are voluntary 
and include only people who choose to take part.  Please read this consent form carefully and take your 
time making your decision. As your study doctor or study staff discusses this consent form with you, 
please ask him/her to explain any words or information that you do not clearly understand.  We 
encourage you to talk with your family and friends before you decide to take part in this research study.  
The nature of the study, risks, inconveniences, discomforts, and other important information about the 
study are listed below.
Please tell the study doctor or study staff if you are taking part in another research study.
Dr. Sudarshan Rajagopal will conduct the study and it is funded by United Therapeutics Corporation.  
United Therapeutics Corporation, will pay Duke University to perform this research, and these funds 
may reimburse part of Dr. Sudarshan Rajagopal salary.  Dr. Rajagopal also receives personal 
compensation from United Therapeutics for serving on their advisory board.
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, your doctors will be Drs. Sudarshan Rajagopal, M.D, Bastiaan Driehuys, 
Ph.D, and Jospeh Mammarappalil, M.D., Ph.D and they will be in contact with your regular health care 
provider throughout the time that you are in the study and afterwards, if needed.  
This is a research study to find out if magnetic resonance imaging (MRI) using inhaled hyperpolarized 
xenon gas can help visualize lung function in patients with pulmonary hypertension.  The study will also 
find out if this MRI with  xenon gas can detect lung and body changes after treatment with inhaled 
treprostinil (Tyvaso) that is taken as standard of care for pulmonary hypertension. 
Participants will have three MRI scans on one day.  The first MRI scan will be done right before you take 
an inhaled treprostinil (Tyvaso) treatment, the second scan right after the inhaled treprostinil treatment, 
and the third scan is done 2-4 hours after the inhaled treprostinil treatment. Each scan will take around 1 
hour each from start to finish. The total time for three MRI scans and other study activities will take 
around 6 hours of your time. There is no direct medical benefit to you for taking part of this study.  This 
information learned during the study may help others with pulmonary hypertension in the future. The 
MRI or Magnetic resonance imaging uses a magnet and radio waves to make diagnostic medical images 
of the body.  There have been no ill effects reported from exposure to the magnetism or radio waves used 
in this test.  Risks of the xenon gas are slight numbness in legs, nausea, a feeling of well-being, mild 
tingling in fingertips.  Study team will use pulmonary function tests that are available from the medical 
record 
The information presented in this section may be discussed in greater detail later in the consent form.  If 
you are in interested in learning more about this study, please continue to read below. 
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 07/09/2020
IRB EXPIRATION DATE: 02/08/2021
V
O
I
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Consent to Participate in a Research Study
Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
Page 2 of 8
Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Please note that Dr. Driehuys holds several patents related to the technology used in this study. These 
patents are licensed to Polarean, Inc for commercial development. While Polarean, Inc. is not sponsoring 
the present study, Dr. Driehuys does have an ownership stake in this company.  However, the findings 
from this study could lead to financial benefit for Polarean. 
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to determine whether magnetic resonance imaging (MRI) using inhaled 
hyperpolarized xenon gas can help visualize impaired lung function and detect changes over time in 
patients receiving treatment. Hyperpolarization is done by exposing the xenon gas to a special type of 
laser light, and does not change the chemical properties of the gas in any way. 129Xe is a special type of 
xenon gas and when inhaled during MRI may be able to show areas of abnormal thickening of parts of 
the lungs. These images may provide a better way to look at lung structure and function in patients with 
pulmonary hypertension.  We anticipate that the images acquired in this study will provide more specific 
information about lung disease than standard lung function tests. The use of 129Xe MRI is 
investigational.  “Investigational” means that these tests have not yet been approved by the US Food and 
Drug Administration and are being tested in research studies like this one.  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 15 people will take part in this study at Duke.
WHAT IS INVOLVED IN THE STUDY?
If you agree to be in this study, you will be asked to sign and date this consent form. You will have the 
following tests and procedures to make sure that you are eligible. 
The study involves the following study visits:

Screening: This will take place before your first MRI scan.  You will be asked for your medical 
history, record of medications, and your vital signs will be measured. You will be asked to fill 
out a questionnaire to ensure that you are eligible to undergo an MRI scan. Also, the following 
procedures will be performed:

You may have a finger sensor portable machine placed on one of your fingers to check 
your oxygen carrying capacity in your blood (hemoglobin level),

If you are female of child-bearing potential, you will be required to undergo urine 
pregnancy test and it must be negative before you can continue to participate in this 
study. 

Imaging Study Visit.  This visit may will occur at the same time as the screening visit or shortly 
after. This visit will take around 6 hours. The following will occur:
1. An IV will be placed in your arm to allow us to draw your blood. 
2. MRI:. For each of the three MRI scans, you will lie on your back on a table, wearing a 
vest that transmits and receives signals for the MRI and a small sensor will be applied to 
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 07/09/2020
IRB EXPIRATION DATE: 02/08/2021
V
O
I
D


Consent to Participate in a Research Study
Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
Page 3 of 8
Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
your finger to monitor your pulse rate and blood oxygen levels. The table will be slid into 
the bore of the MRI scanner (a tunnel about 6 feet long and 25 inches in diameter) and we 
will obtain one or more (up to a maximum of 5) MRI scans of your lungs. After this, you 
will be instructed to inhale a small calibration dose of hyperpolarized 129Xe from a plastic 
bag through a mouthpiece.  Following this, you will be asked to inhale additional doses 
of hyperpolarized 129Xe to acquire different kinds of lung scans (up to a maximum of 5). 
For each 129Xe dose you will be asked to hold your breath for approximately 15 seconds 
while the scan is obtained. During each scan, your heart rate and your oxygen saturation 
will be monitored. After each 129Xe dose, the table will slide out of the MRI bore so that 
you can communicate with study personnel. When you are ready, the next xenon dose 
will be administered.  After the MRI examination, you will remain with study personnel 
until you feel recovered from any study effects and your heart rate and oxygen saturation 
are within an acceptable range. You will then be free to go home. At any time after the 
exam, you may contact a member of the study team if you feel that you are having any 
symptoms or effects related to your participation in the study.  Each scan will take around 
1 hour each from start to finish.  

The first MRI scan will take place just prior to your treprostinil dose.  After the first 
MRI scan, you will take your inhaled treprostinil treatment as prescribed by your PH 
care doctor.  The second scan will be done after you have completed your treatment.  
The third MRI scan will be done around 3- 4 hours after this inhaled treprostinil 
treatment and right before the next dose.  You will not take your inhaled treprostinil 
any differently than prescribed to you by your PH doctor as part of this study.  You 
will be provided with space and time to complete your inhaled treprostinil treatment 
outside the MRI machine room.  
3. Blood Draw: 3 blood samples (about 2 tablespoons each time) will be taken from your 
IV.  The first samples will be taken prior to or right after the first MRI scan and before 
you take your inhaled treprostinil treatment.  The second blood sample will be taken after 
you take the inhaled treprostinil treatment and are preparing for the second MRI scan or 
right after.  The third blood sample will be taken 2-4 hours after the inhaled treprostinil 
treatment.  The blood samples will be taken to determine the amount of treprostinil that is 
in your bloodstream at different time points.
4. Imaging of the hands:  You will have 3 scans done of your hands at the same time point 
before your blood is taken.  The scans are done to assess the how much blood flow there 
is to your hands.  The scan involves 3 laser images of your hands. First scan will be of 
your right hand, second scan will be of your left hand and the third will be with your 
dominant hand while you have a blood pressure cuff on your upper arm. The blood 
pressure cuff be inflated and deflated once for a total of 15 seconds. These scans are not 
invasive. The scanner does not touch your skin. 
5. Pulmonary Function Tests: Study team will use the PFTs that are available from the 
medical record
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 07/09/2020
IRB EXPIRATION DATE: 02/08/2021
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Assessing Response to Inhaled Prostacyclin with 
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Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
The study doctor may stop your participation in this study at any time without your consent. Potential 
reasons for ending your participation may include safety concerns or general reasons related to the 
conduct of the research study itself.  The total time for three MRI scans and other listed study activities 
will take around 6 hours of your time. 
HOW LONG WILL I BE IN THIS STUDY?
Your study involvement will last approximately1-2 days for scanning and follow-up. 
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled. However, if you decide to stop participating in the study, we encourage you to talk to your 
doctor first.
WHAT ARE THE RISKS OF THE STUDY?
As a result of your participation in this study, you are at risk for the following side effects. You should 
discuss these with the study doctor and your regular health care provider if you choose. 
There is a potential risk of loss of confidentiality.  Every effort will be made to protect your confidential 
information but this cannot be guaranteed.
Risks associated with inserting an IV (intravenous) catheter into your arm include momentary 
discomfort and/or bruising. Infection, excess bleeding, clotting, or fainting are also possible, although 
unlikely.
MRI Risks:
Magnetic resonance imaging (MRI) uses a magnet and radio waves to make diagnostic medical images 
of the body.  There have been no ill effects reported from exposure to the magnetism or radio waves 
used in this test.  However, it is possible that harmful effects could be recognized in the future.  A 
known risk is that the magnet could attract certain kinds of metal.  Therefore, we will carefully ask you 
about metal within your body (this includes certain dyes found in tattoos).  If there is any question about 
potentially hazardous metal within your body, you will be excluded from participation in this research 
study.  
The study involves entering a large room in which a magnet is present.  You will be placed on a narrow 
bed and then slid into a small tunnel approximately 6 feet in length and 25 inches in diameter.  You will 
be asked to lie still for about one hour on this bed.  During MRI scanning you will hear loud machine-
like noises.  You may be asked to have a harmless monitoring device applied during the study.  During 
the study, you can have voice contact and physical contact with someone in attendance if you desire. 
The MRI scan can be stopped at any time if you request it.
You should be aware that the MRI images are for research purposes only and will not be reviewed for 
the purposes of your healthcare.
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 07/09/2020
IRB EXPIRATION DATE: 02/08/2021
V
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Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
 
Risks of Xenon Gas:
Inhalation of xenon gas may cause you to feel the following effects: 
•
Slight numbness in the legs
•
Nausea
•
A sensation similar to smelling flowers
•
A feeling of well-being or elation 
•
Mild tingling in the fingertips
If you experience these effects they typically resolve within 1-2 minutes of exhaling the xenon gas.
This breath of xenon will not contain any oxygen. This could briefly cause the oxygen levels in your 
blood to decrease. These oxygen levels will return to normal when you begin normal breathing again. 
The oxygen level in your blood will be monitored at all times by the study team.
Female
Being a part of this study (MRI with 129Xe) while pregnant may expose the unborn child to significant 
risks, some of which may be currently unforeseeable. Therefore, pregnant women will be excluded from 
the study.  Females, who are of child bearing potential will have a urine pregnancy test on the day of the 
MRI, and a negative result is required to participate in the study. 
Risks of Drawing Blood: Risks associated with drawing blood from your arm include momentary 
discomfort and/or bruising.  Infection, excess bleeding, clotting, or fainting are also possible, although 
unlikely.
There may be risks, discomforts, drug interactions or side effects that are not yet known.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there will not be direct medical benefit to you.  We hope that in 
the future the information learned from this study will benefit other people with your condition.  
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
information may be viewed by individuals involved in this research and may be seen by people 
including those collaborating, funding, and regulating the study. We will share only the minimum 
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law. 
As part of the study, results of your study-related laboratory tests and procedures may be reported to 
United Therapeutics and its affiliates. In addition, your records may be reviewed in order to meet federal 
or state regulations. Reviewers may include representatives from the Food and Drug Administration, 
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 07/09/2020
IRB EXPIRATION DATE: 02/08/2021
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Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
representatives and affiliates of United Therapeutics, the Duke University Health System Institutional 
Review Board, and others as appropriate. If any of these groups review your research record, they may 
also need to review your entire medical record.
As part of this study, you will be asked to have certain tests, MRIs, and/or procedures performed. Some 
of these tests, x-rays and/or procedures would have been done as part of your regular care. The study 
doctor will use these test results both to treat you and to complete this research.  These test results will 
be recorded in your medical record and will be reported to the representatives and affiliates of United 
Therapeutics. Results of tests and studies done solely for this research study and not as part of your 
regular care will not be included in your medical record.
The study results will be retained in your research record for at least six years after the study is 
completed. At that time either the research information not already in your medical record may be 
destroyed or information identifying you will be removed from such study results at DUHS.  Any 
research information in your medical record will be kept indefinitely.
This information may be further disclosed by the sponsor of this study.  If disclosed by the sponsor, the 
information is no longer covered by federal privacy regulations.
If this information is disclosed to outside reviewers for audit purposes, it may be further disclosed by 
them and may not be covered by federal privacy regulations.
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed.
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information.
WHAT ARE THE COSTS?
You or your insurance provider will be responsible and billed for all costs related to your routine 
medical care, including copayments and deductibles. Routine medical care services are those that you 
would have received for your condition if you were not participating in this research study. Not all 
services are covered by insurance.  Some procedures or scans may require pre-authorization by your 
insurance plan. We will notify you if we learn that a service is not covered by your insurance plan as 
part of the pre-authorization process. If it is not covered, you will be responsible for paying for it.  The 
amount of your out-of-pocket expense will depend on your insurance plan.  For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study.  You 
may have more or higher co-pays than with a Medicare Advantage plan.  Please discuss the costs of the 
study with Dr. Sudarshan Rajagopal.  At your request, a Financial Counselor in the clinic may provide 
you with an estimate of costs for routine services.
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 07/09/2020
IRB EXPIRATION DATE: 02/08/2021
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Assessing Response to Inhaled Prostacyclin with 
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Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
The study sponsor, United Therapeutics, has agreed to pay for services and procedures that are done 
solely for research purposes.  Please talk with the PI/study team about the specific services and 
procedures that the sponsor will pay for, and the ones for which you or your insurance will be 
responsible.
We will monitor your DUHS patient care charges to make sure that costs are directed appropriately.  If 
you have any questions or concerns about appropriate billing, contact your study team coordinator so 
that he/she can help find a resolution.
WHAT ABOUT COMPENSATION?
You will be paid $150 for your participation in the study. 
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., your Duke physicians, or the funding source for 
this study, United Therapeutics Corporation, to provide monetary compensation or free medical care to 
you in the event of a study-related injury.
For questions about the study or research-related injury, contact Dr. Rajagopal at 919-684-6237 during 
regular business hours.  After hours, weekends, and holidays please call the hospital to page Dr. 
Rajagopal at 919-684-8111.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the 
study at any time. If you withdraw from the study, no new data about you will be collected for study 
purposes unless the data concern an adverse event (a bad effect) related to the study.  If such an adverse 
event occurs, we may need to review your entire medical record.  
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke.  If you do 
decide to withdraw, we ask that you contact Dr. Rajagopal in writing and let him know that you are 
withdrawing from the study.  His mailing address is:
DUMC
Box 102351
Durham, NC 27710
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study.
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 07/09/2020
IRB EXPIRATION DATE: 02/08/2021
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*
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if your study doctor determines that it is no longer in your best interest to continue.  The 
sponsor or regulatory agencies may stop this study at anytime without your consent. If this occurs, you 
will be notified and your study doctor will discuss other options with you.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will 
include a summary of the results.  You can search this Web site at any time.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. Rajagopal at 919-684-6237 during regular business hours.  
After hours, weekends, and holidays please call the hospital to page Dr. Rajagopal at 919-684-8111.
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111.
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this consent form."
_________________________________________                          __________      ___________
Signature of Subject
Date
   Time
_________________________________________
Printed Name of Person signing Consent
__________________________________________
___________     ____________
Signature of Person Obtaining Consent
Date
   Time
________________________________________
Printed Name of Person Obtaining Consent
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 07/09/2020
IRB EXPIRATION DATE: 02/08/2021
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Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
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Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
You are being asked to take part in this research study because you are a patient with pulmonary 
hypertension (PH) being treated with a medication called treprostinil.  Research studies are voluntary 
and include only people who choose to take part.  Please read this consent form carefully and take your 
time making your decision. As your study doctor or study staff discusses this consent form with you, 
please ask him/her to explain any words or information that you do not clearly understand.  We 
encourage you to talk with your family and friends before you decide to take part in this research study.  
The nature of the study, risks, inconveniences, discomforts, and other important information about the 
study are listed below.
Please tell the study doctor or study staff if you are taking part in another research study.
Dr. Sudarshan Rajagopal will conduct the study and it is funded by United Therapeutics Corporation.  
United Therapeutics Corporation, will pay Duke University to perform this research, and these funds 
may reimburse part of Dr. Sudarshan Rajagopal salary.  Dr. Rajagopal also receives personal 
compensation from United Therapeutics for serving on their advisory board.
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, your doctors will be Drs. Sudarshan Rajagopal, M.D, Bastiaan Driehuys, 
Ph.D, and Jospeh Mammarappalil, M.D., Ph.D and they will be in contact with your regular health care 
provider throughout the time that you are in the study and afterwards, if needed.  
This is a research study to find out if magnetic resonance imaging (MRI) using inhaled hyperpolarized 
xenon gas can help visualize lung function in patients with pulmonary hypertension.  The study will also 
find out if this MRI with  xenon gas can detect lung and body changes after treatment with inhaled 
treprostinil (Tyvaso) that is taken as standard of care for pulmonary hypertension. 
Participants will have three MRI scans on one day.  The first MRI scan will be done right before you take 
an inhaled treprostinil (Tyvaso) treatment, the second scan right after the inhaled treprostinil treatment, 
and the third scan is done 2-4 hours after the inhaled treprostinil treatment. Each scan will take around 1 
hour each from start to finish. The total time for three MRI scans and other study activities will take 
around 6 hours of your time. There is no direct medical benefit to you for taking part of this study.  This 
information learned during the study may help others with pulmonary hypertension in the future. The 
MRI or Magnetic resonance imaging uses a magnet and radio waves to make diagnostic medical images 
of the body.  There have been no ill effects reported from exposure to the magnetism or radio waves used 
in this test.  Risks of the xenon gas are slight numbness in legs, nausea, a feeling of well-being, mild 
tingling in fingertips.  Study team will use pulmonary function tests that are available from the medical 
record 
The information presented in this section may be discussed in greater detail later in the consent form.  If 
you are in interested in learning more about this study, please continue to read below. 
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 01/31/2023
IRB EXPIRATION DATE: 02/08/2024


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Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
Page 2 of 8
Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Please note that Dr. Driehuys holds several patents related to the technology used in this study. These 
patents are licensed to Polarean, Inc for commercial development. While Polarean, Inc. is not sponsoring 
the present study, Dr. Driehuys does have an ownership stake in this company.  However, the findings 
from this study could lead to financial benefit for Polarean. 
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to determine whether magnetic resonance imaging (MRI) using inhaled 
hyperpolarized xenon gas can help visualize impaired lung function and detect changes over time in 
patients receiving treatment. Hyperpolarization is done by exposing the xenon gas to a special type of 
laser light, and does not change the chemical properties of the gas in any way. 129Xe is a special type of 
xenon gas and when inhaled during MRI may be able to show areas of abnormal thickening of parts of 
the lungs. These images may provide a better way to look at lung structure and function in patients with 
pulmonary hypertension.  We anticipate that the images acquired in this study will provide more specific 
information about lung disease than standard lung function tests. The use of 129Xe MRI is 
investigational.  “Investigational” means that these tests have not yet been approved by the US Food and 
Drug Administration and are being tested in research studies like this one.  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 15 people will take part in this study at Duke.
WHAT IS INVOLVED IN THE STUDY?
If you agree to be in this study, you will be asked to sign and date this consent form. You will have the 
following tests and procedures to make sure that you are eligible. 
The study involves the following study visits:

Screening: This will take place before your first MRI scan.  You will be asked for your medical 
history, record of medications, and your vital signs will be measured. You will be asked to fill 
out a questionnaire to ensure that you are eligible to undergo an MRI scan. Also, the following 
procedures will be performed:

You may have a finger sensor portable machine placed on one of your fingers to check 
your oxygen carrying capacity in your blood (hemoglobin level),

If you are female of child-bearing potential, you will be required to undergo urine 
pregnancy test and it must be negative before you can continue to participate in this 
study. 

Imaging Study Visit.  This visit may will occur at the same time as the screening visit or shortly 
after. This visit will take around 6 hours. The following will occur:
1. An IV will be placed in your arm to allow us to draw your blood. 
2. MRI:. For each of the three MRI scans, you will lie on your back on a table, wearing a 
vest that transmits and receives signals for the MRI and a small sensor will be applied to 
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 01/31/2023
IRB EXPIRATION DATE: 02/08/2024


Consent to Participate in a Research Study
Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
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Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
your finger to monitor your pulse rate and blood oxygen levels. The table will be slid into 
the bore of the MRI scanner (a tunnel about 6 feet long and 25 inches in diameter) and we 
will obtain one or more (up to a maximum of 5) MRI scans of your lungs. After this, you 
will be instructed to inhale a small calibration dose of hyperpolarized 129Xe from a plastic 
bag through a mouthpiece.  Following this, you will be asked to inhale additional doses 
of hyperpolarized 129Xe to acquire different kinds of lung scans (up to a maximum of 5). 
For each 129Xe dose you will be asked to hold your breath for approximately 15 seconds 
while the scan is obtained. During each scan, your heart rate and your oxygen saturation 
will be monitored. After each 129Xe dose, the table will slide out of the MRI bore so that 
you can communicate with study personnel. When you are ready, the next xenon dose 
will be administered.  After the MRI examination, you will remain with study personnel 
until you feel recovered from any study effects and your heart rate and oxygen saturation 
are within an acceptable range. You will then be free to go home. At any time after the 
exam, you may contact a member of the study team if you feel that you are having any 
symptoms or effects related to your participation in the study.  Each scan will take around 
1 hour each from start to finish.  

The first MRI scan will take place just prior to your treprostinil dose.  After the first 
MRI scan, you will take your inhaled treprostinil treatment as prescribed by your PH 
care doctor.  The second scan will be done after you have completed your treatment.  
The third MRI scan will be done around 3- 4 hours after this inhaled treprostinil 
treatment and right before the next dose.  You will not take your inhaled treprostinil 
any differently than prescribed to you by your PH doctor as part of this study.  You 
will be provided with space and time to complete your inhaled treprostinil treatment 
outside the MRI machine room.  
3. Blood Draw: 3 blood samples (about 2 tablespoons each time) will be taken from your 
IV.  The first samples will be taken prior to or right after the first MRI scan and before 
you take your inhaled treprostinil treatment.  The second blood sample will be taken after 
you take the inhaled treprostinil treatment and are preparing for the second MRI scan or 
right after.  The third blood sample will be taken 2-4 hours after the inhaled treprostinil 
treatment.  The blood samples will be taken to determine the amount of treprostinil that is 
in your bloodstream at different time points.
4. Imaging of the hands:  You will have 3 scans done of your hands at the same time point 
before your blood is taken.  The scans are done to assess the how much blood flow there 
is to your hands.  The scan involves 3 laser images of your hands. First scan will be of 
your right hand, second scan will be of your left hand and the third will be with your 
dominant hand while you have a blood pressure cuff on your upper arm. The blood 
pressure cuff be inflated and deflated once for a total of 15 seconds. These scans are not 
invasive. The scanner does not touch your skin. 
5. Pulmonary Function Tests: Study team will use the PFTs that are available from the 
medical record
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 01/31/2023
IRB EXPIRATION DATE: 02/08/2024


Consent to Participate in a Research Study
Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
Page 4 of 8
Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
The study doctor may stop your participation in this study at any time without your consent. Potential 
reasons for ending your participation may include safety concerns or general reasons related to the 
conduct of the research study itself.  The total time for three MRI scans and other listed study activities 
will take around 6 hours of your time. 
HOW LONG WILL I BE IN THIS STUDY?
Your study involvement will last approximately1-2 days for scanning and follow-up. 
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled. However, if you decide to stop participating in the study, we encourage you to talk to your 
doctor first.
WHAT ARE THE RISKS OF THE STUDY?
As a result of your participation in this study, you are at risk for the following side effects. You should 
discuss these with the study doctor and your regular health care provider if you choose. 
There is a potential risk of loss of confidentiality.  Every effort will be made to protect your confidential 
information but this cannot be guaranteed.
Risks associated with inserting an IV (intravenous) catheter into your arm include momentary 
discomfort and/or bruising. Infection, excess bleeding, clotting, or fainting are also possible, although 
unlikely.
MRI Risks:
Magnetic resonance imaging (MRI) uses a magnet and radio waves to make diagnostic medical images 
of the body.  There have been no ill effects reported from exposure to the magnetism or radio waves 
used in this test.  However, it is possible that harmful effects could be recognized in the future.  A 
known risk is that the magnet could attract certain kinds of metal.  Therefore, we will carefully ask you 
about metal within your body (this includes certain dyes found in tattoos).  If there is any question about 
potentially hazardous metal within your body, you will be excluded from participation in this research 
study.  
The study involves entering a large room in which a magnet is present.  You will be placed on a narrow 
bed and then slid into a small tunnel approximately 6 feet in length and 25 inches in diameter.  You will 
be asked to lie still for about one hour on this bed.  During MRI scanning you will hear loud machine-
like noises.  You may be asked to have a harmless monitoring device applied during the study.  During 
the study, you can have voice contact and physical contact with someone in attendance if you desire. 
The MRI scan can be stopped at any time if you request it.
You should be aware that the MRI images are for research purposes only and will not be reviewed for 
the purposes of your healthcare.Risks of Xenon Gas:
Inhalation of xenon gas may cause you to feel the following effects: 
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 01/31/2023
IRB EXPIRATION DATE: 02/08/2024


Consent to Participate in a Research Study
Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
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Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
•
Slight numbness in the legs
•
Nausea
•
A sensation similar to smelling flowers
•
A feeling of well-being or elation 
•
Mild tingling in the fingertips
If you experience these effects they typically resolve within 1-2 minutes of exhaling the xenon gas.
This breath of xenon will not contain any oxygen. This could briefly cause the oxygen levels in your 
blood to decrease. These oxygen levels will return to normal when you begin normal breathing again. 
The oxygen level in your blood will be monitored at all times by the study team.
Female
Being a part of this study (MRI with 129Xe) while pregnant may expose the unborn child to significant 
risks, some of which may be currently unforeseeable. Therefore, pregnant women will be excluded from 
the study.  Females, who are of child bearing potential will have a urine pregnancy test on the day of the 
MRI, and a negative result is required to participate in the study. 
Risks of Drawing Blood: Risks associated with drawing blood from your arm include momentary 
discomfort and/or bruising.  Infection, excess bleeding, clotting, or fainting are also possible, although 
unlikely.
There may be risks, discomforts, drug interactions or side effects that are not yet known.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there will not be direct medical benefit to you.  We hope that in 
the future the information learned from this study will benefit other people with your condition.  
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
information may be viewed by individuals involved in this research and may be seen by people 
including those collaborating, funding, and regulating the study. We will share only the minimum 
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law. 
As part of the study, results of your study-related laboratory tests and procedures may be reported to 
United Therapeutics and its affiliates. In addition, your records may be reviewed in order to meet federal 
or state regulations. Reviewers may include representatives from the Food and Drug Administration, 
representatives and affiliates of United Therapeutics, the Duke University Health System Institutional 
Review Board, and others as appropriate. If any of these groups review your research record, they may 
also need to review your entire medical record.
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 01/31/2023
IRB EXPIRATION DATE: 02/08/2024


Consent to Participate in a Research Study
Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
Page 6 of 8
Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
As part of this study, you will be asked to have certain tests, MRIs, and/or procedures performed. Some 
of these tests, x-rays and/or procedures would have been done as part of your regular care. The study 
doctor will use these test results both to treat you and to complete this research.  These test results will 
be recorded in your medical record and will be reported to the representatives and affiliates of United 
Therapeutics. Results of tests and studies done solely for this research study and not as part of your 
regular care will not be included in your medical record.
The study results will be retained in your research record for at least six years after the study is 
completed. At that time either the research information not already in your medical record may be 
destroyed or information identifying you will be removed from such study results at DUHS.  Any 
research information in your medical record will be kept indefinitely.
This information may be further disclosed by the sponsor of this study.  If disclosed by the sponsor, the 
information is no longer covered by federal privacy regulations.
If this information is disclosed to outside reviewers for audit purposes, it may be further disclosed by 
them and may not be covered by federal privacy regulations.
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed.
An external investigator from the University of Virginia will be helping analyze the MRI images for this 
study. They will have access to your historical data for your right heart catheterizations, pulmonary 
function tests, laboratory results, echocardiograms as well as other pertinent data to help with analyzing. 
Minimal information about you will be shared with this external investigator. Identifiable data shared 
can include sex, ethnicity, birthdate and date of study procedures and/or labs. We will share only the 
minimum necessary information in order to conduct the research.
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information.
WHAT ARE THE COSTS?
You or your insurance provider will be responsible and billed for all costs related to your routine 
medical care, including copayments and deductibles. Routine medical care services are those that you 
would have received for your condition if you were not participating in this research study. Not all 
services are covered by insurance.  Some procedures or scans may require pre-authorization by your 
insurance plan. We will notify you if we learn that a service is not covered by your insurance plan as 
part of the pre-authorization process. If it is not covered, you will be responsible for paying for it.  The 
amount of your out-of-pocket expense will depend on your insurance plan.  For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study.  You 
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 01/31/2023
IRB EXPIRATION DATE: 02/08/2024


Consent to Participate in a Research Study
Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
Page 7 of 8
Subject*Initials__________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
may have more or higher co-pays than with a Medicare Advantage plan.  Please discuss the costs of the 
study with Dr. Sudarshan Rajagopal.  At your request, a Financial Counselor in the clinic may provide 
you with an estimate of costs for routine services.
The study sponsor, United Therapeutics, has agreed to pay for services and procedures that are done 
solely for research purposes.  Please talk with the PI/study team about the specific services and 
procedures that the sponsor will pay for, and the ones for which you or your insurance will be 
responsible.
We will monitor your DUHS patient care charges to make sure that costs are directed appropriately.  If 
you have any questions or concerns about appropriate billing, contact your study team coordinator so 
that he/she can help find a resolution.
WHAT ABOUT COMPENSATION?
You will be paid $150 for your participation in the study. 
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., your Duke physicians, or the funding source for 
this study, United Therapeutics Corporation, to provide monetary compensation or free medical care to 
you in the event of a study-related injury.
For questions about the study or research-related injury, contact Dr. Rajagopal at 919-684-6237 during 
regular business hours.  After hours, weekends, and holidays please call the hospital to page Dr. 
Rajagopal at 919-684-8111.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the 
study at any time. If you withdraw from the study, no new data about you will be collected for study 
purposes unless the data concern an adverse event (a bad effect) related to the study.  If such an adverse 
event occurs, we may need to review your entire medical record.  
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke.  If you do 
decide to withdraw, we ask that you contact Dr. Rajagopal in writing and let him know that you are 
withdrawing from the study.  His mailing address is:
DUMC
Box 102351
Durham, NC 27710
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 01/31/2023
IRB EXPIRATION DATE: 02/08/2024


Consent to Participate in a Research Study
Assessing Response to Inhaled Prostacyclin with 
Hyperpolarized 129Xe MRI
Page 8 of 8
*
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study.
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if your study doctor determines that it is no longer in your best interest to continue.  The 
sponsor or regulatory agencies may stop this study at anytime without your consent. If this occurs, you 
will be notified and your study doctor will discuss other options with you.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will 
include a summary of the results.  You can search this Web site at any time.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. Rajagopal at 919-684-6237 during regular business hours.  
After hours, weekends, and holidays please call the hospital to page Dr. Rajagopal at 919-684-8111.
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111.
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this consent form."
_________________________________________                          __________      ___________
Signature of Subject
Date
   Time
_________________________________________
Printed Name of Person signing Consent
__________________________________________
___________     ____________
Signature of Person Obtaining Consent
Date
   Time
________________________________________
Printed Name of Person Obtaining Consent
DUHS IRB
IRB NUMBER: Pro00086282
IRB REFERENCE DATE: 01/31/2023
IRB EXPIRATION DATE: 02/08/2024