Conditions: Pulmonary Vascular Disease
Keywords: right heart catheterization for evaluation of PAH or other cardiac or pulmonary disease
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 62
Healthy volunteers: no

Brief summary:
This study seeks to deploy several forms of 129Xe MRI contrast as well as emerging conventional proton MRI technqiues 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. In addition, to characterize perfusion and vascular dimensions directly, patients will undergo a gadolinium-enhanced perfusion scan.

Detailed description:
This study seeks to deploy several forms of 129Xe MRI contrast as well as emerging conventional proton MRI technqiues 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. In addition, to characterize perfusion and vascular dimensions directly, patients will undergo a gadolinium-enhanced perfusion scan. The overall aims of the study are as follows:

Aim 1. Perform 129Xe MRI scans in cohorts of patients with PVD, isolated left sided heart failure and isolated lung disease:

1.1 Deploy and optimize 129Xe gas exchange MR spectroscopy and imaging, 129Xe ventilation MRI, structural 1H UTE MRI, and breath-hold 1H perfusion MRI.

1.2 Conduct comprehensive 1H-129Xe MRI in 10 patients with pure pulmonary arterial hypertension (PAH) 1.3 Conduct comprehensive MRI in 10 patients with pure left heart failure 1.4 Conduct comprehensive MRI in 10 patients with pure lung disease but no pulmonary hypertension 1.5 Conduct comprehensive MRI in 5 patients with Chronic thromboembolic pulmonary hypertension (CTEPH) pre and post PTE surgery.

Aim 2. Develop diagnostic criteria for optimizing the sensitivity and specificity of 129Xe MRI for the diagnosis of PVD:

2.1 Develop quantification/scoring methods based on PAH, left heart disease, and lung disease MRI 2.2 Develop reader training materials and train 3 expert readers 2.3 Begin prospective recruitment of 92 patients being evaluated for PAH for MRI scans. These patients may be asked to return for a second scan in the study, at a time no earlier than 48hr after their last xenon dose.

Aim 3. Perform a larger, single-blind study testing the diagnostic accuracy of 129Xe MRI for diagnosis of PVD:

3.1 Trained readers will evaluate 129Xe MRI, while blinded to the subject's disease state and will determine the presence and severity of PVD 3.2 Diagnostic accuracy of 129Xe MRI will be compared to the gold standard of hemodynamic and clinical criteria of PAH

1. For this PFTs are not necessary, so they are ancillary
2. However, they are a standard way to characterize patients for publications, etc, so we would like to get them if we can. Getting them from the medical record is perfectly adequate for this pur-pose.

i. If PFTs are not available from the medical record, they are not so critical as to pre-vent us from enrolling the subject. In publications we will simply acknowledge the realities of COVID for this missing data.

This will be an single-blinded, open-label study enrolling volunteers and patients with pure PAH (10 subjects), pure left heart disease (10 subjects) and pure lung disease (10 subjects) \[Aim 1\] followed by a larger cohort of 92 subjects being evaluated for PAH \[Aim 2\]. The investigators plan to consent to 127 subjects.

The sample size calculation is based on testing whether the proposed diagnostic test based on Xe MRI has accuracy comparable to imaging diagnostic procedures in clinical practice, such as mammography. To this end, the investigator proposes to test the hypotheses H0: AUC = 0.72 vs. H1: AUC \> 0.85, where area under the curve (AUC) is a summary measure of diagnostic accuracy obtained as the the area under the receiver operating characteristic (ROC) curve which displays the tradeoff between sensitivity and specificity for our proposed Xe MRI based diagnostic test. Here AUC = 0.72 represents a moderately accurate test while AUC = 0.85 represents accuracy comparable to clinical mammography. Based on a one sided, one sample test with variances approximated using the binormal model, the investigator estimates a minimum sample size of 46 normals and 46 with disease will be required to test the above hypotheses at a significance level of 5% with 80% power.

Arms:
arm 1: Patients with Pulmonary Vascular Disease (10 subjects), isolated left sided heart failure (10 subjects), and isolated lung disease(10 subjects) will undergo Xe MRI scans with GE-141, Hyperpolarized 129Xenon gas to develop diagnostic criteria for optimizing the sensitivity and specificity of XeMRI for the diagnosis of PVD arm 2: 92 subjects being evaluated for undergoing right heart catheterization for evaluation of PAH or other cardiac or pulmonary disease for testing of diagnostic accuracy of XeMRI for diagnosis of PVD

Interventions: intervention 1: GE-141, Hyperpolarized 129Xenon gas intervention 2: MRI
Intervention descriptions: intervention 1: XeMRI scans will provide 3D images of ventilation and gas exchange. Subjects will inhale HP 129Xe from the dose delivery bags. Then the subject will be moved into the scanner and they will undergo basic 1H localizer and anatomical scans. Once localization is complete, subjects will under-go several MRI scans after inhalation of HPXe intervention 2: Perform MRI scans with administration of GE-141, Hyperpolarized 129Xenon

Protocol document:
Prot_SAP_000.pdf: 
Non-Invasive Diagnosis of Pulmonary 
Vascular Disease Using Inhaled 129Xe 
Magnetic Resonance Imaging 
 
 
NCT03078192 
 
 
Protocol Version: 07Jul2020 


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Research Summary 
 
 
1.  Protocol Title: Non-Invasive Diagnosis of Pulmonary Vascular Disease Using Inhaled 129Xe Magnetic 
Resonance Imaging 
 
2.  Purpose of the Study: To develop a novel, non-invasive means of comprehensively diagnosing and 
monitoring response to therapy in PVD using MR imaging (MRI). Our approach uses hyperpolarized 
129Xenon (129Xe)-MRI, a novel technology that images lung ventilation, microstructure, and gas exchange. 
 
3.  Background & Significance:  
Pulmonary arterial 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. For example, patients 
with mild to moderate left heart disease or chronic obstructive pulmonary disease, which are common 
in older patients, technically cannot be diagnosed with PAH because severe left heart and lung disease 
can cause PH. Similarly, hemodynamic criteria are limited by arbitrary cutoffs for mean pulmonary 
artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), and pulmonary vascular re-
sistance (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 addi-
tional cutoff of PVR ≥ 3 Woods units. Moreover, it is currently unclear what constitutes abnormal he-
modynamics in the setting of concomitant heart disease, which can increase the filling pressures of the 
heart (the PCWP), or 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. It has been used in 5 
IRB protocols, 3 of which are currently active. 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 ob-
tained (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 repre-
sent 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 idio-
pathic fibrosis. Among the objectives of this proposal is to clarify and strengthen these distinguishing fea-
tures.  
 
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 


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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. 
 
4.  Design & Procedures:  
 
 
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. The overall 
aims of the study are as follows: 
 
Aim 1. Perform 129Xe MRI scans in cohorts of patients with PVD, isolated left sided heart failure 
and isolated lung disease: 
1.1 Deploy and optimize 129Xe gas exchange MR spectroscopy and imaging, 129Xe ventilation MRI,  
structural 1H UTE MRI, and breath-hold 1H perfusion MRI. 
1.2 Conduct comprehensive 1H-129Xe MRI in 10 patients with pure PAH 
1.3 Conduct comprehensive MRI in 10 patients with pure left heart failure 
1.4 Conduct comprehensive MRI in 10 patients with pure lung disease but no pulmonary hypertension 
1.5  Conduct comprehensive MRI in 5 patients with Chronic thromboembolic pulmonary hypertension 
(CTEPH) pre and post PTE surgery. 
 
Aim 2. Develop diagnostic criteria for optimizing the sensitivity and specificity of 129Xe MRI for the 
diagnosis of PVD: 
2.1 Develop quantification/scoring methods based on PAH, left heart disease, and lung disease MRI 
2.2  Develop reader training materials and train 3 expert readers 
2.3  Begin prospective recruitment of 92 patients undergoing right heart catheterization for evaluation of 
PAH or other cardiac or pulmonary disease for MRI scans. These patients may be asked to return for 
a second scan in the study, at a time no earlier than 48hr after their last xenon dose.  
 
Aim 3. Perform a larger, single-blind study testing the diagnostic accuracy of 129Xe MRI for 
diagnosis of PVD: 
3.1 Trained readers will evaluate 129Xe MRI, while blinded to the subject’s disease state and will determine 
the presence and severity of PVD 
3.2 Diagnostic accuracy of 129Xe MRI will be compared to the gold standard of hemodynamic and clinical 
criteria of PAH 
3.2.1 The primary focus of Aim 3 is to compare 129Xe MRI capability to detect absence/presence of 
pre/post-capillary PH to the gold standard of RHC 
a. For this PFTs are not necessary, so they are ancillary 
b. However, they are a standard way to characterize patients for publications, etc, so we would like 
to get them if we can. Getting them from the medical record is perfectly adequate for this pur-
pose. 
                                               i.      If PFTs are not available from the medical record, they are not so critical as to prevent 
us from enrolling the subject. In publications we will simply acknowledge the realities of 
COVID for this missing data. 
 
This will be a single-blinded, open-label study enrolling volunteers and patients with pure PAH (10 sub-
jects), pure left heart disease (10 subjects), pure lung disease (10 subjects) and CTEPH (5 subjects) [Aim 
1] followed by a larger cohort of 92 subjects who are undergoing right heart catheterization for evaluation 
of PAH or other cardiac or pulmonary disease. [Aim 2]. We plan to consent 127 subjects. No subject will 
be excluded from the study on the basis of gender or ethnicity. Female subjects of childbearing potential 
will undergo urine pregnancy testing before each MRI. The urine pregnancy test must be negative to 
continue participating in the study. To refine the precision of 129Xe MRI for imaging gas transfer efficiency, 


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we will acquire a hemoglobin level by finger sensor device for each subject testing at each study visit. 
Informed consent will be obtained before a subject begins any study intervention. Subjects will undergo 
an approximately hour long comprehensive MRI protocol 
Patients with PAH, CTEPH, left heart disease and lung disease will be recruited using minimally restrictive 
inclusion/exclusion criteria. The Duke Center for Pulmonary Vascular Disease sees approximately 150 
patients for evaluation of PAH including CTEPH in a year. For the first phase of the study, whether patients 
are receiving approved therapies, enrolled in clinical trials, or receiving no therapy, all will be eligible for 
inclusion in this MRI study. For the second phase of the study, patients who have PAH and receiving 
approved therapies, patients who are being evaluated for PVD or other cardiac or pulmonary disease will 
be included in the study. 
 
Each study session will begin with a collection of relevant patient history and symptoms, measurement 
of hemoglobin levels, and urine pregnancy testing (if applicable) and finally pulmonary function testing. 
Pulmonary function testing will include one or more of spirometry, lung volumes and DLCO. Study team 
will use the PFTs that are available from the medical record. The subject will be escorted to the MRI suite 
where they will be fitted with a 129Xe transmit-receive vest coil. They will then be positioned supine on the 
scanner bed. They will be coached about how to inhale HP 129Xe from the dose delivery bags. Then the 
subject and bed will be moved into the scanner and they will undergo basic 1H localizer and anatomical 
scans. Once localization is complete, subjects will undergo several MRI scans after inhalation of HP 129Xe. 
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 admin-
istered 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. After completing the 129Xe portion 
of the scan, the 129Xe coil will be removed and patients fitted with a torso array 1H coil. They will then 
undergo a free-breathing ultra-short-echo time 1H MRI to delineate lung structure. This completes the MRI 
exam, after which subjects will be free to go home or continue with their standard clinical care.  Altogether, 
the procedures will take approximately 3-4 hours.  
 
5.  Selection of Subjects: 
We propose to recruit and consent 10 subjects with known PAH, 10 subjects with isolated left heart 
disease, 10 subjects with isolated lung disease (either chronic obstructive pulmonary disease or interstitial 
lung disease) and 5 patients with CTEPH, followed by 92 subjects undergoing or having undergone an 
evaluation for PAH over the course of this research. These subjects will undergo an approximately hour 
long comprehensive MRI protocol, including hyperpolarized 129Xe administration. No subject will be ex-
cluded from the study on the basis of gender or ethnicity. Female subjects of childbearing potential will 
undergo pregnancy testing at study entry, and before each procedure. Informed consent will be obtained 
before a subject begins any study. 
 
Definition of PAH: Mean PA pressure ≥ 25 mmHg with PCWP ≤ 15 mmHg and PVR ≥ 3 WU in the 
absence of significant left heart disease, lung disease, chronic pulmonary embolism, hemolytic anemia, 
sarcoidosis and cancer. 
 
Definition of isolated left heart disease: Any of the following: 
1) A mean PA pressure >= 25 mmHg with PCWP > 15 mmHg and PVR < 3 Woods units at right heart 
catheterization. 
2) LVEF =< 40% with mild or less RV enlargement and dysfunction on echocardiogram. 
Evidence of diastolic dysfunction (as assessed by expert reader) with mild or less RV enlargement and 
dysfunction on echocardiogram. 
Definition of isolated lung disease: A mean PA pressure < 25 mmHg at right heart Cath AND/OR an 
estimated right ventricular systolic pressure of < 40 on echocardiography AND/OR no diagnosis of heart 


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failure or pulmonary hypertension IN THE SETTING OF obstruction (FEV1/FVC < 0.7)) on pulmonary 
function testing AND/OR radiographic evidence of lung disease. 
 
Definition of CTEPH: Subjects with a history of a mean PA pressure >= 25 with evidence of chronic 
thromboembolic disease on imaging studies. Images may be obtained before and/or after pulmonary 
thrombendarterectomy (PTE) surgery for removal of blood clots form the lungs. 
 
 
Inclusion criteria  
1. Outpatients of either gender, age > 18 
2. Willing and able to give informed consent and adhere to visit/protocol schedules. (Consent must 
be given before any study procedures are performed)  
3. Women of childbearing potential must have a negative urine pregnancy test.  This will be confirmed 
before participation in this investigational protocol. 
4. Either have a diagnosis of PAH, isolated left heart disease or lung disease (chronic obstructive 
pulmonary disease or interstitial lung disease) or CTEPH using established clinical criteria. 
5. Patients undergoing right heart catheterization for evaluation of PAH or other cardiac or pulmonary 
disease for MRI scans 
 
Exclusion criteria   
1. Medical or psychological conditions which, in the opinion of the investigator, might create undue 
risk to the subject or interfere with the subject’s ability to comply with the protocol requirements 
2. Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to lie supine)  
 
      6.  Subject Recruitment & Compensation: 
Patients will be recruited based on predetermined inclusion/exclusion criteria. They will be recruited in 
the pulmonary and cardiology clinics and inpatient services at Duke by their providers. The patient’s pro-
vider will initiate conversation with the subject about the research trial and assess their interest in partici-
pation.  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 sub-
ject will sign and date the consent form. A copy of the signed consent will be provided to the subject.  
After informed consent is obtained, potential subjects will be screened to determine if they satisfy all 
inclusion and exclusion criteria. If subjects agree to participate, they will be consented into the study by 
the clinical coordinator in a private room. All potential subjects will be given a description of the procedures, 
have the opportunity to read the consent form, and to ask any questions. All subjects are free to decide 
whether or not to participate. It will be made clear to all subjects that their decision to participate or decline, 
will in no way affect their medical care. For all subjects, informed consent will be documented by having 
the patient sign a standard research consent form approved by the Duke IRB. 
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 pro-
vides 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. 
 
7.  Consent Process: see Section 14 of the e-IRB submission form.  


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8.  Subject’s Capacity to Give Legally Effective Consent: Subjects without capacity to give consent 
will not be recruited into this study. 
 
9.  Study Interventions:  
Hyperpolarized xenon will be administered in multiple doses in volumes up to 25% of subject TLC 
followed by a breath hold of up to 15 seconds. Subsequent 129Xe doses will only be administered once 
the subject is ready to proceed. Hyperpolarized 129Xe MRI will be used to acquire one or all of the following 
data: 
 
1. 
129Xe calibration dose to test coil tuning and loading in each subject to permit optimal setting of imaging 
parameters. 
2. 
129Xe distribution after inhalation and breath-hold as an indicator of regional pulmonary ventilation.  
3. 
129Xe signal dissolved in the pulmonary interstitial spaces and capillary blood as an indicator of pul-
monary gas exchange. 
4. 
129Xe spectroscopy to follow the dynamics of gaseous and dissolved-phase 129Xe. 
5. Any of these 129Xe exams may be repeated if deemed necessary by the study team.  
6. Conventional 1H MRI will be used to provide anatomical reference scans, as well as pulmonary perfu-
sion. These will include some or all of the following: 
7. 3-Plane Localizer 
8. A variety of breath-hold 3D 1H MRI scans to delineate the thoracic cavity 
9. Free-breathing UTE 1H MRI to image tissue density and edema 
 
 
Study Visit Schedule 
 
 
1 for women of child bearing potential, a urine pregnancy test will be performed on the day of the MR 
examination. The test must be negative before MRI. The pregnancy test will be conducted and interpreted 
by study personnel who have completed competency training from the Duke Office of Clinical Research 
(DOCR).  
2 An MRI screening form will be completed at the screening session and will be verified prior to starting 
the imaging session. If a MRI is performed on a different day from the screening session, subject will need 
to complete a new MRI screen form.  
Protocol Activities 
Screening 
(V0) 
Study 
Visit 
(V1) 
Study Visit 
(6V2) only 
for CTEPH 
subjects) 
Follow Up/Release 
(after last dose) 
Follow-up     
contact w/in 
24 hr 
Informed Consent 
X 
 
 
 
 
History re: Disease 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Pregnancy Test1 
(X) 
(X) 
    (X) 
 
 
MRI Screening2 Form 
X 
   (X) 
X 
 
 
Imaging Session3. 
 
    X 
X 
 
 
Pulmonary Function 
Testing4 
(X) 
   (X) 
 
 
 
Adverse Events5 
 
    X 
 
        X 
    X 
Vital Signs Assess-
ment with optional 
non-invasive, optical 
Hemoglobin 
measurement 
X 
    X 
X 
        X 
 


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3The MRI session will be conducted on the CAMRD research MRI scanner. Hyperpolarized 129Xe is 
produced and delivered by the study team. Macrocyclic contrast agents are available at the scanner. 
.During the 1-hr MRI session, a qualified medical professional (MD, DO, PA, LNP, RN, RT or MT) will be 
on hand to monitor subjects during MRI and note any symptoms related to xenon MRI or contrast admin-
istration. 
 4 PFTs may not be acquired if subjects are undergoing scans for technical development purposes only or 
have such data available in their medical record. 
 
5 Based on the known pharmacokinetics of xenon, no additional effects are expected after subject is re-
leased from the imaging study. However, subjects will be contacted 24 hours after their participation to 
enable them to report any additional effects or events.  
6 Subjects will CTEPH will be ask to return for a second MRI. The second MRI will done post-surgically. 
 
 
10. 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 im-
aging.  
 
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 con-
centrations, 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.  
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. Numerous studies have now been published demonstrating the safety and tolerability of hy-
perpolarized 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 pre-
vent potential loss of confidentiality. All MRI will be conducted in the presence of a qualified healthcare 
professional trained and certified in the American Heart Association’s Advanced Cardiac Life Support 
(ACLS) training. This individual will be present in the MRI suite during 129Xe administration and will mon-
itor all aspects of the subjects well-being 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 


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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 de-identified prior to publication or presentation. All study personnel will have completed their institu-
tion’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. How-
ever, 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. 
 
11. Costs to the Subject: 
There are no additional costs to the subject for the MRI examination. Subjects will be compensated 
$100.00 for travel/parking and time for each study visit via a ClinCard. This does not include the screening 
visit. 
 
12. Data Analysis & Statistical Considerations: 
Sample size 
Our sample size calculation is based on testing whether the proposed diagnostic test based on Xe 
MRI has accuracy comparable to imaging diagnostic procedures in clinical practice, such as mammog-
raphy. To this end, we propose to test the hypotheses H0: AUC = 0.72 vs. H1: AUC > 0.85, where AUC 
is a summary measure of diagnostic accuracy obtained as the the area under the receiver operating 
characteristic (ROC) curve which displays the tradeoff between sensitivity and specificity for our proposed 
Xe MRI based diagnostic test. Here AUC = 0.72 represents a moderately accurate test while AUC = 0.85 
represents accuracy comparable to clinical mammography. Based on a one sided, one sample test with 
variances approximated using the binormal model, we estimate a minimum sample size of 46 normals 
and 46 with disease will be required to test the above hypotheses at a significance level of 5% with 80% 
power.  
 
Correlation 
Our preliminary Xe MRI studies on patients with PAH, in combination with our previous experience 
with normals as well as those with other diseases, have helped us formulate quantitative metrics based 
on Xe MRI studies with high diagnostic potential for PAH. These metrics include the proportion of voxels 
with low RBC/Gas transfer and the amplitude of the wave seen in Xe MRI based spectroscopy.  In Aim 
2, our goal is to identify a combination of these metrics which optimally correlates with the current diag-
nostic standard for PAH which is based on measurements obtained from right heart catheterization, in a 
training set of 30 patients with and without the disease. The optimal combination will be obtained using 
discriminant analysis, in which the Xe MRI based metrics will be used as predictors and the diagnosis 
obtained from right heart catheterization as outcome. To identify the optimal combination and associated 
thresholds, we will consider all possible combinations of predictors, as well as a variety of discriminant 
analysis techniques, such as linear discriminant analysis and support vector machines. To avoid optimis-
tic bias from overfitting, we will use leave out one cross validation to obtain an unbiased estimate of 
prediction error in the training set, which will be used to rank the most predictive discriminant rules. The 
actual diagnostic accuracy will be evaluated on a separate validation set of 92 patients in Aim 3.   
 


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13. Data & Safety Monitoring:  
All of the protocols in this proposal trial will be approved by Institutional Review Boards and reviewed 
periodically (every 12 months). Furthermore, all protocols are submitted as part of our investigational new 
drug application (IND# 109,490). 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 an-
esthetic/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, numb-
ness, 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. 
 
14. 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.  
 

ICF_001.pdf: 
Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 1 of 10
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 arterial 
hypertension (PAH) or a patient with heart disease or a patient with lung disease. 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.
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, your doctors will be Drs. Sudarshan Rajagopal, M.D, Joseph G 
Mammarappallil. M.D. Ph.D. and Bastiaan Driehuys, 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.
CONCISE SUMMARY
This is a research study to determine whether magnetic resonance imaging (MRI) using inhaled 
hyperpolarized 129Xe gas can help visualize impaired lung function and detect changes over 
time in patients receiving treatment. 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 heart 
and lung disease. This visit will be 3-4 hours and will consist of taking a medical history and 
MRI.
There is no direct medical benefit to you for taking part of this study. Our ultimate goal is to 
predict how a particular patient might respond to a particular therapy and to observe such 
responses earlier than conventional tests. We anticipate that the images acquired in this study 
will provide more specific information about lung disease than standard lung function tests. 
The 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. Risks of the xenon gas are slight numbness in legs, nausea, a feeling of well-being, and 
mild tingling in fingertips. You will have pulmonary function testing for the study, you may 
experience breathlessness or dizziness during or immediately following these tests. There is 
also a small risk of collapsed lung in people with certain types of lung disease.
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: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 2 of 10
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.
A grant from the National Institutes of Health (NIH)’s National Heart, Lung, and Blood Institute 
(NHLBI) will fund this study. Portions of Drs. Rajagopal, Mammarappallil, & Driehuys and their 
research team’s salaries will be paid by this grant.
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to determine whether magnetic resonance imaging (MRI) using inhaled 
hyperpolarized 129Xe gas, can help visualize impaired lung function and detect changes over time in 
patients receiving treatment. 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 combined with images 
taken with injected contrast agents or other types of MRI may provide a better way to look at lung 
structure and function in patients with heart and lung disease. Our ultimate goal is to predict how a 
particular patient might respond to a particular therapy and to observe such responses earlier than 
conventional tests. 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 127 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. The study involves the following study visits:
Screening Visit – At the screening visit, you will be asked for your medical history, 
record of medications, and your vital signs including hemoglobin (optional) by finger 
sensor device 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:

If you are female of child-bearing potential, you will be required to 
undergo a urine pregnancy test and it must be negative before you can 
continue to participate in this study.
Visit 1 - Imaging Study Visit. This visit may also occur at the same time as the 
screening visit or shortly after.
DUHS IRB
IRB NUMBER: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 3 of 10
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Description of Imaging Study Visit
This visit will take about 3-4 hours. The visit will begin with a review of your relevant history, 
symptoms, medications and rescreening for eligibility to participate, including:
a urine sample for pregnancy testing for women of child-bearing potential
by finger sensor device for hemoglobin level the day of the MRI.
Either after screening or on a separate day you will undergo pulmonary function testing to assess your 
global lung function using standard clinical tests. If pulmonary function test results are already 
available from your medical record, the pulmonary function tests will not be done.
MRI using inhaled hyperpolarized 129Xe gas
After pulmonary function testing you will participate in the MRI portion of the study. For the 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 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 measured 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.

Visit 2 - Imaging Study Visit. For Chronic Thromboembolic Pulmonary      
Hypertension (CTEPH) subjects ONLY
If you give consent, you will need to return post-surgery for a second visit at least 4 weeks 
post-surgical to have another MRI. Before the MRI, females who are of child bearing 
potential will have a urine pregnancy test performed and must have a negative result. You will 
need to complete a MRI screening form. You will be in the MRI no more than 1hr.
Follow-up
You will be followed-up by a short phone contact no more than 30 minutes long approximately 24 
hours later following study visit 1 and visit 2 (if applicable). You may be asked to return for a second 
scan in the study, at a time no earlier than 48hrs after your last xenon dose.
DUHS IRB
IRB NUMBER: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 4 of 10
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
In addition, the team may obtain information from your DUHS medical record and use this data to 
analyze the MRI scans obtained as part of this study. 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.
HOW LONG WILL I BE IN THIS STUDY?
Your study involvement will last approximately 1 to 2 weeks depending on scheduling of the Visit 1 
- Imaging Study Visit. CTEPH patients study involvement may last longer depending on scheduling 
of the post-surgical MRI scan.
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.
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.
Study Activities
Screening
Study Visit
1
Study Visit (2 
*only for 
CTEPH 
subjects)
Follow Up/
Release
(after last 
dose)
Follow-
up     
contact 
w/in 24 
hrs.
Informed Consent
X
History re: Disease
X
Medical History
X
Pregnancy Test (urine)
     (X)
(X)
     (X)
MRI Screening Form
X
       (X)
X
Imaging Session
        X
X
Adverse Events
        X
  X
 X
Vital Signs Assessment with 
optional non-invasive, 
optical Hemoglobin
measurement
X
        X
X
  X
DUHS IRB
IRB NUMBER: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 5 of 10
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
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 collected for this study are only used for research 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:
•
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 will be 
done on the day of your MRI study, and it must be negative before you can continue in this 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 PVD.
DUHS IRB
IRB NUMBER: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 6 of 10
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
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, the study team will record the results of your study-related laboratory tests 
including imaging results. These could include pulmonary function tests and MRI scans of the lungs 
with gas. In addition, the study team may obtain information from your DUHS medical record and use 
this to analyze the MRI scans obtained for this research study. The date and time included in your MRI 
scans will be stored indefinitely.
As part of the study, results of your study-related laboratory tests and procedures may be reported to 
National Institutes of Health (NIH), 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 NIH and the Duke University Health 
System Institutional Review Board. 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, and/or procedures performed. Some of 
these tests 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 research data office at Duke OR representatives 
and affiliates of National Institutes of Health (NIH). 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 forever. Any research information in your 
medical record will also 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. This data will be de-identified, meaning minimal information about you will 
be shared with this external investigator. Data shared can include sex, ethnicity, birthdate and date 
DUHS IRB
IRB NUMBER: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 7 of 10
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
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.
Certificate of Confidentiality:
The Department of Health and Human Services (HHS) has issued a Certificate of Confidentiality to 
further protect your privacy. With this Certificate, the investigators may not disclose research 
information that may identify you in any Federal, State, or local civil, criminal, administrative, 
legislative, or other proceedings, unless you have consented for this use. Research information protected 
by this Certificate cannot be disclosed to anyone else who is not connected with the research unless:
1)
there is a law that requires disclosure (such as to report child abuse or 
communicable diseases but not for legal proceedings);
2)
you have consented to the disclosure, including for your medical treatment; or
3)
the research information is used for other scientific research, as allowed by 
federal regulations protecting research subjects.
Disclosure is required, however, for audit or program evaluation requested by the agency that is 
funding this project or for information that is required by the Food and Drug Administration (FDA).
You should understand that a Confidentiality Certificate does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your involvement in this research. If 
you want your research information released to an insurer, medical care provider, or any other person 
not connected with the research, you must provide consent to allow the researchers to release it. This 
means that you and your family must also actively protect your own privacy.
Finally, you should understand that the investigator is not prevented from taking steps, including 
reporting to authorities, to prevent serious harm to yourself or others.
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 
DUHS IRB
IRB NUMBER: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 8 of 10
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
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.
WHAT ABOUT COMPENSATION?
You will be reimbursed up to $100 for your expenses related to your participation in completion 
of Study Visits.
Screening visit $50.00 
Study visit 1     $50.00
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., or your Duke physicians 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.
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. 
DUHS IRB
IRB NUMBER: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 9 of 10
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
The sponsor or regulatory agencies may stop this study at any time 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.
DUHS IRB
IRB NUMBER: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ADULT
Non-Invasive Diagnosis of Pulmonary Vascular Disease Using 
Inhaled 129Xe Magnetic Resonance Imaging: VITA
Page 10 of 10
*
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
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: Pro00079617
IRB REFERENCE DATE: 09/02/2020
IRB EXPIRATION DATE: 01/19/2021