Using Xenon MRI to Evaluate the Efficacy of Therapies for Idiopathic Pulmonary Fibrosis
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Duke University

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Using Xenon MRI to Evaluate the Efficacy of Therapies for Idio-
pathic Pulmonary Fibrosis 
 
 
Robert M Tighe, MD – Principal Investigator  
Duke University, School of Medicine 
Department of Medicine 
Division of Pulmonary, Allergy and Critical Care 
Robert.tighe@duke.edu 
 
Bryan Kraft, MD – Co Investigator 
Duke University, School of Medicine 
Department of Medicine 
Division of Pulmonary, Allergy and Critical Care 
Bryan.Kraft@duke.edu 
 
Lake Morrison, MD – Co Investigator 
Duke University, School of Medicine 
Department of Medicine 
Division of Pulmonary, Allergy and Critical Care 
Lake.Morrison@duke.edu 
 
Joseph Mammarappallil, MD PhD – Co Investigator 
Duke University, School of Medicine  
Department of Radiology 
joseph.mammarappallil@dm.duke.edu 
 
Bastiaan Driehuys, Ph.D. – Co- Investigator 
Duke University, School of Medicine  
Department of Radiology 
bastiaan.driehuys@dm.duke.edu 
 
 
 
 
 
 
Sponsor: Genentech 
 
NCT04071769 

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RESEARCH SUMMARY 
 
1. Protocol Title: Using Xenon MRI to Evaluate the Efficacy of Therapies for Idiopathic 
Pulmonary Fibrosis 
2. Purpose of the Study: The purpose of this PI initiated, industry sponsored study is to 
perform a carefully controlled study to assess if Xenon MR imaging can be used to deter-
mine treatment efficacy of Idiopathic Pulmonary Fibrosis (IPF) therapies. IPF is a devas-
tating disease affecting more than 100,000 US residents. Patients with IPF have poor 
prognosis, with a mean survival time of only 35.2 months. The hallmark of the disease is 
a progressive process of scaring in the lung that results in thickening of the pulmonary 
blood-gas barrier and impaired gas exchange. In 2014, two medications became available 
for treatment of IPF. Over the 52 week studies, pirfenidone and nintedanib were demon-
strated to slow, but not halt, the decline in lung function (as defined by reduction in forced 
vital capacity (FVC)) associated with progressive pulmonary fibrosis. Since delayed de-
cline in FVC is the treatment response, it remains difficult to determine if therapies are 
helping an individual patient as physicians are not able to compare the individuals rate of 
decline off therapy. Additionally, testing new therapies for IPF require long term studies to 
assess changes in physiologic parameters. This makes developing potential new thera-
pies both time and resource limited.  
We intend to address this problem by using a MRI-based 3D imaging approach to predict 
and observe regional therapeutic response. The objective of this study is to use these MRI 
approaches to identify regional diffusion limitation, and then use them to predict and ob-
serve therapeutic response earlier than standard methods (such as decline in FVC). Our 
central hypothesis is that Xenon MRI by identifying the leading edge of disease, where 
recovery of lung function remains possible, will allow us to define treatment responses to 
IPF therapies. The rationale for the proposed research is that therapeutic response is dif-
ficult if not impossible to detect using global metrics and thus, 3D non-invasive imaging is 
needed to visualize recoverable areas. If this is the case, it would allow providers to de-
velop targeted treatments for individuals with IPF and would enable more rapid assess-
ment of potential therapeutic efficacy with potential novel IPF therapies. 
The protocol will leverage advances in MR imaging that facilitate the assessment gas ex-
change, as well as pulmonary structure, ventilation, and perfusion within a single inte-
grated MRI exam. Pulmonary ventilation and gas exchange are assessed 3-dimensionally 
by using inhaled hyperpolarized 129Xe MRI, which has been developed at Duke over the 
past 6 years under IRB protocol Pro00025110 (among others) and IND #109,490. As 
demonstrated in a recent publication by our group, we can execute a fully 3D MRI protocol, 
capable of assessing all relevant aspects of pulmonary structure and function in a single 
exam. Since this approach does not use ionizing radiation, it can more safely be utilized 
to follow patients over time to facilitate following treatment responses.  
The study has the following Specific Aims: 1) Clearly establish baseline Xenon MRI char-
acteristics in newly diagnosed IPF patients and compare them to standard measures 
(HRCT, Pulmonary Function testing and 6 minute walk distance), 2) Use 129Xe exchange 
MRI to monitor progression and response to IPF therapies by comparing baseline MRI 
characteristics to alterations following initiation of treatment at specific time points. Our 
ultimate scientific objective is to develop a diagnostic paradigm that can predict patient 
therapeutic responses.   
3. Background and Significance: Idiopathic pulmonary fibrosis (IPF) is a progressive 
interstitial lung disease that in a majority of cases leads to morbidity and mortality. The 

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median survival time from diagnosis is less than 3 years, and the disease affects an esti-
mated 134,000 Americans, though this prevalence is likely an underrepresentation of the 
true disease burden. IPF is characterized by gas exchange impairment from thickening of 
the pulmonary blood-gas barrier. Although high-resolution CT is integral to the initial diag-
nosis of IPF, it has not proven useful as a means to monitor disease progression or therapy 
response. As noted by the American Thoracic Society, “…the diagnosis and management 
of patients with IPF continues to pose a significant challenge.” Despite the two recently 
approved therapies (Nintedanib and Pirfenidone), no IPF therapies have yet been devel-
oped that meaningfully reverse this progressive lung fibrosis. Furthermore, genetic and 
clinical studies clearly demonstrate significant disease heterogeneity. This suggests that 
IPF patients will required personalization of their therapies. This requires sensitive and 
accurate measure to assess disease progression and response to treatment. Presently 
the field is hampered by poor techniques for assessing lung function and development of 
fibrosis. Therefore, there is a pressing need for improved methods to monitor disease 
progression and detect response to therapy. It is becoming increasingly clear that the pri-
mary roadblock facing the treatment of IPF is not necessarily a lack of viable therapies, 
but rather a lack of adequate means to test them.   
IPF manifests in a spatially heterogeneous manner pathologically defined as areas of nor-
mal lung in close approximation to areas of fibrosis. Therefore, we expect that therapeutic 
responses would be regional. Thus, to detect progression and therapy requires localizing 
effects on structure and function, and monitoring these regions over time. Advances in 3D 
pulmonary magnetic resonance imaging (MRI) now make this possible. Although high res-
olution computed tomography (HRCT) is required for IPF diagnosis, it is poorly suited to 
monitor therapeutic response. CT detects structural abnormalities, but the earliest harbin-
ger of changing disease status is function. Additionally, CT scans and particularly HRCTs 
require use of ionizing radiation. The ability to image both function and structure is now 
ideally served by recent advancements in MRI. Because 129Xe, like oxygen, must traverse 
the interstitial barrier to reach capillary blood, 129Xe signal in RBCs is exquisitely sensitive 
to barrier thickness. 129Xe in RBCs has a unique frequency shift, allowing it to reveal inter-
stitial thickening of only a few microns. The exquisite sensitivity to increased blood-gas-
barrier thickness makes 129Xe MRI uniquely suited to study pulmonary fibrosis without 
ionizing radiation. This has the potential to accelerate clinical trials for IPF by literally vis-
ualizing the therapeutic response on the timescale of months versus years.  
Hyperpolarized 129Xe MRI has been shown to be safe and well tolerated in a phase I clin-
ical trial for HP 129Xe MRI that was completed at Duke and published in the journal Radi-
ology in 2012. Additionally, we have now published on the use of this technology in pa-
tients with IPF, asthma, COPD, and pulmonary vascular disese. These studies have en-
rolled in excess of 250 patients and healthy volunteers and demonstrated that inhalation 
of up to four 1 liter doses of HP 129Xe was well-tolerated, generated no notable changes 
in measured physiologic parameters and resulted in no SAEs or withdrawals. Thus, Duke 
has the technical experience and infrastructure to conduct this study. 
4. Design and Procedures: This will be an unblinded, open-label study enrolling newly 
diagnosed patients with IPF. We plan to consent 50 subjects including screen fails with a 
goal of obtaining 30 newly diagnosed individuals with IPF prior to initiation of IPF thera-
pies. 20 subjects will be monitored after the initiation of therapy, 10 subjects will be en-
rolled that do not start antifibrotic therapy. No subject will be excluded from the study on 
the basis of gender or ethnicity. IPF is an aging disease with highest incidence in subjects 
>50 years of age, and therefore subjects will be expected to be >50 years of age. Subjects 
will be obtained from providers in the Duke Pulmonary Clinics. Informed consent will be 

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obtained before a subject begins any study intervention. Subjects will undergo an approx-
imately hour long comprehensive MRI protocol, including administration of multiple doses 
of HP 129Xe. The subjects will have this initial study prior to initiation of IPF therapies. Then 
the subjects will have repeat studies at 3, 6 and 12 months following the initation of ther-
apy. Additional studies including pulmonary function studies, serum for biomarkers, 6 mi-
nute walk distance (only at screening visit, 3 month and 6 month visit) and a HRCT (only 
at the screening visit and 6 month visit) will be performed to determine how 129Xe MRI 
performs relative to standard of care evaluations for IPF. Finally, following the study visits 
the research team will prospectively follow the patients’ clinical course through periodic 
reviews of the medical record.  
 
Prior to consideration for the study, all patients will have their IPF diagnosis formally con-
firmed at the Duke multidisciplinary ILD conference. Either through discussions at the mul-
tidisciplinary conference or through referral from the patient’s pulmonolgist, the study co-
ordinator will identify potential patients. With their primary doctors approval, the coordina-
tor will have an initial screening phone call with the patient to assess their interest in the 
study (V0). If the patient is interested, a screening visit will occur (V1). The screening visit 
will start with a history and physical exam and a review of the protocol to obtain informed 
consent. Following informed consent, the patient will undergo spirometry including lung 
volume and a DLCO measurement, assessment of a 6 minute walk distance (6MWD) and 
a HRCT scan if not done at the initial visit with the pulmonary provider. Venous blood will 
be obtained to get cells for DNA and RNA and plasma for biomarkers, a nasal swab will 
be performed, and a urine sample will be obtained from the subject. 
Following these initial screening studies, the patient will undergo a 129Xe – MRI exam. The 
details of the 129Xe MRI are as follows. 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 cur-
rently 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 dynamic spectroscopy and calibration, and 129Xe gas exchange MRI. Any 
given 129Xe MRI scan may be repeated, if necessary. After completing this sequence, the 
subject will get off the MRI table, rest for 5 minutes and then undergo the same scans to 
assess repeatability. 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.  
 
Following visit V1, the coordinator will ask the patient and/or contact the patient to confirm 
the start date of an FDA approved IPF therapies (pirfenidone and nintedanib). The deci-
sion of which type of therapy will be completely at the discretion of the patient and their 
primary pulmonologist but will be recorded by the coordinator. Following initiation of ther-
apy, the subject will return for visits at 3 (V3), 6 (V4) and 12 (V5) months following initiation 
of therapy. At that time, the subjects will undergo a physical exam, spirometry and a 
6MWD (only at screening visit, 3 month and 6 month visit)if not performed as a part of 
their usual care. At 6 months, the subjects will also undergo a HRCT scan. This will not 

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be performed at the other pre-specified visits. At these 3, 6 and 12 month visits, as a part 
of the study, subjects will undergo repeat 129Xe MRI studies and a venous blood draw to 
obtain cells for RNA and serum for biomarkers, a nasal swab, and urine sample collection. 
Following the 12 month visit, a chart review will be performed at 6 month intervals and 
clinical IPF characteristics will be recorded to determine clinical outcomes, for a period of 
5 years (V6). No additional direct study contact with the patients will occur after the 12 
month visit (V5). For subjects lost to follow-up prior to completing all 4 in person visits, 
we will request written permission in the informed consent to use their standard of care 
(SOC) assessments to obtain clinical data such as physical exam, vitals, PFTS and 6MWD 
that pertain to the timepoints noted above (3 months, 6 months and 12 months post initia-
tion of therapy).  
 
5. Selection of Subjects: The population to be studied will consist of patients with a phy-
sician diagnosis of idiopathic pulmonary fibrosis. 
 
Inclusion/Exclusion Criteria  
 
Inclusion Criteria  
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the trial  
 
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. Clinical diagnosis of IPF by confirmed by multidisciplinary diagnosis and naïve to 
treatment with an approved IPF therapy (either nintedanib or pirfenidone) 
 
Exclusion Criteria 
 Subjects presenting with any of the following will not be included in the trial: 
1. Subject is less than 18 years old 
2. Subjects who have been previously on either pirfenidone or nintedanib 
3. MRI is contraindicated based on responses to MRI screening questionnaire 
4. Subject is pregnant or lactating 
5. Resting oxygen saturation on room air <90% on supplemental oxygen 
6. Respiratory illness of a bacterial or viral etiology within 30 days of MRI 
7. Subject with ventricular cardiac arrhythmia in the past 30 days. 
8. Subject has history of cardiac arrest within the last year 
9. Subject does not fit into 129Xe vest coil used for MRI 
10. Subject deemed unlikely to be able to comply with instructions during imaging 
11. Recent exacerbation (within 30 days) defined by the need for antibiotics and/or 
systemic steroids  
12. 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 
 
Subject Identification: Subjects will be enrolled in the study by a unique identifier, which 
will be used for all subsequent analyses. Image acquisition is done by entering the sub-
ject’s year of birth along with height and weight into the scan set-up page. 129Xe and 1H 
MR images will be analyzed with respect to age, gender, heart rate, relevant medical his-
tory, and prior image findings. Any such personal health information (PHI) will be obtained 

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from the records only by trained clinical research personnel and will then be associated 
with this unique patient identifier. CT scans will be paid for by grant funds, if not performed 
for clinical reasons by the provider, and will transferred to PACs.  
 
6. Subject Recruitment and Compensation: Subjects with IPF will be recruited from 
providers in the Duke pulmonary clinics via flyers, and website postings and from identifi-
cation at multidisciplinary diagnosis conference. Patients with IPF will be informed about 
study participation by their physician or a nurse during their clinic visit. If they are inter-
ested in participating and appear to meet all inclusion criteria they will be referred to the 
study coordinator for formal consenting. Recruitment will be open to all demographic 
groups. Subjects will be compensated $100.00 after each MRI visit for their travel/parking 
and time. A total for 4 MRI studies will be performed to complete the study for a total 
compensation of $400.00. If a procedure has to be cancelled for technical reasons after a 
subject has arrived on site, the subject will be compensated as though he/she had com-
pleted that visit. The subject will be encouraged, but not required, to return at a later date 
to complete the procedure. If the subject returns, he/she will be compensated again. Pa-
tients may withdraw from the study at any time for any reason.  
 
7. Consent Process: The study coordinator will consent prospective participants. If nec-
essary, the participants will have no less than 24 hrs to consider their participation. The 
consenting will take place in the private room or laboratory setting with closed doors. Only 
the coordinator and prospective participant will be in the room during the consent process. 
We will encourage potential subjects to ask questions and to take as much time as needed 
to consider participation. If the subject wishes to consider the study overnight or longer, 
an additional appointment will be made for the subject to continue the consent process. 
From the time of initial contact until the participant completes the study they will have a 
coordinator’s contact information. 
  
 
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. Subse-
quent 129Xe doses will only be administered once the subject is ready to proceed. Hy-
perpolarized 129Xe MRI will be used to acquire one or all of the following data: 
 
Pre- treatment (Study V1)  
1. 3-Plane Localizer  
2. 
129Xe dynamic spectroscopy and calibration to test coil tuning and loading in each 
subject to permit optimal setting of imaging parameters. 
3. 
129Xe distribution dissolved in the pulmonary interstitial spaces and capillary blood 
as an indicator of pulmonary gas exchange. 
4. Breath-hold 3D radial MRI to delineate the thoracic cavity  
5. Subjects will dismount the MRI table, rest for 5 minutes  
6. 3-Plane Localizer  
7. 
129Xe dynamic spectroscopy and calibration to test coil tuning and loading in each 
subject to permit optimal setting of imaging parameters. 
8. 
129Xe distribution dissolved in the pulmonary interstitial spaces and capillary blood 
as an indicator of pulmonary gas exchange. 
9. Breath-hold 3D radial MRI to delineate the thoracic cavity  
  

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Post Treatment (V3, V4, and V5)  
1. 3-Plane Localizer 
2. 
129Xe dynamic spectroscopy and calibration to test coil tuning and loading in each 
subject to permit optimal setting of imaging parameters. 
3. 
129Xe distribution dissolved in the pulmonary interstitial spaces and capillary blood 
as an indicator of pulmonary gas exchange. 
4. Breath-hold 3D radial MRI to delineate the thoracic cavity  
 
If any of these scans are deemed by the study team to require repeating, this may be 
done as needed 
 
 
HRCT scans will be done in the prone position at both inspiration and expiration using the 
protocol commonly used in IPF clinical trials. 
 
10. Risk/Benefit Assessment: As this is the first rigororous prospective study of its kind 
for using MRI to monitor patients with IPF, it is not known if the data generated will be of 
direct benefit to the patients participating. However, the knowledge gained from these 
studies is expected to benefit future patients with IPF. 
 
Risks of Hyperpolarized 129Xe 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.  
 
Risk of HRCT: Ionizing radiation exposure for the low dose CT is estimated at 2mSievert 
for each scan. For both inspiratory/and expiratory scans, the total dose is estimated at 
4mSievert, roughly the equivalent of 1 year of natural radiation exposure. 
 
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. 
Therefore, 129Xe is not mixed with O2 within the dose delivery bag, but only once it is 
inhaled. Administration of a single anoxic 1-liter breath has been well tolerated by subjects 
undergoing both 3He MRI and 129Xe MRI. After a single breath, the residual oxygen in the 
subject’s lungs is sufficient to maintain blood O2 saturation during the breath-hold. For 
each subject, their blood-oxygenation will be monitored throughout the time they are in the 
MRI scanner. To reduce risk, a baseline resting oxygen saturation of 90% on supplemental 
oxygen will be required.  Furthermore, supplemental oxygen will be provided during the 
MRI exam as indicated. 
 
Incidental Findings – Incidental findings will be handled according to the policies of the 
Duke IRB. That is, anatomic 1H MR images will not be routinely reviewed by a radiologist. 
However, if the technologist or study personnel note suspicious findings in the anatomic 
(1H) images at the time of MRI, images from those subjects will be reviewed by a radiolo-
gist within 10 business days for incidental findings (tumors, hernias, aneurisms, etc). Such 
incidental findings will be communicated to the subject’s physician. Copies of images will 
be made available to the subject’s physician upon their request. If subjects undergo low-

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dose CT as part of this protocol, those scans will be reviewed for incidental findings by a 
radiologist on the study team. 
11. Costs to the Subject and Compensation: There are no additional costs to the sub-
ject for the MRI examination and possible CT scan. Subjects will be compensated $100.00 
for travel/parking and time for each study visit. This does not include the initial screening 
phone call and the phone call to document initiation of IPF therapy. 
 
12. Data Analysis & Statistical Considerations: All images will be reviewed by the study 
team. Given that this is an early phase study with no clinical experience this will be a 
research interpretation and not a clinical read. Images and spectra will be analyzed by a 
varieity of quantitative metrics using established methods. Imaging metrics include the 
ventilation defect percentage (VDP), percentage of lung with high barrier uptake (Barri-
erhigh), and percentage of lung with defects in red blood cell transfer (RBClow). Spectro-
scopic markers will include the ratio of 129Xe transfer to RBCs vs barrier (RBC:barrier) as 
well as RBC oscillation and frequency oscillation amplitudes. CT scans will be evaluated 
by a chest radiologist using established criteria to produce a mean fibrosis score based 
on the extent of reticulation and honeycombing and and will range from 0-100%.  
 
Although sensitivity to therapy response is expected to be highest for the imaging metrics, 
the study has been conservatively powered on the basis of the spectroscopic RBC:barrier 
ratio, which thus far, is most well-documented of the 129Xe metrics in the literature. Early 
studies, which did not control carefully for lung inflation reported a variability of 6.6% in 
this metric. Moreover, a recent study of natural progression in a group of IPF patients 
(n=18, on a mix of treatments or untreated) revealed a decline in RBC:barrier of 20% in 
this metric over the course of 6 months. We assume that we will observe a smaller decline 
in RBC:barrier in our cohort, which will all receive treatment, and estimate that only a 10% 
decline will be observed at 12 months. Given this estimate of variability and effect size, 
and requiring 90% power, would be achived with a sample of only 5 patients. Based on 
established patterns in our clinics, we expect roughly half the patients to receive 
pirfenidone with the other half receiving nintedanib. Assuming that one of the drugs re-
duces RBC:barrier decline to only 5% over 12 months, whereas the other yields a decline 
of 10%, would require a sample of 19 patients, which is just achievable with the sample of 
20 patients expected to be enrolled.  
 
Baseline Repeatability and Prespecified Futility Analysis – As this is a new clinical study 
with unknown efficacy in detection a preliminary analysis of the data will be performed. 
Following completion of the first 10 patients in the study the study team will perform an 
analysis for futility based on test – retest variability. Baseline repeatability of each of the 
129Xe metrics will be assessed using Bland- Altman plots, and a pairwise, two-tailed t-test 
will be used to check for significant differences. For each derived parameter, the coeffi-
cient of variation will be calculated. Our threshold to stop the study is if the RBC:Barrier 
ratio is outside of 95% CI on test-retest of ±20% of the dynamic range. We estimate the 
95% confidence interval to be better than ±10% with this sample size.  
 
Correlation between 129Xe metrics, CT scores, and clinical tests will be evaluated using 
the Pearson correlation coefficient.  
   
To measure changes from baseline, we will calculate the mean, standard deviation, me-
dian and range of each metric, and at each time point, the 95% confidence interval for 
means and averaged changes relative to baseline will be provided. Changes compared to 

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baseline will be tested using the Wilcoxon Singed-Rank test. In all analyses, P < 0.05 (two-
sided) will be considered the criterion for statistical significance. There will be no adjust-
ment for multiple testing, because of the small number of hypothesis tests considered. 
The trajectory changes of these endpoints over time will be evaluated using linear models 
for repeated measures. Point estimates and confidence intervals for relevant parameters 
will be provided for descriptive purposes. 
 
Baseline images will be analyzed for functional or structural indicators that may predict 
therapeutic response using mixed linear models. We will conduct this modeling, while con-
sidering differences in treatment group, clinical/demographic covariates (fixed effects), 
and subject (random effect). Diagnostic plots will be obtained to assess possible violations 
in model assumptions. All statistical analyses and graphics will be generated in R, or sim-
ilar statistical package. 
 
13. Data and Safety Monitoring: 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 de-
scribe how they feel as well as about specific symptoms including: dizziness, light-head-
edness, numbness, euphoria, sleepiness, and tingling in extremities. Heart rate will be 
measured before and after each xenon dose. Changes in heart rate of greater than +/- 
20% are considered significant. If the subject is to receive another dose, the next dose will 
not be administered until the heart rate is within 20 % of its baseline value. If the subject 
has received their last dose, they will be observed until their heart rate is within +/- 20% 
of its base line value or until the end of the observation period, whichever is longer. 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.  
 
Research Specimens: Research material, which will be collected from human subjects 
and includes; serum, and DNA.  These data will be collected for research purposes, but 
remain available, if need and agreed to, by the subject for future research use. DNA will 
be stored indefinitely. Samples will be de-identified by assigning a code only accessible 
to PIs and study team, DNA will primarily be used for this study but could also be used 
for future studies (outlined in the consent using standardized language). If sample is pro-
vided to outside investigators, the DNA and clinical information will only be identified by 
the assigned code. 
 
Discontinuation - Participation in this study is voluntary and subjects are free to withdraw 
at any time and for any reason. Furthermore, the individual subject will be withdrawn from 
the trial should they develop any worsening of health or new medical illness that is deemed 
to be a result of this study. Parameters to be evaluated include but are not limited to: 
shortness of breath, heart rate or decreased blood oxygenation related to xenon admin-
istration. If a subject experiences a decrease in oxygenation that is greater than or equal 
to 5% that persists for more than 5 minutes post xenon administration, they will be with-
drawn from the trial. Similarly, if patients experience a change in heart rate of more than 

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20% on more than one occasion after xenon administration they will be withdrawn. Other 
reasons for discontinuation include subject becomes uncomfortable in the magnet, subject 
becomes unresponsive or is unable to protect their airway, subject requests study discon-
tinuation, or other concerns. If any subject experiences a serious adverse drug experience 
(as defined in 21 CFR Part 312.32(a)), the trial will be discontinued immediately.  
 
 
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 investiga-
tor. 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. The data is stored in a password protected, controlled 
access account with authentication and mandatory password change features. After all 
manuscripts have been published the key to the code will be destroyed.  
 
 
Schedule of Events 
Protocol  
Activities 
Screening 
Phone Call 
(V0)1 
Study  
Visit 
(V1) 
Study 
Visit (V2) 
Study 
Visit (V3)  
Study  
Visit (V4) 
Study  
Visit (V5) 
Prospective 
Clinical F/U (V6) 
Patient phone call  X 
 
X 
 
 
 
 
Informed 
Con-
sent1 
 
X 
 
 
 
 
 
Medical History2 
 
X 
 
(X) 
(X) 
(X) 
 
MRI 
Screening 
Form 
 
X 
 
(X) 
(X) 
(X) 
 
Pulmonary Func-
tion Testing3 
 
X 
 
X 
X 
X 
 
6 minute walk dis-
tance4 
 
X 
 
X 
X 
 
 
Pregnancy Test5 
 
(X) 
 
(X) 
(X) 
(X) 
 
HRCT6 
 
(X) 
 
 
(X) 
 
 
MRI Session7 
 
X 
 
X 
X 
X 
 
Subject 
monitor-
ing8 
 
X 
 
X 
X 
X 
 
Vital signs 
 
X 
 
X 
X 
X 
 
Adverse 
events 
followup9 
 
X 
 
X 
X 
X 
 
Prospective/Ret-
rospecitve clinical 
monitoring 
in 
chart10 
 
 
 
 
 
 
X 
 
1. For most subjects, screening and study visit 1 will occur on the same day. How-
ever, these visits can be conducted separately if needed. 
2. Full medical history will be obtained at intial visit. On subsequent visits, changes 
in history will be assessed if not performed as a part of the patients routine care.   
3. Pulmonary function testing will include one or more of spirometry, lung volumes, 
DLCO. If some or all PFT information is already available from the patient record 
(performed in the context of usual care) and deemed sufficient by study personnel, 
PFTs may not be collected. 

Using Xenon MRI to Evaluate the Efficacy of Therapies for Idi-opathic Pulmonary Fibro-
sis 
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4. If 6MWD (only at screening visit, 3 month and 6 month visit)  is already available 
from the patient record performed in the contest of usual care) and deemed suffi-
cient by the study personnel, 6MWD may not be collected.  
5. Any female patients of child-bearing potential will receive a urine pregnancy test 
at screening. The test must be negative before MRI. The pregnancy test will be 
conducted and interpreted by study personnel who have completed appropriate 
competency training per their institution’s guidelines.  
6. HRCT will be performed by the study at these intervals if not a part of the patient’s 
usual clinical care. 
7. The MRI session will be conducted by the imaging study team, who will provide 
the necessary volumes of hyperpolarized 129Xe per their standard SOPS.  
8. 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 symp-
toms related to xenon MRI or contrast administration.  
9. Based on the known pharmacokinetics of xenon, no additional effects are expected 
after subject is released from the imaging study. However, subjects will be pro-
vided contact information for the study coordinator so they can report any concerns 
over the 24 hours after undergoing MRI and HRCT scan.  
10. This will be to monitor the ongoing clinical care of individuals following completion 
of the MRI portions of the study, for a period of 5 years. This will not involve patient 
contact but just review of the available clinical information as a part of the individ-
uals IPF care. In particular will focus on changes in lung function, death, lung trans-
plant and changes in IPF therapy.