Imaging and Understanding Bronchiolitis Obliterans Syndrome (BOS) in Lung Transplantation With Hyperpolarized 129Xenon MR Lung Imaging
Phase: PHASE1
Conditions: Bronchiolitis Obliterans
Sponsor: Children's Hospital Medical Center, Cincinnati

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Cover Page 
 
 
Title: Imaging and Understanding Bronchiolitis Obliterans Syndrome (BOS) in Lung Transplantation 
with Hyperpolarized 129Xenon MR Lung Imaging 
 
NCT: NCT03603899 
 
Study Doc Version: 19Sep2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Imaging and Understanding Bronchiolitis Obliterans 
Syndrome (BOS) in Lung Transplantation with 
Hyperpolarized 129Xenon MR Lung Imaging 
 
 
 
 
 
 
 
Sponsor/Principal Investigator:  Jason C. Woods, PhD 
Professor of Pediatrics & Radiology, 
Director, Center for Pulmonary Imaging Research, 
Division of Pulmonary Medicine 
Department of Radiology 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Ave 
Cincinnati, Ohio 45229 
Jason.Woods@cchmc.org 
 
 
 
 
 

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1. ABSTRACT:   
Lung transplantation has evolved into an effective therapeutic option for a large number of 
pediatric patients with end-stage pulmonary disease. Long-term survival after lung 
transplantation, however, is far worse than after the transplantation of other solid organs. Chronic 
allograft rejection in the form of obliterative bronchiolitis (BO) affects 50-60% of lung transplant 
recipients who survive 5 years after transplant. The time between transplantation and onset of 
bronchiolitis obliterans syndrome (BOS) can range from a few months to several years.  
 
An established mouse model of BOS exists and gives insight to BOS mechanisms of specific 
epithelial injury and aberrant repair but mouse models do not translate perfectly to human 
pathophysiology. Additionally, we have developed MR-imaging biomarkers that will allow targeted 
biopsy and longitudinal monitoring without ionizing radiation.  
 
This protocol aims to  
 
• 
Develop new imaging methods that are sufficiently sensitive to allow early diagnosis of 
BOS. 
• 
Improve patient treatment outcomes through earlier diagnosis of changes leading to BOS 
by obtaining image guided clinical biopsies of transplanted lung.  
• 
Provide image guided research biopsies, where applicable, for use in future research of 
ex vivo biomarkers of BOS and in the development of treatments through future clinical 
trials. 
 
We will achieve these aims through a prospective, non-randomized, longitudinal, observational 
study that will recruit about 5 subjects a year for 5 years. We will follow these post lung transplant 
patients at 6 months and 1 year with 129Xe MRI (Hyperpolarized 129Xenon Magnetic Resonance 
Imaging) and image guided bronchial biopsies to detect early BOS and to better understand BO 
disease progression. The research biopsies will provide samples for future research for rapid 
determination of cellular and molecular mechanisms that lead to BOS and to facilitate 
identification and validation of translatable pharmaceutical targets. 
 
 
2. PURPOSE OF STUDY:   
Lung transplantation has evolved into an effective therapeutic option for a large number of 
pediatric patients with end-stage pulmonary disease. Long-term survival after lung 
transplantation, however, is far worse than after the transplantation of other solid organs. Chronic 
allograft rejection in the form of obliterative bronchiolitis (BO) affects 50-60% of lung transplant 
recipients who survive 5 years after the transplant (1) and represents the most formidable 
challenge in this field. The time between transplantation and onset of bronchiolitis obliterans 
syndrome (BOS, the clinical surrogate of obliterative bronchiolitis) can range from a few months 
to several years, but this rejection is not well understood (2, 3). Current clinical practice calls for 
periodic post-transplant visits, where pulmonary function tests and airway biopsies determine a 
near-binary decision on the need for alteration of immunosuppression (4).  The rational way 
forward to address the issue of long-term survival is a comprehensive, multidisciplinary and 
translational approach that combines image-guided biopsy, multi-modality longitudinal monitoring 
in lung-transplant recipients, and an established mouse model of BOS to understand this specific 
epithelial injury and aberrant repair.  We intend to lay the framework here for such a combined 
approach that has a likelihood of improving clinical care in our own transplant recipients, while 
simultaneously determining molecular mechanisms of epithelial injury and repair related to BOS. 
 

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The histological hallmark of BOS is partial or complete occlusion of the lumina of terminal and 
respiratory bronchioles by fibrous tissue which leads to diminished airflow and attenuated alveolar 
function in a punctuate, heterogeneous pattern (Fig 1). The mechanisms that initiate and 
contribute to chronic rejection are not known, and there are no known biomarkers that predict the 
progression of BO lesions. Our lack of understanding of these mechanisms has made it difficult 
to successfully design immunosuppressive or other modalities that could treat or prevent the 
disease. BOS is likely initiated from a combination of epithelial injury and many allo-immune-
dependent and independent factors.   
 
We have recently established the first mouse 
model transplantation and BOS, which is a left-
lung allograft transplant.  After transplantation we 
can conditionally deplete all bronchiolar Clara 
cells of the graft, which is similar to an epithelial 
injury in humans that can be caused by influenza, 
smoking and other environmental stresses. While 
a normal lung (in a healthy, non-transplant 
patient/mouse) completely repairs within 1-2 
weeks, the transplanted lung graft develops BO 
lesions and advances to chronic graft rejection. 
With the mouse model we are now able to 
specifically induce BO and follow disease 
progression by imaging, histopathology, and 
immune-phenotyping via flow cytometry and 
molecular analysis for protein and gene 
expression. This will allow rapid determination 
of cellular and molecular mechanisms that lead 
to BOS and facilitate identification and 
validation 
of 
translatable 
pharmaceutical 
targets. This thorough analysis of the mouse 
model 
will 
provide 
us 
with 
the 
basic 
understanding of BO disease progression but to translate into human models, we will work to 
validate with the biopsies from our patient cohort.  
 
We have developed MR-imaging biomarkers that will allow targeted biopsy and longitudinal 
monitoring without ionizing radiation.  Hyperpolarized 129Xe Magnetic Resonance Imaging (HP 
129Xe MRI) can enable non-invasive, high-resolution imaging of lung structure and function. We 
have recently shown HP 129Xe MRI to visualize pulmonary ventilation with high resolution, as well 
as the ability to show abnormalities of the alveolar microstructure (5-7). We have also 
demonstrated the fundamentally new capability to directly visualize the uptake of 129Xe into the 
pulmonary capillary blood and tissues (8-10), which can provide an even more complete picture 
of pulmonary function by supplying regional gas-exchange information with or without exercise. 
New 129Xe MRI techniques have potential for early BOS detection, with broad applicability across 
the spectrum of pulmonary disease.  These techniques will also be used to easily follow regional 
progression in individual transplant recipients, in parallel with standard pulmonary function and 
blood tests, among others. 
 
 
 
 
 
Figure 1: Representation of the initial progression of BOS at the 
last conducting and first respiratory airways (at the so-called 
“diffusion front”).  Pathological findings indicate that fibrous 
tissue exists in both the terminal conducting airways and in the 
upper acinus in early BOS.  It is believed that epithelial injury and 
its aberrant repair leads to myofibroblast infiltration, and fibrous 
tissue expands throughout the lower conducting and upper 
respiratory airways, causing restriction, obstruction, or both. 
129Xe MRI can detect these changes regionally, both by images of 
ventilation (obstruction) and restricted diffusion.  

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The purposes of this study are: 
• 
Aim 1: To use HP 129Xe and 1H MRI to assess regional ventilation defects in post-
transplant for BOS patients, during routine clinical visits near 6 months and 12 months 
and when BOS is suspected post-transplantation. This will help to guide the collection of 
relevant clinical biopsy samples for clinical decision-making purposes.  
• 
Aim 2: To use imaging from Aim 1 to guide the selection of an additional 1-3 biopsy 
specimens, where applicable at the discretion of the clinician, per patient-visit during 
routine clinical biopsies post transplantation near 6 months, 12 months, and at any 
subsequent clinical visit when BOS is being screened for.  Care will be taken to attempt 
that at least one specimen is in a high-likelihood BOS lesion (ventilation defect) and at 
least one specimen is from a putatively normal region. We will acquire specimens at time 
of transplant and through image guided biopsy from scheduled clinical bronchoscopy at 6 
months, 12 months, and at any additional time points if BOS is suspected.  Specimens 
collected for research purposes will be added to an existing tissue repository for future 
research.  
 
 
3. BACKGROUND:   
The twenty-third report by the registry of the International Society for Heart and Lung 
Transplantation reported survival rates of 49% and 25% 5 and 10 years after lung transplantation, 
respectively, which underscores the low long-term survival after lung transplantation (1). Chronic 
allograft rejection in the form of bronchiolitis obliterans represents the most formidable challenge 
in this field. The time between transplantation and onset of bronchiolitis obliterans syndrome can 
be as small as a few months; the probability is increased in patients with primary-graft-dysfunction 
scores (2).  The histological hallmark of chronic lung allograft rejection is partial or complete 
occlusion of the lumina of terminal and respiratory bronchioles by inflammatory and fibrous tissue 
(Figure 1).  It is generally thought that injury to airway epithelial cells and subepithelial structures 
with subsequent aberrant tissue repair ultimately leads to excessive fibroproliferation (3). Risk 
factors for the development of bronchiolitis obliterans following lung transplantation can be 
categorized into alloimmune-dependent (immune-mediated pathways such as rejection and 
autoimmune-like mechanisms), and alloimmune-independent factors. There is strong evidence 
for a relationship between the frequency and severity of acute rejection episodes and the 
subsequent development of chronic rejection (2). Alloimmune-independent risk factors include 
ischemia-reperfusion injury, bacterial and viral respiratory infections and gastroesophageal reflux 
(4). These alloimmune-independent risk factors are inflammatory stimuli that may damage the 
airway epithelium directly or alter the milieu in the lung allograft to increase antigenicity and 
thereby indirectly influence the alloimmune response. Therapeutic options for established 
bronchiolitis obliterans are limited as this condition is generally not reversible.  Medical therapy 
such as augmentation of immunosuppression fails to prevent the progression of fibrotic airway 
obliteration in the majority of these patients and re-transplantation remains the only option. 
 

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Since BOS is often heterogeneously distributed in 
the lung, an imaging modality which is sensitive to 
ventilation defects due to decreased airway 
diameters 
in 
the 
terminal 
and 
respiratory 
bronchioles (Figure 1) will be particularly useful for 
localization of BOS lesions (11).  Hyperpolarized 
gas MRI (3He or 129Xe) is currently the only 
technique that provides the ability to monitor real-
time regional ventilation at high resolution (Figures 
2 and 3) (12).  Further, maps of restricted 129Xe 
diffusion provide quantitation of alveolar duct size 
and geometry, which are presumably some of the 
first areas affected by BOS (11, 13-15).  Methods 
developed by our research consortium have been 
shown recently to accurately measure the average 
major and minor diameters of acinar airways, 
allowing calculations (via imaging alone) of 
alveolar size and surface area, mean linear 
intercept, and total alveolar number (14).  
 
MRI with hyperpolarized gases, however, requires 
specialized laser polarization equipment and customized MRI techniques and analyses.  The PI 
and colleagues in Radiology are pioneers in the field of hyperpolarized-gas MRI in nuclear-spin 
polarization, technique development, and translation of imaging to clinical relevance; indeed over 
the past 3 years, the PI and colleagues have established 3He and 129Xe MRI capabilities at 
CCHMC with over 100 subjects (pediatric and adult) imaged to-date. We have developed myriad 
methods 
of 
obtaining 
restricted 
diffusion-
weighted 
images 
that 
inform on acinar structure 
(13, 
16-20). 
 
These 
techniques 
have 
been 
shown 
to 
be 
highly 
sensitive 
to 
early 
pulmonary disease (14). 
 
To 
date, 
studying 
immunological responses 
to lung transplantation has 
relied 
heavily 
on 
vascularized lung transplant models in large animals or rats (21-23).  While these models have 
provided valuable insight into possible genetic targets that lead to the development of BOS 
lesions, most of these data have yet to be validated in human lung allograft recipients.  The 
reasons for this disparity arise from the difficulty in finding early BOS lesions with conventional 
techniques in human lung allograft recipients and the fact that expression patterns of genes 
change over time.  By identifying ventilation defects that precede the development of lesions in 
human allograft recipients, we will attempt to localize, capture and assess differential gene 
patterns that precede disease progression. 
 
 
 
Figure 2:  3He ventilation (top) and restricted 
diffusion (bottom, color) of two pediatric post-
transplant patients.  Patient 6 has focal 
ventilation defects (dark areas) and reduced 
diffusion (restricted airspaces, red on the color 
maps) 
10 
months 
before 
clinical 
BOS 
diagnosis, similar to Patient 9 after clinically-
diagnosed 
“stable” 
BOS. 
These 
same 
techniques are available with 129Xe gas. 
Figure 3:  UTE 1H and 129Xe MR images in a 12 y.o. patient with BOS. 
There is a near absence of ventilation in the left lung and ventilation 
deficits in the right lung, which spatially correspond to regions of lower 
signal (trapped gas) in the UTE images, supporting these techniques as 
biomarkers to assess regional structure-function in BOS. 

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4. STUDY DESIGN:   
This is a prospective, non-randomized, longitudinal, observational study to complete the following 
aims: 
 
Aim 1: To use HP 129Xe and 1H MRI MRI to assess regional ventilation defects in post-transplant 
for BOS patients, during routine clinical visits near 6 months and 12 months and when BOS is 
suspected post-transplantation. This will help to guide the collection of relevant clinical biopsy 
samples for clinical decision-making purposes.   
 
Aim 2: To use imaging from Aim 1 to guide the selection of an additional 3 biopsy specimens, 
where applicable at the discretion of the clinician, per patient-visit during routine clinical biopsies 
post transplantation near 6 months, 12 months, and at any subsequent visit when BOS is 
suspected.  Care will be taken to ensure that at least one specimen is in a high-likelihood BOS 
lesion (ventilation defect) and at least one specimen is from a putatively normal region. We will 
acquire specimens at time of transplant and through image guided biopsy from scheduled clinical 
bronchoscopy at 6 months, 12 months, and at any additional time points if BOS is suspected.  
Specimens collected for research purposes will be added to an existing tissue repository for future 
research, maintained by the Heart Institute (and Dr Schecter). 
 
Dr. Schecter and his team routinely acquire 5-10 biopsies at each post-transplant bronchoscopy. 
Specimens will be shared with the tissue repository as the volume of specimens allow (if the 
clinician finds that additional samples beyond what is needed for clinical decision-making may 
safely be obtained for research purposes).  The primary use of the biopsy material will be for 
clinical decision making purposes. However, if for example, 6 biopsy samples are taken and 
sufficient for clinical use, the clinician may utilize judgement in the collection of up to 3 additional 
samples for research purposes and still be within the routine acquisition of up to 10 biopsy 
samples. 
 
At a minimum the tissue repository will acquire research specimens taken at time of transplant 
and from scheduled clinical bronchoscopy with image guided specimens at 6 months, 12 
months, and at any additional time points if BOS is suspected. Based on conservative 
numbers, we anticipate a total of around 15-18 biopsy research specimens per year/ per patient 
may be collected. Additionally, we will enroll an unknown number of subjects (approximately 15-
20) who are post lung transplant within the past 10 years and may transfer to CCHMC Lung 
Transplant Center to be followed clinically. We will collect specimens at the first clinical 
bronchoscopy after they enroll in the study (study baseline) and at any additional time points if 
BOS is being screened for. We feel this allows a reasonable probability of several early BO 
lesions to be identified.  Research biopsies will be processed for frozen sections and stained for 
histopathological assessment and validation of molecular targets identified in our related mouse 
model of transplantation. DNA will be processed and stored for current and future lung transplant 
studies.  
 
 
5. DURATION:   
We expect to be able to consent and scan 45 patients in the study over approximately 5 years. 
We will continue to monitor outcomes data for the enrolled subjects for 10 years post-transplant 
or until close of study. 
 
 
6. SELECTION AND RECRUITMENT OF PARTICIPANTS 
 

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A. Number of Participants 
The study group will include approximately 25 subjects who are scheduled for lung 
transplant.  
 
An additional unspecified number of subjects (approximately 15-20) may be enrolled 
who are post lung transplant within the past 10 years and are being followed clinically 
through CCHMC lung transplant center.  
 
B. Inclusion Criteria: 
• Lung Transplantation within the last 10 years or being assessed for possible lung 
transplantation.  
• Male or female participants will be considered for inclusion. 
• 6 years of age and up. 
• Participant must be able to hold their breath for up to 16 seconds. 
 
C. Exclusion Criteria: 
• Standard MRI exclusion criteria  
• Bleeding disorders 
• Participant is claustrophobic or otherwise unable to tolerate the imaging 
• Pregnancy or positive pregnancy test 
• Symptoms of respiratory infection within the past two weeks. 
• Baseline oximetry at MRI visit of less than 95% on room air or less than 95% on a 
previously prescribed dosage of oxygen delivered by nasal cannula.  
 
D. Recruitment:   
Eligible patients will be identified at CCHMC through Dr. Marc Schecter, Director of Lung 
Transplantation at CCHMC or his team.   
 
Recruitment of participants will include initial contact made by individuals (Dr. Schecter 
and team) who either are known to the potential participant or their legally authorized 
representative, or must have access to the potential participant and representatives by 
virtue of providing routine care and services, unless such contact has been previously 
authorized. Follow-up calls after the initial contact may be made by study personnel not 
directly involved in the patient’s care. Any recruitment materials will be submitted for IRB 
approval before use. Eligibility based on inclusion/exclusion criteria will be reviewed before 
contacting potential study participants. Eligible candidates who are interested, willing to 
participate and give informed consent will be enrolled.  After potential study subjects are 
identified, the study team will discuss with them the study and provide a copy of the 
consent form to interested subjects.  
 
E. Vulnerable Populations: 
For subjects under 18 years of age, additional efforts will be made to protect this 
vulnerable population. Assent will be obtained after age appropriate explanation of the 
study.  The child is informed that participation in research (clinical trials) is voluntary and 
that they may decline or withdraw at any time for any reason independent of their 
parent/guardian.  Assent will be reaffirmed before study procedure is performed. They will 
be informed that participation in the research (trial) will not affect their clinical care. 
 

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7. PLAN FOR OBTAINING CONSENT:  
We are asking for a waiver of documented consent for screening that will include review of the 
MRI Safety Review Form, medical history information and inclusion/exclusion criteria with review 
of medical record and or patient provided information. We are requesting a waiver of 
documentation of consent for screening only because the questions that will be asked do not 
require documentation outside of research and the risk to subject confidentiality are minimal. We 
are requesting waiver of HIPAA authorization because this requirement would make it impossible 
to do the screening component of the study and add inconvenience to the participant and the 
family.  Also, the risks to subject confidentiality for the HIPAA waiver are minimal. 
 
For participants (parents) who express interest, the participants or if the participants is a child, his 
or her parent will be given the consent for the study, and it will be reviewed and time given for 
questions.  When possible, the consent will be sent in advance of screening visit by mail or e-mail 
to allow additional time for review. All prospective subjects will have the study explained by a 
member of the research team in language that is understandable to them.  The nature of the tests 
and procedures to be done will also be explained along with the potential hazards, possible 
adverse reactions, and financial costs.  It will be clearly stated that participation is voluntary and 
that refusal to participate will involve no penalty or loss of benefits to which they are otherwise 
entitled.  The participants and parent will sign the assent or consent after all questions are 
answered and a signed copy of the consent form will be given to the participants to keep.  Consent 
will allow for multiple visits for capture of longitudinal data. No study related procedures will be 
done prior to consent being signed.  
 
Non-English speaking participants will be consented using a short form consent process as per 
CCHMC SOP 41-1.8.  The approved long consent form will serve as the summary of research. 
 
Age of assent will be determined by the IRB, and those assenting will sign after all questions are 
answered. The study staff will obtain assent for children when the child reaches age of 
assent or at the next visit for those children previously enrolled in the study by parental permission 
only.  Subjects who become adults during the research will be re-consented after they become 
18 years of age. 
 
 
8. STUDY PROCEDURES:  
For the first year post-lung transplant, the clinical care plan includes post-operative visits at 2 
weeks, 5-6 weeks, 3 months, 6 months, 9 months, and 1 year. These visits are considered as 
standard-of-care visits. Additionally as standard of care, surveillance trans-bronchial biopsies 
(TBB) are performed at 2 weeks, 6 weeks, 3 months, 6 months, 9months, 12 months, 18 months, 
and 24 months post-transplant.    During the clinical consent process, patients/families are told 
that between 5-10 TBBs are taken.  These biopsies are taken to assess clinical status and to 
provide information that may indicate signs of rejection after transplant. Clinical determination of 
rejection requires at least 4-6 TBBs.  Since standard of care is to obtain up to 10 TBBs, additional 
samples above those required to determine possible lung rejection may be obtained/retained for 
research and still be within a routine amount of biopsy sampling.  
 
Research imaging visits will be scheduled around the clinically scheduled visits at Baseline, 6 
months post-transplant, and 12 months post-transplant. An open number of additional 
research visits will be scheduled in conjunction with any clinic visit if treating transplant physician 
suspects BOS and schedules a clinical bronchoscopy.  Once BOS is diagnosed, research visits 
will continue to occur in conjunction with scheduled clinical bronchoscopies. It is not expected for 

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each clinical visit post diagnosis of BOS to include a research visit. Research visits will be decided 
by consultation and agreement between PI and treating transplant physician. All research visits 
will follow the same routine as below except Baseline Visit (Visit 1).  For Visit 1, biopsies will be 
obtained during the transplant surgery, not during bronchoscopy. Remnant lung tissue from 
explanted lungs will also be collected at this time. 
 
 

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Time and Events for Aim 1 and 2: 
 
Planned clinical visit 
schedule 
Screening 
Research 
Visit 1 
Pre-
transplant2 
Transplant 
2 
weeks 
5-6 weeks 
3 months 
Research 
Visit 2 
6 months 
9 months 
Research 
Visit 3 
12 
months2 
Visits up to 
10 years 
post –
transplant  
Review of medical 
record and MRI safety 
sheet6 
X 
X 
 
X 
X 
X 
X 
X 
X 
X1 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
Review of medical 
history and medication 
 
X 
 
 
 
 
X 
 
X 
X1 
Height, weight, vital 
signs5 
 
X 
 
X 
X 
X1 
Physical assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
X1 
Urine pregnancy test4 
 
X4 
 
 
 
 
X4 
 
X4 
X1,4 
Spirometry (as tolerated 
and if none conducted 
within 6 months) 
 
X 
 
 
 
 
X 
 
X 
X1 
Pulse oximetry 
 
X 
 
 
 
 
X 
 
X 
 
Research MRI  
 
X 
 
X 
X 
X1 
Collection of remnant 
explanted lung tissues 
 
 
X 
 
 
 
 
 
 
 
Biopsies at Transplant 
Surgery 
 
 
X 
 
 
 
 
 
 
 
Image guided bronchial 
biopsies  at clinical 
bronchoscopy 
 
 
 
X2 
X2 
X2 
X 
X2 
X 
X1 
Safety assessment: 
Day of MRI, 1 day (+3), 
and  7 days (+3 to -1) 
after MRI3 
 
X 
 
X3 
X3 
X3 
X 
X3 
X 
X1 
1 Additional research imaging visits may be scheduled around any clinical visit, up to 10 years post-transplant where BOS is suspected.  
2 Image guided bronchial biopsies at clinical bronchoscopy as above and performed at 18 and 24 months; may also be performed if BOS is being screened for/suspected. 
3 Follow up can be conducted in person or by phone.  Day 1 follow up should be performed prior to the clinical bronchoscope if feasible. Follow up will also be performed for additional 
visits when BOS is being screened for/suspected.  
4 Urine pregnancy test will be performed prior to any 129Xe MRI; urine pregnancy test will not be conducted on males, pre-pubescent girls or post-menopausal women or women 
who have undergone a hysterectomy. 
5 Vital signs include heart rate, respiratory rate and blood pressure. Clinical data may be used if collected on the same day. 
6 Medical record review may include demographics, diagnoses, lung tests, radiologic reports, imaging data, status of lung transplant

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Imaging will occur before the clinically-scheduled bronchoscopy. The scan will take approximately 
60 minutes.  Anatomical lung MRI (1H MRI) will be performed with coached spontaneous 
breathing with the intention of obtaining images at pulmonary FRC and FRC plus a tidal volume. 
This may include relaxed breaths and full inhalations with brief breath holds, as well as navigator-
triggered free-breathing acquisitions. 
 
129Xe MR images will be acquired during a coached breath-hold maneuver (maximum duration 16 
seconds) of hyperpolarized Xe gas. Pediatric subjects will be imaged with a Xe dose no greater 
than 1/6 of their predicted total lung capacity per ATS plethysmography-based estimates which 
uses subject demographics to predict TLC (24). The Xe dose for adult subjects will be no greater 
than 1 L. During the MRI, subjects will have routine monitoring pulse-oximetry with a licensed 
medical professional (e.g., MD, DO, NP, APN, RRT, or RN) present during the scan. In addition 
to an initial 1L or less Xe dose for calibrating the MR scanner, up to 4 doses of Xe gas may be 
administered during an imaging session. Image analysis will be performed after the MRI; a report 
on regional ventilation and corresponding 129Xe diffusivity (both at the level of lung segments) will 
be prepared within following imaging and prior to the clinical bronchoscopy.  All ventilation defects 
will be noted; and the PI will ensure that the clinical bronchoscopist and treating transplant 
physician receives the report before the clinical bronchoscopy. 
 
The lung lavages and biopsy specimens are performed as a part of routine clinical care. Where 
research biopsy samples are deemed safe and appropriate by the clinical staff, the target areas 
for the 1-3 research biopsy specimens will be any two lung segments with the worst 129Xe MRI 
ventilation defects (as determined by image as reduced diffusivity) and a segment with uniform 
129Xe ventilation and normal diffusivity.  Since our regional specificity for biopsies will be at the 
level of lung segments, we anticipate no significant problems obtaining the image-targeted biopsy 
samples. Final decision on obtaining research biopsies will be made by the clinical 
bronchoscopist and treating transplant physician at the time of the bronchoscopy based 
on patient safety and their clinical judgment. If image guided biopsies cannot be obtained on 
a research visit for safety reasons, the subject will be continued through the study with image 
guided biopsies at future visits as clinical condition allows. 
 
The Pulmonary Division and Heart Institute will be responsible for ensuring that specimens are 
collected, registered and stored properly.   
 
Standardized Hyperpolarized 129Xe MRI Procedure 
Subject will be supine in imaging chamber with ear protection.  
 
Prior to the MR scan, subjects will practice the inhalation and breath-hold maneuver with the 
Tedlar or polyethylene (PE) bag using room air.  
 
Subject will be supine in imaging chamber with ear protection and oximetry monitoring. There will 
be one bag with a breathing tube and mouthpiece near the subject’s head. This bag will contain 
hyperpolarized 129Xe gas mixture (Xe gas may be dilute with nitrogen). 
 
Total time in the MR scanner will be about 60 minutes.  
• 
Once the subject has been placed and is acclimated to the scanner, baseline vitals 
including SpO2 and heart rate will be collected. These vitals will be used for safety 
monitoring throughout the scans involving xenon gas administration, and monitoring for 
safety parameters. 

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• 
The MR portion of the procedure will include anatomic proton (1H) scans (no gas 
inhalation). 
• 
After anatomic MR scans, a calibration scan will be performed with a small amount of 
xenon. The participant will be instructed to exhale a tidal volume (down to functional 
residual capacity, FRC) and then inhale 129Xe and hold breath for up to 16 seconds. The 
subject will be instructed to exhale the breath at the end of the scan sequence and take 
deep breaths of room air, talk, etc. 
• 
For the Xenon MRI scan, the subject will be instructed to exhale a tidal volume (down to 
functional residual capacity, FRC) and then inhale the 129Xe and hold breath for up to 16 
seconds. Subject will be instructed to exhale directly into room air after imaging and to 
take deep breaths of room air, talk, etc.  
 
SpO2 will be monitored before, during and through 2 minutes after 129Xe maneuver. Lowest SpO2 
and time to recovery to pre-maneuver and/or baseline SpO2 will be recorded. If the subject’s blood 
oxygen saturation and heart rate do not return to within 5% of the established baseline SpO2 and 
the heart rate to within 20 bpm of baseline within 2 minutes, the medical professional will continue 
to encourage the subject to breathe/talk and try to get SpO2 and heart rate back to acceptable 
levels on their own.   If the subject’s blood oxygen saturation drops greater than 10% from their 
reclining baseline value or their heart rate rises by 40 bpm, oxygen may be administered to assist 
the subject in returning to the acceptable SpO2 and heart rate levels. If the subject returns to 
acceptable SpO2 and HR values, they may be given the decision to continue to the next inhalation. 
Prior to additional doses, if applicable, the subject will breathe normal room air for at least 2 
minutes. 
Afterwards, the patient will exhale fully and breathe normal air before repeating this procedure. 
Subjects may be given more than one dose but each dose will be separated by at least 2 minutes 
of breathing room air. In addition to small MR-scanner calibration dose, a maximum of 4 129Xe 
doses will be given. 
 
About 129Xe MRI 
The PI and colleagues in Radiology have been pioneers in the field of hyperpolarized-gas MRI—
in nuclear-spin polarization, technique development, and translation of imaging to clinical 
relevance and developing myriad methods of obtaining restricted diffusion-weighted images that 
inform on acinar structure (13, 16-20).  These techniques have been shown to be highly sensitive 
to early pulmonary disease (14) 
 
MR imaging will be directed by Dr. Woods, with medical oversight for review of adverse events 
and clinical interpretations of unexpected MR findings from a physician within the Pulmonary 
Division. Dr. Woods has extensive experience acquiring and analyzing hyperpolarized-gas 
images. Images of gaseous 129Xe will be acquired during separate breath holds: typically using 
high-resolution FLASH (for ventilation) or multi-b-value diffusion-weighted MR (for measurement 
of acinar-airspace narrowing), both via fast-gradient echoes. Both sequences are in place and 
have been utilized in studies conducted at CCHMC (5, 6). Ventilation and dissolved 129Xe uptake 
may also be evaluated using other MRI sequences such as SPIRAL or UTE. Spectroscopy scans 
may also be used. However, in no instance will the breath-hold period exceed 16 seconds.  
Image analysis will be performed after MRI including a report on regional ventilation, 
corresponding 129Xe diffusivity, or 129Xe exchange as appropriate for the type of imaging 
performed.  
 
Image analysis will be performed after MRI including a report on regional ventilation and 
corresponding 129Xe diffusivity (both at the level of lung segments).   

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Process for hyperpolarization of 129Xe 
Hyperpolarized 129Xe will be produced, by trained staff, using research polarizers housed at 
Cincinnati Children’s Hospital Medical Center. Each dose will be produced with its own unique 
batch record. The dose of xenon for imaging will consist of no more than 1 liter of either natural-
abundance xenon (26% 129Xe isotope), or isotopically-enriched xenon (>26% 129Xe), with medical 
grade UHP N2 added as needed to adjust the total dose volume. Xenon will be diluted in situ within 
the dose bag prior to inhalation. This will be accomplished by delivering the xenon and the diluent 
gas directly to the bag through a gas-handling manifold made of a suitable, non-relaxing material 
such as aluminum or inert polymer. The exact xenon percentage in the mixture will depend on 
the technical details of the studies. In high resolution ventilation imaging, it may be necessary to 
have subjects inhale 100% xenon for the individual short breath hold. In spectroscopy, where the 
signal intensity demands are more modest, a more dilute mixture may be delivered to reduce the 
risks of paresthetic effects. In general, we will use the minimum xenon percentage need to achieve 
the study goals, and we anticipate that the xenon percentages will range from 100% to 10%. The 
decision to release an HP 129Xe dose for administration will be made based on its measured 
polarization, and which is obtained by a calibrated measurement station in conjunction with the 
polarizer. 
 
Hyperpolarized 129Xe will be dispensed in preparation for each MRI based on the dose (xenon 
volume) required for that subject and study, and each dose will consist of up to 1L of xenon for 
adults or a fraction of that for children, based on predicted Total Lung Capacity calculations. Only 
one dose of gas will be transported to the MRI chamber at a time. This is to ensure that a magnetic 
environment is maintained and the polarization of the dose is maintained. Additionally, this spatial 
control of the dose serves to mitigate multiple doses being administered without adequate 
monitoring and room air in between. The total gas dose volume (xenon and any diluent gas) will 
be delivered in a single breath, and the timing of inhalation will be controlled by the administrator 
of the gas. This will ensure that the subject will not inhale more than one breath from the gas bag 
and will not inhale additional gas until monitoring has taken place. If an additional dose is required 
to continue the study, it will be placed and delivered by the administrator per the protocol 
assessment requirements. After the dose is exhaled into the room, ambient air will immediately 
dilute the xenon concentration to levels well below the paresthetic threshold. 
 
At present, 129Xe has been classified by the FDA as a drug but has not been given FDA approval 
despite the long record of safety of xenon in medical use.  
 
About the MRI: Coil safety data:   Custom MRI coils built in-house by the CCHMC Imaging 
Research Center (IRC) Engineering Lab will be used for MR imaging. 
 
Specific Absorption Rate (SAR):  The radio frequency (RF) field is an oscillating 
electromagnetic field, pulses of which are used to generate the MR signal.  The body absorbs a 
portion of the transmitted RF energy that may result in tissue heating.  SAR is a measure of the 
amount of RF power absorbed per unit of mass of tissue.  It serves as an indicator of heating 
potential and is the dosimetric means used to report the estimated amount of heat dose received 
by the patient. This value is expressed as watts of power per kilogram of the patient’s body weight 
(W/kg) and is routinely estimated by Philips MRI operating system software.  The SAR algorithms 
for the MR systems calculate SAR values for each MR acquisition and prevent the system from 
operating above FDA mandated guidelines.  
 
 

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9. DATA ANALYSIS METHODS: 
Biopsy specimens: 50% of total surviving patients are diagnosed with BOS 5 years post-
transplant.  Assuming 6 lung transplants per year during the enrollment period of this study, we 
expect 5-6 patients to be in our study cohort during the first year.  With 1-3 biopsy specimens 
per patient per time point, we anticipate a total of useable 15-18 biopsy specimens at the 
conclusion of the study, which allows a reasonable probability of several early OB lesions to be 
identified, providing good preliminary data for our future R01 proposal in 2 years.  Biopsies will 
be processed for frozen sections and stained for histopathological assessment and validation of 
molecular targets identified in our related mouse model of transplantation. 
 
One analytic focus of this project is to evaluate the accuracy of using MRI imaging to detect the 
presence of BOS under the assumption that the biopsy yields the gold standard determination.  
Accuracy measures including sensitivity (sen), specificity (spc), positive predictive value (PPV), 
and negative predictive value (NPV) will be estimated at the lung segment level based on the 
sample collected at each research visit time post lung transplantation as well as the total sample 
collected during the study. Appropriate correction for the correlation within a patient will be applied 
when estimating the variance of the accuracy measures. In addition, for those patients with at 
least one BOS lesion determined by biopsy during the study period (i.e. BOS patients), the 
number of apparent MRI-false positives will be summarized at each time point to show if MRI can 
detect BOS earlier than biopsy. 
 
Sample size consideration: The goal of this study is to collect biopsy samples from three locations 
(2 at 129Xe MRI-detected segments with ventilation defect and 1 at a segment with normal 
ventilation) in the lung at each of three time points in about 15 patients for a total of 135 samples. 
The sample size justification is based on the biopsy samples collected at 12 months post lung 
transplantation and the precision with which we can estimate the expected positive predictive 
value (the proportion of true BOS determined by biopsy among those detected by MRI based on 
ventilation defect). Assuming 5 lung transplant patients are enrolled per year in the study, we will 
have 15 patients enrolled during the three years enrollment. Considering the reported 83% 1-year 
survival rate for pediatric lung transplant patients, we will have 12 patients surviving with 36 
(=12x3) biopsy samples collected at 12 months (24 MRI detected possible BOS lesions, 12 
normal).  With 24 samples with MRI detected possible BOS lesions, the 95% confidence interval 
of the PPV will extend 19% from the observed value for an expected PPV of 65%. In the case of 
low enrollment, for example only 2 patients enrolled per year, we will have 6 patients within three 
years enrollment. With the same assumption of 83% 1-year survival rate, 5 patients will remain in 
the study with 15 MRI guided biopsy samples (10 MRI detected BOS lesions, 5 normal) collected 
at 12 months post-transplant. With 10 samples with MRI detected possible BOS lesions, the 95% 
confidence interval of the PPV will extend 30% from the observed value for an expected PPV of 
65%.  
 
 
10. FACILITIES and PERFORMANCE SITES:  
Study Location: Cincinnati Children’s Hospital Medical Center (CCHMC) Imaging Research 
Center (IRC)  
CCHMC Department of Radiology 
CCHMC Surgical Suites 
CCHMC Heart Institute Bio-Repository, R Basement  
 
 

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11. POTENTIAL BENEFITS: 
We do not anticipate any direct benefit to any participant. However, it is possible that we may 
discover unanticipated findings that are clinically relevant. The treatment of these unanticipated 
findings could result in improved outcomes.  Future lung transplant patients and the scientific 
community may benefit from the knowledge obtained from this study. 
 
 
12. POTENTIAL RISKS, DISCOMFORTS, INCONVENIENCES AND PRECAUTIONS:  
Other than lack of oxygen during the brief period (10-16 seconds) the participant is breathing the 
129Xe MRI, we know of no serious risks related to 129Xe. To mitigate the risks associated with the 
129Xe, administration of the gas will be done with a licensed medical professional (MD, DO, NP, 
APN, PA, RRT, RN) present and the subject will be monitored throughout the visit until all scans 
involving study drug are complete and the subject’s vital signs and SPO2 have returned to 
adequate values per protocol. Additionally, the administrator of the gas will control the delivery of 
the single dose of gas and the timing of inhalation. Only one dose will be available in the MRI 
suite at any time as the gas is stored in the polarizer to maintain adequate polarization for optimal 
imaging, thus the volume of gas available to the subject will be controlled. Furthermore, using 
minimal 129Xe percentages per experimental goals will mitigate additional risk. 
 
Risks  
 
129Xe : 
Common:  
• 
Mild paresthesia which includes  
o Light headedness 
o Dizziness 
o Tingling  
• 
Euphoria 
 
We expect the duration of Xe effects to be short in duration; typically about 3 minutes after 
exhalation is expected 
 
Breath-Hold: 
Common: 
• 
Decline in SPO2 due to the administering of an anoxic gas mixture,  with usual return 
to baseline values within the next minute after exhalation 
Uncommon 
• 
Heart rate change  
MRI: 
Common: 
• 
Discomfort from being confined in the small space of the MRI. Comfort measures will 
be used as appropriate. They may include watching movies or swaddling. 
• 
Loud noise. Ear plugs and head phones will be used to protect hearing. 
Uncommon: 
• 
Panic (claustrophobia). If this happens, we will stop the test. Subject will be able to stop 
the test at any time.  
Rare: 

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• 
Injury from ferrous metal inside the magnet room. All subjects are screened to prevent 
any injury from metal and the MRI magnet. 
Pulse Oximetry: 
Common: 
• 
Temporary pressure marks from monitor probe 
 
Transbronchial Biopsy:  
All bronchoscopies are being done for clinical purposes.  We feel the incremental risk from 1-3 
additional biopsies is small. The final decision on patient safety for obtaining the biopsies will be 
decided by the clinical judgment of the bronchoscopist and treating transplant physician on the 
day of the bronchoscopy. 
 
Common 
• 
Minor bleeding within the airways and lungs that will be controlled with local 
bronchoscopic measures,  
• 
Mild hemoptysis during the 24 hours after the procedure; temporary hoarseness and 
sore throat. 
 
Rare:  
• 
There is a 1% risk of a pneumothorax (collapsed lung) with chest tube placement 
necessary to re-expand the lung in many of those instances. 
• 
Hypoxemia (decreased oxygenation), infection, and respiratory and/or cardiovascular 
instability leading to death 
 
Pregnancy: 
There is no known risk from MRI or xenon to pregnant women or fetuses but for additional safety, 
we will exclude pregnant women from this research study. Clinical testing as part of pre-surgical 
preparation may be used to confirm non-pregnancy at visit 1 if available. Urine pregnancy tests 
will be performed prior to MRI scans and negative results confirmed prior to MRIs. 
 
 
13. RISK/BENEFIT ANALYSIS:  
Although this study involves slightly greater than minimal risk there may be a direct benefit to the 
study subject.  The treating physician will receive through high resolution MR images that may 
help in the early diagnosis of BOS.   Additionally, this study may help in the development of 
improved outcomes for lung transplant patients from advancing our understanding of the 
biochemical mechanisms that occur after lung transplantation and their imaging correlates. 
 
 
14. DATA SAFETY & MONITORING:  
No Data Safety Monitoring Board (DSMB) will be created for this study. The Data Safety 
Monitoring Plan (DSMP) will be through oversight of the PI in reporting all adverse events. Medical 
management and decision for unexpectedness, relatedness and severity of adverse events due 
to bronchial biopsies will be determined by the treating transplant physician.  
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 

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International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s).  
 
• 
Monitoring for this study will be performed by a monitor independent of the study team. 
 
• 
Initial monitoring visits will focus on review of the consenting process, eligibility criteria, 
and investigator/staff training and qualifications.  On-going visits will occur at least 
annually; additional monitoring may occur at the discretion of the sponsor. On-going 
visits will include targeted verification of safety and efficacy endpoint data of a 
percentage of enrolled subjects.  The percentage will be determined based on 
enrollment. Additional monitoring activities will take place when needed to supplement 
the scheduled monitoring visits and ensure follow-up on any outstanding issues noted at 
scheduled visits. If systemic issues are identified during monitoring visits (i.e., consent 
process, ineligible participants, regulatory violations, missing data, etc.) re-training of the 
site staff will be suggested and the need for additional review will be assessed. A close 
out visit will be conducted once all participants have completed, withdrawn or been 
declared lost to follow-up and all data queries have been resolved.  Any outstanding 
issues from previous monitoring reports will be reconciled.  
 
• 
The sponsor will be provided copies of monitoring reports after allowing sites sufficient 
time to respond/resolve discrepancies from the list of findings provided to the site 
immediately following the review.  The monitoring reports will include a visit summary, 
any issues for follow-up, and any pertinent conversations with study staff surrounding 
monitoring activities.   
 
• 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. 
 
 
 
15. ASSESSMENT OF SAFETY 
The participants will be monitored before, immediately following and after each inhalation of 
129Xe, per study procedures above, to assess for adverse events and changes in vital signs.  
 
Parameters monitored may also include the following: 
• 
Participant assessment of anesthetic/analgesic effects, heart rate, and SPO2. The 
participant’s sense of analgesia is assessed by in inquiring about how the participant 
feels after administration of the xenon dose. The participant will be asked to describe 
how they feel as well as well as about symptoms such as: dizziness, light-headedness, 
numbness, euphoria, and tingling. 
• 
Heart rate and SpO2 will be measured while the subject is supine in the imaging 
chamber prior to any imaging to establish a baseline by which to compare subsequent 
measurements after inhalation of the Xenon gas. SpO2 is monitored by percentage 
based on absolute percent change (ie, 95%-90% is a 5% drop in value). 
• 
Heart rate will also be measured immediately following each inhalation and through a 
minimum of two minutes after the inhalation. Changes in heart rate of with increases by 
40 bpm are considered significant. If the participant is to receive another dose, the next 

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dose will not be administered until the heart rate is within 20bpm of its baseline 
monitoring value. If the participant has received their last dose, they will be observed for 
2 minutes post-inhalation or until their heart rate has returned to within 20 bpm of the 
base line value. 
• 
In addition to baseline, SPO2 is also measured immediately following and through 2 
minutes of each xenon dose. A decrease of SPO2 by greater than 5% is considered 
significant. If the participant is to receive another dose, the next dose will not be 
administered until the SPO2 is within 5% of its baseline monitoring value. If the 
participant has received their last dose, they will be observed for 2 minutes post-
inhalation or until the SPO2 is within 5% of its baseline value or until the end of the 
observation period, whichever is longer. 
• 
The participant will be monitored for the duration of the xenon treatment and post 
procedural period by a trained medical professional.  Additional assessments of adverse 
events will be conducted by study staff on Day 1, preferably prior to the clinical 
bronchoscopy, but if not feasible, a +3 day window is allowed.  Follow up will also occur 
on Day 7 (+3/-1). 
• 
Data for each subject collected during the study, including medical history, physical 
assessment results, data during the MRI, any protocol deviations as well as Adverse 
Events and Serious Adverse Events will be reviewed by delegated medical study staff 
and will also be reviewed by the study PI at the end of the subject’s follow up, at a 
minimum, for acknowledgement and awareness of study data and subject safety. 
Serious Adverse events related to the study or study drug will be reported to the PI 
within 24 hours of learning of the event. 
 
Adverse Events Defined 
Adverse events for this study will be defined as any change from baseline that occurs from 
admission to IRC to follow-up phone call after each study visit from enrollment until completion or 
withdrawal from study. 
 
1. Unexpected versus Expected Adverse Events 
An unexpected adverse event is one that has not been listed previously in the protocol, 
consent form, or Investigator’s Brochure and is not associated with known risks of 
bronchial biopsy or the subject’s underlying disease. 
 
Expected events as outlined in study documents will not be recorded as adverse events 
unless they become moderate and require medical intervention or discontinuation from 
the study. 
 
2. Relatedness (Attributions) 
Attribution 
Description 
Unrelated 
The event is unrelated.   
Unlikely 
The event is unlikely related. 
Possibly 
Related 
The event or severity of event is not usually associated; there is no strong 
evidence to link the event.  

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Probably 
Related 
The event or severity of event is such that it can likely be correlated.  
Definitely 
Related 
There is a strong correlation. 
 
  
3. 
Severity Descriptors 
 
Severity  
Numerical 
Value  
Description  
Mild 
1 
Aware of sign, symptom, or event, but easily tolerated; 
does not interfere with daily routine 
Moderate 
2 
Discomfort enough to interfere with daily routine and may 
require some therapeutic intervention  
Severe 
3 
Incapacitating, significantly affects clinical status; 
requires therapeutic intervention  
Life 
Threatening 
4 
Life-threatening; immediate intervention required  
Death  
5 
Adverse event causes death.  
 
 
Adverse Event Reporting 
All adverse events that meet criteria for expedited reporting to the FDA will be reported per 21 
CFR §312.32(c).  This includes events that are determined to be at least possibly related to the 
use of the drug, unexpected, and serious.  Serious adverse events are defined as: 
• 
Death 
• 
Life-threatening  
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability or incapacity 
• 
Congenital anomaly/birth defect 
• 
Medical events that when, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.   
Serious events that are fatal or life-threatening will be reported as soon as possible but in no event 
later than 7 calendars days after the sponsor’s initial receipt of information.  All other serious 
events shall be reported as soon as possible but in no event later than 15 calendar days after the 
sponsor’s initial receipt of the information.   
 
All adverse events that are unexpected and related to the study or involve an accidental release 
of PHI will be reported to the IRB as a Reportable Event.  Since all subjects will have clinical 
biopsies along with additional research biopsies, it may not be possible to distinguish 
bronchoscopic adverse events due to research or clinical care. The PI will report to the IRB as a 
Reportable Event within 48 hours of being made aware the following events: 
• 
Death within 48 hours of bronchoscopy where research biopsy samples were obtained. 
• 
Hemorrhage requiring intervention such as transfusion, surgery, bedside cauterization 
within 48 hours of bronchoscopy where research biopsy samples were obtained. 
• 
Pneumothorax within 48 hours of bronchoscopy where research biopsy samples were 
obtained. 

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Adverse events that do not meet the criteria for Reportable Events will be submitted in table form 
at the next continuing review.  
 
 
16. PRIVACY and CONFIDENTIALITY: 
 
All subjects enrolled in this study will be identified by a unique study number only.  Personal 
identifiers such as name and medical record number will be removed from each case as the study 
subject’s information is entered into a secure database.  Protected health information other than 
dates (date of birth and visit date) will not be retained.  A single copy of a list linking medical 
record number to study number will be kept locked and available only to study investigators.  All 
records will be kept in a locked cabinet at CCHMC and maintained by the study investigator.  All 
computerized records will be kept on the CCHMC secure network. 
 
Case report forms will be created for this study.  Study specific data will be recorded directly on 
to the case report forms; therefore, the case report form will serve as a source document.  
Electronic case report forms (eCRF) will be retained in a secure database. 
 
In order to protect the privacy of the medical information, access to the identifying information will 
be limited to research personnel.  No individual identifiers will be used in publications or reports 
resulting from the study.  After the study is completed and results are published, the code linking 
the records to PHI will be destroyed and databases will be reviewed to confirm they are de-
identified except for dates. 
 
Future use: 
Specimens will be stored in the Heart Institute Bio-Repository (IRB#: 2011-2856). Specimens will 
be labelled and stored with the date and study ID. The code linking the study ID to PHI will be 
maintained separately from the specimens.  A separate anonymized database containing study 
data (PHI will include dates of procedures) will link with the specimen ID. Longitudinal data will be 
acquired from subjects for up to 10 years to follow transplant outcome or until re-transplantation 
or death. 
 
Subjects and families will be given contact information with instructions on how to withdraw 
consent for future use. 
 
 
17. COST OF PARTICIPATION: 
There will be no cost to the subjects for the MRI.  
 
 
18. PAYMENT FOR PARTICIPATION:   
Subjects will be compensated for their participation in the study. Compensation will be provided 
to the participant via ClinCard. 
$25.00 per MRI visit.  
$25.00 per biopsy visit 
 
 
19. STUDY COMPLIANCE 
 

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This study will be conducted as outlined by the protocol approved by the CCHMC IRB, and 
according to Good Clinical Practice standards. No changes to the protocol will be implemented 
without the approval by the Institutional Review Board and notification of the FDA, except if 
following the protocol would endanger the health and safety of the research participant. Should 
this occur, the protocol alteration will be reported to the IRB and submitted to our IND 
 

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Grossman EJ, Shilling RA. Bronchiolitis obliterans in lung transplantation: the good, the bad, and 
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