Using Ultrasound Elastography to Predict Development of Sinusoidal Obstruction Syndrome
Phase: NA
Conditions: Bone Marrow Transplant Complications, Sinusoidal Obstruction Syndrome, Veno-occlusive Disease, Stem Cell Transplant Complications
Sponsor: Children's Mercy Hospital Kansas City

SHORT TITLE: BMT Elastography (Internal) 
 
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Version 1.4 dated 7.13.18 
 
PROTOCOL TITLE: 
Using Ultrasound Elastography to Predict Development of Sinusoidal Obstruction 
Syndrome 
 
NCT03858530 
 
PRINCIPAL INVESTIGATOR: 
 
Sherwin Chan, MD PhD 
Department of Radiology 
816-324-3273 
sschan@cmh.edu 
 
Co-Investigator: 
Rakesh Goyal, MD 
Department of Hematology/Oncology 
Rgoyal@cmh.edu 
 
 
VERSION NUMBER/DATE: 
V2: 1-28-2019 
V3: 2-28-2019 
V4: 5-16-2019 
V5: 6-5-2019 
V6: 1-31-2020 
V7: 4-7-2020 
 
REVISION HISTORY 
 
This Revision History table is provided for the benefit of study team version 
control.  If this table will not be useful to your team, you do not need to include it. 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
2 
1-28-2019 
Adding CEUS exams 
Y 
3 
2-28-2019 
Revising CEUS language 
Y 
4 
5-16-2019 
Adding patient calendar handouts 
N 
5 
6-5-2019 
Blinding clinicians from results 
Y 
6 
1-31-2020 
Adding CIBTR data collection 
Y 

SHORT TITLE: BMT Elastography (Internal) 
 
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Version 1.4 dated 7.13.18 
7 
4-7-2020 
Adding Dr. Averkiou and University of 
Washington to study 
N 
 
 
 

SHORT TITLE: BMT Elastography (Internal) 
 
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Table of Contents 
1.0 
Study Summary ........................................................................................................ 4 
2.0 
Objectives ................................................................................................................ 5 
3.0 
Background .............................................................................................................. 5 
4.0 
Study Endpoints ....................................................................................................... 8 
5.0 
Study Intervention/Investigational Agent ................................................................ 9 
6.0 
Procedures Involved............................................................................................... 10 
7.0 
Data and Specimen Banking .................................................................................. 13 
8.0 
Genetic Analysis Information ................................................................................ 13 
9.0 
Sharing of Results with Subjects ........................................................................... 13 
10.0 Study Timelines ..................................................................................................... 13 
11.0 Inclusion and Exclusion Criteria ............................................................................ 13 
12.0 Vulnerable Populations .......................................................................................... 14 
13.0 Local Number of Subjects ..................................................................................... 14 
14.0 Screening and Recruitment Methods ..................................................................... 14 
15.0 Reimbursement, Payment and Tangible Property provided to subjects ................ 14 
16.0 Withdrawal of Subjects .......................................................................................... 15 
17.0 Risks to Subjects .................................................................................................... 15 
18.0 Potential Benefits to Subjects ................................................................................ 16 
19.0 Investigator Assessment of Risk/Benefits Ratio. ................................................... 16 
20.0 Data Management and Confidentiality .................................................................. 16 
21.0 Provisions to Monitor the Data to Ensure the Safety of Subjects .......................... 16 
22.0 Provisions to Protect the Privacy Interests of Subjects .......................................... 17 
23.0 Compensation for Research-Related Injury ........................................................... 18 
24.0 Economic Burden to Subjects ................................................................................ 18 
25.0 Permission/Assent/Consent Process ...................................................................... 19 
26.0 Process to Document Permission/Assent/Consent................................................. 19 
27.0 Setting .................................................................................................................... 19 
28.0 Resources Available............................................................................................... 19 
29.0 Multi-Site Research ............................................................................................... 20 
30.0 International Research ........................................................................................... 21 
 
 
 

SHORT TITLE: BMT Elastography (Internal) 
 
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1.0 
Study Summary 
 
Study Title 
Using Ultrasound Elastography to Predict Development of 
Sinusoidal Obstruction Syndrome 
Study Design 
Single-site prospective cohort study to evaluate grayscale 
US, Doppler US, CEUS and SWE examinations in BMT 
patients younger than 21 years. 
Primary Objective 
Our central hypothesis is that SWE changes will precede 
clinical and conventional ultrasound diagnostic criteria for 
SOS. We would like to perform a prospective cohort trial to 
establish optimal timing to test for SOS using SWE.  
Secondary 
Objective(s) 
a) Determine if SWE can provide earlier SOS diagnosis 
compared to clinical criteria and  
b) Quantify the difference in SWE values between SOS 
patients who would benefit from drug treatment 
versus those who do well with supportive care 
c) Quantify relative ability of CEUS 
parameters versus grayscale and Doppler ultrasound. 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
Shear wave ultrasound elastography (SWE) 
 
Lumason (sulfur hexafluoride lipid-type A microspheres)  
injectable suspension 
IND/IDE #  
 
Study Population 
Children and adults, ages 1 month through 21 years who are 
undergoing allogenic or autologous myeloablative stem cell 
transplant. 
Sample Size 
80 patients 
Study Duration for 
Individual 
Participants 
Until discharge from BMT admission or to Day +100 after 
BMT, whichever comes first. 
Study Specific 
Abbreviations/ 
Definitions  
BMT: Blood and Marrow Transplant 
CEUS: Contrast Enhanced Ultrasound 
SOS: Sinusoidal Obstruction Syndrome 
SWE: Shear Wave Elastography 
US: Ultrasound 
VOD: Veno Occlusive Disease 
 
 

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2.0 
Objectives 
2.1 Our central hypothesis is that SWE changes will precede clinical and 
conventional ultrasound diagnostic criteria for SOS. We would like 
to perform a prospective cohort trial to establish optimal timing to 
test for SOS using SWE 
2.2 Determine if SWE can provide earlier SOS diagnosis compared to 
clinical criteria. 
2.3 Quantify the difference in SWE values between SOS patients who 
would benefit from drug treatment versus those who do well with 
supportive care. 
2.4 Quantify relative ability of CEUS parameters versus grayscale and 
Doppler ultrasound 
3.0 
Background 
3.1  Hepatic sinusoidal obstructive syndrome (SOS) is a complication of 
blood and marrow transplant (BMT) that is associated with high 
morbidity and mortality. 57,000 patients in the United States and 
Europe undergo BMT annually (1, 2), and SOS affects up to 15% of 
these patients (3). SOS pathogenesis is thought to be caused by 
damage to the hepatic venous endothelium due to the preparative 
regimen used before BMT. This damage results in obstruction of 
blood flow through the liver. Pathology shows collagen deposition in 
the sinusoids and fibrosis of venous lumens (10). The severity of the 
disease is correlated to the number and severity of the histological 
changes. Mild and moderate SOS can resolve with supportive 
treatment. Severe SOS (30% of SOS) is commonly associated with 
multi-organ failure and has a mortality rate of 80% despite available 
prophylaxis and treatment (Table 1) (4).  
 
Table 1.   Staging of VOD/SOS 20 
Mild :  Resolved without interventions  
Moderate : Requires treatment  
• Bilirubin > 6 mg/dl  
• AST > 5 times upper limit of normal  
• Weight gain > 5 %  
• Ascites  
Severe : Progression to Multi-organ dysfunction syndrome  
• Respiratory failure ( O2 saturation < 90 %) 
• Hepato renal syndrome  
• Encephalopathy  

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• Severe renal failure ( creatinine > x 2) 
• Bilirubin > 20 mg/ dl  
 
SOS is most commonly defined by two clinical criteria: the modified 
Seattle criteria and the Baltimore criteria (Table 2) (11, 12). The 
modified Seattle criteria state that at least two of the following 
criteria must be present within 20 days of BMT: bilirubin > 2mg/dL; 
hepatomegaly and/or ascites; and/or weight gain > 5% above 
baseline weight (11). Pediatric SOS incidence in BMT is 20% and is 
higher compared to adults (13-15). Death or multi-organ dysfunction 
affects 30-60% children who develop SOS (16, 17). The most 
common definition of severe SOS is retrospective, namely death 
from SOS-related causes or persistent multi-organ dysfunction at 
100 days post BMT. However, the European Society for Blood and 
Marrow Transplantation has proposed a new prospective SOS 
grading scheme that will likely become standard of care since it is 
pediatric patient specific and it is can be performed prospectively 
and thus can guide treatment (5). 
Table 2. A table to show the clinical criteria for veno-occlusive disease 
 
 Modified Seattle Criteria  
 
Two of the following criteria must be 
present with in 20 days of SCT 
 
Baltimore Criteria  
 
Bilirubin must be >  2mg/dL before 21 
days SCT and two of the following 
criteria must be present 
Bilirubin > 2mg/dL 
 
 Ascites ( Physical exam or radiographic) 
Hepatomegaly increased over baseline 
 
Weight gain > 5 %above baseline weight 
* 
Ascites ( Physical exam or radiographic) 
and /or Weight gain > 5 %above baseline 
weight  
 
Hepatomegaly increased over baseline 
 
3.2 Recently, a promising drug for SOS treatment has been discovered, 
defibrotide, which is a DNA derivative from porcine intestine that 
protects and repairs endothelial cells. Prior trials showed that 
defibrotide decreased the incidence of multi-organ failure and death 
from SOS. The main caveat is that treatment must be initiated very 
close to the time of clinical diagnosis using the Baltimore criteria to 
be effective (7). A study showed that 31/33 (94%) patients had 
complete remission of their SOS when treated with defibrotide <3 
days after diagnosis, whereas only 3/12 (25%) patients had complete 
remission when treated >3 days of diagnosis (7). However, universal 

SHORT TITLE: BMT Elastography (Internal) 
 
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prophylaxis is infeasible due to high drug costs ($155,000 for 
patient) (8). There is a critical need for an early and effective SOS 
diagnostic test that can identify patients who would benefit from 
defibrotide treatment.  
Several adult and pediatric prospective studies have evaluated the 
efficacy of grayscale and Doppler ultrasound (US) in diagnosing 
SOS (18-20) and have concluded that the clinical criteria are 
superior to US criteria for SOS diagnosis. The main reason for this 
conclusion is that conventional US is able to diagnose SOS only 
after the clinical diagnosis (18-20). This research has resulted in 
multiple recent guidelines recommending US only for confirming 
clinical diagnoses or following disease progression and not for 
primary diagnosis (5, 6). Ultrasound shear wave elastography (SWE) 
has been shown to effectively diagnose passive hepatic congestion. 
Fontan physiology is the best studied example. SWE values 
markedly increased after the Fontan operation. This surgery connects 
the hepatic venous circulation to the pulmonary arteries exposing the 
liver to increased resistance from the pulmonary circulation thereby 
increasing hepatic venous congestion (21). Additionally, the effect 
sizes in the Fontan studies are large compared with the effect sizes in 
hepatic fibrosis studies (21, 22). The common thread of hepatic 
venous congestion between Fontan physiology and SOS physiology 
led us to hypothesize that SWE could be useful in SOS diagnosis. 
Additionally, preliminary SWE studies in adults showed that it might 
be useful in the setting of SOS (23). In addition to SWE, the use of 
contrast-enhanced ultrasound (CEUS) for evaluation of variability of 
blood flow in patients with SOS versus those without has also 
become of interest. 
CEUS uses an intravenous injection of microbubble contrast agents 
and is an established method to detect and characterize focal liver 
lesions; it also has been used to diagnose liver vein thrombosis. 
[Wilson, Abdom Radiol (NY), 2018; Dietrich, Ultrasound Int Open, 
2018; Trenker, BMT, 2018] The value of CEUS in VOD/SOS is 
evolving; however, the findings from two case reports suggest that 
the performance of CEUS could help to facilitate an early diagnosis 
and clinical follow-up of VOD/SOS. [Fontanilla, J Ultrasound Med, 
2011; Trenker, BMT, 2018] For example, in a case report of a 
patient who developed signs and symptoms of VOD/SOS 44 days 
after HSCT, CEUS showed heterogeneous uptake of contrast in 
VOD/SOS, and the areas of delayed enhancement corresponded to 
stiff areas on SWE; the contrast-enhanced sonographic pattern 
normalized after specific treatment. [Fontanilla, J Ultrasound Med, 
2011] In another case report—this one in a patient with a clinical 
diagnosis of VOD/SOS after HSCT—CEUS showed a normal 
arterial and portal venous contrast medium inflow, but almost no 
portal venous and parenchymal hepatic enhancement. [Trenker, 

SHORT TITLE: BMT Elastography (Internal) 
 
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BMT, 2018] The CEUS findings were novel, representing 
VOD/SOS pathophysiology and 
hepatic microvascularization dysfunction for the first time. [Trenker, 
BMT, 2018] Since SOS is a heterogeneous disease, we believe that 
contrast enhanced ultrasound may be useful in characterizing areas 
that are more severely involved in SOS and areas that are less 
severely involved. By interrogating both areas using contrast kinetics 
and SWE and correlating the values to disease severity, we hope to 
gain more insight into which areas (severely involved or less 
severely involved) are most responsible for the clinical sequelae and 
outcomes in SOS.  
3.3 The long-term goal of our research is to accurately identify SOS 
patients who would benefit from defibrotide treatment using US 
SWE. The overall objective of this study is to validate SWE as an 
early diagnostic marker for SOS. Our central hypothesis is that SWE 
changes will precede clinical and conventional US diagnostic criteria 
for SOS. Our hypothesis has been formulated on the basis of our 
own preliminary data.  We completed the first prospective cohort 
trial demonstrating that US SWE provides SOS diagnosis (80% 
sensitivity and 67% specificity) nine days earlier than current clinical 
criteria (9). SWE is widely available, has no known side effects, and 
is easy to learn and interpret. Our study enrolled 25 high-risk BMT 
patients over 18 months (five with SOS and two with severe SOS). 
More data is needed to determine the optimal window for testing to 
balance between improved test characteristics and early detection of 
disease. We propose conducting a prospective cohort study with 80 
additional patients, 12 of which will likely develop SOS (including 
four with severe SOS) to optimize SWE timing. This study will 
increase the confidence in the findings from our preliminary study 
and allow us to test SWE against newly published clinical criteria. 
The rationale for the proposed research is that, if SWE can diagnose 
SOS earlier than clinical criteria, then SWE can guide early initiation 
of SOS treatment. 
4.0 
Study Endpoints 
4.1 To perform a prospective cohort trial to establish optimal timing to 
test for SOS using SWE.  
4.2 Determine if SWE can provide earlier SOS diagnosis compared to 
clinical criteria. 
4.3 Quantify the difference in SWE values between SOS patient who 
would benefit from drug treatment versus those who do well with 
supportive care. 
4.4 Quantify relative ability to CEUS parameters versus grayscale and 
Doppler ultrasound. 

SHORT TITLE: BMT Elastography (Internal) 
 
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5.0 
Study Intervention/Investigational Agent 
5.1 
Lumason (sulfur hexafluoride lipid-type A microspheres) for injectable 
suspension is used to prepare the ultrasound contrast agent.  The single use kit 
contains the following three items: 
 
•  One clear glass 10mL vial containing 25mg of lyophilized powder lipid-
type A, 60.7 mg of sulfur hexafluoride gas and capped with a blue flip-cap  
 
• One prefilled syringe containing 5 mL Sodium Chloride 0.9% Injection, 
USP (Diluent) 
 
• One Mini-Spike 
 
Each vial is formulated as a 25 mg sterile, pyrogen-free lyophilized powder 
containing 24.56 mg of polyethylene glycol 4000, 0.19 mg of 
distearoylphosphatidyl-choline (DSPC), 0.19 mg of 
dipalmitoylphosphatidylglycerol sodium (DPPG-Na) and 0.04 mg of 
palmitic acid. The headspace of each vial contains 6.07 mg/mL (± 2 %) 
sulfur hexafluoride, SF6, or 60.7 mg per vial.  
 
Each prefilled syringe with 5 mL of diluent 0.9% Sodium Chloride Injection 
is sterile, nonpyrogenic, preservative free containing 9 mg sodium chloride 
per mL.  
 
Upon reconstitution with 5mL diluent, Lumason is a milky white, 
homogeneous suspension containing sulfur hexafluoride lipid-type A 
microspheres. The suspension is isotonic and has a pH of 4.5 to 7.5; it is 
only for intravenous administration.  
 
The sulfur hexafluoride lipid microspheres are composed of SF6 gas in the 
core surrounded by an outer shell monolayer of phospholipids consisting 
DSPC and DPPG-Na with palmitic acid as a stabilizer. Sulfur hexafluoride 
has a molecular weight of 145.9. Each milliliter of reconstituted Lumason 
suspension contains 1.5 to 5.6 x108 microspheres, 68 mcg SF6 (12 mcL), 
0.038 mg DSPC, 0.038 mg DPPG-Na, 4.91 mg polyethylene glycol 4000 
and 0.008 mg palmitic acid. The sulfur hexafluoride associated with the 
microspheres suspension is 45 mcg/mL. Fifteen to twenty three percent of 
the total lipids in the suspension are associated with the microspheres. The 
sulfur hexafluoride lipid microsphere characteristics are listed in Table 2:  
 
 
 
 
 
 

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6.0 
Procedures Involved 
6.1 Single-site prospective cohort study to evaluate grayscale US, 
Doppler US, CEUS and SWE examinations in BMT patients 
younger than 21 years. Patients will be identified by the study team 
during a weekly conference that involves the study team and the 
Children’s Mercy BMT team. All eligible patients will be 
approached for written informed consent by a member of the study 
team and if they consent, then they will be enrolled into the study 
prior to the start of their conditioning regimen.  
 
Ultrasound Examinations and Timeline 
After enrollment and within two weeks prior to starting their conditioning 
regimen, a limited abdominal US with Doppler measurements of the hepatic 
arteries, hepatic and portal veins, contrast enhanced ultrasound (CEUS) of the 
liver, as well as SWE will be performed.  
 
Subjects will be undergo US examinations based on disease course as outlined below:  
 
1. All Patients: Patients will undergo limited abdominal US with Doppler, CEUS 
and SWE once a week upon admission for conditioning until the patient day +30 
BMT or discharge, whichever comes first. 
 
2. Inpatient SOS: patients will undergo limited abdominal US with Doppler, CEUS 
and SWE once a week upon admission for conditioning until resolution of SOS. 
 
3. Late Onset SOS: patients will undergo limited abdominal US with Doppler, 
CEUS and SWE once a week upon admission for conditioning until resolution of 
SOS. 
 
 
The clinical team will order US, CEUS and SWE exams when patients have clinical 
suspicion for SOS and we will include these exams in our analysis. All imaging will be 
performed using GE Logiq E9 US machines by dedicated pediatric sonographers and 
interpreted by board-certified pediatric radiologists. Twelve shear wave velocity 
measurements will be taken 2-3 cm below the liver capsule at the mid-clavicular line in 
the right hepatic lobe and another 12 will be taken in the left hepatic lobe near midline 
Microsphere Characteristics 
Mean diameter range 
1.5 – 2.5 μm  
 
Percent of microspheres  
≤ 10 μm ≥ 99%  
 
Upper size limit 
100.0% ≤ 20 μm  
 
 

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avoiding areas of vasculature (24). By necessity, the sonographer and interpreting 
radiologist will not be blinded to the clinical status of the patient. US and clinical data 
will be collected weekly and managed using REDCap electronic data capture tools hosted 
at Children’s Mercy Hospital (25). 
 
Table 3. Ultrasound Timeline 
 
 
ALL PATIENTS 
INPATIENT SOS 
LATE ONSET SOS 
Prior to 
Conditioning 
Start of Conditioning 
through Day +30 
 Through 
Resolution of SOS 
  Through Resolution of 
SOS  
Screening 
Once per Week 
Once per Week 
Once per Week 
Limited 
Abdomen 
and Limited 
Abdominal 
Doppler 
Ultrasound 
X 
  
X 
  
X 
X 
Contrast 
Enhanced 
Ultrasound  
X 
X 
X 
X 
Ultrasound 
Elastography 
X 
X 
X 
X 
 
6.2 Describe: 
• 
There are no known risks to medical ultrasound imaging. 
• 
CEUS Lumason® (sulfur hexafluoride lipid type-A 
microspheres) will be obtained through IDS pharmacy and 
administered through an already existing IV catheter by an RN 
or a radiology technologist trained and certified to administer 
the Lumason® contrast agent, and an abdominal ultrasound 
will be completed. 
• 
  Lumason (sulfur hexafluoride lipid-type A microspheres) is 
the investigational product. The recommended dose of 
Lumason for children is 0.03 mL/kg up to a maximum dose of 
2.4mL injected into a peripheral intravenous catheter.  See 
individualization of dose below.  
1. Follow the Lumason injection with a flush of 5 ml of 0.9% 
Sodium Chloride Injection, USP.  
2. The maximum total dose for children as listed in the 
package insert should not exceed 2.4 mL in any 10-minute 
period. With a maximal total dose of 4.8 mL in any one 
patient during a single exam. 

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6.3 Protected health information (PHI) to be collected for the purpose of 
this study alone will include; MRN, date of transplant, dates of 
ultrasound exams (attached data collection sheet). This information 
will be documented in RedCap.  Within RedCap, there will be two 
separate files.  One file will include minimal PHI (dates of service) 
and contain study data according to an assigned study ID number.  
The second file, will contain a master list of subjects linking the 
subject PHI with the assigned study ID number.  The research record 
generated will consist of an excel spreadsheet from the data 
dictionary within RedCap. Security measures include: storage of the 
data on a password protected computer in a restricted assess 
departmental folder limited to only study personnel. 
6.4 Participants in this study have two options regarding data collection, 
they may consent to take part in the CIBMTR Research Database or 
they may take part in only this study. 
Data Collection Procedures for those that consent to take part in the  
CIBMTR Research Database: 
Subjects may have already consented to take part in the CIBMTR 
Research Database (IRB# 11120281). If they are not yet taking part 
in that study, they  will be given the option to consent for CIBMTR 
Research Database at the time they are consenting for this study. 
If a subject chooses to take part in the CIBMTR database, data 
entered as part of this protocol will be entered into the CIBMTR 
database at the end of local site enrollment.  
Data will provided to CIBMTR in the form of a spreadsheet and will 
be password protected and sent to CMH only for data analysis. 
Clinical and outcome data, including DOB, dates of service, exams, 
lab values and clinical timepoints will be evaluated. 
Data Collection Procedures for those that do not consent to take part in the  
CIBMTR Research Database: 
For subjects that consent to BMT Elastography (Internal) study, but 
do not consent to have their data entered into the CIBMTR database 
will have their clinical variables entered into a local REDCap 
database. Those data points will include DOB, dates of service, 
exams, lab values and clinical timepoints 
Data Collection Procedures for both groups: 
Additional clinical variables (not captured in the CIBMTR database 
needed to define our objectives) and elastography variables will be 
retrospectively extracted from the patients’ electronic medical 
records and entered into REDCap. We will collect a number of 
variables based on the CIBMTR +100 Day outcome form and we 
will collect variables related to the modified Seattle criteria, 

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Baltimore criteria and the new EBMT criteria. We will also collect 
clinical and laboratory parameters of liver disease to help us evaluate 
for other hepatic complications from HCT. We will use the adult and 
pediatric EBMT criteria to determine the date on which the patient 
was first diagnosed with SOS. The date of diagnosis will be the first 
day on which the patient meets the EBMT criteria for their cohort 
(adult or pediatric). We will also use clinical data to grade SOS 
severity, to detect other hepatic complications from HCT, and to 
inform our SOS predictive modeling. For SOS grading, the day on 
which the patient meets the severity criteria for that particular grade 
will be recorded.  
 
7.0 
Data and Specimen Banking 
7.1 N/A 
8.0 
Genetic Analysis Information 
8.1 N/A 
 
9.0 
Sharing of Results with Subjects 
9.1 US SWE results will be blinded from clinicians and patients. 
9.2 Any unexpected findings will be communicated to the ordering 
physician by Dr. Chan via phone or email. 
10.0 Study Timelines 
10.1 Describe: 
• 
An individual’s participation in the study will be during their 
inpatient stay for their BMT. Once the patient is discharged or 
Day +100 after BMT is reached, whichever comes first, subject 
will no longer be in the study. 
• 
July 1, 2018 through June 30, 2020 
• 
June 30, 2021 
11.0 Inclusion and Exclusion Criteria 
11.1 Describe the criteria that define who will be included or excluded in 
your final study sample. 
Inclusion Criteria 
• Subject’s age 1 month through 21 years whom are undergoing 
myeloblative conditioning regimen prior to BMT are eligible for the study. 
• Subjects will be identified by treating BMT physician 
• 1 month through 21 years 

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• July 1, 2018 through June 30, 2020 
Exclusion Criteria 
• Any other medical or social condition that in the opinion of the investigator 
would make them unsuitable to participate. 
•  Indicate specifically whether you will include or exclude each of the 
following special populations: (You may not include members of the 
following populations as subjects in your research unless you indicate this 
in your inclusion criteria.) 
• 
Adults unable to consent:  Include 
• 
Individuals who are not yet adults: Include 
• 
Pregnant women: Exclude 
• 
Prisoners: Exclude 
• 
Wards of the state: Exclude 
12.0 Vulnerable Populations 
12.1 If the research involves individuals who are vulnerable to coercion 
or undue influence, describe additional safeguards included to 
protect their rights and welfare. 
• 
All subjects and family will be given sufficient time to review 
and determine if they would like to participate in the study.  
• 
Subjects over the age of 7 will be required to provide assent for 
study procedures. Subject enrollment is completely voluntary.  
13.0 Local Number of Subjects 
13.1 We anticipate enrolling 80 subjects. 
14.0 Screening and Recruitment Methods 
14.1 Candidates for the study will be identified by BMT physician and 
approached for consent prior to start of conditioning regimen. 
14.2 BMT patients are the source of subjects 
14.3 Subjects will be identified and referred by BMT provider 
14.4 A Waiver of HIPAA Authorization for Recruitment purposes only is 
requested to ensure subjects meet eligibility criteria for enrollment. 
Pre-screening information will not be recorded.  
14.5 Subjects will be informed of the study by their treating BMT 
physician and then approached by a member of the study team for 
consent. 
15.0 Reimbursement, Payment and Tangible Property provided to 
subjects 

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15.1 N/A 
 
16.0 Withdrawal of Subjects 
16.1 Subjects may be withdrawn at the discretion of their treating 
physician or at the LAR/subject request at any time during their 
inpatient stay. All data collected prior to the date of withdrawal will 
be kept for analysis. 
16.2 Notification of request of withdrawal to study team is required 
16.3 This is a minimal risk study, thus no follow-up is needed. 
17.0 Risks to Subjects 
17.1 We do not anticipate any additional risks to this study as all patients 
will already have IV access per SOC for BMT and no additional line 
placements will be required as part of this study. All subjects will be 
monitored during the Lumason CEUS examination by radiology 
personnel and by BMT staff after the exam for any adverse events. 
Reported risks related to Lumason administration include:  
Serious cardiopulmonary reactions, including fatalities, have 
occurred uncommonly in adults during or shortly following 
administration of ultrasound contrast agents, including Lumason. 
These reactions typically occurred within 30 minutes of 
administration. Hypersensitivity reactions such as skin erythema, 
rash, urticaria, flushing, throat tightness, dyspnea, or anaphylactic 
shock have uncommonly been observed following the injection of 
Lumason. The exclusion criteria eliminate any subjects with a 
known cardiac abnormality or a known sensitivity to sulfur 
hexafluoride, so we do not anticipate that these reactions will occur. 
Resuscitation personnel and equipment will be available during the 
study treatment and follow-up period. 
 
17.2 This study poses a minor increase over minimal risk as it does not 
hold the prospect of direct benefit for the individual subject, but the 

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Version 1.4 dated 7.13.18 
intervention presents an experience that is reasonably commensurate 
with those inherent to the subject’s medical situation and is likely to 
yield generalizable knowledge about the disorder which is of vital 
importance to the detection of VOD/SOS.  Physicians will be 
blinded to the results of the imaging. 
18.0 Potential Benefits to Subjects 
18.1 There are no potential benefits to subjects for participation to this 
study. 
19.0 Investigator Assessment of Risk/Benefits Ratio: (IRB makes the 
final determination) Based upon your response in Sections 17.0 and 18.0, 
please provide your assessment of risk and benefits in below table. 
 
Select as applicable: 
Pediatric Risk Category: 
 
Category 1  Research not involving greater than minimal risk  
(45 CFR §46.404 and 21 CFR §50.51)   
 
Category 2 
Research involving greater than minimal risk but 
presenting the prospect of direct benefit to the 
individual 
subjects. (45 CFR §46.405 and 21 CFR §50.52) 
X 
Category 3 
Research involving greater than minimal risk and no 
prospect of direct benefit to individual subjects, but 
likely to yield generalizable knowledge about the 
subject's disorder or condition.  
(45 CFR §46.406 and 21 CFR §50.53) 
 
Category 4 
Research not otherwise approvable which presents 
an opportunity to understand, prevent, or alleviate a 
serious problem affecting the health or welfare of 
children. (45 CFR §46.407 and 21 CFR §50.54) 
Select if applicable: 
Adult Risk Category: 
 
Not Greater than Minimal Risk 
 
Greater than Minimal Risk 
 
20.0 Data Management and Confidentiality 
20.1 All identifiable data will be stored in REDCap and InteleViewer 
(PACS viewing system used by Department of Radiology) housed at 
CMH and will be password protected. Patient DOB, MRN and exam 
date and type are necessary to identify data points of interest. A 
separate master linking list with patient MRN will be kept within 
CMH internal server and will be destroyed upon completion of the 
study. All recorded dates (e.g. dates of US SWE, HCT and 
conditioning regimen) will be destroyed upon completion of data 
analysis. 
20.2 Dr. Averkiou will have access to our Research PACS, which is a 
limited to exams performed for research purposes. These exams are 
manually placed into the research PACS by a member of the 
radiology research team. All data in the research PACS is 

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identifiable for purposes of this research study, but Dr. Averkiou will 
only access this information as part of this research study.  
20.3 A certificate of confidentiality will not be sought for this study. 
20.4 Study data will be evaluated by the PI throughout the duration of the 
study for QA. 
20.5 Patient information will be maintained in a REDCap application and 
will be housed within the CMH Data Center by the Division of 
Biomedical Informatics.  The hosting server has an internal failover 
two-node cluster.  The CMH Data Center is constantly staffed by 
qualified personnel and physical access is limited to authorized 
personnel.  The Center has optimized conditions for the servers and 
stabilized electrical supply.  The database has a full backup.  The 
database server is located inside the CMH corporate firewall.  A 
person must have CMH system access to loin.  Additional security 
for the study patient database restricts access to only those persons 
specifically granted authorization by the Principle Investigator. It is 
possible for data to be downloaded from REDCap.  Individuals who 
lack authority to see confidential data can download reports with 
non‐identifiable data only. The core research group will have the 
ability to download sensitive fields and if such a download occurs, 
REDCap maintains a record of who, what, when, and to where 
copies of the database were imported.   
20.6 Consented subjects will be provided a printed calendar outlining 
their research ultrasound schedule at the time of admission for the 
duration of their enrollment in the study. Each calendar will be 
specific to each subject’s treatment and clinical course, which is 
being performed as standard of care.  
For subjects that are enrolled in additional research ultrasound 
studies, all research ultrasound exams will be listed on the same 
calendar. 
21.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
21.1 Describe: 
• 
All data collected on subjects who receive study drug will be 
analyzed for safety. The proportion of patients with specific 
adverse events will be reported as well as the worst grade 
observed across all adverse events. The maximum confidence 
interval width for these estimates is 16.8%. If the observed 
estimated adverse event proportion is 10%, the 95% confidence 
interval is (5.3, 15.6%). 
• 
Safety information will be collected at the time of study visit 
when the patient is monitored during contrast administration. 
• 
Safety data collection will begin with the first participant and 
participants will be monitored in real time. 

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• 
The PI or an assigned co-investigator will be responsible for 
monitoring the data. 
• 
Cumulative data will be reviewed on a weekly basis beginning 
with the first study participant. 
• 
All data collected on subjects who receive study drug will be 
analyzed for safety. The proportion of patients with specific 
adverse events will be reported as well as the worst grade 
observed across all adverse events. The maximum confidence 
interval width for these estimates is 16.8%. If the observed 
estimated adverse event proportion is 10%, the 95% confidence 
interval is (5.3, 15.6%). 
• 
Any adverse event resulting from the contrast agent requiring 
an ICU admission will trigger an immediate suspension of the 
research. 
22.0 Provisions to Protect the Privacy Interests of Subjects 
22.1 Privacy interests for subjects will be maintained by limiting 
interaction with subjects and LAR to only study personnel at the 
discretion of the treating physician. 
22.2 This study is voluntary, the physicians involved do not have any 
financial gain or interest with the study. Subjects may withdraw 
participation at any time and their care and treatment at CMH will 
not be compromised. Subjects and their families will be told that 
there participation is voluntary and that they may stop at any time. 
22.3 Only IRB approved members of the study team will be granted 
access to the study folder located on the network drive or the 
REDCap database.  Additionally, study team members who are 
responsible for collected data only will be granted limited access to 
REDCap, allowing them to record data only.  
22.4 PHI to be accessed and/or recorded for this research study includes: 
DOB, MRN, dates of service (US SWE exams, conditioning 
regimen, HSCT, lab dates and dates of severity milestones and death 
of applicable) will be recorded. 
22.5 HIPAA authorization will be wrapped into 
permission/assent/consent form. 
23.0 Compensation for Research-Related Injury 
23.1 Regular clinical review will minimize the risk of complications or 
harm as a result of study participation. In the event that an adverse 
event results from the study procedure, it will be reviewed by the 
principal investigator, reported to the IRB, and dealt with per 
institutional policy. Treatment will be available at CMH and will be 
provided at the usual charge.  Payment for this treatment will be the 
participant’s responsibility as this research study does not have funds 

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set aside to pay research participants if the research results in harm 
or complications.  The approved IRB P/A/C will include known 
possible adverse events of study participation as well as payment 
responsibility for any adverse event.  
24.0 Economic Burden to Subjects 
24.1 There is no costs to patients for participating in this research study.  
Patients who agree to study participation will not be charged for the 
ultrasound examinations or Lumason contrast agent.   
25.0 Permission/Assent/Consent Process 
25.1 Indicate whether you will you be obtaining 
permission/assent/consent, and if so describe: 
• 
P/A/C will take place in clinic, radiology department of 
inpatient floor prior to start of conditioning regimen. 
• 
Subjects will be given time to review the P/A/C for consent up 
to the day before the start of conditioning regimen to ensure 
that pre-BMTT US abdominal limited, Doppler, CEUS and  
SWE can be performed. 
Subjects who are not yet adults (infants, children, teenagers) 
One parental/LAR permission will be required for all subjects under 
the age of 18.  
Subjects over the age of 7 will be required to provide assent for the 
study and will be documented on P/A/C.  
Consent at 18 years of age, when minor subjects become adults 
25.2 Subjects that turn 18 years of age during the study period will be re-
consented with a short form addendum for continuation in the study.  
Non-English Speaking Subjects 
• 
P/A/C forms will be translated into Spanish and Arabic by ORI 
Translations program. 
26.0 Process to Document Permission/Assent/Consent 
26.1 P/A/C will be documented by CMH research policy.  
 
27.0 Setting 
27.1 Describe the sites or locations where your research team will 
conduct the research. 

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• 
Subjects will be identified by treating BMT physician and will 
be approached for consent in clinic, radiology department or 
inpatient floor. 
• 
Research procedures will be performed at CMH Adele Hall 
according to site specific regulations and standards. 
 
28.0 Resources Available 
28.1 Describe the resources available to conduct the research: For 
example, as appropriate: 
• 
From our preliminary data, patients with no SOS or mild SOS 
have an average increase in velocity over baseline of 0.056 m/s 
at day +5 with (SD of 0.22 m/s). Our four patients with 
moderate and severe SOS who received defibrotide had an 
average increase in velocity over baseline of 0.25 m/s at day +5 
(SD 0.185 m/s), we would need 245 patients (13 with moderate 
or severe SOS and 232 with no SOS or mild SOS) to have a 
power of 80% to detect a difference with alpha of 0.05. We 
perform approximately 40 HSCT transplants at CMH every 
year and in combination with the other sites, we anticipate an 
enrollment rate of >60% to appropriately recruit enough 
subjects to complete the study. 
• 
We anticipate needing two years to recruit enough subjects to 
appropriately power the study and an additional one year to 
analyze results. 
• 
CMH radiology department has three GE Logiq E10 ultrasound 
machines and 12 dedicated sonographers to perform the 
imaging requirements.  
• 
IDS pharmacy will supply the Lumason Contrast agent. 
• 
All participating sites will be required to obtain IRB approval 
at their local institution and CMH research coordinators will 
ensure all modifications, amendments, continuing reviews and 
AE/SAE’s are electronically transferred to each site. Study 
SOP will be utilized for document transfers and documentation 
of receipt will be kept. 
 
29.0 Multi-Site Research 
29.1 Study-Wide Number of Subjects: 80 
29.2 
Study-Wide Recruitment Methods: CMH will be the only site 
recruiting subjects. The University of Washington – Seattle’s 
involvement is to provide imaging consulting. Dr. Averkiou will have 
access to our PACS system for evaluation of the imaging for analysis and 
image protocol validation. 

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Version 1.4 dated 7.13.18 
• 
All required approvals (initial, continuing review and 
modifications) will be submitted to CMH IRB (IRB of record) 
for approval and letter of correspondence provided by CMH 
IRB will be sent to each site for local IRB (relying IRB) 
approval. Each site will be required to send documentation of 
local IRB approval.  
• 
All modifications will be communicated to sites and approved 
(including approval by the site’s IRB of record) before the 
modification is implemented. 
• 
All engaged participating sites will safeguard data, including 
secure transmission of data, as required by local information 
security policies. 
• 
All local site investigators conduct the study in accordance 
with applicable federal regulations and local laws. 
• 
All non-compliance with the study protocol or applicable 
requirements and any unanticipated problems will be reported 
in accordance with local policy. 
29.3 Describe the method for communicating to engaged participating 
sites: 
• 
All education and training to researchers and research staff will 
be provided by CMH and documentation of training will be 
recorded. 
• 
All reportable events must be communicated within 5 business 
days of notification of reportable event to CMH study staff 
for submission to CMH IRB (IRB of record). 
• 
Interim results will be communicated through virtual meetings 
and electronic communication as they become available.  
• 
The closure of a study will be communicated through 
electronic documentation of correspondence letter from IRB of 
record to participating sites for relying IRB documentation. 
• 
 
30.0 International Research 
29.1.  
NA