Clinical trial NCT03147690
Conditions: Abdominal Injury
Keywords: Solid Organ Injury
Sponsor: David Mooney
Start date: 2017-11-01; Completion date: 2019-10-07
Enrollment: 74 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study proposes to evaluate the accuracy of contrast-enhanced ultrasound (CEUS) in diagnosing abdominal solid organ injuries in pediatric patients. 146 subjects will be enrolled across approximately 8 sites in the US. All subjects will have had a Computerized Tomography (CT) scan as part of standard of care, confirming at least one solid organ abdominal injury. All subjects will have an abdominal ultrasound without contrast, followed by a contrast-enhanced ultrasound using the contrast agent Lumason. Ultrasound and contrast-enhanced ultrasound results will be compared to the CT scan results. The study procedures will take place within 48 hours of injury.

Detailed description:
This is an interventional study proposes to evaluate the accuracy of contrast-enhanced ultrasound (CEUS) in diagnosing abdominal solid organ injuries in pediatric patients. 146 subjects will be enrolled across approximately 8 sites in the US. All subjects will have had a Computerized Tomography (CT) scan as part of standard of care, confirming at least one solid organ abdominal injury. All subjects will have an abdominal ultrasound without contrast, followed by a contrast-enhanced ultrasound using the contrast agent Lumason. Ultrasound and contrast-enhanced ultrasound results will be compared to the CT scan results. The study procedures will take place within 48 hours of injury. At conclusion of enrollment of all subjects a centralized review of CT vs. CEUS will occur to compare to real time readings.

Arms: arm 1: All subjects will have an abdominal non-contrast ultrasound performed. Lumason will then be administered at a dose of 0.03mL/kg up to a maximum dose of 2.4mL and a contrast-enhanced ultrasound will be performed. The dose will be given twice, for a total maximum dose per subject of 4.8mL
Interventions: intervention 1: Lumason
Intervention descriptions: intervention 1: Lumason will be administered at a dose of 0.03 mL/kg up to a maximum dose of 2.4mL injected into a peripheral intravenous catheter. An abdominal contrast enhanced ultrasound will be performed to look for solid organ injury. The will be given twice during the intervention, for a total maximum dose per subject of 4.8mL.

Protocol documents:
Prot_SAP_002.pdf: 
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PROTOCOL TITLE: A Multicenter Trial of Contrast-Enhanced Ultrasound in the Evaluation 
of Abdominal Solid Organ Injuries in Pediatric Trauma Patients  
 
NCT NUMBER: NCT03147690  
 
DOCUMENT DATE: 10/16/2019


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PROTOCOL  
PROTOCOL TITLE 
A Multicenter Trial of Contrast-Enhanced Ultrasound in the 
Evaluation of Abdominal Solid Organ Injuries in Pediatric 
Trauma Patients  
PROTOCOL NUMBER 
P00025242 
STUDY DESIGN (PHASE) 
Prospective non-randomized cohort 
PROTOCOL VERSION 
Version 4 
IND NUMBER 
N/A 
INVESTIGATIONAL 
PRODUCT 
Lumason 
INDICATION 
To enhance visualization of abdominal solid organ injuries in 
children 
SPONSOR 
David P. Mooney, MD, MPH 
300 Longwood Avenue 
Boston, MA 02115 
617 355-0535 
PRINCIPAL INVESTIGATOR 
David P. Mooney, MD, MPH 
 
 
 
 
Good Clinical Practices 
This study was conducted under Good Clinical Practices, in accordance with the Declaration of Helsinki, in 
compliance with the International Conference on Harmonisation (ICH) guidelines. 
Confidentiality Statement 
This document contains confidential information of the Sponsor. This information is to be disclosed only to the 
recipient study staff and the Institutional Review Board or Institutional Ethics Committee reviewing this protocol. 
This information can be used for no other purpose than evaluation or conduct of this study without prior written 
consent from the Sponsor. 
 


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SYNOPSIS 
Name of Sponsor 
David P. Mooney, MD, MPH 
 
Coordinating Center 
Boston Children’s Hospital 
 
 
Investigational Product 
Lumason 
Indication (phase) 
To improve ultrasound visualization of pediatric abdominal solid 
organ injuries 
Title of Study 
A Multicenter Trial of Contrast-Enhanced Ultrasound in the 
Evaluation of Abdominal Solid Organ Injuries in Pediatric Trauma 
Patients 
Protocol Date 
October 16, 2019 
Protocol Version 
Version 4 
OBJECTIVES 
● To improve the ultrasonic visualization of abdominal solid organ injuries in children 
METHODOLOGY 
Study Design 
Prospective non-randomized cohort 
Treatments 
Lumason intravenous contrast 
Treatment 
Duration 
50 to 90 minutes 
Study Drug and 
Formulation 
Lumason is provided by the manufacturer (Bracco Diagnostics) in single use 5 mL vials.  
Dose and Route of 
Administration  
Dosing and Administration information can be found in section 3.4. 
 
Concomitant and 
Excluded Therapy 
There are no concomitant or excluded therapies. 
SUBJECT POPULATION 
Number Planned  
132 subjects are to complete this study: all in the treatment arm.  Each patient will have at 
least one injured organ and their other organs will serve as controls compared to the other 
study subjects. Any subjects who do no complete the study will not count toward this 
number. 
Major Inclusion 
Criteria 
● Age 8 to 17 years inclusive   
● Abdominal solid organ injury visualized on computerized tomography 
● Hemodynamically stable 


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Name of Sponsor 
David P. Mooney, MD, MPH 
 
Coordinating Center 
Boston Children’s Hospital 
 
 
Investigational Product 
Lumason 
ASSESSMENTS 
Efficacy  
Lumason will be considered efficacious if ≥90% of the abdominal solid organ injuries 
identified on computerized tomography are able to be visualized on contrast enhanced 
ultrasound. 
Pharmacokinetics 
and 
Pharmacodynamics 
 
No pharmacokinetics or pharmacodynamics will be performed. 
Safety 
Study subjects will be monitored for the development of any adverse reactions for 30 
minutes following the final infusion of Lumason.  No laboratory or other imaging studies 
are planned.  
STATISTICAL METHODS AND ANALYSIS 
Efficacy 
Lumason will be considered efficacious if ≥90% of the abdominal solid organ injuries 
identified on computerized tomography are able to be visualized on contrast enhanced 
ultrasound. 
Pharmacokinetics 
and 
Pharmacodynamics 
No pharmacokinetics or pharmacodynamics will be performed. 
Safety 
Study personnel will monitor subjects for 30 minutes following the last infusion of 
Lumason.  Patients will be maintained on a cardiopulmonary monitor through this time 
period.  All adverse events will be graded according to the criteria specified by the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (NIH, June 14, 
2010). 
 


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TABLE OF CONTENTS 
 
Page 
ABBREVIATIONS AND DEFINITIONS ......................................................................................7 
1. 
BACKGROUND .................................................................................................................8 
1.1 
Name and Description of Investigational Product ...................................................9 
1.2 
Results of Nonclinical Studies ...............................................................................10 
1.3 
Results of Clinical Studies .....................................................................................10 
2. 
STUDY OBJECTIVES ......................................................................................................11 
3. 
INVESTIGATIONAL PLAN ............................................................................................12 
3.1 
Overall Study Design and Plan ..............................................................................12 
3.1.1 Study Endpoints .........................................................................................12 
3.2 
Discussion of Study Design, Including Choice of Control Groups .......................13 
3.3 
Selection of Study Population ................................................................................13 
3.3.1 Inclusion Criteria .......................................................................................14 
3.3.2 Exclusion Criteria ......................................................................................14 
3.3.3 Removal of Subjects from Therapy or Assessment ...................................14 
3.3.3.1 Subject Withdrawal or Early Termination ..................................15 
3.3.3.2 Planned Follow-up for Discontinued Subjects ............................15 
3.4 
Study drug ..............................................................................................................15 
3.4.1 Identity of Investigational Product.............................................................15 
3.4.2 Packaging and Labeling .............................................................................15 
3.4.3 Dosage Administered .................................................................................16 
3.4.4 Selection of Doses in the Study .................................................................16 
3.4.5 Investigational Product Accountability ......................................................16 
3.4.6 Prior and Concomitant Treatments ............................................................17 
3.4.6.1 Prior and Concomitant Therapies ................................................17 
3.4.6.2 Prior and Concomitant Medications ............................................17 
3.5 
Assessments ...........................................................................................................17 
3.5.1 Schedule of Study Activities ......................................................................17 
3.5.2 Assessment of Efficacy ..............................................................................18 
3.5.2.1 Screening Assessments ................................................................18 
3.5.2.2 Assessments during Study Procedure ..........................................19 
3.5.2.3 Follow-up Assessments ...............................................................19 
3.5.3 Assessment of Safety .................................................................................20 
3.5.3.1 Adverse Events ............................................................................20 
3.5.3.1.1 Definition of Adverse Events .....................................20 
3.5.3.1.2 Definition of Serious Adverse Events ........................20 
3.5.3.1.3 Documentation and Reporting of Adverse Events .....21 
3.6 
Safety Issues Related to Investigational Product ...................................................22 
3.7 
Data Quality Assurance .........................................................................................23 
3.7.1 Data Collection, Monitoring, and Transfer ................................................23 


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3.7.2 Data and Safety Monitoring Plan ...............................................................24 
3.7.3 Study Monitoring and Auditing .................................................................24 
3.8 
Statistical Methods Planned in the Protocol and Determination of Sample Size ..24 
3.8.1 Sample Size and Power Considerations .....................................................24 
3.8.2 Statistical Analysis Plan .............................................................................25 
3.8.3 Study Duration ...........................................................................................25 
3.8.4 Interim Analysis .........................................................................................25 
3.8.5 Safety Analysis ..........................................................................................25 
3.9 
Compliance Statement ...........................................................................................25 
3.10 
Subject Information and Consent...........................................................................26 
4. 
COMPENSATION, INSURANCE AND INDEMNITY ..................................................26 
5. 
REFERENCE LIST ...........................................................................................................27 
6. 
APPENDIX I .....................................................................................................................29 


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ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Term 
AE 
Adverse event 
BCH 
Boston Children’s Hospital  
BP 
Blood pressure 
CEUS 
Contrast Enhanced Ultrasound 
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CT 
Computerized Tomography 
CTC 
Common Toxicity Criteria 
EKG 
Electrocardiography 
FAST 
Focused Abdominal Sonography for Trauma 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
Kg 
Kilogram 
MA 
Massachusetts 
Min 
Minute 
mL 
NPV 
PPV 
milliliter 
Negative Predictive Value 
Positive Predictive Value 
RR 
Respiratory Rate 
SAE 
Serious adverse event 


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1. 
BACKGROUND 
Injury is the most common cause of morbidity and mortality among children.  Children are more 
susceptible to multisystem trauma than adults given their anatomic and physiologic 
characteristics.   Computed tomography (CT) with intravenous (IV) contrast is the gold standard 
test for evaluating the abdomen in children with suspected injury.  CT is used liberally since 
abdominal injuries are often suspected and difficult to rule out with history and physical 
examination alone.  There is a 60-75% rate of normal abdominal CTs for trauma in the pediatric 
population reported in the literature (1).  Literature suggests that children may have an increased 
risk of cancer related to the radiation exposure required to perform an abdominal CT.  This risk 
may be as high as 1 in 300 in children under 5 years of age (2).  In addition, there is a 1 in 200 
chance of a reaction to the IV contrast agent used (3).   
To date, CT is the only reliable and accurate diagnostic modality to evaluate for intra-abdominal 
injuries in children.  Although FAST (Focused Abdominal Sonography for Trauma) exams are 
used frequently in adults, this test has not been demonstrated to have sufficient sensitivity to 
detect abdominal organ injury in the pediatric patient (4, 5). If contrast enhanced ultrasound 
(CEUS) improves the sensitivity and specificity of sonography in diagnosing an abdominal solid 
organ injury, it may become a valuable diagnostic tool, supplanting CT. 
In Europe, CEUS using SonoVue, the European brand-name for Lumason, has been used 
clinically for more than a decade, reported mainly in adults.  Valentino, et al. published results of 
a prospective study performed in Italy comparing the sensitivity and specificity of ultrasound and 
CEUS to abdominal/pelvis CT with IV contrast.  A total of 27 patients were prospectively 
studied and they found CEUS to have a 92.9% sensitivity, 100% specificity, 100% positive 
predictive value (PPV) and 93.8% negative predictive value (NPV) compared to CT (6).    
Valentino published a subsequent study of 133 adult trauma patients with blunt abdominal solid 
organ injury on CT who underwent CEUS and found 96.4% sensitivity, 98% specificity, 98.8% 
PPV and 94% NPV (7) compared to CT.   
 


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Clinical experience with the use of CEUS has been limited in the United States.  An as yet 
unpublished pilot study conducted by Zalieckas et al enrolled 18 children with 21 abdominal 
solid organ injuries identified on CT.  Children underwent greyscale and Doppler ultrasound 
studies, then CEUS using the contrast agent Optison.  They found that greyscale/Doppler 
ultrasound had a 45.2% sensitivity, 96.4% specificity, a 79.2% PPV, and an 85.3% NPV 
compared to CT. CEUS had an 85.7% sensitivity, 98.6% specificity, 94.7% PPV and 95.8% 
NPV. Two of the 3 missed injuries were in one 100 kilogram pediatric patient, suggesting that 
further trials be limited to patients otherwise considered to be good candidates for abdominal 
sonography. 
Optison and Lumason are both contrast agents used to perform CEUS. Lumason is now FDA-
approved for use in the characterization of focal liver lesions in adult and pediatric patients. It 
has been studied and used used in Europe, under the brand name SonoVue, to identify abdominal 
solid organ injuries. Because Lumason is FDA-approved for a closely related indication in a 
pediatric population, we have chosen to use Lumason for this study. 
1.1 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT 
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:  
1) one clear glass 10 mL vial containing 25 mg of lyophilized powder lipid-type A, 60.7 mg of 
sulfur hexafluoride gas and capped with a blue flip-cap  
2) one prefilled syringe containing 5 mL Sodium Chloride 0.9% Injection, USP (Diluent)  
3) 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.  


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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 the following table:  
Microsphere Characteristics 
Mean diameter range 
1.5 – 2.5 µm 
Percent of microspheres 
≤ 10 µm ≥ 99% 
Upper size limit 
100.0% ≤ 20 µm 
1.2 
RESULTS OF NONCLINICAL STUDIES 
In a study reported by Tang et al using a dog model of induced liver and spleen injuries, CEUS 
using SonoVue showed a high level of concordance with CT (8).  
1.3 
RESULTS OF CLINICAL STUDIES 
Preliminary Studies  
Several European trials have investigated the use of CEUS to identify abdominal solid organ 
injuries seen on CT in children.  These studies have used SonoVue, which is the European brand-
name of Lumason.  Sessa reported a retrospective series of 254 adults and children aged from 7 


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to 82 who underwent ultrasound, CEUS using SonoVue and CT to evaluate their abdomen after 
injury.  84 abdominal injuries were noted on CT, 50 of which were seen on ultrasound. The use 
of CEUS allowed the visualization of 81 of 84 injuries with no adverse events related to contrast 
administration (9). 
 Valentino et al reported a prospective study of the sensitivity and specificity of ultrasound and 
CEUS (CEUS) versus CT.  27 children were enrolled, with a mean age of 9 years.   SonoVue 
was injected as a bolus followed by a normal saline bolus. 12 patients had 14 abdominal solid 
organ injuries seen on CT.  13 injuries were identified on CEUS (sensitivity 92.9%, specificity 
100%, PPV 100%, NPV 93.8%).  No adverse events were reported from contrast administration 
(10). 
Menichini et al reported a retrospective series of 73 children who presented to a single 
emergency department with concern for an abdominal injury. 67 of the 73 children had an 
abdominal solid organ injury, only 26 of which were seen on standard ultrasound.  Using CEUS 
with two 1.2 mL doses of SonoVue all 67 solid organ injuries seen on CT were able to be seen 
for a sensitivity, specificity, PPV and NPV of 100%. No adverse events were noted related to the 
SonoVue administration (11). 
Rosado and Riccabona reviewed the off-label use of intravenous ultrasound contrast in 502 
children distributed over 19 published studies (12).  The most common agent used was SonoVue, 
in 447 children, and the second most common reason was to identify abdominal solid organ 
injuries.  Ten patients (2%) were reported to have an adverse event, with 9 of the events being 
minor and transient.  One patient (0.2%) suffered an anaphylactic reaction to the contrast agent 
and this resolved with proper treatment (12). This adverse event profile compared favorably to 
that seen with CT contrast (13). 
2. 
STUDY OBJECTIVES 
The primary goal of the study is to evaluate whether the use of ultrasound contrast can improve 
the sensitivity and specificity of ultrasound in diagnosing abdominal solid organ injuries in 
pediatric patients, thereby making it a valuable diagnostic tool.   


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Since all patients entered on the study will have CT positive results, the primary endpoint is the 
proportion of patients for whom all organs identified by CT with injuries are also identified by 
CEUS, regardless of injury grade. This will provide an estimate of the sensitivity assuming CT 
as the gold standard.   
The secondary objectives are to determine:  1) for each organ, the proportion of patients for 
whom the organ is identified by CT and CEUS as injured, 2) proportion of injuries identified by 
CEUS which are within 1 grade of the injury identified by CT, 3) the proportion of patients 
where the absence or presence of peritoneal fluid identified by CT is also identified by CEUS, 
and 4) the comparison between ‘real-time’ and centralized interpretation of CEUS images.  
3. 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN AND PLAN  
To address the primary objective, we propose a multi-center study with participation from 7-10 
sites to enroll 132 subjects who complete the study aged 8-17 over 2-3 years. Dr. David Mooney 
is the Sponsor Investigator, with Boston Children’s Hospital acting as the coordinating center. 
Prior to enrollment, each subject will have already undergone an abdominal CT that identified at 
least one solid organ abdominal injury. As part of the study, subjects will undergo a 
greyscale/Doppler ultrasound and CEUS within 48 hours of injury. The study will measure the 
number of organ injuries identified, and the severity of organ injury. The ultrasound studies will 
be performed by a radiologist who is blinded to the results of the CT. The findings on 
greyscale/Doppler ultrasound and CEUS will be compared to the CT, using the CT findings as 
the standard. 
3.1.1 
Study Endpoints 
 Primary endpoint is the proportion of patients for whom all organs identified by CT with 
injuries are also identified by CEUS, regardless of injury grade. 
 Secondary endpoints:   
o For each organ, the proportion of patients for whom the organ is identified by CT 
and CEUS as injured. 


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o The proportion of injuries identified by CEUS which are within 1 grade of the 
injury identified by CT. 
o  The proportion of patients where the absence or presence of peritoneal fluid 
identified by CT is also identified by CEUS. 
o The proportion of patients with agreement between ‘real-time’ and centralized 
interpretation of CEUS images. 
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL 
GROUPS 
Children who have an abdominal solid organ injury visualized on abdominal computerized 
tomography form the study group. Computerized tomography is the current gold standard for the 
diagnosis of these injuries in children.  The purpose for choosing children who have already 
undergone abdominal computerized tomography is to be able to compare the new imaging 
technique: contrast enhanced ultrasound, to the gold standard. Children from age 8 through 17 
years have been chosen to assure that they are able to assent to the study. At least 1 of the 5 
abdominal solid organs (liver, spleen, pancreas, left kidney, right kidney) will be injured per 
patient and each subject will serve as their own control.  CTs will be interpreted by radiologists 
at the participating institution. Sonographers will be blinded to the results of the computerized 
tomography.  
This study will take place at 7-10 participating institutions. Based on prior data, approximately 
30 potentially eligible patients are expected to present at each institution per year. We estimate 
enrollment will take 2-3 years to enroll 132 subjects who complete the study.  
3.3 
SELECTION OF STUDY POPULATION 
Subjects who fulfill the following eligibility criteria will be recruited regardless of their race 
or gender. Prior to receiving a CT scan, all menarchal females will have a urine pregnancy test as 
per clinical care. The results of this test can be found in the medical record. If the pregnancy test 
is positive, the subject will not receive a CT scan and will therefore not be eligible for the study. 
No pregnancy tests will be administered for research purposes.  


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3.3.1 
Inclusion Criteria 
To be eligible to participate in this trial, subjects must meet all of the following criteria: 
All study participants must be: 
 Hemodynamically stable, as determined by the trauma team 
 Age 8 through 17 years  
 Interpretable CT of the abdomen and pelvis that demonstrates at least one abdominal 
solid organ injury among the liver, spleen, pancreas, and kidneys 
 Plan for observation or admission to the hospital 
 Candidate for abdominal ultrasound based on body habitus 
 Have a Glasgow Coma Score of 15 
 Able to complete the study procedures within 48 hours of injury 
 
3.3.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
 Known cardiac abnormality 
 Pulmonary hypertension 
 Known sensitivity to sulfur hexafluoride, polyethylene glycol 4000, 
distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol sodium 
(DPPG-Na), or palmitic acid 
 Unable to roll over 
 Unable to assent 
 Pregnant 
 Lactating  
 CT images not available for transmission to central image repository 
 
3.3.3 
Removal of Subjects from Therapy or Assessment 
Stopping Point 
The study will be suspended immediately for any two Serious Adverse Events and will not 
resume until an investigation by the DSMB has concluded that the study should resume. 


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3.3.3.1 
Subject Withdrawal or Early Termination 
Subjects could choose to discontinue from the study at any time, for any reason, specified or 
unspecified, and without prejudice. Subjects could be discontinued from the study for any of the 
following reasons: 
● At the subject’s or their parent/guardian’s request 
● At the discretion of the site Investigator, if deemed appropriate, for any reason, such as the 
subject’s medical status worsening. 
3.3.3.2 
Planned Follow-up for Discontinued Subjects 
The study has a single phase which lasts 50-90 minutes. We do not anticipate any discontinued 
subjects. 
3.4 
STUDY DRUG 
3.4.1 
Identity of Investigational Product 
Lumason (sulfur hexafluoride lipid-type A microspheres) is the investigational product.  
3.4.2 
Packaging and Labeling 
Lumason (sulfur hexafluoride lipid-type A microspheres) is available in a carton of five 5 mL 
single use vials. (NDC 0270-7099-16) 
 
DOSAGE AND ADMINISTRATION  
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. This will be repeated once to ensure all organs are 
visualized. 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.  For this study, over any 10-minute period we intend to 
administer the approved dose of 0.03 mL/kg up to a maximum of 2.4 mL. 
3. The maximum total dose for children as listed in the package insert should not exceed 4.8 
mL in any one patient during the full time on study.  In this study, we intend to administer a 


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total dose in any one patient during the full time on study of 0.06 mL/kg with a maximal dose 
of 4.8 mL. 
 
3.4.3 
Dosage Administered 
Licensed study personnel will administer Lumason 0.03 mL/kg in two separate injections to a 
maximum of 2.4 mL per injection: 
Injection 1: Image right side: right kidney and then liver (transverse and sagittal sweeps) and 
pancreas (transverse sweeps). 
The second injection will be administered a minimum of 10 minutes after the first injection. 
Injection 2:  Image left side: left kidney and then spleen (transverse and sagittal sweeps) and 
pancreas (transverse sweeps).  
 
The maximum dose will not exceed 0.03 mL/kg up to a maximum of 2.4 mL in any 10 minute 
period.  The total allowable dose for any one patient is 0.06mL/kg up to a maximum of 4.8mL. 
  
Following each Lumason contrast push injection, a flush of 5 mL of 0.9% sodium chloride will 
be administered intravenously.   
3.4.4 
Selection of Doses in the Study 
The doses to be used have been chosen because they have been approved by the FDA for the 
visualization of focal liver lesions in children. The liver is one of the most common organs 
injured in trauma and it is expected that an ultrasound contrast dose that results in good 
visualization of the liver will also result in good visualization of the other abdominal organs. In 
addition, the selected dose, which may be repeated twice, is in line with the dose used in 
European studies which safely performed CEUS for abdominal solid injuries in children using 
SonoVue, the European brand-name for Lumason.   
3.4.5 
Investigational Product Accountability 
The Sponsor will be responsible for Drug Accountability requirements for this trial. Lumason is 
an FDA approved agent available for sale for patient use in the United States. It will be 
purchased directly from the market, subject to the same manufacturing safety standards as other 
FDA approved agents on the market. 
The agent will be stored in the research pharmacy equivalent at each institution and will be 
provided to study personnel once confirmation of consent has been obtained, per each 
participating hospital’s research pharmaceuticals protocol.    A drug accountability log will be 


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maintained by each sites’ appropriately designated research pharmacy, including the study 
subject number alongside the product number of the vial used for that subject.  
One sealed vial of agent will be used for each subject. The contents will be drawn up in sterile 
fashion by licensed study personnel and will be administered into an existing peripheral 
intravenous line. The dose used will vary by subject body weight as previously stated.  At the 
completion of each subject’s CEUS, all vials, including any residual agent left over, will be 
returned to the Research Pharmacy equivalent where it will be handled according to proper drug 
accountability procedures.    
3.4.6 
Prior and Concomitant Treatments 
3.4.6.1 
Prior and Concomitant Therapies 
There are no prior or concomitant therapies in this study.  
3.4.6.2 
Prior and Concomitant Medications 
There are no prior or concomitant medications in this study.  
3.5 
ASSESSMENTS 
3.5.1 
Schedule of Study Activities 
Study Timeline  
 Potential subjects who meet inclusion criteria, including having undergone a CT that 
demonstrates an abdominal solid organ injury, will be identified in the participating 
institutions’ Emergency Departments. CTs may have been performed by a participating 
institution or a referring institution, in which case the CT has been delivered to the 
participating institution. These CTs will be read by the study staff at the participating 
institution and eligibility criteria will be assessed by reviewing medical records. 
 Eligible subjects and their guardians will be approached and invited to participate. After 
sufficient time to allow thoughtful consideration of participation, appropriately 
designated study personnel will obtain consent from the guardian and assent from the 


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subject. Subjects may be consented and enrolled at any time during their hospital stay as 
long as the study procedures can be performed within 48 hours of injury. 
 After evaluation and diagnostic studies are completed for the medical care of the subject, 
he/she will be taken to the Radiology department. If the subject is in the ICU, bedside 
ultrasounds may be performed instead of going to the Radiology department. 
 Ultrasound personnel, blinded to the results of the CT and the medical records of the 
subject, will perform a greyscale/Doppler abdominal ultrasound and record the results. 
 Licensed study personnel will then administer Lumason via an existing peripheral IV, 
and the sonographer will perform a contrast-enhanced abdominal ultrasound and record 
the results. Any physical findings on the subject’s abdomen will also be recorded. 
 The subject will be monitored for 30 minutes after the final Lumason injection as detailed 
in the Assessments sections. 
 After completion of the ultrasounds, subsequent patient care will be as medically 
indicated. 
3.5.2 
Assessment of Efficacy 
The presence or absence of an injury as well as the grade of the injury will be determined for the 
liver, spleen, pancreas, and each kidney in each patient.  In addition, the presence or absence of 
peritoneal fluid as well as a rough estimate of the amount of fluid will be determined for each 
patient.  These data will be determined by a sonographer for each of the study subjects.  Inter-
rater reliability will be determined by comparing the “real-time” read to a central read. These 
data will then be compared to the findings on computerized tomography, using the tomography 
as the standard. Sensitivity and specificity of the sonograms and the CEUS to identify injuries 
diagnosed on computerized tomography will be determined. Lumason will be considered 
effective if ≥90% of the injuries identified by CT are visualized by CEUS. 
3.5.2.1 
Screening Assessments 
All subjects will have undergone a CT identifying at least one abdominal solid organ injury prior 
to being approached for the study. If the CT was performed at a referring institution, the CT will 


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be delivered to the participating institution and will be re-read at the participating institution by 
study staff. Study personnel will assess all inclusion and exclusion criteria for each potential 
subject. Only subjects who meet all criteria will be consented into the study. 
Subjects may be consented and enrolled at any time during their hospital stay as long as the 
study procedures can be performed within 48 hours of injury. 
The de-identified CTs for all enrolled subjects will be sent to a repository at Boston Children’s 
Hospital, the coordinating center, for a central read.  
3.5.2.2 
Assessments during Study Procedure 
Subjects will be transported to the Radiology department for the study treatment. If the subject is 
in the ICU, bedside ultrasounds may be performed instead of moving to the Radiology 
department. The sonographer will first perform a greyscale/doppler ultrasound and record 
findings, including presence or absence of injury for each organ, grade of injury if applicable, 
presence or absence of peritoneal fluid, and approximate amount of fluid if applicable. Licensed 
study personnel will then inject the contrast agent and the sonographer will perform a CEUS and 
record the same findings as listed above. A second injection will be given a minimum of ten 
minutes after the first injection to complete the CEUS procedure. Any physical findings on the 
abdomen will also be recorded.  
The ultrasounds for all enrolled subjects will be sent to a repository at Boston Children’s 
Hospital, the coordinating center, for a central read.  
3.5.2.3 
Follow-up Assessments  
All patients will be maintained on a cardiopulmonary monitor as a standard part of the clinical 
care of their injury. Vital signs, including blood pressure, heart rate, respiratory rate, and oxygen 
saturation will be monitored prior to the injection of the contrast agent and continuing for 30 
minutes after the final injection. The vital signs will be recorded at 5 minute intervals by the 
study personnel. The study personnel will ask the patient about any side effects he/she 
experiences pre-contrast injection, after each contrast bolus, and at the completion of the 30 
minute observation period. 


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After the completion of the ultrasounds, subsequent patient care will be as otherwise indicated 
per the trauma team for the management of their injuries. 
3.5.3 
Assessment of Safety 
Patients will be monitored for adverse events for 30 minutes after completion of the final 
contrast injection.  
3.5.3.1 
Adverse Events 
3.5.3.1.1 
Definition of Adverse Events 
For purposes of this study, an adverse event will be defined as any unfavorable and unintended 
diagnosis, symptom, sign, syndrome or disease which either occurs during the study, having 
been absent at baseline, or, if present at baseline, appears to worsen. 
An unexpected adverse event will be defined as any adverse event that is not listed as a risk in 
the current version of the Protocol or Package Insert. 
An adverse reaction will be defined as any adverse event caused by the Investigational Product. 
A suspected adverse reaction will be defined as any adverse event for which there is a reasonable 
possibility that the Investigational Product caused the event. 
All adverse events will be graded by the site investigator according to the criteria specified by 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (NIH, June 14, 
2010).  
Adverse events that have been reported as possibly related to the study procedure include the 
following: headache, nausea, dysgeusia, injection site warmth or pain, feeling hot, chest 
discomfort or pain, dizziness, cardiopulmonary reactions, and hypersensitivity reactions. 
3.5.3.1.2 
Definition of Serious Adverse Events 
An AE occurring with any study treatment regimen should be classified as “Serious” if it meets 
one of the following criteria: 
● It results in death (ie, the AE caused or led to death). 


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● It is life threatening (ie, the AE placed the subject at immediate risk of death). This 
classification does not apply to an AE that hypothetically might cause death if it is more 
severe. 
● Event severe enough to require airway management, ICU admission, hypotension requiring 
fluid or IV vasopressor administration. 
● It requires or prolongs inpatient hospitalization (ie, the AE requires at least a 24-hour 
inpatient hospitalization or prolongs a hospitalization beyond the expected length of stay). 
Hospitalizations for elective medical or surgical procedures, scheduled treatments, or routine 
checkups are not SAEs by this criterion. 
● It is disabling or incapacitating (ie, the AE results in a substantial disruption of the subject’s 
ability to carry out normal life functions). 
● It is a congenital anomaly or birth defect (ie, an adverse outcome in a child or fetus of a 
subject exposed the molecule or study treatment regimen before conception or during 
pregnancy). 
● It does meet any of the above criteria, but could jeopardize the subject and might require 
medical or surgical intervention to prevent one of the outcomes listed above.  
● Any other CTCAE event of grade 3 or greater deemed possibly or definitely related to the 
study drug.  
3.5.3.1.3 
Documentation and Reporting of Adverse Events 
The severity of toxicities will be graded in accordance with the Common Terminology Criteria 
for AE (CTCAE) version 4.0.3.  Grade 2 AEs deemed possibly, probably, or definitely related to 
study medication and all Grade 3 and higher AEs, regardless of suspected causal relationship to 
study drug, will be recorded as AEs in the CRFs.  
All SAEs must be reported to the Sponsor or designee within 24 hours of site awareness, 
regardless of the relationship of the event to the study treatment regimen. Refer to the previous 
section for the definition of a serious adverse event. The completed SAE form will be scanned 
and emailed securely within 24 hours to the Sponsor at david.mooney@childrens.harvard.edu 


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and Leah Cheng at leah.cheng@childrens.harvard.edu. Relevant follow-up information will be 
submitted to the Sponsor or its designee as soon as it becomes available. 
Boston Children’s Hospital PI will inform the DSMB, as well as the Boston Children’s Hospital 
IRB according to Institutional guidelines for reporting. The occurrence of 2 or more serious 
adverse events will result in a pause in the study while an investigation is conducted by the 
DSMB to determine if the study should resume. 
3.6 
SAFETY ISSUES RELATED TO INVESTIGATIONAL PRODUCT 
Anticipated Risks 
All patients will have at least one functioning intravenous catheter in place as a part of standard 
medical care and no new IV access will be required. We expect that there may be some mild 
discomfort related to the performance of the ultrasound study itself and will monitor for this.  
Other than the discomfort from the ultrasound probe, we do not expect any other ultrasound-
related adverse events.  Patients will be monitored during the study interval and for 30 minutes 
after final contrast injection by licensed study personnel, and only hemodynamically stable 
patients will be selected, making it very unlikely that there will be a hemodynamic issue during 
the brief time of the study. 
Licensed study personnel will administer Lumason and monitor the patient during injection and 
for 30 minutes afterward for any adverse effects.  A questionnaire will be filled out during the 
study to record any potential reactions to Lumason.  Resuscitation equipment and trained 
personnel will be available during the administration of Lumason and the follow-up period. 
Reported risks related to Lumason administration include:  
 
Adverse Reactions in 6,856 patients receiving Lumason 
Adverse Reaction 
Number 
(%) 
Any Adverse Reaction 
340 
5 
Headache 
65 
1 
Nausea 
37 
0.5 
Dysgeusia 
29 
0.4 


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Injection site pain 
23 
0.3 
Feeling hot 
18 
0.3 
Chest discomfort 
17 
0.2 
Chest pain 
12 
0.2 
Dizziness 
11 
0.2 
Injection site warmth 
11 
0.2 
 
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. As 
stated above, resuscitation personnel and equipment will be available during the study treatment 
and follow-up period. 
3.7 
DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of standard practices and 
procedures. These are described in the following sections. 
3.7.1 
Data Collection, Monitoring, and Transfer 
All clinical research data will be recorded and maintained on study specific case report forms 
(CRFs).  These CRFs will be stored within individual subject binders in accordance with Good 
Clinical Practice Standards.  Study materials will be kept in designated locked file cabinets and 
access will be restricted to authorized study staff only.  Subject confidentiality will be 
maintained by recording subject-specific data using a unique confidential study identifier. 
All study data will be entered into a REDCap database and monitored for data accuracy. Data 
and source documents will be maintained in compliance with ICH-GCP and local and national 
regulatory requirements. 
The coordinating center will maintain a central repository of all de-identified CT and US scans 
for all subjects across all sites in order to provide the scans to the central reviewers. 


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3.7.2 
Data and Safety Monitoring Plan 
A Data and Safety Monitoring Board (DSMB) will be created with members with expertise in 
ultrasonography, statistics, and trauma surgery. The DSMB will meet at a minimum of twice per 
year. Details of the reporting procedures to the DSMB are included in the DSMB Charter. The 
DMSB will provide recommendations to change the study or to continue the study. 
3.7.3 
Study Monitoring and Auditing 
This study will be monitored in accordance with the BCH Program Data Safety Monitoring Plan. 
Monitoring and auditing procedures as outlined in the BCH Program Data Safety Monitoring 
Plan will be followed to ensure that the entire study is conducted, documented, and reported in 
accordance with the IRB approved protocol, the International Conference on Harmonization 
(ICH) Good Clinical Practice (GCP) guidelines, and applicable regulatory requirements of 
Boston Children’s Hospital. 
Monitoring of timeliness of Adverse Event and Serious Adverse Event reporting will be done as 
events are reported to the coordinating center. Case report forms for each subject enrolled into 
the study will be monitored for completeness and quality. 
3.8 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE 
3.8.1 
Sample Size and Power Considerations 
Sample size for the study was determined based on the precision of the confidence interval for 
the primary endpoint.  This approach will be considered promising if the true proportion of 
subjects with all injuries identified by CT also identified by CEUS is greater than or equal to 
90%.   Assuming we observe 90% of subjects with all injuries identified by CT and by CEUS, a 
sample size of 132 patients will attain a two-sided 95% confidence interval with a width equal to 
11%, with exact Clopper-Pearson lower and upper confidence limits of 83.6% and 94.5% 
respectively. For secondary endpoints, a sample size of 132 patients will produce 95% 
confidence intervals with a maximum width of 17.6%.  


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3.8.2 
Statistical Analysis Plan 
We will summarize patient demographic and clinical characteristics using descriptive statistics: 
means, standard deviations, medians, and ranges for continuous measures; frequencies and 
proportions for categorical measures. For the primary objective, we will calculate the proportion 
and 95% confidence interval. For the secondary objectives, we will calculate the proportion and 
95% confidence interval. We will also report the sensitivity and specificity of the CEUS relative 
to CT in identifying individual organ abnormalities in separate models and combined models. In 
the combined analysis, sensitivity and specificity will be estimated using random effects model 
or generalized estimating equations to adjust for potential correlation between organs within an 
individual. Statistical analysis will be performed using standardized packages (SPSS version 
19.0 from SPSS Inc./IBM, Chicago, IL or SAS version 9.4 from SAS Institute Inc., Cary, NC).)  
3.8.3 
Study Duration 
To attain the target sample size of 132, we expect to enroll 1-2 patients/month/site across 7-10 
sites for enrollment over 2-3 years. The total study duration, including analysis, will be 3-5 
years. 
3.8.4 
Interim Analysis 
An interim analysis will be conducted after the first 73 patients. At this time, the conditional 
power will be calculated. If the probability of obtaining a point estimate ≥ 90% for the primary 
endpoint is less than 10% at the interim analysis, we will consider stopping the study for futility. 
3.8.5 
Safety Analysis 
All 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 17.6%. If the observed 
estimated adverse event proportion is 10%, the 95% confidence interval is (5.5,16.4%). 
3.9 
COMPLIANCE STATEMENT 
The study will be conducted in accordance with the protocol, Good Clinical Practices, the 
relevant ICH guidelines, the applicable regulatory requirements, and the ethical principles that 
have their origins in the Declaration of Helsinki. As required by United States Food and Drug 


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Administration (FDA) Code of Federal Regulations (CFR) (21 CFR 56) and the Declaration of 
Helsinki, the study protocol, amendments, and Informed Consent form will be reviewed and 
approved, according to 21 CFR §50 and §56, respectively, by our center’s IRB. 
3.10 
SUBJECT INFORMATION AND CONSENT 
The study will be explained to each subject and their guardian and before enrollment in the 
study, an Informed Consent form will be signed by each subject’s guardian and assent will be 
obtained. A copy of the signed consent form will be given to each guardian.  
For any sites that choose to execute an IRB reliance agreement, Boston Children’s Hospital 
Investigational Review Board, as part of the reliance agreement, will provide each site with the 
informed consent template with prompted areas for each institution’s required language. The 
Sponsor will review the written Informed Consent forms for each study center and submit to 
BCH IRB (as well as any sites whose IRB maintains local review) for final approval. These 
documents will meet requirements for subject information, as outlined in FDA regulations 
(21 CFR 50), ICH Guideline E6, and the Declaration of Helsinki. The Sponsor requires that all 
subjects be given this information before study participation. 
4. 
COMPENSATION, INSURANCE AND INDEMNITY 
There will be no compensation provided for participation in this study.  
 


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5. 
REFERENCE LIST 
 
1. Fenton, SJ, et al.  CT Scan and the Pediatric Trauma patient – Are we Overdoing it?  
Journal of Pediatric Surgery 2004. 39(12): 1877-1881. 
2. Brenner DJ, Hall EJ.Computed tomography--an increasing source of radiation exposure. 
N Eng J Med. 2007 Nov 29;357(22):2277-84 
3. Callahan MJ, Poznauskis L, Zurakowski D, Taylor GA. Nonionic iodinated intravenous 
contrast material-related reactions: incidence in large urban children's hospital--
retrospective analysis of data in 12,494 patients. Radiology. 2009 Mar;250(3):674-81 
4. Coley, BD, Mutabagani KH, Martin LC, et al. Focused Abdominal Sonography for 
trauma (FAST) in Children with Blunt Abdominal Trauma.  J Trauma. 2000. 48(5): 
902-906. 
5. Sola, JE, Cheung MC, Yang R. Pediatric FAST and Elevated Liver transaminases: An 
effective screening tool in blunt abdominal trauma. J of Surgical Research. 2009. 157: 
103-107. 
6. Valentino, M, et al. Blunt Abdominal Trauma: Diagnostic Performance of Contrast 
enhanced US in Children – Initial Experience. Radiology. 2008 246(3) 903-909. 
7. Valentino, M. Contrast enhanced ultrasonography in blunt abdominal trauma: 
considerations after 5 years of experience. Radiol Med. 2009. 114: 1080-1093. 
8. Tang J, Li W, Lv F, Zhang H, Zhang L, Wang Y, Li J and Yang L. Comparison of Gray-
Scale Contrast-Enhanced Computed Tomography in Different Grading of Blunt 
Hepatic and Splenic Trauma: an Animal Experiment. Ultrasound in Med and Biol. 
2009; 35(4): 566-75. 
9. Sessa B, Trinci M, Ianniello S, Manchini G, Galluzzo M, Miele V. Blunt abdominal 
trauma: role of contrast enhanced ultrasound (CEUS) in the detection and staging of 
abdominal traumatic lesions compared to US and CE-MDCT. La Radiologica Medica 
2015; 120(20): 180-9.   
10. Valentino, M, et al. Blunt Abdominal Trauma: Diagnostic Performance of Contrast 
enhanced US in Children – Initial Experience. Radiology. 2008 246(3) 903-909. 
11. Menichini G, Sessa B, Marherita T, Galluzzo M, Miele V. Accuracy of contract enhanced 
ultrasound (CEUS) in the identification and characterization of traumatic solid organ 
lesions in children: a retrospective comparison with baseline US and CE-MDCT. 
Abdominal Radiology 2015. 120:989-1001. 
12. Rosado E and Riccabona M. Off-Label Use of Ultrasound Contrast Agents for 
Intravenous Applications in Children. J Ultra Med 2016; 35:487-96.  


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13. Callahan MJ, Poznauskis L, Zurakowski D, Taylor GA. Nonionic iodinated intravenous 
contrast material-related reactions: incidence in large urban children's hospital--
retrospective analysis of data in 12,494 patients. Radiology. 2009 Mar;250(3):674-81 
 


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6. 
APPENDIX I 
 
Study Title:  
A Multicenter Trial of Contrast-Enhanced Ultrasound in the 
Evaluation of Abdominal Solid Organ Injuries in Pediatric 
Trauma Patients 
Protocol Number:  
P00025242 
Protocol Version:  
Version 4: 10/16/2019 
 
 
I have read the protocol and agree that it contains all the details necessary for carrying out this 
study, and I will conduct the study as described herein.  
 
 
Investigator’s Signature:   
 
 
 
 
 
 
 
 
    
 
Investigator (Printed name):    
 
 
 
 
 
 
  
 
Date:    
 
 
 
 
 
 
 
 
 
 
  
 
Institution: