Clinical trial NCT03687502
Conditions: Acute Appendicitis
Sponsor: Children's Mercy Hospital Kansas City
Start date: 2019-01-04; Completion date: 2022-07-05
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study seeks to determine the efficacy of Contrast Enhanced Ultrasound (CEUS) in improving the diagnosis of acute appendicitis in children, when compared to the standard grey-scale ultrasound.

Detailed description:
This will be a single-center, non-randomized trial that will add to our institution's current diagnostic algorithm using Contrast Enhanced Ultra Sound (CEUS) in subjects who are clinically suspicious for acute appendicitis.

For those who consent to study participation, we propose obtaining a CEUS after the initial gray-scale ultrasound. Once the initial ultrasound is complete, the contrast Lumason® (sulfur hexafluoride lipid type-A microspheres) will be administered through an already existing IV catheter and an abdominal scan will be completed. The patient will then continue with standard of care treatment per his treating physician. The CEUS image will be read at a future time by a Children's Mercy Hospital radiologist blinded to the results of the gray scale ultrasound and computed tomography (CT) scan if one was obtained; these will be used for comparison.

Arms: arm 1: IV sulfur hexafluoride lipid-type A microspheres, 0.03 mL/kg, up to 2 doses per examination, total dose not to exceed 4.8 mL. Single examination per patient.
Interventions: intervention 1: Sulfur hexafluoride lipid-type A microspheres
Intervention descriptions: intervention 1: Contrast Enhanced Ultrasound of the appendix

Protocol documents:
Prot_000.pdf: 
CEUS Appy 
IRB#00000329 
 
Page 1 of 19 
Version 1.4 dated 7.13.18 
PROTOCOL TITLE: 
 
The Role of Contrast Enhanced Ultrasound to Diagnose Children with Appendicitis 
 
PRINCIPAL INVESTIGATOR: 
Tolulope Oyetunji, MD, MPH 
Department of Pediatric Surgery 
Children’s Mercy Hospital 
taoyetunji@cmh.edu 
 
Co-Principal Investigator: 
Jason Fraser, MD 
 
Department of Pediatric Surgery 
Children’s Mercy Hospital 
 
jdfraser@cmh.edu 
 
Co-Investigators: 
Manish Kotecha, MD 
Shawn St. Peter, MD 
Douglas Rivard, MD 
David Juang, MD 
 
Kelly Sinclair, MD 
Frances Turcotte-Benedict, MD 
 
 
Research Personnel: 
Yara Duran, BSN, RN  
Pete Muenks, MA 
 
VERSION NUMBER/DATE: 
Protocol Version:  4.0  
 
 
 
Protocol Date: July 20, 2020 
REVISION HISTORY 
 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
02 
01/21/2019 
Extend enrollment to 9-5 pm 
N 
03 
06/04/2019 
Extend enrollment to 24 hours/ day, 7 days per 
week 
N 
04 
07/20/2020 
Addition of e consent. Addition of MD to those 
who may administer Lumason 
N 
 
 
 
 
 
 
 
 
 
 
 


CEUS Appy 
IRB#00000329 
 
Page 2 of 19 
Version 1.4 dated 7.13.18 
Table of Contents 
1.0 
Study Summary ........................................................................................................ 3 
2.0 
Objectives ................................................................................................................ 4 
3.0 
Background .............................................................................................................. 4 
4.0 
Study Endpoints ....................................................................................................... 5 
5.0 
Study Intervention/Investigational Agent ................................................................ 5 
6.0 
Procedures Involved ................................................................................................. 6 
7.0 
Data and Specimen Banking .................................................................................... 8 
8.0 
Genetic Analysis Information .................................................................................. 8 
9.0 
Sharing of Results with Subjects ............................................................................. 8 
10.0  Study Timelines ....................................................................................................... 8 
11.0  Inclusion and Exclusion Criteria .............................................................................. 8 
12.0  Vulnerable Populations ............................................................................................ 9 
13.0  Local Number of Subjects ....................................................................................... 9 
14.0  Screening and Recruitment Methods ....................................................................... 9 
15.0  Reimbursement, Payment and Tangible Property provided to subjects ................ 10 
16.0  Withdrawal of Subjects .......................................................................................... 10 
17.0  Risks to Subjects .................................................................................................... 11 
18.0  Potential Benefits to Subjects ................................................................................ 12 
19.0  Investigator Assessment of Risk/Benefits Ratio. ................................................... 12 
20.0  Data Management and Confidentiality .................................................................. 12 
21.0  Provisions to Monitor the Data to Ensure the Safety of Subjects ...................... 1314 
22.0  Provisions to Protect the Privacy Interests of Subjects .......................................... 14 
23.0  Compensation for Research-Related Injury ........................................................... 15 
24.0  Economic Burden to Subjects ................................................................................ 15 
25.0  Permission/Assent/Consent Process ...................................................................... 15 
26.0  Process to Document Permission/Assent/Consent ................................................. 17 
27.0  Setting .................................................................................................................... 17 
28.0  Resources Available ............................................................................................... 17 
29.0  Multi-Site Research ............................................................................................... 18 
30.0  International Research ........................................................................................... 18 
 
 
 


CEUS Appy 
IRB#00000329 
 
Page 3 of 19 
Version 1.4 dated 7.13.18 
1.0 
Study Summary 
 
Study Title 
The Role of Contrast Enhanced Ultrasound to Diagnose 
Children with Appendicitis 
Study Design 
Single institution non-randomized clinical trial 
Primary Objective 
Determine the efficacy of contrast enhanced ultrasound 
(CEUS) in improving the diagnosis of  acute appendicitis in 
children 
Secondary 
Objective(s) 
 Utility of CEUS in making a definitive diagnosis of acute 
appendicitis 
 Utility of CEUS in decreasing Rates of CT scan utilization  
 Outcomes of patients who undergo CEUS for appendicitis 
 Negative appendectomy rates 
 Costs 
 
 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
Lumason (sulfur hexafluoride lipid-type A microspheres)  
injectable suspension 
IND/IDE #  
N/A 
Study Population 
Children between the ages of 8 and 17 
Sample Size 
250 subjects 
Study Duration for 
Individual 
Participants 
 
30-60 minutes 
Study Specific 
Abbreviations/ 
Definitions  
CEUS- contrast enhanced ultra sound 
CT- computed tomography 
MRI- magnetic resonance imaging 
CMH- Children’s Mercy Hospital  
DSDR- Department of Surgery Data Repository 
DOB- date of birth 
MRN- medical record number 
OSH- outside hospital 
PAS- pediatric appendicitis score 
LAR- legally authorized representative 
IV- intravenous 
PI-principal investigator 
ICU- intensive care unit  
P/A- permission/assent 
ED Emergency Department  
 
 


CEUS Appy 
IRB#00000329 
 
Page 4 of 19 
Version 1.4 dated 7.13.18 
2.0 
Objectives 
2.1 The main objective of this study is to determine the efficacy of 
Contrast Enhanced Ultrasound (CEUS) in improving the diagnoses 
of acute appendicitis in children. 
2.2 We hypothesize that CEUS can be used effectively to make a 
definitive diagnosis when gray-scale ultrasound is inconclusive. 
3.0 
Background 
3.1 Pediatric appendicitis represents the most common pediatric abdominal 
surgical disease with the highest incidence found in children aged ten to 
19years old (1).  The diagnosis of appendicitis commonly consists of a 
thorough history, physical exam and laboratory evaluation along with 
diagnostic imaging.  With both a high sensitivity and specificity, CT scan 
remains the most commonly used imaging modality for diagnosis (2).  With 
reports in the literature showing the adverse effects of radiation exposure in 
children from computed tomography (CT) imaging (3, 4), alternative 
methods to diagnose acute appendicitis have been applied including 
Magnetic Resonance Imaging (MRI) (4) and ultrasound (US).  MRI 
eliminates ionizing radiation when compared to CT however, its widespread 
use is limited due to its high cost, limited availability and the potential need 
for sedation in young children.  Trans-abdominal ultrasound is widely 
available and also eliminates ionizing radiation but is user dependent. The 
utilization of CEUS to enhance the diagnostic capabilities for appendicitis is 
a novel alternative to CT imaging.   
 
3.2 A recent report in the literature demonstrates the effective use of CEUS to 
evaluate blunt solid organ injuries in children with abdominal trauma (5).  
 
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. 
 
Lumason is now FDA-approved for echocardiography in adults, 
characterization of liver lesions in both the adult and pediatric population, 
and vesicoureteral reflux in pediatrics.  
3.3 The potential use of CEUS to diagnose pediatric appendicitis 
remains unknown.  The goal of this trial is to determine the utility of 


CEUS Appy 
IRB#00000329 
 
Page 5 of 19 
Version 1.4 dated 7.13.18 
CEUS to enhance diagnostic capabilities in children with suspected 
appendicitis.  We hope that our study will give physicians an added 
diagnostic tool for children with abdominal pain.  
4.0 
Study Endpoints 
4.1 The primary endpoint is the proportion of patients for whom the 
appendix is enhanced by CEUS when using the same diagnostic 
criteria as gray scale ultrasound. Lumason will be considered 
effective if the sensitivity of grayscale ultrasound is enhanced in 
more than 50% of images as determined by the blinded interpreting 
pediatric radiologist. 
Secondary endpoints include: 
•Utility of CEUS in making a definitive diagnosis of acute 
appendicitis 
•Utility of CEUS in decreasing rates of CT scan utilization  
• Negative appendectomy rates 
 
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.  
 


CEUS Appy 
IRB#00000329 
 
Page 6 of 19 
Version 1.4 dated 7.13.18 
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:  
 
 
 
 
5.2 
The control drug used in this protocol will follow the established, 
approved, approved organization SOP entitled Investigational Drug 
Service Product Storage.  
5.3 N/A  
 
6.0 
Procedures Involved 
6.1 This will be a single-center non-randomized trial that will add to our 
institution’s current diagnostic algorithm one CEUS to subjects whom are 
clinically suspicious for acute appendicitis. Currently, a gray-scale 
abdominal ultrasound is performed to help establish the diagnosis. When the 
results of the gray-scale abdominal ultrasound are inconclusive, the treating 
physician may choose to refer the patient for a CT scan in order to establish 
a definitive diagnosis. Our study does not look to alter that process. 
6.2 For those who consent to study participation, we propose obtaining a 
CEUS after the initial gray-scale ultrasound. Once the initial 
ultrasound is complete, the contrast Lumason® (sulfur hexafluoride 
lipid type-A microspheres) will be administered through an already 
existing IV catheter by an MD, RN or a radiology technologist 
trained and certified to administer the Lumason® contrast agent, and 
Microsphere Characteristics 
Mean diameter range 
1.5 – 2.5 μm  
 
Percent of microspheres  
≤ 10 μm ≥ 99%  
 
Upper size limit 
100.0% ≤ 20 μm  
 


CEUS Appy 
IRB#00000329 
 
Page 7 of 19 
Version 1.4 dated 7.13.18 
an abdominal scan will be completed. The patient will then continue 
with standard of care treatment per his treating physician. The CEUS 
image will be read at a future time by a CMH radiologist blinded to 
the results of the gray scale ultrasound and CT if one was obtained as 
these will be used for comparison. 
6.3 
 
 Lumason will be administered by radiology personnel 
(radiologist, US technologist, or Sedation RN). Subjects 
will be monitored during the entirety of the procedure.  
Once the study procedure has been completed, patients will 
continue to go through the standard of care process and 
return to the ED (Emergency Department) or floor while 
they await the results of their gray-scale ultrasound and CT, 
if one was obtained.  ED/ floor staff will continue to 
monitor patients for any adverse events.   
  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. 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 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.    
6.4 Data extracted from the electronic medical record will be entered 
into a secure REDCap database and stored in a password protected 
file on the CMH network. A master list containing only the assigned 
study ID and linking MRN will be kept in a separate REDCap 
instrument. All electronic files will be kept on the secure password-
protected computers of the research staff and principal investigator.  
Data points to be collected include the following: demographics, 
findings on radiology imaging (US, CEUS, and CT if applicable), 


CEUS Appy 
IRB#00000329 
 
Page 8 of 19 
Version 1.4 dated 7.13.18 
pathology, intraoperative findings, other/ comments. Reports of 
headache, nausea, altered taste, injection site reaction, feeling hot/ 
flushed, chest pain, or dizziness will also be recorded. 
6.5 N/A  
6.6 N/A  
7.0 
Data and Specimen Banking 
7.1 N/A  
7.2 Participants who enroll in this study will be given the opportunity to have 
their de-identified data rolled into the Department of Surgery Data 
Repository (DSDR) IRB# 18020079.  We will continue to protect and 
safeguard study data under the provisions of the DSDR. 
7.3 N/A 
7.4 N/A 
7.5 N/A 
8.0 
Genetic Analysis Information 
N/A 
9.0 
Sharing of Results with Subjects 
N/A 
10.0 Study Timelines 
 
An individual subject’s participation in the study will comprise 
of one study procedure (contrast enhanced ultrasound will take 
10 to 20 minutes total) we anticipate study duration will take 
approximately 30-60 minutes in length.  Additionally data 
generating from SOC will obtained from chart. 
 
Assuming an accrual rate of 15-20 subjects per month, we 
estimate enrollment will take 12-15 months to enroll 250 
subjects.  
 
The Approximate study end date will be 3 years after IRB 
approval.  
11.0 Inclusion and Exclusion Criteria 
 
 
Inclusion Criteria 
 Present to Children’s Mercy Adele Hall campus with a clinical concern for 
acute appendicitis 
 Age 8 through 17 years  
 seen between IRB approval date and 12/31/2020 
 Has had an IV catheter placed as part of their standard of care 


CEUS Appy 
IRB#00000329 
 
Page 9 of 19 
Version 1.4 dated 7.13.18 
 
Exclusion Criteria 
 Known cardiac abnormality  
 Pulmonary hypertension  
 Known sensitivity to sulfur hexafluoride, polyethylene glycol 4000, 
distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol 
sodium (DPPG-Na), or palmitic acid  
 Does not had an IV catheter placed  
 Unable to roll over  
 Unable to assent  
 Pregnant  
 Lactating  
 Received an ultrasound image from an OSH 
 
11.1   These patients will be excluded from the study  
 
Adults unable to consent 
 
Pregnant women 
 
Prisoners 
 
Wards of the state 
12.0 Vulnerable Populations: Individuals who are not yet adults 
(infants, children, teenagers)   
12.1 Adequate provisions have been made for soliciting the permission of 
parents or guardians as well as for soliciting the assent of children.  
Lumason is FDA approved for the use in the pediatric population to 
identify other abdominal abnormalities, specifically focal liver 
lesions The intervention presents an experience that is reasonably 
commensurate with that inherent in the subjects medical situation, 
and is likely to yield generalizable knowledge about the condition, 
which is of vital importance for the amelioration of pediatric 
appendicitis. 
13.0 Local Number of Subjects 
13.1 This study will enroll 250 subjects.  Assuming an accrual rate of 15-
20 subjects per month, we estimate it will take 12-15 months to 
complete enrollment.   
13.2 Based on prior data, approximately 375 children are diagnosed with 
appendicitis at our institution per year. We plan to screen up to 750 
potential subjects for eligibility over the course of the study. 
14.0 Screening and Recruitment Methods 
14.1 Potential subjects will be recruited in their hospital room, ED, or radiology 
department by a member of the general surgery team.  Per standard of care, 
the general surgery team will be alerted by the emergency department when 


CEUS Appy 
IRB#00000329 
 
Page 10 of 19 
Version 1.4 dated 7.13.18 
a patient presents with concern for acute appendicitis.  The general surgery 
staff will screen for eligibility criteria.  Those meeting all inclusion and no 
exclusion criteria will be invited to participate. PAC will be obtained on 
either a paper or electronic form.  
14.2 The source of subjects will be the CMH Adele Hall campus   
emergency department.  
14.3 Potential subjects will be identified when, per standard of care, the 
general surgery team is alerted by emergency department staff of a 
patient presents with concern for acute appendicitis.  The general 
surgery staff will screen for eligibility criteria.  Those meeting all 
inclusion and no exclusion criteria will be invited to participate. 
14.4 A pre-screening log will be maintained for the purpose of tracking 
enrollment. Patients who are referred to the department of surgery 
for concern of acute appendicitis will have the date of referral, DOB, 
MRN, PAS, whether or not they met inclusion, were approached for 
participation and their choice to participate recorded on the pre-
screen log.  We are requesting a Waiver of HIPAA Authorization for 
recruitment purposes only.  The PHI recorded on the screening log 
will help ensure required reporting elements at time of study 
publication, including the percentage of eligible patients enrolled and 
reasons patients decline enrollment.  The pre-screen log will be 
destroyed at the conclusion of the study. 
14.5 
N/A 
14.6 
N/A     
15.0 Reimbursement, Payment and Tangible Property provided to 
subjects 
 
N/A  
16.0 Withdrawal of Subjects 
16.1 As this study consists of a one-time intervention, we do not 
anticipate any circumstance in which a subject will be withdrawn 
without their consent.  
16.2 Subjects may choose to discontinue study participation at any time, 
for any reason, specified or unspecified, and without prejudice. 
Subjects may be discontinued from the study for any of the 
following reasons: 
 At the subject’s or their parent’s/LAR’s request 
 At the discretion of the site investigator as deemed 
appropriate for any reason 
Procedures for orderly termination will include a discussion with the 
parents or LAR for the reasons behind early termination.  


CEUS Appy 
IRB#00000329 
 
Page 11 of 19 
Version 1.4 dated 7.13.18 
16.3 If a subject withdraws from the research study, data that has already 
been collected may still be used; however, no new information will 
be collected except information related to adverse events or other 
safety issues. 
17.0 Risks to Subjects 
17.1 As part of SOC, all patients enrolling in this study will have at least one 
functioning intravenous catheter placed during the SOC blood draw, hence 
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 discomfort. Patients will be 
monitored by licensed personnel during the study interval. Per standard of 
care, patients will return to the ED while the results of their gray scale 
ultrasound and CT, if one was taken, are obtained. ED staff will continue to 
monitor patients for any adverse event.     
 
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 Lumason will 
be used off-label, but the intervention presents an experience that is 
reasonably commensurate with those inherent to the subject’s 
medical situation.  The only risks attributable to the study are those 


CEUS Appy 
IRB#00000329 
 
Page 12 of 19 
Version 1.4 dated 7.13.18 
of the adverse reactions listed above, as these patients will have 
already had an IV placed, and would have ultrasound as part of their 
appendicitis workup.  Furthermore, Lumason is currently FDA 
approved, and in use at CMH, for other abdominal CEUS 
applications such liver lesions and vesicoureteral reflux in pediatrics.  
17.3 N/A  
17.4 N/A 
17.5 N/A  
18.0 Potential Benefits to Subjects 
18.1 
There is some possibility of potential benefit to subjects 
participating in this research.  Although Lumason is not yet approved for 
use in diagnosing appendicitis, it is possible that the improved quality of 
US images produced will provide better information to providers treating 
these patients.  It is also possible that the improved quality imaging could 
result in incidental findings, such as abdominal anomalies other than 
appendicitis.  If such anomalies are found, the investigator could 
recommend to parents to follow up with appropriate services. 
19.0 Investigator Assessment of Risk/Benefits Ratio: (IRB makes the 
final determination)  
 
Select as applicable: 
Pediatric Risk Category: 
 
Category 1  Research not involving greater than minimal risk  
(45 CFR §46.404 and 21 CFR §50.51)   
X 
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) 
 
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 The captured CEUS images will be evaluated by a single Children’s Mercy 
Hospital pediatric radiologist to determine and establish a pattern compared 
to the standard gray scale ultrasound report. This radiologist will be blinded 
to the final reads from the gray scale reports. For the children who meet the 
criteria of appendicitis, they will be followed post-operatively to confirm 
and correlate the intra-operative findings with the gray scale read.  


CEUS Appy 
IRB#00000329 
 
Page 13 of 19 
Version 1.4 dated 7.13.18 
Descriptive analysis of demographics and patient-level data will be 
performed using STATA. Direct comparisons will be made with parametric 
or nonparametric measures depending on the distribution of the data. 
20.2 This study will be made up of a convenience sampling of children 
presenting to the CMH Adele Hall emergency department with 
concerns for appendicitis.  Enrollment will consist of up to 250 
participants.    
20.3 All data will be entered into a REDCap database that is accessible 
only to researchers named on the study. Data will be stored on the 
CMH secure network. The list of chart identifiers which meet 
inclusion criteria along with dates of birth will be maintained 
separately from data that will be used for analysis. Each chart will be 
reviewed by research staff and data entered directly into the research 
records. The researchers alone will have full access to the data; we 
will assign a study ID to the medical records in order that we can 
reference our information during the course of our research.  A 
master list linking Study ID to MRN, Name and other identifiers will 
be kept separately from the study data, and accessible only to the 
study team. 
20.4 N/A  
20.5 All data will be entered into a REDCap database that is accessible 
only to researchers named on the study. Data will be stored on the 
CMH secure network. The list of chart identifiers which meet 
inclusion criteria along with dates of birth will be maintained 
separately from data that will be used for analysis. Each chart will be 
reviewed by research staff and data entered directly into the research 
records. The researchers alone will have full access to the data; we 
will assign a study ID to the medical records in order that we can 
reference our information during the course of our research.  A 
master list linking Study ID to MRN and other identifiers will be 
kept separately from the study data, and accessible only to the study 
team. 
20.6 All data will be entered into a REDCap database that is accessible only to 
researchers named on the study. Data will be stored on the CMH secure 
network. The list of chart identifiers which meet inclusion criteria along 
with dates of birth will be maintained separately from data that will be used 
for analysis. Each chart will be reviewed by research staff and data entered 
directly into the research records. The researchers alone will have full access 
to the data; we will assign a study ID to the medical records in order that we 
can reference our information during the course of our research.  A master 
list linking Study ID to MRN and other identifiers will be kept separately 
from the study data, and accessible only to the study team. 
 
21.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 


CEUS Appy 
IRB#00000329 
 
Page 14 of 19 
Version 1.4 dated 7.13.18 
This study proposes a one-time intervention of CEUS.  Subjects will be 
monitored in real time at the time of and following the CEUS. Data 
collected will be evaluated after the first 10 subjects are enrolled. 
    
 
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. 
Participants will be monitored in real time. 
 
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 Subject confidentiality and privacy will be maintained by recording 
only de-identified data onto the REDCap research record.  A subject-
specific ID will be assigned to each record. A linking master list will 
be created and kept in a separate REDCap data instrument.  
22.2 During the informed consent process the purpose of the research 
study, study procedure, potential risks and societal benefits will be 
thoroughly explained to the subject and his/her parents or LAR.  
They will be given the opportunity to ask questions during the 
informed consent process and at any time during or after study 
participation. 
22.3 The research team will access the patient’s medical record in order to collect 
pertinent data points generated through clinical care. Only the minimum 
necessary data will be recorded in REDCap.  The researchers alone will 


CEUS Appy 
IRB#00000329 
 
Page 15 of 19 
Version 1.4 dated 7.13.18 
have full access to the REDCap database. A subject-specific ID will be 
assigned to each record. A linking master list will be created and kept in a 
separate REDCap data instrument.  
22.4 PHI to be accessed and/or recorded for this research study includes 
the following: 
  names/initials- accessed 
  dates- recorded 
  medical record number-recorded 
  hospital account number-recorded 
22.5 HIPAA Authorization from subjects/parents to access and/or record 
PHI for this research study will be included within the 
permission/assent form(s).  
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 
set aside to pay research participants if the research results in harm 
or complications.  The approved IRB P/A will include known 
possible adverse events of study participation as well as payment 
responsibility for any adverse event.  
23.2 N/A. 
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 
Lumason contrast agent nor for the CEUS.  They will be charged for 
all standard of care procedures including the standard (non-contrast/ 
gray scale) ultrasound, and any other diagnostic workup and 
treatment for appendicitis they would receive whether or not they 
were enrolled in the study.  
25.0 Permission/Assent/Consent Process 
25.1 Permission/assent will be obtained on all subjects wishing to 
participate.  
 
The p/a process will take place in the ED at the patient’s 
bedside. 


CEUS Appy 
IRB#00000329 
 
Page 16 of 19 
Version 1.4 dated 7.13.18 
 
While eligible candidates will be given all necessary 
information to make an informed decision and will have every 
opportunity to ask questions, the waiting period available 
between informing the prospective subject and obtaining p/a 
will be limited as this study does not intend to delay standard 
of care treatment. A potential subject who has not affirmatively 
signed the p/a form prior to the standard gray scale ultrasound 
will continue through SOC treatment without prejudice.  
 
We will be following CMH research policies on informed 
consent.   
 
We will not be obtaining permission/assent via telephone as 
such is not feasible for this study. 
 
This pediatric research study will be conducted entirely in the 
state of Missouri and will involve enrolling minors under the 
age of 18. 
 
Parental permission will be obtained from one parent or LAR. 
 
Other than biological parents, LARs such as an adoptive parent 
will be allowed to consent for a child’s participation in this 
study.   
 
Assent will be obtained from all children participating in this 
study unless the study team member attempting to obtain P/A 
determines the child is not cable of providing assent. 
 
The child’s assent will be documented on the combined P/A 
form. 
 
In the event assent may not be obtained, the reason(s) will be 
documented in the provided section of the P/A form. 
 
Consent at 18 years of age, when minor subjects become adults 
We are requesting a Waiver of Consent at Age 18.  Active 
participation of the subject will be concluded, as this is a single-
visit ultrasound study.  Data collection will be completed before 
the subject turns 18.  Data analysis might continue after some 
subjects have turned 18, but this is explained in the 
Permission/Assent form they would have signed at the time of 
enrollment.  Furthermore, re-consenting at age 18 would be 
impracticable for this study, as these subjects will be emergency 
appendicitis patients at CMH, and most will be unlikely to 
return for follow up appointments after reaching 18. 
Waiver or Alteration of Parental Permission or Child Assent Process 
(permission and/or assent will not be obtained, required information 
will not be disclosed, or the research involves deception) 
N/A  


CEUS Appy 
IRB#00000329 
 
Page 17 of 19 
Version 1.4 dated 7.13.18 
Waiver or Alteration of Consent Process (consent will not be 
obtained, required information will not be disclosed, or the research 
involves deception) 
   N/A  
Non-English Speaking Subjects 
   N/A 
Cognitively Impaired Adults 
N/A 
Adults Unable to Consent 
   N/A  
26.0 Process to Document Permission/Assent/Consent 
26.1 Study staff will be following CM Research Policy 10.04 Obtaining 
Permission/Assent/Consent.  
26.2 N/A  
26.3 N/A  
 
27.0 Setting 
27.1  
 
Study team members (specifically surgery fellows and 
attending’s) will identify patients presenting to the CMH Adele 
Hall Emergency Department with concerns of appendicitis, and 
will approach patients/parents to recruit for the study. 
 
Ultrasounds will be performed in the Radiology department at 
CMH Adele Hall.  Data will be collected by study team 
members at CMH Adele Hall Emergency, Radiology and 
Surgery departments. 
28.0 Resources Available 
28.1 Resources available to conduct this research study include the 
following:  
 
The research team anticipates access to approximately 375 
potential subjects as prior data reveals 375 children are 
diagnosed with appendicitis at our institution each year. 


CEUS Appy 
IRB#00000329 
 
Page 18 of 19 
Version 1.4 dated 7.13.18 
 
This study will take place entirely within CMH Adele Hall 
campus, specifically in the Emergency, Radiology and Surgery 
departments. 
 
The study will involve approximately 60 minutes of patient 
interaction.  Data collection and review of aggregate data will 
continue while the project is ongoing.  
 
While it is not anticipated that subjects will need additional 
medical or psychological services as a result of participating in 
this study, care will be available at CMH and will be provided 
at the usual charge should the need arise. 
 
All study team members will have read the protocol and any 
standard operating procedures for the study.  All study team 
members will have completed their required research trainings 
to conduct research at CMH and be knowledgeable of their 
duties and functions as evidenced by their signature in the 
study delegation log.  
    
 
 
29.0 Multi-Site Research 
N/A  
30.0 International Research 
N/A  
 
 


CEUS Appy 
IRB#00000329 
 
Page 19 of 19 
Version 1.4 dated 7.13.18 
References: 
 
1. 
Rentea RM, St Peter SD. Pediatric Appendicitis. Surg Clin North 
Am. 2017;97(1):93-112. 
2. 
Hernanz-Schulman M. CT and US in the diagnosis of appendicitis: 
an argument for CT. Radiology. 2010;255(1):3-7. 
3. 
Pearce MS, Salotti JA, Little MP, McHugh K, Lee C, Kim KP, et 
al. Radiation exposure from CT scans in childhood and subsequent risk of 
leukaemia and brain tumours: a retrospective cohort study. Lancet. 
2012;380(9840):499-505. 
4. 
Meulepas JM, ronckers CM, Smets AMJB, Nievelstein RAJ, 
Gradowska P, Lee C, Jahnen A, van Straten M, de Wit MY, Zonnenberg 
B, Klein WM, Mercks JH, Visser O, van Leeuwen FE, Hauptmann M. 
Radiation exposure from pediatric CT scans and subsequent cancer risk in 
the Netherlands. J Natl Cancer Inst. 2018 Jul 18. Doi: 
10.1093/jnci/djy104. [Epub ahead of print] PubMed PMID: 30020493. 
5. 
Kulaylat AN, Moore MM, Engbrecht BW, Brian JM, Khaku A, 
Hollenbeak CS, et al. An implemented MRI program to eliminate 
radiation from the evaluation of pediatric appendicitis. J Pediatr Surg. 
2015;50(8):1359-63. 
6. 
Armstrong LB, Mooney DP, Paltiel H, Barnewolt C, Dionigi B, 
Arbuthnot M, et al. Contrast enhanced ultrasound for the evaluation of 
blunt pediatric abdominal trauma. J Pediatr Surg. 2017. 
7. 
Valentino, M, et al. Blunt Abdominal Trauma: Diagnostic 
Performance of Contrast enhanced US in Children – Initial Experience. 
Radiology. 2008 246(3) 903-909. 
8. 
Valentino, M. Contrast enhanced ultrasonography in blunt 
abdominal trauma: considerations after 5 years of experience. Radiol Med. 
2009. 114: 1080-1093.