Ultrasound Evaluation of Crohn's Disease
Phase: PHASE4
Conditions: Crohn Disease
Sponsor: Mayo Clinic

 
 
Ultrasound Evaluation of Crohn’s Disease 
 
 
NCT03235180 
 
September 28, 2017 

Minimal Risk Protocol Template [IRB 10429.006] 
 
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IRB Minimal Risk Protocol Template 
 
General Study Information 
 
Principal Investigator:       Shigao Chen, David Bruining, John Knudsen 
 
 
 
 
 
 
 
 
Study Title:    Ultrasound Evaluation of Crohn’s Disease 
 
Protocol version number and date:     9/28/17 
 
Purpose 
 
Hypothesis: Small bowel stiffness and vascularity measured by ultrasound imaging are useful biomarkers for 
Crohn’s disease. 
 
Aims, purpose, or objectives:  
The overall goal is to investigate the value of ultrasound measurements of small bowel stiffness and vascularity 
as new biomarkers for Crohn’s disease.  
 
Background (Include relevant experience, gaps in current knowledge, preliminary data, etc.):   
Crohn’s Disease (CD) is a chronic inflammatory condition in the bowel that affects over 1 million Americans, 
costing billions of dollars every year. Due to the relapsing nature of the disease, frequent imaging follow-ups 
are often necessary over many years to monitor treatment response to guide therapy adjustments. An ideal CD 
imaging method should be able to evaluate both inflammation and fibrosis, as patients with predominantly 
inflammatory lesions are more likely to respond to medical therapy, while patients with fibrostenotic lesions 
usually require surgery. Ultrasound is safe, cost-effective, and widely accessible, thus provides an attractive 
alternative to the clinical standard Computed Tomography (CT, risks of radiation) and Magnetic Resonance 
Imaging (MRI, more expensive and limited accessibility). Because ultrasound may not be able to image bowel 
loops deep in the body, its main role is to follow-up after initial screening by CT or MRI (especially for 
terminal ileum, which is easily accessible by ultrasound and the most frequently affected bowel segment for 
CD). 
 
In this project, we will study the efficacy of ultrasound shear wave elastography and vascularity imaging for CD 
evaluation. Literature evidences demonstrate that bowel stiffness is correlated with fibrosis, while bowel 
vascularity and perfusion is correlated with inflammation. Therefore, we expect the combination of shear wave 
elastography and vascularity imaging can increase the sensitivity and specificity of CD evaluation. 
 
Aim 1: To evaluate the correlation of ultrasound measurements with clinically indicated Magnetic Resonance 
Enterography (MRE). 
Aim 2: To investigate if ultrasound measurements can be used to predict treatment response for Crohn's disease. 
 
 

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Subject Information – charts, records, images, or specimens are considered ‘subjects’ 
 
Target accrual is the proposed number of subjects to be included in your study at your site. “Subjects” may 
include Mayo Clinic charts, records, or specimens, and/or charts, records, or specimens received at Mayo 
Clinic from external sources for collaborating analysis by the investigator under this IRB application:    
 
Target accrual: 100 
 
Subject population: patients with confirmed or suspected Crohn’s disease. 
 
Inclusion criteria: Crohn’s disease patients with involvement of terminal ileum (thickness > 3mm) or other 
segments of small or large bowel, age above 18,.  
Exclusion criteria: patients with change of medicine or going to surgery over the 6-months follow-up period, 
patients with unreliable ultrasound images due to conditions such as large body habitus or poor ultrasound 
imaging window; adults lacking capacity to consent; vulnerable subjects such as prisoners. Pregnant women, 
nursing mothers, patients with known or suspected right-to-left, bi-directional, or transient right-to-left cardiac 
shunts, patients with history of hypersensitivity allergic reactions to ultrasound contrast agents.  
 
 Yes  
  No   Will a Certificate of Confidentiality (COC) be obtained from NIH?  If yes, 
Who is obtaining the COC: Mayo Clinic investigator, study sponsor, other:  
Explain why a COC is needed:   
 
 
 
Study Design  
 
Methods: Describe, in detail, the research activities that will be conducted under this protocol:   
 
Study Design: We will study the terminal ileum of 100 Crohn’s disease patients to investigate the efficacy of 
ultrasound measurements for disease evaluation and treatment outcome prediction. Patients with ongoing 
medical therapy or starting a new medical therapy will be recruited. Inflammation and fibrosis evaluated by 
contrast enhanced MR enterography at baseline and 6-months post therapy will be used as the reference 
standard. Ultrasound will be performed at baseline, 4-weeks, and 6-months. For Aim 1, correlation of 
ultrasound measurements with MR enterography results will be evaluated at baseline and 6-months. For Aim 2, 
we will access the association of the percentage change in ultrasound parameters from baseline to 4-weeks with 
the percentage change in MR enterography scores from baseline to 6-months. More information about data 
analysis can be found in the statistical section below. 
 
Ultrasound Procedure: Patients will be fasting for 4 hours before ultrasound scans to reduce bowel air and 
peristalsis. The ultrasound transducer will be sanitized as per clinical routine before each use. The terminal 
ileum (TI) will be located by B-mode ultrasound. The TI lesion with the most significant thickening will be 

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identified in B-mode images for subsequent measurements. Repeated measurements of shear wave speed 
(which represents bowel stiffness) at the TI lesion will be obtained using the GE Logiq E9 ultrasound scanner.   
Vascularity images of the TI lesion will be obtained using the Verasonics ultrasound scanner. We will obtain 
ultrasound images before and after the administration of contrast microbubbles to evaluate the benefit of 
contrast agents. Lumason, a FDA approved ultrasound contrast agent for liver imaging, will be used (IV 
injection) for this study. The subject will be instructed to briefly hold his/her breath during each ultrasound 
acquisition. Sometimes it can be difficult to find the same bowel lesion for imaging for longitudinal studies. We 
will measure the distance of the lesion from the ileocecal valve and use this information to help locating the 
same lesion for longitudinal studies. 
 
Safety of Lumason Administration: Lumason is approved by FDA as an ultrasound contrast agent for routine 
clinical use. In this study, the dosage and route of administration of Lumason will comply with the guideline of 
the package insert of Lumason. Our study team member will screen participants to exclude pregnant women, 
nursing mothers, patients with known or suspected right-to-left, bi-directional, or transient right-to-left cardiac 
shunts, patients with history of hypersensitivity allergic reactions to ultrasound contrast agents. If a female 
patient with childbearing potential is not sure of her pregnancy status, a urine pregnancy test will be done. 
Potential side effects will be monitored by sonographer and/or radiologists: Radiology has protocols on how to 
respond to adverse reaction of Lumason and Definity ultrasound contrast agents 
 
 
Resources: Describe the available resources to conduct the research (personnel, time, facilities, mentor 
commitment, etc.):  
We have commitments from all participating personnel. Patients will be referred and recruited by participating 
physicians. We have a GE Logiq E9 and a Verasonics ultrasound scanner that can be used for this study. 
 
Check all that apply. If none apply, leave blank: 
 
  This is a multisite study involving Mayo Clinic and non-Mayo Clinic sites.  
When checked, describe the research procedures/activities being conducted only at Mayo Clinic: 
 
  Mayo Clinic staff will be engaged in research activity at a non-Mayo Clinic site.  When checked, provide 
the location and a detailed description of the Mayo Clinic research staff involvement. 
 
 
  This study is to establish and/or maintain an ongoing database or registry for research purposes only. 
 
  The research involves contact or interaction with subjects, for example, surveys, questionnaires, 
observation, blood draw. 
 
  The study involves photographing, audiotaping or videotaping subjects (and guests).  
 
 
 
 

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Blood Collection 
 
If this study involves prospective blood collection by finger, heel, ear stick or venipuncture, complete the 
following:  
 
 
  From healthy, non pregnant, adult subjects who weigh at least 110 pounds. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed 550ml in an 8 week period 
and collection may not occur more frequently than 2 times per week. 
Volume per blood draw: _____ml   
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) _______ 
 
 
  From other adults and children considering age, weight, and health of subject. For a minimal 
risk application, the amount of blood drawn from these subjects may not exceed the lesser of 50 ml or 3 
ml per kg in an 8 week period, and collection may not occur more frequently than 2 times per week. 
Volume per blood draw: _____ml 
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.)_______  
 
 
 
 
Review of Chart, Images, Specimens 
Provide the date range for collection of data and/or specimens that will be included in your research dataset.  
Example: 01/01/2000 to 12/31/2013 or all records through mm/dd/yyyy.  
4/1/2017 to 4/1/2025 
For a retrospective chart review, enter the date range:   
 
Check all that apply: 
 
  This study involves only data and/or specimens that exist at the time this application is submitted to the IRB 
(IRB submission date). No data or specimens will be collected beyond this date.  
 
 
  This study involves only data and/or specimens that will be collected after submission to the IRB. 
 
  The study involves data and/or specimens that exist at the time of submission to the IRB and data and/or 
specimens that will be collected after submission to the IRB, for example a study that includes collection of 
existing data and prospective collection of specimens. 

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  Data and/or specimens used in this study are collected under another IRB protocol. When checked, provide 
the IRB number(s) from which the research material will be obtained. When appropriate, check the box below 
to attest that subjects have provided consent for future use of their data and/or specimens, as described in this 
protocol.  
 
 
IRB Number/s - Data Only:  _____________________________________________ 
 
IRB Number/s - Specimens Only: _________________________________________ 
 
IRB Number/s - Data and Specimens:  _____________________________________ 
 
Note:  When subjects provided consent for use of their data and/or specimens, as described in this protocol. 
 
  Other data sources will be utilized in this study, e.g. receiving data/specimens from an external party. When 
checked, provide all data sources: 
 
 
 
 
 
 
 
 
 
 
 
Data Confidentiality, HIPAA Subject Identifiers 
 
Review the list of subject identifiers below and, if applicable, check the box next to each subject identifier being 
recorded at the time you are collecting/abstracting data/specimens for use in this study. 
 
Subject Identifiers:  Individually identifiable information, including demographic data, that identifies the 
individual or for which there is reasonable basis to believe it can be used to identify the individual.  NOTE: 
Identifiers apply to subjects enrolled in your study and to the subject’s relatives, household members, 
employers, etc. 
 
Internal refers to subject identifiers that will be included in the dataset maintained by the study team. 
External refers to subject identifiers that will be shared with persons outside of the immediate study team, for 
example, sent to an external collaborator or shared with a national registry.  
 
 

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SUBJECT IDENTIFIERS 
Check all that apply 
INTERNAL 
IDENTIFIER 
EXTERNAL 
IDENTIFIER 
Name 
x 
 
Social Security number 
 
 
Medical record/patient registration number, lab accession, specimen or 
radiologic image number 
x 
 
Study number, subject ID, or any other unique identifying number, 
characteristic or code that can be used to link the identity of the subject to the 
data 
x 
 
Dates: All elements of dates [month, day, and year] directly related to an 
individual. Their birth date, date of death, date of diagnosis, etc.   
Note: Recording a year only is not a unique identifier.  
x 
 
Medical device identifiers and serial numbers 
 
 
Biometric identifiers, including finger and voice prints, full face photographic 
images and any comparable images 
 
 
Web Universal Resource Locators (URLs), Internet Protocol (IP) address 
numbers, email address 
 
 
Street address, city, county, precinct, zip code, and their equivalent geocodes 
 
 
Phone or fax numbers 
 
 
Account, member, certificate or professional license numbers, health 
beneficiary numbers 
 
 
Vehicle identifiers and serial numbers, including license plate numbers 
 
 
If None of the above identifiers will be recorded or maintained in the 
dataset and/or sent outside of the study team, please check “None”. 
 None 
 None 
 
 

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Statistical Information 
 
Note: Power analyses and study endpoints are not needed for a pilot or feasibility studies.  
 
 
 No statistical information. If checked, please explain: 
 
Statistical Considerations 
 
Power Statement:   
The sample-size for the present investigation was determined for the primary aim of assessing the correlation 
between ultrasound parameters and the MaRIA score (a score calculated from MR enterography, which reflects 
bowel inflammation [1]). For ultrasound to have meaningful clinical utility we would require a correlation with 
MaRIA score of at least 0.70. For the primary analysis, the correlation between ultrasound measurements and 
MaRIA score will be compared to 0.70 using a two-tailed, alpha=0.05 level test. Under the assumption that the 
“true” correlation is 0.82, a sample-size of N=100 will provide statistical power of 82% for the primary 
analysis. 
 
Data Analysis Plan:  
Disease activity measurements will be obtained via MR enterography at baseline and 6-months following 
treatment, and via ultrasound at baseline, 4-weeks and 6-months after treatment. Two quantitative ultrasound 
parameters will be obtained: A) shear wave speed obtained from the GE Logiq E9; B) vessel density (the 
percentage of pixels in the bowel lesion with blood flow compared to the total area of the lesion) obtained from 
the Verasonics. For each ultrasound parameter, the mean of all repeated measurements will be used as the 
representative value for a given patient at a given time. Measurements obtained following baseline will be 
expressed as percentage change from baseline. For inflammation evaluation, the correlation of each ultrasound 
parameter with MaRIA score will be assessed using a point estimate and 95% confidence interval. In addition, 
using a MaRIA cut-point of 11, patents will be categorized as having mild versus severe disease [1]. As a 
secondary analysis, logistic regression with corresponding ROC (Receiver Operating Characteristic) analysis 
will be used to assess whether ultrasound measurements can distinguish between mild versus severe 
inflammation. Findings from these analyses will be summarized using the point-estimate and 95% confidence 
interval for the area under the ROC curve (AUROC). In addition to univariate analyses, exploratory 
multivariable analyses will be performed to assess whether combination of ultrasound parameters can increase 
the performance relative to the univariate findings. Similar analyses will be performed to assess whether 
ultrasound parameters are useful for fibrosis evaluation: for these analyses, the MR enterography percentage 
gain change (PGC) will be used for correlation analysis, and a PGC cut point of 23.5% will be used to 
categorize fibrosis as mild or severe for ROC analysis [2]. 
For Aim 2, a series of analyses will be performed to assess whether ultrasound parameters obtained at baseline 
and 4-weeks can predict 6-month treatment outcome. A correlation analysis will be performed to assess the 
association of the percentage change in ultrasound parameters from baseline to 4-weeks with the percentage 
change in MaRIA score from baseline to 6-months. In addition, treatment outcome will be dichotomized 
(responder, non-responder) based on the 6-month MR enterography. Univariable and multivariable logistic 

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regression with corresponding ROC analyses will be used to assess whether percentage change in ultrasound 
measurements at 4-weeks can predict treatment outcome. Findings from these analyses will be summarized 
using the point-estimate and 95% confidence interval for the AUROC. In all cases, distributional assumptions 
will be evaluated with transformations or non-parametric methods used as appropriate. Two-tailed p-values < 
0.05 will be considered statistically significant.  
 
Endpoints 
Primary: please see detailed description above. 
       
 
 
 
Secondary: please see detailed description above. 
 
References: 
1. 
Rimola, J., et al., Magnetic Resonance Imaging for Evaluation of Crohn's Disease: Validation of 
Parameters of Severity and Quantitative Index of Activity. Inflammatory Bowel Diseases, 2011. 17(8): 
p. 1759-1768. 
2. 
Rimola, J., et al., Characterization of Inflammation and Fibrosis in Crohn's Disease Lesions by 
Magnetic Resonance Imaging. American Journal of Gastroenterology, 2015. 110(3): p. 432-440.