Clinical trial NCT03652636
Conditions: Hepatic Disease
Sponsor: Indiana University
Start date: 2019-08-05; Completion date: 2023-07-21
Enrollment: 47 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In patients with hepatic lesions, to evaluate the efficacy of contrast enhanced ultrasound compared to MRI in differentiating focal nodular hyperplasia and hepatic adenoma.

Detailed description:
Hepatic imaging plays an important role in identifying and differentiating both benign and malignant neoplasms of the liver. One of the clinical and radiologic dilemmas facing hepatic medicine is the accurate differentiation of focal nodular hyperplasia (FNH) and hepatic adenoma (HA). This is a question of some import, as there are significant prognosis and treatment differences between these entities, as well as overlap in the patient populations in whom they occur.

FNH is the second most common benign neoplasm of the liver, with a strong female predilection. These lesions are usually asymptomatic and incidentally discovered, and carry only a small risk of complication such as bleeding. There is no malignant potential. Hepatic adenomas (HAs) are more rare benign neoplasms that also have a female predilection. However, these lesions are more likely to be symptomatic, and carry a higher bleeding risk especially as they grow over 4 cm. In addition, they harbor a small risk of malignant transformation to hepatocellular carcinoma (HCC). Of note, patients may present with both types of lesion concurrently.

Currently, MRI with hepatobiliary contrast agents is the standard for differentiation of these lesions. These agents (such as gadoxetate disodium, or Eovist) are actively transported into hepatocytes, which are present in FNH and only in very rare cases with HA. Previous research (such as from Grazioli et al.) has shown that hepatobiliary agents can differentiate these lesions with excellent accuracy. However, there is still overlap between these lesions on imaging, and for certain patients MRI may be difficult or impossible.

FDA approval of contrast enhanced ultrasound (CEUS) agents in 2016 has opened a new avenue for abdominal imaging. CEUS utilizes gas containing lipid microbubbles to provide pure intravascular contrast, allowing for evaluation of vascular and solid organ perfusion. It has an excellent safety profile and is not excreted by the kidneys, allowing for use in patients with acute and chronic renal disease. It has been used for some time outside of the US for liver lesion evaluation, and the enhancement patterns of both FNH and HA have been described in the literature by Kim et al. as having different appearances. CEUS can be especially useful for focal liver lesion imaging for patients who cannot or will not undergo MRI, and it has the advantages of flexibility, increased temporal resolution, and decreased cost. This study aims to compare the utility of CEUS for differentiating FNH and HA with the current standard of hepatobiliary contrast MRI.

Arms: arm 1: Patient scheduled to get MRI will also be asked to receive an ultrasound of the liver
Interventions: intervention 1: Sulfur Hexafluoride Microspheres
Intervention descriptions: intervention 1: 2.5 mL intravenous injection given at the time of ultrasound, with second 2.5 mL intravenous injection given during ultrasound as needed to improve visualization

Protocol documents:
Prot_002.pdf: 
Protocol Version: August 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of the efficacy of contrast enhanced ultrasound compared to MRI 
for differentiation of hepatic lesions 
 
 
 
NCT03652636 
 
 
 
August 20, 2019 
 


Protocol Version: August 2019 
Evaluation of the efficacy of contrast enhanced ultrasound compared to MRI 
for differentiation of hepatic lesions 
 
Principal investigator:  Jordan K. Swensson, M.D.  
Radiology 
 
Aim 
 
In patients with hepatic lesions, to evaluate the efficacy of contrast enhanced ultrasound (CEUS) 
compared to MRI in differentiating focal nodular hyperplasia (FNH) and hepatic adenoma. 
Studies from Europe (Dietrich et al, Roche et al) have described different patterns of 
enhancement between FNH and hepatic adenoma. MRI is the current imaging modality of choice 
for making this determination, but has limitations. This pilot study aims to test the hypothesis 
that CEUS has similar ability to differentiate FNH and adenoma, using MRI as the gold standard. 
 
Rationale 
 
Hepatic imaging plays an important role in identifying and differentiating both benign and 
malignant neoplasms of the liver. One of the clinical and radiologic dilemmas facing hepatic 
medicine is the accurate differentiation of focal nodular hyperplasia (FNH) and hepatic adenoma 
(HA). This is a question of some import, as there are significant prognosis and treatment 
differences between these entities, as well as overlap in the patient populations in whom they 
occur. 
 
FNH is the second most common benign neoplasm of the liver, with a strong female 
predilection. These lesions are usually asymptomatic and incidentally discovered, and carry only 
a small risk of complication such as bleeding. There is no malignant potential. Hepatic adenomas 
(HAs) are more rare benign neoplasms that also have a female predilection. However, these 
lesions are more likely to be symptomatic, and carry a higher bleeding risk especially as they 
grow over 4 cm. In addition, they harbor a small risk of malignant transformation to 
hepatocellular carcinoma (HCC). Of note, patients may present with both types of lesion 
concurrently. 
 
Currently, MRI with hepatobiliary contrast agents is the standard for differentiation of these 
lesions. These agents (such as gadoxetate disodium, or Eovist) are actively transported into 
hepatocytes, which are present in FNH and only in very rare cases with HA. Previous research 
(such as from Grazioli et al.) has shown that hepatobiliary agents can differentiate these lesions 
with excellent accuracy. However, there is still overlap between these lesions on imaging, and 
for certain patients MRI may be difficult or impossible. 
 
FDA approval of contrast enhanced ultrasound (CEUS) agents in 2016 has opened a new avenue 
for abdominal imaging. CEUS utilizes gas containing lipid microbubbles to provide pure 
intravascular contrast, allowing for evaluation of vascular and solid organ perfusion. It has an 
excellent safety profile and is not excreted by the kidneys, allowing for use in patients with acute 
and chronic renal disease. It has been used for some time outside of the US for liver lesion 
evaluation, and the enhancement patterns of both FNH and HA have been described in the 
literature as having different appearances. CEUS can be especially useful for focal liver lesion 


Protocol Version: August 2019 
imaging for patients who cannot or will not undergo MRI, and it has the advantages of 
flexibility, increased temporal resolution, and decreased cost. This study aims to compare the 
utility of CEUS for differentiating FNH and HA with the current standard of hepatobiliary 
contrast MRI. 
 
Performance site 
 
University Hospital 
Methodist Hospital 
 
Patient selection 
 
Inclusion criteria 
 
1.  Males and females  
2. Age 18 years or greater 
3. Recently have undergone (within 365 days) or are scheduled to undergo abdominal MRI with 
contrast at a performance site for evaluation of a hepatic lesion(s). 
 
Exclusion criteria 
 
1.  History of acute cardiac ischemia 
2.  History of hypersensitivity reaction to Lumason 
3.  Pregnancy 
 
Methods 
 
Potential subjects will be identified by three methods. 
 
1)  From the MRI schedule at the performance site, a radiology investigator will 
prospectively identify patients who are to undergo abdominal MRI with hepatobiliary 
contrast and who otherwise meet entry criteria.  Exclusion criteria will be evaluated by 
consulting the medical record.  At the time of MRI scanning, a radiology investigator will 
meet with the potential subject, confirm that exclusion criteria are not met, explain the 
study, answer any questions, and seek written informed consent.  If consent is granted, 
CEUS of the liver will be scheduled. 
2) From the surgery/hepatology clinic schedule, a surgery or hepatology investigator will 
identify patients who meet entry criteria.  The investigator will explain the study to the 
patient; if he/she expresses interest, the investigator will give a copy of the informed 
consent to the potential subject, and contact radiology and have the patient scheduled for 
CEUS of the liver.  At the time of CEUS, a radiology investigator will meet with the 
potential subject, confirm that exclusion criteria are not met, explain the study, answer 
any questions, and seek written informed consent.   
3) The principle investigator will retroactively review the radiology database, DORIS, for 
patients who have had a recent MRI with hepatobiliary contrast and who otherwise meet 
entry criteria that may have been missed by the previous methods mentioned.  A study 


Protocol Version: August 2019 
radiology investigator will reach out to the patient’s hepatologist about enrolling them in 
the trial and obtain best contact information.  A study coordinator will contact the patient 
by email or phone, with IRB approved script, to seek consent to contact for recruitment 
purposes. 
 
The subjects will be scanned in the University or Methodist Hospital ultrasound department by 
technicians trained in use of CEUS, under supervision of one of the study's key personnel. The 
contrast agent used will be Lumason (sulfur hexafluoride lipid-type A microspheres) distributed 
by Bracco Diagnostics Inc. Previous MRI images will be reviewed, and up to two of the largest 
lesions will be evaluated. Each lesion will be interrogated with a single intravenous dose of 
contrast (2.5 mL). If there is a single lesion, a second 2.5 mL injection may be used as needed to 
improve lesion visualization. If there are two lesions, each will be evaluated with one injection. 
Since the intention to treat includes all lesions chosen from MRI, if the injection(s) do not 
provide adequate images, the lesion in question will not be excluded from the study. 
 
Once the study is closed to enrollment and all subjects have completed the research CEUS scan.  
The obtained CEUS images will then be reviewed in consensus by two radiologist investigators, 
blinded to clinical information and MRI findings.  Each lesion assessed will be given a presumed 
diagnosis of FNH, HA, or indeterminate. At the completion of the study, the CEUS data will be 
compared to the official reports from the MRIs dictated by IUH radiologists to assess 
concurrence between the two imaging modalities.   
 
The PI and another investigator will quarterly review data quality, subject recruitment, accrual, 
outcome and adverse event data; assess scientific reports or therapeutic development, results of 
related studies that may impact subject safety, and procedures designed to protect the privacy of 
subjects. 
 
We will compile descriptive statistics comparing the sensitivity, specificity, and accuracy of 
CEUS for differentiating FNH and hepatic adenoma, compared with MRI results as the gold 
standard. 
 
Enrollment 
 
As this study explores a new method of diagnosing hepatic lesions and there is little published 
data on the subject, we do not have sufficient knowledge to do power and sample size 
calculations to demonstrate the number of patients needed to show equivalence between the two 
imaging methods.  The proposed enrollment of 40 patients reflects the availability of both 
Lumason and the approximate number of qualifying patients who would undergo MRI for 
evaluation of these lesions in one year. 
 
Resources/Budget 
 
At the performance site, patients with suspected FNH or HA typically undergo MRI of the liver 
as part of standard of care, and the patient or insurer will be billed for the examination and 
radiologic interpretation.  CEUS is not routinely performed in this population.  The cost 


Protocol Version: August 2019 
associated with CEUS and the time of the investigators will be the responsibility of the 
Department of Radiology and Imaging Sciences. 
 
Subjects will be compensated for their time and effort with a $50.00 gift card upon completion of 
research imaging. 
 
References 
 
Bieze M, van den Esschert JW, Nio CY, et al.  Diagnostic accuracy of MRI in differentiating 
hepatocellular adenoma from focal nodular hyperplasia: prospective study of the additional value 
of gadoxetate disodium.  AJR Am J Roentgenol 2012; 199:26-34. 
 
Dietrich CF, Schuessler G, Trojan J, Fellbaum C, Ignee A.  Differentiation of focal nodular 
hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound.  Br J Radiol 2005; 
78:704-707. 
 
Grazioli L, Morani G, Kirchin GA, Schneider G.  Accurate differentiation of focal nodular 
hyperplasia from hepatic adenoma at gadobenate dimeglumine–enhanced MR imaging: 
prospective study.  Radiology 2005; 236:166-177. 
 
Kim TK, Jang HJ, Burns PN, Murphy-Lavallee J, Wilson SR.  Focal nodular hyperplasia and 
hepatic adenoma: differentiation with low-mechanical-index contrast-enhanced sonography.  
AJR Am J Roentgenol 2008; 190:58-66. 
 
Kong WT, Wang WP, Huang BJ, et al.  Contrast-enhanced ultrasound in combination with color 
Doppler ultrasound can improve the diagnostic performance of focal nodular hyperplasia and 
hepatocellular adenoma.  Ultrasound Med Biol 2015; 41:944-951. 
 
Purysko AS, Remer EM, Coppa CP, et al.  Characteristics and distinguishing features of 
hepatocellular adenoma and focal nodular hyperplasia on gadoxetate disodium-enhanced MRI.  
AJR Am J Roentgenol 2012; 198:115-123. 
 
Quaia E, Calliada F, Bertolotto M, et al.  Characterization of focal liver lesions with contrast-
specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic 
performance and confidence. Radiology 2004; 232:420-430. 
 
Roche V, Pigneur F, Tselikas L, et al.  Differentiation of focal nodular hyperplasia from 
hepatocellular adenomas with low-mechanical-index contrast-enhanced sonography (CEUS): 
effect of size on diagnostic confidence.  Eur Radiol 2015; 25:186-95.  
 
Roux M, Pigneur F, Calderaro J, et al.  Differentiation of focal nodular hyperplasia from 
hepatocellular adenoma: Role of the quantitative analysis of gadobenate dimeglumine-enhanced 
hepatobiliary phase MRI.  J Magn Reson Imaging 2015; 42:1249-1258.  
 


Protocol Version: August 2019 
Taimr P, Bröker MEE, Dwarkasing RS, et al.  A Model-Based Prediction of the Probability 
of Hepatocellular Adenoma and Focal Nodular Hyperplasia Based on Characteristics on 
Contrast-Enhanced Ultrasound.  Ultrasound Med Biol 2017; 43:2144-2150. 
 

SAP_003.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of the efficacy of contrast enhanced ultrasound compared to MRI 
for differentiation of hepatic lesions 
 
 
 
NCT03652636 
 
 
 
August 20, 2019 
 


Sensitivity, specificity, ROC / AUC values were calculated using SPSS software (version 28, 
IBM). Separate analyses of sensitivity, specificity, ROC / AUC were performed focusing on all 
lesions, lesions 2 cm in size or greater, and lesions 3 cm in size or greater. 

ICF_004.pdf: 
 
IU IRB ICS Template 
 
 
 
 
 
          Page 1 of 5 
Evaluation of the efficacy of contrast enhanced ultrasound compared to MRI for differentiation of 
hepatic lesions 
 
 
NCT03652636 
 
 
Informed Consent Document 
 
08/20/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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          Page 2 of 5 
 
 
 
 
 
 
 
 
 
INDIANA UNIVERSITY INFORMED CONSENT STATEMENT FOR RESEARCH 
 
Evaluation of the efficacy of contrast enhanced ultrasound compared to MRI for differentiation of 
hepatic lesions 
 
About this research  
You are being asked to participate in a research study.  Scientists do research to answer important 
questions which might help change or improve the way we do things in the future.  
 
This consent form will give you information about the study to help you decide whether you want to 
participate.  Please read this form, and ask any questions you have, before agreeing to be in the study. 
 
Taking part in this study is voluntary 
You may choose not to take part in the study or may choose to leave the study at any time.  Deciding 
not to participate, or deciding to leave the study later, will not result in any penalty or loss of benefits 
to which you are entitled, and will not affect your relationship with the Indiana University School of 
Medicine, Department of Radiology and Imaging Sciences. 
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to find out if the use of a type of intravenous contrast containing tiny 
bubbles (Lumason, Bracco Diagnostics Inc) during ultrasound imaging allows us to distinguish two kinds 
of liver lesions (focal nodular hyperplasia and hepatic adenoma) as well as does the usual imaging 
method, contrast-enhanced magnetic resonance imaging (MRI). 
 
You were selected as a possible participant because your physician has referred you for an MRI scan to 
image your liver lesion(s). 
 
The study is being conducted by Jordan K. Swensson, M.D., of the Indiana University School of 
Medicine, Department of Radiology and Imaging Sciences. 
 
HOW MANY PEOPLE WILL TAKE PART? 
If you agree to participate, you will be one of 40 participants taking part in this research. 
 


 
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WHAT WILL HAPPEN DURING THE STUDY? 
If you agree to be in the study, you will do the following things: 
 
You have had or will have a MRI scan with contrast performed of your liver as ordered by your 
physician.  This is the standard imaging scan for a patient with your condition.  A physician either has 
explained or will explain to you what occurs during a MRI scan of the liver, and the risks of the 
procedure.  You may sign a separate consent form for the physician to perform the MRI scan.  
Information from your medical record will be collected and used for this study as related to the 
standard of care MRI. 
 
After the MRI, you will be scheduled for an ultrasound scan with Lumason performed on your liver, at 
University or Methodist Hospital.  This is the imaging scan that we are studying in this research.  You 
will be given instructions on how to reach this facility. 
 
At the ultrasound suite, a person trained in inserting a needle into a vein will clean an area on the 
inside of one of your elbows.  This person will then inject less than one ounce of a saline solution 
containing Lumason into a vein in this area.  A technologist will then spread a gel that helps us see the 
liver better over the skin above your liver.  The radiologist will move a “wand” over the liver to get 
ultrasound pictures.  If the pictures are unclear, a second injection of the same amount of Lumason 
may be performed, and more pictures will be taken.  The entire ultrasound scan should take 30-45 
minutes to perform.  You will then be free to leave and your participation in the study will be 
complete. 
 
WHAT ARE THE RISKS OF TAKING PART IN THE STUDY? 
While participating in the study, the risks, side effects, and/or discomforts include: 
 
 
There is a small risk of pain, swelling, and/or infection at the site where Lumason is injected.  To reduce 
this risk, only personnel trained in performing this procedure will do so. 
 
Lumason has rarely been associated with heart, circulatory, and breathing problems just after it is 
injected.  It can also rarely cause an allergic reaction (rash, difficulty breathing).   
 
There is theoretical risk that the gas bubbles in the contrast may lead to temporary blockage of tiny 
arteries found throughout the body, which could lead to serious damage to internal organs and tissues. 
However, there have not been any reported cases of this happening, and the drug has been FDA 
approved for use in evaluating liver lesions.  
 
To reduce these risks, you will be monitored during and for several minutes after the injection.  Trained 
personnel and medications to treat these problems are quickly available should they occur.  A group of 
patients at highest risk (history of cardiac shunting) will not be allowed to participate. 
 
In any research study, there is the risk of loss of confidentiality.  We will reduce this risk by limiting the 
number of people who can see study data that is directly linked to you.  If study data is released to 
others, all information that could be used to identify you as a study participant will be removed. 
 
 


 
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WHAT ARE THE POTENTIAL BENEFITS OF TAKING PART IN THE STUDY? 
We don’t expect you to receive any benefit from taking part in this study, but we hope to learn things 
which will help scientists in the future. 
 
 
 
 
HOW WILL MY INFORMATION BE PROTECTED? 
Efforts will be made to keep your personal information confidential.  We cannot guarantee absolute 
confidentiality.  Your personal information may be disclosed if required by law.  No information which 
could identify you will be shared in publications about this study, and databases in which results may 
be stored.  
 
Organizations that may inspect and/or copy your research records for quality assurance and data 
analysis include groups such as the study investigator and his/her research associates, the Indiana 
University Institutional Review Board or its designees, and (as allowed by law) state or federal 
agencies, specifically the Office for Human Research Protections (OHRP) and the Food and Drug 
Administration (FDA) etc., who may need to access your medical and/or research records. 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law.  This 
website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time.  
 
WILL MY INFORMATION BE USED FOR RESEARCH IN THE FUTURE? 
Information for this study may be used for future research studies or shared with other researchers for 
future research.  If this happens, information which could identify you will be removed before any 
information is shared.  Since identifying information will be removed, we will not ask for your 
additional consent.  
 
WILL I BE PAID FOR PARTICIPATION?  
You will not be paid for participating in this study. 
 
WILL IT COST ME ANYTHING TO PARTICIPATE?  
Taking part in this study may lead to added costs to you or your insurance company.  You or your 
insurance company will be responsible for the following costs:  cost of contrast-enhanced MRI scan of 
the liver, and cost of the radiologist who reads the scan.  This is a standard of care procedure that will 
be the responsibility of you or your insurance.   
 
You will not be responsible for these study-specific costs: contrast-enhanced ultrasound of the liver, 
cost of the Lumason contrast, reading of the scan by the radiologist.   


 
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WHO WILL PAY FOR MY TREATMENT IF I AM INJURED?  
In the event of physical injury resulting from your participation in this study, necessary medical 
treatment will be provided to you and billed as part of your medical expenses.  Costs not covered by 
your health care insurer will be your responsibility.  Also, it is your responsibility to determine the 
extent of your health care coverage.  There is no program in place for other monetary compensation 
for such injuries.  However, you are not giving up any legal rights or benefits to which you are 
otherwise entitled.   
 
WHO SHOULD I CALL WITH QUESTIONS OR PROBLEMS? 
For questions about the study, contact the researcher, Jordan K. Swensson, M.D., at (317) 944-1837.  
After business hours, please call (317) 944-5000 and ask for the radiology resident on-call. 
 
In the event of an emergency, you may contact Dr. Swensson at (317) 367-9075.  
 
For questions about your rights as a research participant, to discuss problems, complaints, or concerns 
about a research study, or to obtain information or to offer input, please contact the IU Human 
Subjects Office at 800-696-2949 or at irb@iu.edu. 
 
CAN I WITHDRAW FROM THE STUDY? 
If you decide to participate in this study, you can change your mind and decide to leave the study at 
any time in the future.  The study team will help you withdraw from the study safely.  If you decide to 
withdraw, contact the principal investigator, Dr. Swensson, at the phone number listed above.  
 
PARTICIPANT’S CONSENT 
In consideration of all of the above, I give my consent to participate in this research study.  I will be 
given a copy of this informed consent document to keep for my records.  I agree to take part in this 
study. 
 
Participant’s Printed Name: 
 
 
 
Participant’s Signature: 
Date: 
 
 
 
 
Printed Name of Person Obtaining Consent:  
 
 
 
 
Signature of Person Obtaining Consent: 
Date: