Quantitative Ultrasound With Liver Incytes for Evaluation of Non-Alcoholic Fatty Liver Disease
Phase: NA
Conditions: NAFLD, NASH - Nonalcoholic Steatohepatitis
Sponsor: Indiana University

July 8, 2021 
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Study title:  Quantitative Ultrasound with Velacur for Evaluation of Non-Alcoholic Fatty 
Liver Disease 
PI:  Samer Gawrieh MD 
NCT 04576923 
Document date:  July 8, 2021

 
 
  
July 8, 2021 
 
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Quantitative Ultrasound with Velacur for Evaluation of Non-Alcoholic Fatty Liver Disease 
 
Background 
 
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide 1. It is 
characterized by increased hepatic fat accumulation in the absence of significant alcohol intake. 
NAFLD has a wide spectrum that starts with simple accumulation of triglycerides droplets in 
hepatocytes (macrosteatosis) without associated inflammation, hepatocyte injury or fibrosis, a 
phenotype called non-alcoholic fatty liver (NAFL) 2. A more severe NAFLD phenotype is 
nonalcoholic steatohepatitis (NASH), which in addition to the presence of macrosteatosis is 
characterized by hepatocyte ballooning, lobular inflammation with or without fibrosis. While 
NAFL generally has a benign course, NASH may progress to cause cirrhosis, liver failure and 
hepatocellular carcinoma (HCC) 3, 4. 
The global prevalence of NAFLD in the general population is estimated at 25% and it increases 
with age 1. There is geographic variation in NAFLD prevalence probably due to differences in 
populations’ genetic compositions, dietary habits and environmental aspects. About a quarter of 
the populations in Europe and North America are estimated to have NAFLD, whereas 
populations in South America and the Middle East are estimated to have the highest rates of 
NAFLD globally (range 30-32%)1. NASH is estimated to affect 2% - 6% .of the general 
population, 7% - 30%  of NAFLD patients who had a liver biopsy without a specific clinical 
indication ( e.g. evaluation for liver organ donation), and 59% in NAFLD patients with clinical 
indication for liver biopsy (e.g. elevated liver enzymes) 1. 
Current NAFLD guidelines by the American Association of study of Liver Diseases (AASLD) do 
not recommend routine screening for NAFLD among patients with diabetes or obesity in the 
setting of primary care and obesity clinics 2. Use of non-invasive clinical prediction models and 
detection methods such as vibration-controlled transient elastography by FibroScan® to evaluate 
the presence and severity of fibrosis is proposed 5. Several serum-based non-invasive clinical 
prediction models can be used to screen patients with NAFLD for NASH or advanced fibrosis 6, 7. 
For example, the NAFLD fibrosis score (NFS) allows a non-invasive evaluation of the extent of 
fibrosis using weight, and age and laboratory data which include liver enzymes and serum glucose 
level 8, 9. Another useful clinical tool to estimate fibrosis is Fibrosis-4 score which relies solely on 
laboratory data 10. When available, tools such as transient elastography (FibroScan®) with 
controlled attenuation parameter (CAP) allow simultaneous estimation amount of hepatic fat 
(using CAP) and fibrosis [using the liver stiffness measurement (LSM)] 5, 11.  MR based methods 
can also offer simultaneous assessment of hepatic fat and fibrosis, albeit it is not widely available 
and is more expensive 12. 
While the use of FibroScan® in liver clinics is attractive as a point of care exam that can provide 
immediate indirect data about hepatic steatosis and fibrosis in the clinic, advancement in 
quantitative ultrasound technology may now allow even more detailed and directed non-invasive 
assessment of these measures of liver disease. 

 
 
  
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Velacur offers the ability to simultaneously and non-
invasively measure Attenuation Coefficient Estimate 
(ACE) 
as 
a 
quantitative 
measure 
of 
ultrasound 
attenuation13 and detection of hepatic steatosis in addition 
to LSM which measures deep volumetric liver elasticity 
using steady state shear waves, known as shear wave 
absolute viboelastography (SWAVE). This technology 
enables measurements of liver elasticity to a depth equal 
to the B-mode image, or in excess of 15 cm. The system 
consists of an ultrasound machine, a vibration device to 
excite shear waves in the patient and a ultrasound 
transducer. The vibration device induces shear waves in 
the liver at four different frequencies between 40Hz and 
70Hz simultaneously. The ultrasound volume is acquired 
through the ribs at the same location as a typical transient 
elastography (TE) measurement. Volumes are collected in 
a fan of approximately 15 degrees and taken at a depth of 
15cm, which much deeper than FibroScan® measurement 
(6 cm), and allows for much larger sample measurement 
(100,000 mm3) versus that measured by Fibroscan (3,140 
mm3). 
 
Rationale and Specific Aims 
 
Hypothesis and Specific Aims: Velacur with ACE and LSM measurements is a novel ultrasonic 
device that can estimate both liver steatosis and fibrosis using a sophisticated process. The 
availability of Velacur would allow a health care provider to make a diagnosis of NAFLD with or 
without advanced fibrosis quickly without a need for liver biopsy.  
 
Hypothesis: The diagnosis and severity of NAFLD with or without advanced fibrosis can be 
defined using Velacur. 
Specific Aims: To prospectively evaluate the utility of Velacur in assessing NAFLD with or 
without advanced fibrosis in patients seen in liver clinics for suspected NAFLD diagnosis. 
Specific Aim #1: To prospectively evaluate the performance of Velacur for detecting hepatic 
steatosis and fibrosis in patients with suspected NAFLD by assessing correlation of ACE and 
LSM measured by Velacur to grade of steatosis and stage of fibrosis on liver histology of 
patients with NAFLD who undergo standard of care liver biopsy.  
Specific Aim #2: To compare the performance of Velacur to that of FibroScan® in the same 
patient population to determine if either test is more accurate in correlating with NAFLD 
histology. 
 
Velacur Probe
 

 
 
  
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Specific Aim #3: To compare the performance of Velacur to that of non-invasive blood based 
markers such as APRI, FIB4, and NAFLD fibrosis score in predicting advanced fibrosis in 
biopsy proven NAFLD. 
 
Proposed Study Design: The proposed study will evaluate the performance characteristics of 
LSM as a measure of fibrosis and ACE as a measure of hepatic steatosis by Velacur in patients 
with different stages of NAFLD. In addition, we will compare the diagnostic accuracy of ACE to 
CAP and LSM measured by Velacur to that measured by FibroScan® using liver histology as the 
reference standard. We will also compare the performance of these two methods to that of non-
invasive blood based markers such as APRI, FIB4, and NAFLD fibrosis score in predicting 
advanced fibrosis in biopsy proven NAFLD. 
 
Inclusion/Exclusion Criteria 
 
Inclusion criteria: 
1. Adults aged 18 years or older 
2. History of biopsy proven NAFLD or NASH within 6 months prior to enrollment 
3. Planned liver biopsy for evaluation of NAFLD within 6 months of enrollment 
4. Suspected NAFLD or NASH with planned or recommended standard of care liver biopsy 
5. Ability to provide informed consent 
 
Exclusion criteria: 
1. Fasting for less than three hours prior to the scan 
2. Subject is a pregnant or lactating female 
3. Subject with current, significant alcohol consumption or history of significant alcohol 
consumption for a period of more than 3 consecutive months any time within 1 year prior 
to screening. Significant alcohol consumption is defined as more than 20 gram per day in 
females and more than 30 grams per day in males, on average (a standard drink in the 
US is considered to be 14 grams of alcohol).  
4. Subject is unable to reliably quantify alcohol consumption based upon local study 
physician judgment.  
5. Subject uses drugs historically associated with NAFLD (amiodarone, methotrexate, 
systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those 
used for hormone replacement, anabolic steroids, valproic acid, and other known 
hepatotoxins) for more than 2 weeks in the year prior to screening  
6. Subject with history of cirrhosis and clinical evidence of hepatic decompensation as 
defined by the presence of any of the following abnormalities at screening:  
a. Serum albumin less than 3.5 grams/deciliter (g/dL).  
b. An INR greater than 1.5.  
c. Total bilirubin greater than 2 milligrams per deciliter (mg/dL).  
d. please note that people with compensated cirrhosis are not excluded from the 
study protocol 
7. Subject has a history of bleeding esophageal varices, ascites or hepatic encephalopathy 
8. Subject has history of other forms of chronic liver diseases such as viral hepatitis, 
autoimmune hepatitis, cholestatic liver disease (primary biliary cirrhosis or primary 
sclerosing cholangitis).  
9. Subject with active substance abuse 
10. Acute hepatitis defined as AST/ALT > 500 U/L 
11. Patients with a pacemaker or defibrillator 

 
 
  
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12. Ascites 
 
Enrollment/Randomization 
 
Up to 100 patients will be seen at 3 different sites:  Indiana University, Arizona Liver Institute, 
and Cedars-Sinai Medical Center. 
 
 
Study Procedures 
 
All patients have to be fasting for 3 hours prior to performance of the study. After subject 
identification and informed consent, measurement of liver stiffness with Velacur will be 
performed by a certified technician.  At that time, subject participation in the protocol is 
complete.  Duration of participation for the subject should be no more than one hour. Medical 
information from the subjects, including results of the laboratory and imaging tests, liver biopsy 
results and medical history will be collected from medical records and entered into a database. 
None of these tests would have been performed as part of this study, rather of as part of routine 
clinical care the patient receives. Laboratory data to calculate non-invasive blood based 
markers such as APRI, FIB4, and NAFLD fibrosis score generated within 6 months of the date 
of the liver biopsy will be collected. Additionally, slides from a standard of care liver biopsy will 
be made from the tissue collected during the biopsy and will be read centrally according to the 
NASH CRN system by an experienced pathologist.  Digital slides will be created and read via 
artificial intelligence and the results of the readings will be added to the study database. 
 
Reporting of Adverse Events or Unanticipated Problems Involving Risk to Participants or 
Others 
 
Participation in this study may cause a loss of privacy.  To minimize this risk, all of the patient’s 
personal and medical data will be considered confidential to the extent allowed by law; every 
effort will be made to keep all of the information strictly confidential.  All study information will be 
stored in locked cabinets and on password-protected computers.  Only authorized personnel will 
have access to the samples, databases, and results.  Samples will be labeled with a code.  
When the study is published, no names or other identifying information will be used.   
 
While there are no direct risks from use of Velacur, patients may be uncomfortable lying on their 
back for a brief period of time.  They may experience soreness at the probe site.  There is a 
small risk of an allergic reaction to the gel utilized during the procedure.   
 
Patients will be closely monitored for any evidence of adverse events.  Any adverse events 
associated with the study will be documented and the IRB will be notified per reporting 
guidelines.   
 
Given this is a minimal risk study, no Data Safety and Monitoring Board (DSMB) will be required.   
 
 
 

 
 
  
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Study Withdrawal/Discontinuation 
 
Participants are free to withdraw from the study for any reason and at any time without giving a 
reason for doing so and without penalty or prejudice. The Investigator is also free to terminate a 
subject's involvement in the study at any time if the subject's clinical condition warrants it. 
 
Statistical Considerations 
 
Descriptive statistics such as mean, standard error, and percentages were used to characterize 
the cohort. Comparisons will be made between groups by using Student t test or analysis of 
variance. Pearson correlation coefficient will be used to detect the correlation between continuous 
variables. Multivariate analysis will be performed to examine the independent association 
between dependent and several independent variables. Sample size is based on clinical 
experience and precedent established for studies of similar design.  
 
Privacy/Confidentiality Issues 
 
Participation in this study may cause a loss of privacy.  To minimize this risk, all of the patient’s 
personal and medical data will be considered confidential to the extent allowed by law; every 
effort will be made to keep all of the information strictly confidential.  All study information will be 
stored in locked cabinets and on password-protected computers.  Only authorized personnel will 
have access to the samples, databases, and results.  Samples will be labeled with a code.  
When the study is published, no names or other identifying information will be used.   
 
Follow-up and Record Retention 
 
Use of Velacur is an additional tool for diagnostic purposes and provides physicians with 
additional clinical information to optimize patient care.  Participation in this study entails a one-
time visit.  No direct follow-up with participants is planned.   
Study records and documents will be maintained in accordance with federal, state, local, and 
university laws and guidelines. 
 
References 
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Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver 
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Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of 
nonalcoholic fatty liver disease: Practice guidance from the American Association for the 
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3. 
Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum 
of clinical and pathological severity. Gastroenterology 1999;116:1413-9. 
4. 
Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD 
and elevated liver enzymes. Hepatology 2006;44:865-73. 

 
 
  
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5. 
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Armstrong MJ, Hazlehurst JM, Parker R, et al. Severe asymptomatic non-alcoholic fatty 
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10. 
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11. 
Vuppalanchi R, Siddiqui MS, Van Natta ML, et al. Performance characteristics of vibration-
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Deeba F, Ma M, Pesteie M, et al. Attenuation Coefficient Estimation of Normal Placentas. 
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