Non-invasive Evaluation of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease by Liver Stiffness Measurement Using Liver Incytes
Phase: NA
Conditions: Portal Hypertension, Chronic Advanced Liver Disease
Sponsor: Indiana University

 
 
Gawrieh et al. 
August 5, 2021                                                                                                             - 1 - 
 
 
Protocol title: Non-invasive Evaluation of Portal 
Hypertension in Patients With Compensated 
Advanced Chronic Liver Disease by Liver Stiffness 
Measurement Using Liver Incytes 
 
PI: Samer Gawrieh, MD 
 
NCT04576897 
 
Document Date:  August 5, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Gawrieh et al. 
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Non-invasive Evaluation of Portal Hypertension in Patients with Compensated Advanced 
Chronic Liver Disease by Liver Stiffness Measurement Using Velacur  
 
Principal Investigator 
Samer Gawrieh, MD  
 
Co-Investigators  
Raj Vuppalanchi, MD 
Niha Samala, MD 
Naga Chalasani, MD 
Laura Corbito, PAC 
Lindsay Yoder, PAC 
Regina Weber, BS, RRT 
 
 
Division of Gastroenterology and Hepatology 
Indiana University School of Medicine 
Indianapolis, Indiana  
USA 
 
 
Address: 
702 Rotary Circle, Suite 225 
Indianapolis, IN 46202 
Email: sgawrieh@iu.edu 
Phone: 317-278-9326 
Fax: 317-278-1949 

 
 
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Study Design:  
 
Prospective Observational Study 
 
Number of Patients:  
200 patients with compensated cirrhosis 
 
 
 
 

 
 
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1. Introduction:  
For long, cirrhosis has been considered as end-stage liver disease but it is increasingly 
being realized that the 1-year mortality in cirrhosis varies widely, from 1% to 57%, depending on 
the occurrence of clinical decompensating events.1 Histopathologists have proposed that the 
histological term cirrhosis should be substituted by advanced liver disease, to underline the 
dynamic processes and variable prognosis of the disorder.2 A new term, compensated advanced 
chronic liver disease (cACLD) defining patients in the early phases of severe chronic liver 
disease, including both patients with severe fibrosis or pre-cirrhotic patients and patients with 
compensated cirrhosis is considered very helpful for both clinical practice and research 
purposes. Cirrhosis should no longer be regarded as a terminal disease and the concept of a 
dynamic process is increasingly accepted. A prognostic clinical subclassiﬁcation with four distinct 
stages has been proposed with substantially differing likelihoods of mortality (Figure 1). 
Currently, the management of patients with cACLD includes assessment for severity of 
portal hypertension and risk stratification. Cirrhosis is currently classiﬁed into two main prognostic 
stages: compensated and decompensated cirrhosis.1, 3  This classiﬁcation depends on the 
presence or absence of clinically evident decompensating events (speciﬁcally ascites, variceal 
hemorrhage, and encephalopathy), with a median survival in the compensated stage that exceeds 
12 years, while it is only 1.8 years in patients who develop decompensation (Figure).3   
 
 
Figure. Stages of compensated advanced chronic liver disease and liver-related clinical events 
 
 
The Child-Turcotte-Pugh (CTP) classiﬁcation has been used to stratify patients with 
cirrhosis.4 Patients with cirrhosis belonging to the CTP-A class are compensated, whereas those 
in the CTP-B/C class are mostly decompensated.4 Similarly, Model for End-Stage Liver Disease 
(MELD) is a reliable measure of mortality risk in patients with end-stage liver disease and used to 
help prioritize organ allocation for transplant.5, 6 However, MELD scores of <10, typically seen in 
CTP-A, are unlikely to have prognostic value as the likelihood of clinical events in a 1 to 2-year 

 
 
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time frame is low.1, 7, 8 Therefore, both CTP and MELD scores best stratify cirrhosis patients with 
decompensation and have limited use in compensated cirrhotics who have no liver-related 
symptoms.  
Patients with compensated cirrhosis are substaged based on the severity of portal 
hypertension (Figure 1).9  However, measurement of portal pressure through direct puncture of 
the portal vein is risky and not routinely performed. Therefore, portal pressure is assessed 
indirectly by calculation of hepatic vein pressure gradient (HVPG) by measuring the difference 
between wedge and free hepatic venous pressure.10-12 The normal value of HVPG is between 3 
and 5 mmHg.11, 12 Currently, the severity of portal hypertension is defined as mild when HVPG is 
≥6 but <10 mm Hg,  ≥10 mm Hg as clinically significant portal hypertension (CSPH), and ≥12 mm 
Hg as severe portal hypertension (SPH) .13   Evaluation of a compensated cirrhotic by HVPG is 
ideal for risk stratification as CSPH is associated with an increased risk of varices, 
decompensation (ascites, variceal hemorrhage and/or hepatic encephalopathy) and 
hepatocellular cancer.14-16  However, measurement of HVPG is cumbersome, invasive, non-
standardized and often limited to tertiary care centers due to limited expertise.17  Therefore, there 
is a need for non-invasive tools that can estimate HVPG easily, reproducibly and with high 
diagnostic accuracy. It is thus not a surprise that some investigators have examined the 
prognostic value of AST-to-Platelets Ratio Index (APRI) and fibrosis-4 (FIB-4) for prediction of 
adverse clinical outcomes related to portal hypertension.18, 19   
Liver stiffness measurement (LSM) by vibration controlled transient elastography (VCTE) 
is currently used for non-invasive diagnosis liver fibrosis in patients with chronic liver disease.  In 
patients with cirrhosis, LSM is likely indicative of cumulative stiffness from underlying liver fibrosis 
and portal hypertension. In addition, some studies have reported a good correlation between LSM 
and HVPG and its ability to detect CSPH.20, 21 In fact, in the recent Baveno conference (Baveno 
VI), a screening endoscopy was not recommended in patients with LSM <20 kilopascals (kPa) 
and platelet count >150,000/μl due to very low risk of having varices at high risk of bleeding.21, 22  
In one study that examined the prognostic accuracy of HVPG and serum fibrosis biomarkers, both 
measures worked equally well in predicting clinical outcomes.19   
 
FibroScan® is a commonly used diagnostic device based on VCTE.23, 24 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 
attenuation25 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 an 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 up to 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). 
 
The natural history of chronic liver disease with advanced fibrosis/ cirrhosis across the 
different clinical stages of cirrhosis (Figure) is currently not well understood. Therefore, non-
invasive tools that can assess the severity of cirrhosis and risk stratify prior to decompensation is 
currently an unmet need. The assessment of LSM using Velacur may eventually allow for a 
noninvasive, immediate, objective and efficient method for estimation of disease severity in 
patients with cirrhosis. Moreover, assessment over time of LSM may also allow for assessment 
of disease progression or regression from treatment interventions. We anticipate that baseline 
measurements of LSM and longitudinal changes (ΔLSM/Δt) will serve as a prognostic tool in 
patients with cACLD.   
 
Hypothesis: The severity of portal hypertension in compensated advanced chronic liver disease 
(cACLD) can be assessed measuring LSM by Velacur. 
 
Specific Aim 1: To examine the relationship between LSM by Velacur and the presence of 
esophageal or gastric varices and portal hypertensive gastropathy in patients with compensated 
Liver 
Incytes 
Probe
 

 
 
Gawrieh et al. 
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advanced chronic liver disease (cACLD). We will measure LSM by Velacur in this single center 
clinical study comprising of 200 patients with cACLD (deﬁned by LSM ≥10 kilopascals (kPa) 
according to the Baveno VI recommendations) who have not had a liver transplant.   
 
Specific Aim 2: Compare the performance of LSM by Velacur for predicting CSPH, esophageal 
and gastric varices to that of FibroScan® and other non-invasive markers such as MELD, CPT, 
platelets count, splenomegaly, APRI and FIB4. 
 
Proposed Study Design: This is a cross sectional study that evaluates the relationship between 
LSM by Velacur in patients with cACLD and manifestations of portal hypertension. 
 
Inclusion/Exclusion Criteria 
Inclusion criteria: 
1. Adults aged 18 years or older 
2. Ability to provide informed consent 
3. Diagnosis of cirrhosis based on liver biopsy, imaging, FibroScan®, or Hepatologist 
assessment.  
4. Planned or recommendation of one of the following:   
a. standard of care upper endoscopy to screen for varices within (+/-) 6 months of 
the Velacur study  
b. standard of care transjugular liver biopsy with portal pressure measurement within 
(+/-) 6 months of the Velacur study 
 
Exclusion criteria: 
1. Inability or refusal to provide informed consent 
2. Fasting for less than three hours prior to the scan 
3. Subject is a pregnant or lactating female 
4. Current, significant alcohol consumption 
5. Subject is unable to reliably quantify alcohol consumption based upon local study 
physician judgment  
6. Patients with a pacemaker or defibrillator 
7. Acute hepatitis defined as AST/ALT > 500 U/L 
8. Ascites  
 

 
 
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Screening and Enrollment 
 
Up to 200 patients with cACLD who have not undergone liver transplantation who are seen in the 
liver clinics at IUH-Digestive and Liver Disorder Clinics and at Springmill Clinic will be enrolled 
into this prospective cross sectional study after obtaining informed consent. Standard inclusion 
and exclusion criteria for Velacur will be used. Patients who meet the inclusion criteria will be 
offered the opportunity to undergo additional testing with Velacur to measure LSM after informed 
consent. In addition to history and physical, we will capture pre-specified liver related findings 
using standardized case report forms. Participants will be enrolled over a 24 month period.   
 
Study Procedures 
 
At Enrollment: After subject identification, an informed consent will be obtained. All patients have 
to be fasting for at least three hours prior to performance of the study. Velacur exam will be 
performed by a Velacur certified technician.  Duration of participation for the subject should be no 
more than one hour. Medical information from the subjects, including results of the scans, 
historical laboratory and diagnostic testing data will be obtained from medical records and will be 
entered into a database. Laboratory data for calculating non-invasive markers such as MELD, 
CPT, platelets count, splenomegaly, APRI and FIB4 will be collected from standard of care labs 
done within 6 months of the endoscopy or portal pressure measurement by transjugular liver 
biopsy. 
 
 
Reporting of Adverse Events or Unanticipated Problems Involving Risk to Participants or 
Others 
 
The Division of Gastroenterology/Hepatology at IUSM has considerable experience in the conduct 
of clinical studies.    
 
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 

 
 
Gawrieh et al. 
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access to the samples, databases, and results. 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.   
 
Study Withdrawal/Discontinuation 
The subject is 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. The diagnostic accuracy of LSM will be 
calculated using area under the receiver operator curve analysis. 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 

 
 
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Use of Velacur is an additional tool for diagnostic purposes and provides physicians with 
additional clinical information to optimize patient care.  No direct follow-up with participants is 
planned.  However, the patients may be approached for repeat study and with informed consent 
may be enrolled again to measure any changes in the LSM and SS that may occur over time. 
Study records and documents will be maintained in accordance with federal, state, and university 
laws. 
 

 
 
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References: 
 
1. 
D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival 
in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217-31. 
2. 
Hytiroglou P, Snover DC, Alves V, et al. Beyond "cirrhosis": a proposal from the 
International Liver Pathology Study Group. Am J Clin Pathol 2012;137:5-9. 
3. 
D'Amico G, Morabito A, D'Amico M, et al. New concepts on the clinical course and 
stratification of compensated and decompensated cirrhosis. Hepatol Int 2017. 
4. 
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the 
liver transplant waiting list: a report of a national conference organized by the American 
Society of Transplant Physicians and the American Association for the Study of Liver 
Diseases. Liver Transpl Surg 1997;3:628-37. 
5. 
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the 
liver transplant waiting list: a report of a national conference organized by the American 
Society of Transplant Physicians and the American Association for the Study of Liver 
Diseases. Transplantation 1998;66:956-62. 
6. 
Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with 
end-stage liver disease. Hepatology 2001;33:464-70. 
7. 
Atiemo K, Skaro A, Maddur H, et al. Mortality Risk Factors Among Patients With Cirrhosis 
and a Low Model for End-Stage Liver Disease Sodium Score (</=15): An Analysis of Liver 
Transplant Allocation Policy Using Aggregated Electronic Health Record Data. Am J 
Transplant 2017;17:2410-2419. 
8. 
Leise MD, Kim WR, Kremers WK, et al. A revised model for end-stage liver disease 
optimizes prediction of mortality among patients awaiting liver transplantation. 
Gastroenterology 2011;140:1952-60. 
9. 
Albilllos A, Garcia-Tsao G. Classification of cirrhosis: the clinical use of HVPG 
measurements. Dis Markers 2011;31:121-8. 
10. 
Wongcharatrawee S, Groszmann RJ. Diagnosing portal hypertension. Baillieres Best 
Pract Res Clin Gastroenterol 2000;14:881-94. 
11. 
Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything 
worth doing should be done right. Hepatology 2004;39:280-2. 
12. 
Boyer TD. Wedged hepatic vein pressure (WHVP): ready for prime time. Hepatology 
2006;43:405-6. 
13. 
Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal hypertensive bleeding in cirrhosis: 
Risk stratification, diagnosis, and management: 2016 practice guidance by the American 
Association for the study of liver diseases. Hepatology 2017;65:310-335. 
14. 
Blasco A, Forns X, Carrion JA, et al. Hepatic venous pressure gradient identifies patients 
at risk of severe hepatitis C recurrence after liver transplantation. Hepatology 
2006;43:492-9. 
15. 
Ripoll C, Groszmann RJ, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts 
development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol 
2009;50:923-8. 
16. 
Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts 
clinical decompensation in patients with compensated cirrhosis. Gastroenterology 
2007;133:481-8. 
17. 
Silva-Junior G, Baiges A, Turon F, et al. The prognostic value of hepatic venous pressure 
gradient in patients with cirrhosis is highly dependent on the accuracy of the technique. 
Hepatology 2015;62:1584-92. 
18. 
Natsuda K, Takatsuki M, Tanaka T, et al. Aspartate transaminase-platelet ratio and 
Fibrosis-4 indices as effective markers for monitoring esophageal varices in HIV/hepatitis 

 
 
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C virus co-infected patients due to contaminated blood products for hemophilia. Hepatol 
Res 2017;47:1282-1288. 
19. 
Sebastiani G, Alshaalan R, Wong P, et al. Prognostic Value of Non-Invasive Fibrosis and 
Steatosis Tools, Hepatic Venous Pressure Gradient (HVPG) and Histology in 
Nonalcoholic Steatohepatitis. PLoS One 2015;10:e0128774. 
20. 
Abraldes JG, Bureau C, Stefanescu H, et al. Noninvasive tools and risk of clinically 
significant portal hypertension and varices in compensated cirrhosis: The "Anticipate" 
study. Hepatology 2016;64:2173-2184. 
21. 
Maurice JB, Brodkin E, Arnold F, et al. Validation of the Baveno VI criteria to identify low 
risk cirrhotic patients not requiring endoscopic surveillance for varices. J Hepatol 
2016;65:899-905. 
22. 
de Franchis R. Expanding consensus in portal hypertension: Report of the Baveno VI 
Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J 
Hepatol 2015;63:743-52. 
23. 
Mueller S, Sandrin L. Liver stiffness: a novel parameter for the diagnosis of liver disease. 
Hepat Med 2010;2:49-67. 
24. 
Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive 
method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705-13. 
25. 
Deeba F, Ma M, Pesteie M, et al. Attenuation Coefficient Estimation of Normal Placentas. 
Ultrasound Med Biol 2019;45:1081-1093.