Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03778411 |
| Other study ID # |
1804223843 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 1, 2020 |
| Est. completion date |
March 3, 2023 |
Study information
| Verified date |
April 2024 |
| Source |
Indiana University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Hypothesis: The severity of portal hypertension in compensated advanced chronic liver disease
(cACLD) can be assessed using vibration controlled transient elastography (VCTE) via the
FibroScan® 502 Touch by measuring SS (splenic stiffness) Specific Aims: SS by VCTE will be
measured 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 and 100 subjects who are post-liver transplant. The association between
baseline SS values will be examined in relation to the manifestations of portal hypertension
such as esophageal or gastric varices.
Specific Aim: To examine the relationship between SS and the presence of esophageal and
gastric varices in patients with compensated advanced chronic liver disease (cACLD).
Proposed Study Design: This is a cross sectional study that evaluates the relationship
between SS by VCTE in patients with cACLD and manifestations of portal hypertension.
Description:
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.
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. This classification depends on the
presence or absence of clinically evident decompensating events (specifically ascites,
variceal hemorrhage, and encephalopathy). The Child-Turcotte-Pugh (CTP) classification has
been used to stratify patients with cirrhosis. Patients with cirrhosis belonging to the CTP-A
class are compensated, whereas those in the CTP-B/C class are mostly decompensated.
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. 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 time frame is low.
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 sub-staged based on the severity of portal
hypertension. 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.The normal value of HVPG is between 3 and 5 mmHg.
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). 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.
However, measurement of HVPG is cumbersome, invasive, non-standardized and often limited to
tertiary care centers due to limited expertise. Therefore, there is a need for non-invasive
tools that can estimate HVPG easily, reproducibility and with high diagnostic accuracy.
Liver stiffness measurement (LSM) by vibration controlled transient elastography (VCTE) is
currently used for non-invasive diagnosis liver fibrosis in patients with NAFLD (non
alcoholic fatty liver) and NASH (non alcoholic steatohepatitis). In patients with cirrhosis,
LSM is likely indicative of cumulative stiffness from underlying liver fibrosis and portal
hypertension. Portal hypertension-related splenomegaly is frequently accompanied by patients
with cirrhosis due to portal venous congestion and hyperplasia of splenic tissue, and its
usefulness for diagnosis of portal hypertension has been studied. However, the direct
relationship between the size of the spleen and the severity of portal hypertension is still
under debate. Recent studies have focused on ultrasound-based measurement of spleen stiffness
(SS) as it is reflective of portal hypertension-related changes in the spleen, including
splenomegaly. Measurement of SS has also accurately predicted both the presence of varices
and the degree of portal hypertension. Spleen Stiffness (SS) by VCTE is an emerging tool for
assessment of portal hypertension and its feasibility has been reported both in adults and
children.
FibroScan is a diagnostic device based on VCTE. It measures a mean tissue stiffness (between
25 mm and 65 mm in the liver of non-obese patients) in a medium considered as homogeneous and
isotropic. FibroScan is equipped with a probe composed of an ultrasonic transducer (3.5 MHz
for non-obese patients) mounted on the axis of a vibrator. This vibrator generates a
low-frequency pulse (50 Hz and 2 mm peak-to-peak amplitude for LS measurement in non-obese
patients) that induces a shear wave that propagates through the tissue. Shear wave
propagation is followed by pulse-echo ultrasound and the strains induced in the tissue are
computed as a function of time and depth. Tissue stiffness E is deduced from the shear wave
speed (SWS or Vs) obtained by measuring the slope of the shear wave on the strain matrix
using a time-of-flight algorithm (E = 3ρVs² where ρ is the body mass of the tissue). In soft
tissues, the body mass is close to the one of water. A body mass ρ of 1,000 kg/m3 was used
for the density of the spleen. The ultrasound acquisition is performed between 20 mm and 80
mm below skin surface and the measurement is performed between 25 mm and 55 mm. The stiffness
of the spleen ranges between 5 kPa and 100 kPa. It is currently undergoing regulatory
approval as a diagnostic tool for non-invasive assessment of portal hypertension.
The natural history of NASH or other chronic liver disorders with advanced fibrosis/
cirrhosis across the different clinical stages of cirrhosis 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. Simultaneous assessment of LSM and SS
using VCTE may eventually allow for a noninvasive, immediate, objective and efficient method
for estimation of disease severity in patients with NASH cirrhosis. Moreover, assessment over
time of LSM and SS may also allow for assessment of disease progression or regression from
treatment interventions. It is anticipated that baseline measurements of SS/LSM and
longitudinal changes (ΔSS/Δt or ΔLSM/Δt) will serve as a prognostic tool in patients with
cACLD.
