Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT01747772 |
| Other study ID # |
2009P002791 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
October 31, 2012 |
| Last updated |
November 16, 2014 |
| Start date |
February 2010 |
| Est. completion date |
March 2015 |
Study information
| Verified date |
November 2014 |
| Source |
Massachusetts General Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
HYPOTHESIS: The investigators hypothesize that sonoelastography (SE) provide accurate
quantitative measurements that can be used to stage liver fibrosis in patients with chronic
liver disease.
1. To measure liver stiffness with sonoelastography in adults with suspect diffuse liver
disease who will undergo nonfocal liver biopsy as part of their routine clinical care.
2. To assess the sensitivity and specificity of sonoelastography for the detection and
staging of liver fibrosis
Description:
BACKGROUND Chronic liver disease is an important cause of morbidity and mortality in the
United States. A retrospective cohort study identified 2,353 patients with newly diagnosed
chronic liver disease (63.9 cases/100,000 population)1,2 Extrapolating this incidence rate
there will be approximately 150,000 patients with chronic liver disease diagnosed in
gastroenterology clinics each year 1. Almost 20%, or an estimated 30,000 patients per year,
had established cirrhosis at the time of presentation to the gastroenterologist 3.
Cirrhosis remains a major public health problem and disease-related complications were
associated with nearly 40,000 deaths and more than 1.4 billion dollars spent on medical
services in the US. There is a great need to develop and identify methods of risk
stratification and prognostication for patients with chronic liver disease 4 Hepatic
fibrosis is the final common pathway for many different liver insults and is now known to be
a dynamic process that is at least partially reversible. The diagnosis and quantification of
fibrosis relies on liver biopsy 5, and liver biopsy is currently the gold standard for
detecting and staging hepatic fibrosis 6. However, liver biopsy is an invasive procedure
with significant risks, including hemorrhage, infection and visceral perforation. In
addition, liver biopsy is a poor gold standard, because it is limited by interobserver
variability in interpretation and sampling errors in 25-45% of cases5,6, .
A number of indirect markers and indices of liver fibrosis have been used in clinical
practice. Noninvasive tests can be distinguished by direct vs. indirect measures of fibrosis
and also classified by the modality of the test as serum vs. imaging.7 Biomarkers of the
structural elements of fibrogenesis and the key inflammatory mediators involved in the
genesis or degradation of scar tissue are often referred to as direct components. Indirect
markers can reflect the accompanying alterations in hepatic function.
Fibrotic livers demonstrate increased stiffness. This property can be exploited and measured
using a newly developed ultrasound technology named Ultrasound Elastography (Transient
Elastography (TE) or sonoelastography (SE)8. SE is performed by insonating the patient with
a low energy, low amplitude, and low frequency shear wave created by focused ultrasound or
by a vibrating probe on the skin. The small tissue movements produced by the propagated wave
are then measured with ultrasound. The propagated wave travels faster with increasing
fibrosis: the stiffer the tissue, the faster the shear wave propagates.9 A pulse-echo
ultrasound acquisition allows measurement of the wave velocity and the results are presented
as kilopascals (kPa). Tissue elasticity is calculated as the median of 10 measurements and
ranges from 2.5 to 75 kPa with normal values around 5.5 kPa10 (Normal liver stiffness ranges
between 3.3-7.8 kPa)11 Hepatic stiffness can be measured within a cylinder of tissue 1 cm
wide and 4 cm in length producing an estimated sampling area that is 100 times greater than
a biopsy.12,13 A meta-analysis assessing the capacity of transient elastography to diagnose
moderate fibrosis found pooled estimates for sensitivity and specificity of 70% and 84%
respectively12,13. The mean AUROC for the diagnosis of significant fibrosis was 0.84% with a
optimal cut-off of 7.6 kPa, and the diagnostic accuracy of SE for cirrhosis had an AUROC
ranging from 0.90- 0.99 (mean AUROC 0.94) and cut-off from 9.0 to 26.5 kPa.14,15 The
benefits of SE are that it is inexpensive, reproducible, painless, rapid (< 10 min), easy to
perform, and can be used for diagnosis, prognosis and monitoring disease progression.15
Limitations of sonoelastography are that measurements cannot be obtained in the presence of
marked obesity, ascites, or unusually narrow intercostal spaces when externally applied
vibrating shear wave generators are used. 15,16
SPECIFIC AIMS
1. To evaluate liver stiffness with the diagnostic imaging method of sonoelastography
among adults with suspect liver diseases.
2. To obtain estimates of the sensitivity and specificity of sonoelastography for the
detection and staging of liver fibrosis.
STUDY PROCEDURES Study Visit 1: (SE or sonoelastography )
- Sonoelastography will be performed prior to standard pre-biopsy ultrasound imaging
using a FDA-approved ultrasound unit. This unit will use ultrasound energy within the
limits set by the FDA for diagnostic ultrasound to create a shear wave front that is
progressively distorted as it traverses the tissue. Ultrafast ultrasound imaging will
then be used to detect the speed of propagation of the shear wave front.
- The unit will emit no ionizing radiation and will perform ultrasound acquisition within
the acoustic power and intensity limits established by the
FDA for diagnostic sonography. At these energy levels there are no known bioeffects of
ultrasound. Sonoelastography measurements will require approximately 15 minutes, and will be
painless.
- The unit is a cart-based ultrasound system used to perform non-invasive diagnostic
ultrasound studies. The system functions in a manner identical to all diagnostic
ultrasound systems and transducers for the conventional modes: B-mode, Harmonic
imaging, Spatial Compounding imaging and Power Doppler. Additionally, the system uses a
new imaging mode based on shear wave elastography to map tissue stiffness. The
elastography mode produces color-coded images of different tissues based on their
elasticity. The color scale represents a quantitative assessment of tissue stiffness,
thereby allowing elasticity of tissue to be quantified in units of kilopascals (kPa).
- At the conclusion of Study Visit 1, the patient will return to usual care.
Tests and Parameters:
Sonoelastography parameters:
Mean liver stiffness (elastogram) in kilopascal (kPa). SE normal values approximately 5.5
kPa (Normal liver stiffness ranges between 3.3-7.8 kPa) Significant Fibrosis (F3): = or >
7.6 kPa, Cirrhosis (F4): = or > 9.0- 26 kPa
Data Collection
Data to be collected includes:
- Gender, ethnicity, Age, BMI, History of previous and current medication use, detail
history of alcohol intake, comorbidities, signs and symptoms.
- Biochemical liver tests that are typically performed as part of routine clinical care
(AST, ALT, APH, GGT, TB, IB, DB, Albumin, Total proteins, PT).
Other laboratory data typically performed as part of routine clinical care:
RBC, WBC, Platelets, Glucose, Creatinine, lipid profile. Any laboratory study for the
diagnosis of the suspected diffuse liver disease: Viral serology, including HCV, HBV,
Ferritin, ceruloplasmin, AMA, ANA, Alphafetoprotein.
Any liver histopathologic report.
- Sonoelastography report. TABLE 1: Measure parameters of grading fibrosis/cirrhosis between
the sonoelastography and Histology. 5,8, ,15. STATISTICAL ANALYSIS Fibrosis marker Fibrosis
Cirrhosis SonoElastography Normal liver stiffness ranges between 3.3-7.8 kPa Significant
Fibrosis (F3): 7.6 kPa
Cirrhosis (F4):
9.0- 26 kPa Histology (METAVIR) F0- No fibrosis F1- Portal fibrosis without septa F2- Portal
fibrosis with rare septa F3- Numerous septa without cirrhosis F4- Cirrhosis
Descriptive statistics will be shown as mean ± standard deviation or percentages as
appropriate. The patients will be divided according to fibrosis stage. The groups' binary
diagnostic by different diagnostic methods will be compared with the gold standard by
McNemar's Test. We will use contingency tables to analyze the correlation between
sonoelastographic measurements. Factors independently correlated with liver stiffness will
be assessed by multiple regression analysis. The diagnostic performance of fibrosis and/or
liver stiffness will be determined in terms of sensitivity, specificity, positive and
negative predictive values, diagnostic accuracy and area under receiver operating
characteristics (ROC) curves. This is a pilot study and the investigators are planning to
enroll 100 subjects to include in this study. With 100 patients included in this study the
investigators can have a > 80% power to detect a significant diagnostic power by
SonoElastography with a true AUC between of 0.85 as opposed to the null with an AUC of 0.62
or lower using a two-sided test with 5% type I error. In addition, multivariate linear and
logistic regression models will be used to evaluate the diagnostic power of independent
factors taking into account possible confounders by patient demographic and clinical
characteristics. The primary outcome of interest will be fibrosis.
RISKS AND DISCOMFORTS Ultrasound Elastography: Ultrasound elastography requires the
administration of ultrasound energy at levels similar to those used in diagnostic
ultrasonography. There are no known bioeffects of ultrasound at these energies.
Pregnant women are excluded from this study. There are no known risks of sonoelastography to
an embryo or fetus (a developing baby still in the womb). There may be risks to an embryo or
fetus that are currently unknown.
POTENTIAL BENEFITS Although knowledge about liver diseases and fibrosis has increased
dramatically over the last few years, much remains to be learned. The imaging strategy that
will be evaluated, ultrasound sonoelastography, has the potential to reduce the number of
liver biopsies performed for the diagnosis and monitoring of hepatic fibrosis. This study is
expected to provide a basis for future investigation into non-invasive imaging markers of
hepatic fibrosis. Any data obtained for the purposes of this study will be available to the
subject's primary physicians.
