<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03778411</url>
  </required_header>
  <id_info>
    <org_study_id>1804223843</org_study_id>
    <nct_id>NCT03778411</nct_id>
  </id_info>
  <brief_title>Non-invasive Evaluation of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease by Assessment of Spleen Stiffness Using Vibration Controlled Transient Elastography</brief_title>
  <official_title>Non-invasive Evaluation of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease by Assessment of Spleen Stiffness Using Vibration Controlled Transient Elastography</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Indiana University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Echosens</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Indiana University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypothesis: The severity of portal hypertension in compensated advanced chronic liver disease&#xD;
      (cACLD) can be assessed using vibration controlled transient elastography (VCTE) via the&#xD;
      FibroScan® 502 Touch by measuring SS (splenic stiffness) Specific Aims: SS by VCTE will be&#xD;
      measured in this single center clinical study comprising of 200 patients with cACLD (deﬁned&#xD;
      by LSM ≥10 kilopascals (kPa) according to the Baveno VI recommendations) who have not had a&#xD;
      liver transplant and 100 subjects who are post-liver transplant. The association between&#xD;
      baseline SS values will be examined in relation to the manifestations of portal hypertension&#xD;
      such as esophageal or gastric varices.&#xD;
&#xD;
      Specific Aim: To examine the relationship between SS and the presence of esophageal and&#xD;
      gastric varices in patients with compensated advanced chronic liver disease (cACLD).&#xD;
&#xD;
      Proposed Study Design: This is a cross sectional study that evaluates the relationship&#xD;
      between SS by VCTE in patients with cACLD and manifestations of portal hypertension.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A new term, compensated advanced chronic liver disease (cACLD) defining patients in the early&#xD;
      phases of severe chronic liver disease, including both patients with severe fibrosis or&#xD;
      pre-cirrhotic patients and patients with compensated cirrhosis is considered very helpful for&#xD;
      both clinical practice and research purposes. Cirrhosis should no longer be regarded as a&#xD;
      terminal disease and the concept of a dynamic process is increasingly accepted.&#xD;
&#xD;
      Currently, the management of patients with cACLD includes assessment for severity of portal&#xD;
      hypertension and risk stratification. Cirrhosis is currently classiﬁed into two main&#xD;
      prognostic stages: compensated and decompensated cirrhosis. This classiﬁcation depends on the&#xD;
      presence or absence of clinically evident decompensating events (speciﬁcally ascites,&#xD;
      variceal hemorrhage, and encephalopathy). The Child-Turcotte-Pugh (CTP) classiﬁcation has&#xD;
      been used to stratify patients with cirrhosis. Patients with cirrhosis belonging to the CTP-A&#xD;
      class are compensated, whereas those in the CTP-B/C class are mostly decompensated.&#xD;
      Similarly, Model for End-Stage Liver Disease (MELD) is a reliable measure of mortality risk&#xD;
      in patients with end-stage liver disease and used to help prioritize organ allocation for&#xD;
      transplant. However, MELD scores of &lt;10, typically seen in CTP-A, are unlikely to have&#xD;
      prognostic value as the likelihood of clinical events in a 1 to 2-year time frame is low.&#xD;
      Therefore, both CTP and MELD scores best stratify cirrhosis patients with decompensation and&#xD;
      have limited use in compensated cirrhotics who have no liver-related symptoms.&#xD;
&#xD;
      Patients with compensated cirrhosis are sub-staged based on the severity of portal&#xD;
      hypertension. However, measurement of portal pressure through direct puncture of the portal&#xD;
      vein is risky and not routinely performed. Therefore, portal pressure is assessed indirectly&#xD;
      by calculation of hepatic vein pressure gradient (HVPG) by measuring the difference between&#xD;
      wedge and free hepatic venous pressure.The normal value of HVPG is between 3 and 5 mmHg.&#xD;
      Currently, the severity of portal hypertension is defined as mild when HVPG is 6 but &lt;10 mm&#xD;
      Hg, ≥10 mm Hg as clinically significant portal hypertension (CSPH), and ≥12 mm Hg as severe&#xD;
      portal hypertension (SPH). Evaluation of a compensated cirrhotic by HVPG is ideal for risk&#xD;
      stratification as CSPH is associated with an increased risk of varices, decompensation&#xD;
      (ascites, variceal hemorrhage and/or hepatic encephalopathy) and hepatocellular cancer.&#xD;
      However, measurement of HVPG is cumbersome, invasive, non-standardized and often limited to&#xD;
      tertiary care centers due to limited expertise. Therefore, there is a need for non-invasive&#xD;
      tools that can estimate HVPG easily, reproducibility and with high diagnostic accuracy.&#xD;
&#xD;
      Liver stiffness measurement (LSM) by vibration controlled transient elastography (VCTE) is&#xD;
      currently used for non-invasive diagnosis liver fibrosis in patients with NAFLD (non&#xD;
      alcoholic fatty liver) and NASH (non alcoholic steatohepatitis). In patients with cirrhosis,&#xD;
      LSM is likely indicative of cumulative stiffness from underlying liver fibrosis and portal&#xD;
      hypertension. Portal hypertension-related splenomegaly is frequently accompanied by patients&#xD;
      with cirrhosis due to portal venous congestion and hyperplasia of splenic tissue, and its&#xD;
      usefulness for diagnosis of portal hypertension has been studied. However, the direct&#xD;
      relationship between the size of the spleen and the severity of portal hypertension is still&#xD;
      under debate. Recent studies have focused on ultrasound-based measurement of spleen stiffness&#xD;
      (SS) as it is reflective of portal hypertension-related changes in the spleen, including&#xD;
      splenomegaly. Measurement of SS has also accurately predicted both the presence of varices&#xD;
      and the degree of portal hypertension. Spleen Stiffness (SS) by VCTE is an emerging tool for&#xD;
      assessment of portal hypertension and its feasibility has been reported both in adults and&#xD;
      children.&#xD;
&#xD;
      FibroScan is a diagnostic device based on VCTE. It measures a mean tissue stiffness (between&#xD;
      25 mm and 65 mm in the liver of non-obese patients) in a medium considered as homogeneous and&#xD;
      isotropic. FibroScan is equipped with a probe composed of an ultrasonic transducer (3.5 MHz&#xD;
      for non-obese patients) mounted on the axis of a vibrator. This vibrator generates a&#xD;
      low-frequency pulse (50 Hz and 2 mm peak-to-peak amplitude for LS measurement in non-obese&#xD;
      patients) that induces a shear wave that propagates through the tissue. Shear wave&#xD;
      propagation is followed by pulse-echo ultrasound and the strains induced in the tissue are&#xD;
      computed as a function of time and depth. Tissue stiffness E is deduced from the shear wave&#xD;
      speed (SWS or Vs) obtained by measuring the slope of the shear wave on the strain matrix&#xD;
      using a time-of-flight algorithm (E = 3ρVs² where ρ is the body mass of the tissue). In soft&#xD;
      tissues, the body mass is close to the one of water. A body mass ρ of 1,000 kg/m3 was used&#xD;
      for the density of the spleen. The ultrasound acquisition is performed between 20 mm and 80&#xD;
      mm below skin surface and the measurement is performed between 25 mm and 55 mm. The stiffness&#xD;
      of the spleen ranges between 5 kPa and 100 kPa. It is currently undergoing regulatory&#xD;
      approval as a diagnostic tool for non-invasive assessment of portal hypertension.&#xD;
&#xD;
      The natural history of NASH or other chronic liver disorders with advanced fibrosis/&#xD;
      cirrhosis across the different clinical stages of cirrhosis is currently not well understood.&#xD;
      Therefore, non-invasive tools that can assess the severity of cirrhosis and risk stratify&#xD;
      prior to decompensation is currently an unmet need. Simultaneous assessment of LSM and SS&#xD;
      using VCTE may eventually allow for a noninvasive, immediate, objective and efficient method&#xD;
      for estimation of disease severity in patients with NASH cirrhosis. Moreover, assessment over&#xD;
      time of LSM and SS may also allow for assessment of disease progression or regression from&#xD;
      treatment interventions. It is anticipated that baseline measurements of SS/LSM and&#xD;
      longitudinal changes (ΔSS/Δt or ΔLSM/Δt) will serve as a prognostic tool in patients with&#xD;
      cACLD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 1, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Risks of decompensation</measure>
    <time_frame>Two years</time_frame>
    <description>The relationship between splenic stiffness (SS) and the presence of esophageal and gastric varices in patients with compensated advanced chronic liver disease (cACLD) will be measured with VCTE by the CAP score.&#xD;
CAP is measured in dB/M, with a score range from 100-400. A score of 225 or less is considered to indicate a normal amount of fat in the liver. As the score increases, the amount of steatosis (fat) in the liver is also thought to be elevated.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Risks of decomposition</measure>
    <time_frame>Two years</time_frame>
    <description>The relationship between splenic stiffness (SS) and the presence of esophageal and gastric varices in patients with compensated advanced chronic liver disease (cACLD) will be measured with VCTE with splenic stiffness score.&#xD;
VCTE is measured in units of kPA with a score range from 0-75. An increased number is generally associated with a higher level of liver scarring, but the ranges are based on the underlying liver disease.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">300</enrollment>
  <condition>Advanced Chronic Liver Disease, NASH</condition>
  <arm_group>
    <arm_group_label>cACLD</arm_group_label>
    <description>200 people with compensated advanced chronic liver disease who have not undergone liver transplant</description>
  </arm_group>
  <arm_group>
    <arm_group_label>cACLD-post transplant</arm_group_label>
    <description>100 people with compensated advanced chronic liver disease who have previously undergone liver transplant</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>VCTE with splenic stiffness measurement</intervention_name>
    <description>Subjects will undergo vibration controlled transient elastography to measure liver stiffness (LSM) liver steatosis via controlled attenuation parameter (CAP) and splenic stiffness</description>
    <arm_group_label>cACLD</arm_group_label>
    <arm_group_label>cACLD-post transplant</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        200 patients with compensated advanced chronic liver disease (deﬁned by LSM ≥10 kilopascals&#xD;
        (kPa) who have not had a liver transplant and 100 subjects with compensated advanced&#xD;
        chronic liver disease who are post-liver transplant.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adults aged 18 years or older&#xD;
&#xD;
          2. Ability to provide informed consent&#xD;
&#xD;
          3. Previous Fibroscan with LSM ≥10 kilopascals (kPa)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Inability or refusal to provide informed consent&#xD;
&#xD;
          2. Fasting for less than three hours prior to the scan&#xD;
&#xD;
          3. Subject is a pregnant or lactating female&#xD;
&#xD;
          4. Subject with current, significant alcohol consumption&#xD;
&#xD;
          5. Subject is unable to reliably quantify alcohol consumption based upon local study&#xD;
             physician judgment&#xD;
&#xD;
          6. Patients with a pacemaker or defibrillator&#xD;
&#xD;
          7. Acute hepatitis defined as AST/ALT &gt; 500 U/L&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Raj Vuppalanchi, MD</last_name>
    <phone>317-278-1664</phone>
    <email>rvuppala@iu.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Regina Weber, BS, RRT</last_name>
    <phone>317-278-3584</phone>
    <email>reginaw@iu.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Indiana University School of Medicine</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Raj Vuppalanchi, MD</last_name>
      <phone>317-278-3584</phone>
      <email>rvuppala@iu.edu</email>
    </contact>
    <contact_backup>
      <last_name>Regina Weber, BS, RRT</last_name>
      <phone>317-278-3584</phone>
      <email>reginaw@iu.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>August 30, 2018</study_first_submitted>
  <study_first_submitted_qc>December 14, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>November 22, 2022</last_update_submitted>
  <last_update_submitted_qc>November 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Indiana University</investigator_affiliation>
    <investigator_full_name>Raj Vuppalanchi</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Hypertension, Portal</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03778411
org study id: 1804223843
nct id: NCT03778411
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is us export: No
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.
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.
observational model: Case-Only
time perspective: Cross-Sectional
measure: Risks of decompensation
time frame: Two years
description: The relationship between splenic stiffness (SS) and the presence of esophageal and gastric varices in patients with compensated advanced chronic liver disease (cACLD) will be measured with VCTE by the CAP score.
CAP is measured in dB/M, with a score range from 100-400. A score of 225 or less is considered to indicate a normal amount of fat in the liver. As the score increases, the amount of steatosis (fat) in the liver is also thought to be elevated.
measure: Risks of decomposition
time frame: Two years
description: The relationship between splenic stiffness (SS) and the presence of esophageal and gastric varices in patients with compensated advanced chronic liver disease (cACLD) will be measured with VCTE with splenic stiffness score.
VCTE is measured in units of kPA with a score range from 0-75. An increased number is generally associated with a higher level of liver scarring, but the ranges are based on the underlying liver disease.
arm group label: cACLD
description: 200 people with compensated advanced chronic liver disease who have not undergone liver transplant
arm group label: cACLD-post transplant
description: 100 people with compensated advanced chronic liver disease who have previously undergone liver transplant
intervention type: Device
intervention name: VCTE with splenic stiffness measurement
description: Subjects will undergo vibration controlled transient elastography to measure liver stiffness (LSM) liver steatosis via controlled attenuation parameter (CAP) and splenic stiffness
arm group label: cACLD
arm group label: cACLD-post transplant
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Raj Vuppalanchi, MD
phone: 317-278-1664
email: rvuppala@iu.edu
last name: Regina Weber, BS, RRT
phone: 317-278-3584
email: reginaw@iu.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Indiana University
investigator full name: Raj Vuppalanchi
investigator title: Associate Professor of Medicine
mesh term: Liver Diseases
mesh term: Hypertension, Portal
mesh term: Hypertension
sharing ipd: No