<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/NCT03756051</url>
  </required_header>
  <id_info>
    <org_study_id>STU 102016-012</org_study_id>
    <secondary_id>R01CA212008</secondary_id>
    <nct_id>NCT03756051</nct_id>
  </id_info>
  <brief_title>Harms of Hepatocellular Carcinoma Surveillance</brief_title>
  <official_title>Harms of Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Texas Southwestern Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Parkland Health and Hospital System</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Michael E. DeBakey VA Medical Center</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kaiser Permanente</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Texas Southwestern Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study leverage a multi-center randomized controlled trial assessing screening-related&#xD;
      benefits (i.e. early tumor detection, treatment eligibility, and overall survival) among a&#xD;
      racially and socioeconomically diverse population of patients with cirrhosis. However, the&#xD;
      randomized controlled trial was not budgeted to assess hepatocellular carcinoma&#xD;
      screening-related harms. The goal of this study is to quantify physical, financial, and&#xD;
      psychosocial harms across three healthcare settings.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Leveraging a multi-center randomized controlled trial assessing screening benefits in a&#xD;
      socioeconomically and racially diverse population of patients with cirrhosis followed in 3&#xD;
      healthcare settings over a 4-year period, this study aims to:&#xD;
&#xD;
      Aim 1: Assess the effect of hepatocellular carcinoma screening on a) physical harms due to&#xD;
      follow-up tests, b) financial harms, and c) overdiagnosis in patients with severe liver&#xD;
      dysfunction or comorbid illness, through electronic medical record data, manual chart review,&#xD;
      and validated survey measures.&#xD;
&#xD;
      Aim 2: Assess the effect of hepatocellular carcinoma screening on screening-related&#xD;
      psychosocial harms, e.g. cancer-specific worry, situational anxiety, mood disturbances, and&#xD;
      decisional regret, through longitudinal validated measures and qualitative interviews.&#xD;
&#xD;
      Aim 3: Create and disseminate a balance sheet of benefits and harms to inform patients,&#xD;
      providers, healthcare organizations, payers, and policymakers about the value of&#xD;
      hepatocellular carcinoma screening in patients with cirrhosis.&#xD;
&#xD;
      Over a 4-year period, electronic medical record data will be used to compare&#xD;
      screening-related physical and financial harms between patients undergoing and those not&#xD;
      undergoing hepatocellular carcinoma screening. Psychosocial harms, as ascertained through&#xD;
      longitudinal measurement of validated survey instruments and qualitative interviews, will be&#xD;
      compared between patients with positive or indeterminate screening results and those with&#xD;
      negative results or without any screening. Mixed-effect regression analysis will be used to&#xD;
      determine if screening harms differed by factors at multiple levels including patient (e.g.&#xD;
      degree of liver dysfunction), provider (e.g. subspecialty training), and healthcare&#xD;
      organization (e.g. access to liver transplantation). This study will seamlessly complement&#xD;
      data from the parent randomized controlled trial. By immediately translating these high&#xD;
      quality data about hepatocellular carcinoma screening benefits and harms into a balance&#xD;
      sheet, the investigators will facilitate patient-provider discussions, inform payer decisions&#xD;
      about reimbursement, and guide policy decisions. These data are also crucial to identify&#xD;
      modifiable and high-yield intervention targets and strategies to reduce hepatocellular&#xD;
      carcinoma screening harms in the future.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 1, 2018</start_date>
  <completion_date type="Anticipated">July 31, 2023</completion_date>
  <primary_completion_date type="Actual">June 30, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Physical Harms</measure>
    <time_frame>4 Years</time_frame>
    <description>Physical harms (contrast injury, radiation exposure, and biopsy complications) can result from screening or follow-up testing and extends beyond medical complications to include discomfort. A binary outcome (harm vs. no harm) will be defined for each person and each type of physical harm (contrast injury, radiation exposure, biopsy, and any physical harm). We will report the point estimate and 95% confidence interval for the proportion of patients with each type of harm in each arm, stratified by health system. Using an intention-to-treat principle, we will use Chi squared test to compare the proportion of patients with physical harms between the screening and usual care arms, with a secondary analysis stratified by health system. We will also perform a sensitivity analysis based on test intent, in which we will only include tests (and corresponding harms) performed as a direct result of hepatocellular carcinoma screening.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Financial Harms</measure>
    <time_frame>4 Years</time_frame>
    <description>Financial harms may include anticipated or real costs of hepatocellular carcinoma screening and diagnostic evaluation including, indirect costs such as missed work, and opportunity costs such as distraction from other health-related activities. Financial harms will be summarized for each arm using descriptive analyses as average and range of costs per person. Degree of financial harms will be compared between the hepatocellular carcinoma screening and usual care arms using Student T test, with a secondary analysis stratified by health system. In a secondary analysis, a mixed-effect model approach will be employed to identify patient-, provider- and system-level factors associated with financial harm.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overdiagnosis</measure>
    <time_frame>4 Years</time_frame>
    <description>Defined as hepatocellular carcinoma diagnoses that are unlikely to have an effect on mortality, specifically among patients with: 1) significant comorbid conditions or 2) severe liver dysfunction, i.e. Child Pugh C cirrhosis, who are not candidates for liver transplantation, at hepatocellular carcinoma diagnosis. For the primary analysis, Chi squared test will be used to compare the proportion of patients with overdiagnosis between the screening arm and usual care arm, stratified by health system.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Psychosocial Harms</measure>
    <time_frame>4 Years</time_frame>
    <description>Patients will be divided into 4 categories: true positives, false positives, true negatives, and no screening. True positives will be defined as those who develop hepatocellular carcinoma within 6 months of the screening test; false positives as those who remain without hepatocellular carcinoma diagnosis during 6 months of follow-up; and true negatives as those with normal screening tests and without hepatocellular carcinoma diagnosis during 6 months of follow-up. Psychosocial harms (cancer-specific worry, situational anxiety, mood disturbances, and decisional regret) will be defined by change in survey scores from baseline and will be calculated at 1 month and 6 months for each patient.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Patient-, Provider-, and System-level Factors Associated with Physical Harms</measure>
    <time_frame>4 Years</time_frame>
    <description>As a secondary analysis, we will construct mixed-effect logistic regression models to identify patient-, provider-, and system-level factors associated with physical harms (contrast injury, radiation exposure, biopsy, and any physical harm). Models will include random effects for providers and health systems to account for potential correlation at different levels. Final models will include covariates identified by stepwise variable selection procedure and those considered clinically important a priori (BMI, race, liver dysfunction, and gastroenterology care). Statistical significance will be declared for p&lt;0.05.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-, Provider-, and System-level Factors Associated with Psychosocial Harms</measure>
    <time_frame>4 Years</time_frame>
    <description>We will construct a mixed regression model with the outcome being decisional regret and covariates including patient-, provider- and system-level factors. Decisional regret score, ranging from 0 to 100, will be analyzed as a continuous outcome. The mixed model will include random effects for providers and systems to account for correlation at different levels. The model will include covariates identified through stepwise variable selection and those considered clinically important a priori (age, gender, race and ethnicity, liver dysfunction).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical Harms</measure>
    <time_frame>12 Months</time_frame>
    <description>Physical harms (contrast injury, radiation exposure, and biopsy complications) can result from screening or follow-up testing and extends beyond medical complications to include discomfort.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">2871</enrollment>
  <condition>Carcinoma, Hepatocellular</condition>
  <arm_group>
    <arm_group_label>Cohort</arm_group_label>
    <description>This study will collect prospective longitudinal data to characterize rates and identify correlates of a) physical harms due to follow-up tests, b) financial harms, and c) inappropriate screening using electronic medical record data and manual chart review. The study will also use surveys and semi-structured interviews to characterize rates and identify correlates of screening-related psychological harms, e.g. cancer specific worry, situational anxiety, mood disturbances, and decisional regret. Lastly, investigators will create and disseminate a balance sheet of benefits and harms to inform patients, providers, healthcare organizations, payers, and policymakers about the role of hepatocellular carcinoma screening in patients with cirrhosis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Prospective Longitudinal Data</intervention_name>
    <description>We will prospectively follow the cohort using electronic medical record to document the hepatocellular carcinoma screening process and characterize physical and financial harms related to positive or indeterminate screening results and burden of inappropriate screening. Patients are anticipated to undergo hepatocellular carcinoma screening every 6-12 months, so each patient will have ~4-8 screening encounters over the study duration. We will use manual chart review to determine intent of ultrasound exams (screening vs. diagnostic) and test results. Receipt of follow-up tests after positive or indeterminate screening results will be identified through electronic medical record extraction using Current Procedural Terminology (CPT) codes for CT, MRI, and biopsy.</description>
    <arm_group_label>Cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Surveys and Semi-structured Interviews</intervention_name>
    <description>We will use surveys and semi-structured interviews to characterize psychological harms after positive or indeterminate screening tests. Patient surveys will include patient-reported scales to measure psychosocial factors at three times points: baseline, 1 month after screening result, and 4 months after screening result. Semi-structured interviews will be conducted via telephone to explore patient attitudes toward risk perception, test follow-up, competing demands, and &quot;downstream harms&quot;, particularly financial issues (e.g., out-of-pocket costs, access to insurance, and juggling hepatocellular carcinoma screening process completion with competing demands-work and family).</description>
    <arm_group_label>Cohort</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        All patients from the parent randomized controlled trial will be included in this study.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion and exclusion criteria of the parent randomized controlled trial are as follows:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients (≥ 21 years old)&#xD;
&#xD;
          -  Cirrhosis&#xD;
&#xD;
          -  Outpatient visit in year prior to randomization&#xD;
&#xD;
          -  English or Spanish speaking&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of hepatocellular carcinoma&#xD;
&#xD;
          -  History of liver transplantation&#xD;
&#xD;
          -  Child Pugh C cirrhosis&#xD;
&#xD;
          -  Significant comorbid conditions with life expectancy &lt; 1 year, (e.g., extrahepatic&#xD;
             malignancy)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Amit Singal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Texas Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>November 26, 2018</study_first_submitted>
  <study_first_submitted_qc>November 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 28, 2018</study_first_posted>
  <last_update_submitted>November 30, 2022</last_update_submitted>
  <last_update_submitted_qc>November 30, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Texas Southwestern Medical Center</investigator_affiliation>
    <investigator_full_name>Amit Singal</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Physical Harms</keyword>
  <keyword>Financial Harms</keyword>
  <keyword>Overdiagnosis</keyword>
  <keyword>Psychosocial Harms</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</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/NCT03756051
org study id: STU 102016-012
secondary id: R01CA212008
nct id: NCT03756051
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study leverage a multi-center randomized controlled trial assessing screening-related
      benefits (i.e. early tumor detection, treatment eligibility, and overall survival) among a
      racially and socioeconomically diverse population of patients with cirrhosis. However, the
      randomized controlled trial was not budgeted to assess hepatocellular carcinoma
      screening-related harms. The goal of this study is to quantify physical, financial, and
      psychosocial harms across three healthcare settings.
Leveraging a multi-center randomized controlled trial assessing screening benefits in a
      socioeconomically and racially diverse population of patients with cirrhosis followed in 3
      healthcare settings over a 4-year period, this study aims to:

      Aim 1: Assess the effect of hepatocellular carcinoma screening on a) physical harms due to
      follow-up tests, b) financial harms, and c) overdiagnosis in patients with severe liver
      dysfunction or comorbid illness, through electronic medical record data, manual chart review,
      and validated survey measures.

      Aim 2: Assess the effect of hepatocellular carcinoma screening on screening-related
      psychosocial harms, e.g. cancer-specific worry, situational anxiety, mood disturbances, and
      decisional regret, through longitudinal validated measures and qualitative interviews.

      Aim 3: Create and disseminate a balance sheet of benefits and harms to inform patients,
      providers, healthcare organizations, payers, and policymakers about the value of
      hepatocellular carcinoma screening in patients with cirrhosis.

      Over a 4-year period, electronic medical record data will be used to compare
      screening-related physical and financial harms between patients undergoing and those not
      undergoing hepatocellular carcinoma screening. Psychosocial harms, as ascertained through
      longitudinal measurement of validated survey instruments and qualitative interviews, will be
      compared between patients with positive or indeterminate screening results and those with
      negative results or without any screening. Mixed-effect regression analysis will be used to
      determine if screening harms differed by factors at multiple levels including patient (e.g.
      degree of liver dysfunction), provider (e.g. subspecialty training), and healthcare
      organization (e.g. access to liver transplantation). This study will seamlessly complement
      data from the parent randomized controlled trial. By immediately translating these high
      quality data about hepatocellular carcinoma screening benefits and harms into a balance
      sheet, the investigators will facilitate patient-provider discussions, inform payer decisions
      about reimbursement, and guide policy decisions. These data are also crucial to identify
      modifiable and high-yield intervention targets and strategies to reduce hepatocellular
      carcinoma screening harms in the future.
observational model: Cohort
time perspective: Prospective
measure: Physical Harms
time frame: 4 Years
description: Physical harms (contrast injury, radiation exposure, and biopsy complications) can result from screening or follow-up testing and extends beyond medical complications to include discomfort. A binary outcome (harm vs. no harm) will be defined for each person and each type of physical harm (contrast injury, radiation exposure, biopsy, and any physical harm). We will report the point estimate and 95% confidence interval for the proportion of patients with each type of harm in each arm, stratified by health system. Using an intention-to-treat principle, we will use Chi squared test to compare the proportion of patients with physical harms between the screening and usual care arms, with a secondary analysis stratified by health system. We will also perform a sensitivity analysis based on test intent, in which we will only include tests (and corresponding harms) performed as a direct result of hepatocellular carcinoma screening.
measure: Financial Harms
time frame: 4 Years
description: Financial harms may include anticipated or real costs of hepatocellular carcinoma screening and diagnostic evaluation including, indirect costs such as missed work, and opportunity costs such as distraction from other health-related activities. Financial harms will be summarized for each arm using descriptive analyses as average and range of costs per person. Degree of financial harms will be compared between the hepatocellular carcinoma screening and usual care arms using Student T test, with a secondary analysis stratified by health system. In a secondary analysis, a mixed-effect model approach will be employed to identify patient-, provider- and system-level factors associated with financial harm.
measure: Overdiagnosis
time frame: 4 Years
description: Defined as hepatocellular carcinoma diagnoses that are unlikely to have an effect on mortality, specifically among patients with: 1) significant comorbid conditions or 2) severe liver dysfunction, i.e. Child Pugh C cirrhosis, who are not candidates for liver transplantation, at hepatocellular carcinoma diagnosis. For the primary analysis, Chi squared test will be used to compare the proportion of patients with overdiagnosis between the screening arm and usual care arm, stratified by health system.
measure: Psychosocial Harms
time frame: 4 Years
description: Patients will be divided into 4 categories: true positives, false positives, true negatives, and no screening. True positives will be defined as those who develop hepatocellular carcinoma within 6 months of the screening test; false positives as those who remain without hepatocellular carcinoma diagnosis during 6 months of follow-up; and true negatives as those with normal screening tests and without hepatocellular carcinoma diagnosis during 6 months of follow-up. Psychosocial harms (cancer-specific worry, situational anxiety, mood disturbances, and decisional regret) will be defined by change in survey scores from baseline and will be calculated at 1 month and 6 months for each patient.
measure: Patient-, Provider-, and System-level Factors Associated with Physical Harms
time frame: 4 Years
description: As a secondary analysis, we will construct mixed-effect logistic regression models to identify patient-, provider-, and system-level factors associated with physical harms (contrast injury, radiation exposure, biopsy, and any physical harm). Models will include random effects for providers and health systems to account for potential correlation at different levels. Final models will include covariates identified by stepwise variable selection procedure and those considered clinically important a priori (BMI, race, liver dysfunction, and gastroenterology care). Statistical significance will be declared for p<0.05.
measure: Patient-, Provider-, and System-level Factors Associated with Psychosocial Harms
time frame: 4 Years
description: We will construct a mixed regression model with the outcome being decisional regret and covariates including patient-, provider- and system-level factors. Decisional regret score, ranging from 0 to 100, will be analyzed as a continuous outcome. The mixed model will include random effects for providers and systems to account for correlation at different levels. The model will include covariates identified through stepwise variable selection and those considered clinically important a priori (age, gender, race and ethnicity, liver dysfunction).
measure: Physical Harms
time frame: 12 Months
description: Physical harms (contrast injury, radiation exposure, and biopsy complications) can result from screening or follow-up testing and extends beyond medical complications to include discomfort.
arm group label: Cohort
description: This study will collect prospective longitudinal data to characterize rates and identify correlates of a) physical harms due to follow-up tests, b) financial harms, and c) inappropriate screening using electronic medical record data and manual chart review. The study will also use surveys and semi-structured interviews to characterize rates and identify correlates of screening-related psychological harms, e.g. cancer specific worry, situational anxiety, mood disturbances, and decisional regret. Lastly, investigators will create and disseminate a balance sheet of benefits and harms to inform patients, providers, healthcare organizations, payers, and policymakers about the role of hepatocellular carcinoma screening in patients with cirrhosis.
intervention type: Other
intervention name: Prospective Longitudinal Data
description: We will prospectively follow the cohort using electronic medical record to document the hepatocellular carcinoma screening process and characterize physical and financial harms related to positive or indeterminate screening results and burden of inappropriate screening. Patients are anticipated to undergo hepatocellular carcinoma screening every 6-12 months, so each patient will have ~4-8 screening encounters over the study duration. We will use manual chart review to determine intent of ultrasound exams (screening vs. diagnostic) and test results. Receipt of follow-up tests after positive or indeterminate screening results will be identified through electronic medical record extraction using Current Procedural Terminology (CPT) codes for CT, MRI, and biopsy.
arm group label: Cohort
intervention type: Other
intervention name: Surveys and Semi-structured Interviews
description: We will use surveys and semi-structured interviews to characterize psychological harms after positive or indeterminate screening tests. Patient surveys will include patient-reported scales to measure psychosocial factors at three times points: baseline, 1 month after screening result, and 4 months after screening result. Semi-structured interviews will be conducted via telephone to explore patient attitudes toward risk perception, test follow-up, competing demands, and "downstream harms", particularly financial issues (e.g., out-of-pocket costs, access to insurance, and juggling hepatocellular carcinoma screening process completion with competing demands-work and family).
arm group label: Cohort
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 21 Years
maximum age: N/A
healthy volunteers: No
last name: Amit Singal, MD
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Texas Southwestern Medical Center
investigator full name: Amit Singal
investigator title: Associate Professor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
sharing ipd: No