<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/NCT04476563</url>
  </required_header>
  <id_info>
    <org_study_id>20034</org_study_id>
    <nct_id>NCT04476563</nct_id>
  </id_info>
  <brief_title>Checkpoint Inhibitor-induced Liver Injury</brief_title>
  <acronym>ChILI</acronym>
  <official_title>Checkpoint Inhibitor-induced Liver Injury Study (ChILI)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Nottingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Nottingham</source>
  <oversight_info>
    <has_dmc>Yes</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>
      In this multi-center prospective observational study, the investigators plan to identify the&#xD;
      incidence and risk factors for checkpoint inhibitor-induced liver injury and characterize&#xD;
      biochemical, genetic, immunological, and histological features associated with it.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Checkpoint inhibitor-induced liver injury (ChILI) is a new incompletely understood category&#xD;
      of hepatotoxicity which is distinct from other types of drug-induced liver injury (DILI) such&#xD;
      as direct or idiosyncratic DILI. The data regarding the incidence and risk factors is&#xD;
      lacking. Therefore, 'in-depth phenotyping' together with data from the control group exposed&#xD;
      to checkpoint inhibitors (CPI) is necessary to develop refined algorithms incorporating&#xD;
      CPI-related factors, host genetic and environmental risk factors that would enable&#xD;
      pre-empting ChILI.&#xD;
&#xD;
      The aim of the study is to enroll two deeply phenotyped cohorts (patients who developed ChILI&#xD;
      and patients who are starting checkpoint inhibitors) and obtain biological samples at&#xD;
      multiple time points.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 13, 2020</start_date>
  <completion_date type="Anticipated">August 2023</completion_date>
  <primary_completion_date type="Anticipated">August 2023</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>Incidence of checkpoint inhibitor-induced liver injury (ChILI) and other immune-mediated adverse reactions</measure>
    <time_frame>3 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Identify novel biomarkers associated with the diagnosis of ChILI</measure>
    <time_frame>3 years</time_frame>
    <description>The investigators plan assessment of proposed circulating biomarkers including cytokines, microRNAs (miR-122, miR-4270 and miR-4463), total cytokeratin 18 (K18), macrophage colony-stimulating factor receptor (MCSFR), and any others identified in subsequent publications and measure their diagnostic and prognostic accuracy using the area under the receiver operating curve (AUROC).</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">160</enrollment>
  <condition>Immune-Mediated Hepatitis</condition>
  <arm_group>
    <arm_group_label>ChILI</arm_group_label>
    <description>Patients who are already on CPI therapy and have developed liver injury</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <description>Patients with cancer who are starting on checkpoint inhibitors</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Obtaining biological samples</intervention_name>
    <description>Biological samples (blood, urine, stool). Liver tissue will be obtained from ChILI group when clinically indicated</description>
    <arm_group_label>ChILI</arm_group_label>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      -  Collection and storage of biological samples (blood, urine, stool) from patients with&#xD;
           ChILI at three-time points (the day of liver injury, 1 week, and 1 month after). The&#xD;
           investigators will perform a liver biopsy when it is clinically indicated.&#xD;
&#xD;
        -  Collection and storage of biological samples (blood, urine, and stool) from control&#xD;
           patients at two-time points (before starting CPIs and 6 to14 weeks after commencing&#xD;
           treatment)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        ChILI group:&#xD;
&#xD;
        Adults with cancer receiving checkpoint inhibitors (CTLA-4, PD-1 or PD L1 inhibitor) as&#xD;
        monotherapy or combination (without chemotherapy) and developed acute liver injury&#xD;
        secondary to checkpoint inhibitor.&#xD;
&#xD;
        Control Group:&#xD;
&#xD;
        Patients with malignant melanoma, renal cell carcinoma, non-small cell lung cancer or any&#xD;
        other cancer, receiving single or combination therapy using checkpoint inhibitors (CPIs).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Both patient groups and control group:&#xD;
&#xD;
        • Able to give written informed consent OR Potential participants who have developed&#xD;
        encephalopathy related to ChILI as a response to checkpoint inhibitor therapy, who lack the&#xD;
        capacity to give written informed consent and have a consultee (personal or nominated) -&#xD;
        for ChILI patient group only&#xD;
&#xD;
        ChILI group:&#xD;
&#xD;
        Patients who developed checkpoint inhibitor-induced liver injury and meet the following&#xD;
        criteria:&#xD;
&#xD;
          1. Meets one of the following analytical thresholds at enrolment (visit 1)&#xD;
&#xD;
               -  Alanine transaminase (ALT) exceeding 5 times the upper limit of normal (ULN) OR&#xD;
&#xD;
               -  ALT exceeding 3 times ULN plus bilirubin exceeding 2 times ULN OR&#xD;
&#xD;
               -  Alkaline phosphatase (ALP) exceeding 2 times ULN with accompanying elevations of&#xD;
                  gamma-glutamyl transferase in the absence of known bone metastases driving the&#xD;
                  rise in ALP level&#xD;
&#xD;
          2. Absence of other known causes of liver injury after detailed investigations&#xD;
&#xD;
        Patients who developed ChILI but did not meet the above criteria at enrolment or who were&#xD;
        found to have a different cause for their liver injury after further investigations will be&#xD;
        excluded from the analysis&#xD;
&#xD;
        Control group:&#xD;
&#xD;
        Consecutive patients with cancer who have a clinical indication to start checkpoint&#xD;
        inhibitors. A small proportion of patients will develop ChILI following their checkpoint&#xD;
        inhibitor treatment and will be classified as cases.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are treated with cytotoxic chemotherapy concurrently with checkpoint&#xD;
             inhibitors.&#xD;
&#xD;
          -  On the judgment of chief investigator that the person has certain alternative&#xD;
             explanations to the acute event (rather than ChILI).&#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>Guruprasad Padur Aithal, MBBS, FRCP, PhD</last_name>
    <phone>0115 823 1074</phone>
    <email>guru.aithal@nottingham.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Edmond Atallah, M.D, MRCP(UK)</last_name>
    <email>edmond.atallah@nottingham.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Nottingham</name>
      <address>
        <city>Nottingham</city>
        <zip>NG72RD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kim Byrne</last_name>
      <email>bb-sponsor@exmail.nottingham.ac.uk</email>
    </contact>
    <investigator>
      <last_name>Edmond Atallah, M.D, MRCP(UK)</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>July 2, 2020</study_first_submitted>
  <study_first_submitted_qc>July 14, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>November 1, 2022</last_update_submitted>
  <last_update_submitted_qc>November 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Immune checkpoints inhibitors</keyword>
  <keyword>Immune-related adverse events</keyword>
  <keyword>Hepatotoxicity</keyword>
  <keyword>Liver injury</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis</mesh_term>
  </condition_browse>
  <!-- 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/NCT04476563
org study id: 20034
nct id: NCT04476563
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
In this multi-center prospective observational study, the investigators plan to identify the
      incidence and risk factors for checkpoint inhibitor-induced liver injury and characterize
      biochemical, genetic, immunological, and histological features associated with it.
Checkpoint inhibitor-induced liver injury (ChILI) is a new incompletely understood category
      of hepatotoxicity which is distinct from other types of drug-induced liver injury (DILI) such
      as direct or idiosyncratic DILI. The data regarding the incidence and risk factors is
      lacking. Therefore, 'in-depth phenotyping' together with data from the control group exposed
      to checkpoint inhibitors (CPI) is necessary to develop refined algorithms incorporating
      CPI-related factors, host genetic and environmental risk factors that would enable
      pre-empting ChILI.

      The aim of the study is to enroll two deeply phenotyped cohorts (patients who developed ChILI
      and patients who are starting checkpoint inhibitors) and obtain biological samples at
      multiple time points.
observational model: Cohort
time perspective: Prospective
measure: Incidence of checkpoint inhibitor-induced liver injury (ChILI) and other immune-mediated adverse reactions
time frame: 3 years
measure: Identify novel biomarkers associated with the diagnosis of ChILI
time frame: 3 years
description: The investigators plan assessment of proposed circulating biomarkers including cytokines, microRNAs (miR-122, miR-4270 and miR-4463), total cytokeratin 18 (K18), macrophage colony-stimulating factor receptor (MCSFR), and any others identified in subsequent publications and measure their diagnostic and prognostic accuracy using the area under the receiver operating curve (AUROC).
arm group label: ChILI
description: Patients who are already on CPI therapy and have developed liver injury
arm group label: Control
description: Patients with cancer who are starting on checkpoint inhibitors
intervention type: Diagnostic Test
intervention name: Obtaining biological samples
description: Biological samples (blood, urine, stool). Liver tissue will be obtained from ChILI group when clinically indicated
arm group label: ChILI
arm group label: Control
-  Collection and storage of biological samples (blood, urine, stool) from patients with
           ChILI at three-time points (the day of liver injury, 1 week, and 1 month after). The
           investigators will perform a liver biopsy when it is clinically indicated.

        -  Collection and storage of biological samples (blood, urine, and stool) from control
           patients at two-time points (before starting CPIs and 6 to14 weeks after commencing
           treatment)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Guruprasad Padur Aithal, MBBS, FRCP, PhD
phone: 0115 823 1074
email: guru.aithal@nottingham.ac.uk
last name: Edmond Atallah, M.D, MRCP(UK)
email: edmond.atallah@nottingham.ac.uk
facility: 
status: Recruiting
contact: 
investigator: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Hepatitis