Checkpoint Inhibitor-induced Liver Injury

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Checkpoint Inhibitor-induced Liver Injury Study (ChILI)

Conditions
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Immune-Mediated Hepatitis

Intervention / Treatment
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* Diagnostic Test: Obtaining biological samples


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Both patient groups and control group: • Able to give written informed consent OR Potential participants who have developed encephalopathy related to ChILI as a response to checkpoint inhibitor therapy, who lack the capacity to give written informed consent and have a consultee (personal or nominated) - for ChILI patient group only ChILI group: Patients who developed checkpoint inhibitor-induced liver injury and meet the following criteria: Meets one of the following analytical thresholds at enrolment (visit 1) Alanine transaminase (ALT) exceeding 5 times the upper limit of normal (ULN) OR ALT exceeding 3 times ULN plus bilirubin exceeding 2 times ULN OR Alkaline phosphatase (ALP) exceeding 2 times ULN with accompanying elevations of gamma-glutamyl transferase in the absence of known bone metastases driving the rise in ALP level Absence of other known causes of liver injury after detailed investigations Patients who developed ChILI but did not meet the above criteria at enrolment or who were found to have a different cause for their liver injury after further investigations will be excluded from the analysis Control group: Consecutive patients with cancer who have a clinical indication to start checkpoint inhibitors. A small proportion of patients will develop ChILI following their checkpoint inhibitor treatment and will be classified as cases. Exclusion Criteria: Patients who are treated with cytotoxic chemotherapy concurrently with checkpoint inhibitors. On the judgment of chief investigator that the person has certain alternative explanations to the acute event (rather than ChILI).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ChILI<br>Patients who are already on CPI therapy and have developed liver injury | Diagnostic Test: Obtaining biological samples<br>* Biological samples (blood, urine, stool). Liver tissue will be obtained from ChILI group when clinically indicated<br>|
| Control<br>Patients with cancer who are starting on checkpoint inhibitors | Diagnostic Test: Obtaining biological samples<br>* Biological samples (blood, urine, stool). Liver tissue will be obtained from ChILI group when clinically indicated<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of checkpoint inhibitor-induced liver injury (ChILI) and other immune-mediated adverse reactions |  | 3 years | 
| Identify novel biomarkers associated with the diagnosis of ChILI | 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). | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune checkpoints inhibitors, Immune-related adverse events, Hepatotoxicity, Liver injury