APAP-CYS Protein Adduct Concentrations in Patients With Liver-Directed Therapy Intended to Treat Hepatic Tumors

Phase 4WithdrawnNCT02911961

Denver Health and Hospital Authority

Overview

The objective of this study is to provide preliminary data to describe serum acetaminophen-cysteine protein adduct (APAP-CYS) concentrations following therapeutic doses of acetaminophen in the setting of non-acetaminophen induced liver injury. This study will utilize hepatic embolization as a model of hepatic injury.

Acetaminophen-cysteine protein adducts (APAP-CYS) are formed when acetaminophen is oxidized by CYP 2E-1. When hepatocytes die, these proteins are released into the serum and can be detected. APAP-CYS can therefore be an experimental biomarker of acetaminophen exposure. It is possible that massive necrosis of hepatocytes that contain APAP-CYS from therapeutic doses of acetaminophen can be misinterpreted as acetaminophen overdose as the cause of liver injury. This study aims to describe serum APAP-CYS concentrations in patients taking a therapeutic dose of acetaminophen who develop a liver injury from a cause other than acetaminophen. This study will seek to enroll subjects undergoing a hepatic embolization procedure to treat a secondary liver tumor. This procedure is a reproducible model of non-acetaminophen induced hepatic injury. A small number of subjects who are otherwise eligible to participate but are unwilling to take acetaminophen will be offered participation in the observational arm of the study. They will undergo the same assessments with the exception of acetaminophen dosing. Subjects willing to take acetaminophen will be asked to take extra strength acetaminophen (4g/day) for the 3 days prior to their embolization procedure. All subjects will be asked to keep a detailed medication diary for the three days prior and up to their embolization procedure. Blood samples for the measurement of APAP-CYS concentrations and markers of liver function will be collected prior to acetaminophen dosing, prior to the embolization procedure, and at several time points after the procedure.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

SCREENING

Masking

NONE

Conditions

Acetaminophen Exposure

Interventions

AcetaminophenDRUG

1 gram acetaminophen 4 times a day with at least 6 hour intervals between doses for the 3 days prior to the embolization procedure.

Eligibility

Sex: ALLMin age: 21 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects of any gender or ethnic background who are between 21 and 80 years old * Subjects who are able to provide written, informed consent * Subjects with secondary liver cancer * Subjects undergoing portal vein or bland embolization for the treatment of secondary hepatic tumor * Subjects who are willing to have their blood drawn at least 12 times for study purposes * Subjects who agree to stay for \~18-21 hours after being discharged from the Department of Radiology for research purposes * Subjects who agree to refrain from using acetaminophen, other than the study drug, during the dosing phase through a minimum of 5 days post-procedure * Subjects who agree to consume less than 3 alcoholic drinks per day while taking study drug (acetaminophen group only) * Subjects who are willing to complete a study diary for 3 days prior to and the day of the procedure * Subjects who will be in the Denver metro area for the duration of the study Exclusion Criteria: * Subjects with known cirrhosis * Subjects with a history of moderate to severe anemia at screening as defined by: 1. Moderate: Hemoglobin 8-9.5 g/dL 2. Severe: Hemoglobin \<8 g/dL * Subjects with an ALT or AST greater than 200 IU/L at screening * Subjects with a total bilirubin greater than 1.5 mg/dL at screening * Subjects with an INR greater than 1.3 at screening * Subjects with a platelet count less than 125 10\^9/L at screening * Subjects who are currently taking warfarin (acetaminophen group only) * Subjects with anorexia nervosa (self-reported; acetaminophen group only) * Subjects who weigh ≤50 kg at screening (acetaminophen group only) * Subjects who adhere to a fasting type diet (self-reported; acetaminophen group only) * Subjects with a known hypersensitivity or allergy to acetaminophen (acetaminophen group only) * Subjects who are currently taking isoniazid (acetaminophen group only) * Subjects who are currently taking disulfiram (acetaminophen group only) * Subjects who are pregnant or breastfeeding (female participants only) * Subjects who are currently enrolled in a clinical trial, have participated in a clinical trial within the 30 days prior to the procedure, or who plan to participate in a clinical trial during the 5 day post-procedure follow-up period

Locations (1)

University of Colorado Denver

Denver, Colorado, United States

Outcomes

Primary Outcomes

APAP-CYS Concentrations Over Time - Acetaminophen Group

To describe the course of APAP-CYS concentrations following hepatic embolization in subjects who receive 4 grams/day of acetaminophen for three days prior to the procedure

Time frame: 14 days

Secondary Outcomes

APAP-CYS Concentrations Over Time - Non-Acetaminophen Group

To determine if subjects who report no exposure to acetaminophen prior to the procedure have detectable APAP-CYS concentrations

Time frame: 2 years

Relationship between APAP-CYS and other biochemical markers of liver function

To evaluate the relationship between APAP-CYS concentrations with aspartate aminotransferase (AST), alanine aminotransferase (ALT), and miRNA activity

Time frame: 2 years

Data from ClinicalTrials.gov

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