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

Serum Acetaminophen-Cysteine (APAP-CYS) Adduct Concentrations in Subjects Expected to Develop Aminotransferase Elevations With Liver-Directed Therapy Intended to Treat Hepatic Tumors

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.

Study Overview

• Status: Withdrawn
• Conditions: Acetaminophen Exposure
• Intervention / Treatment: Drug: Acetaminophen

Detailed Description

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
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80045
      • University of Colorado Denver

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acetaminophen; Subjects will take extra strength acetaminophen (4g/day) for the three days prior to the embolization procedure.	Drug: Acetaminophen; 1 gram acetaminophen 4 times a day with at least 6 hour intervals between doses for the 3 days prior to the embolization procedure.; Other Names: Tylenol
No Intervention: Observational - No Acetaminophen; Subjects will take no acetaminophen containing products prior to the embolization procedure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	2 years

Collaborators and Investigators

• Sponsor: Denver Health and Hospital Authority
• Collaborators: University of Colorado, Denver; Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division; Rocky Mountain Poison and Drug Center
• Investigators: Principal Investigator: Kennon Heard, MD, PhD, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2021
• Primary Completion (Anticipated): August 1, 2021
• Study Completion (Anticipated): August 1, 2021

Study Registration Dates

• First Submitted: August 17, 2016
• First Submitted That Met QC Criteria: September 20, 2016
• First Posted (Estimate): September 23, 2016

Study Record Updates

• Last Update Posted (Actual): September 2, 2021
• Last Update Submitted That Met QC Criteria: August 27, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: 16-0031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No