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

August 27, 2021 updated by: Kennon Heard, Denver Health and Hospital Authority

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Withdrawn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

Intervention / Treatment

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

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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
Time Frame: 14 days
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
Time Frame: 2 years
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
Time Frame: 2 years
To evaluate the relationship between APAP-CYS concentrations with aspartate aminotransferase (AST), alanine aminotransferase (ALT), and miRNA activity
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

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

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

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

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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