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

Primary Purpose

Acetaminophen Exposure

Status
Withdrawn
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Acetaminophen
Sponsored by
Denver Health and Hospital Authority
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional screening trial for Acetaminophen Exposure

Eligibility Criteria

21 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Colorado Denver

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Acetaminophen

Observational - No Acetaminophen

Arm Description

Subjects will take extra strength acetaminophen (4g/day) for the three days prior to the embolization procedure.

Subjects will take no acetaminophen containing products prior to the embolization procedure.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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

Full Information

First Posted
August 17, 2016
Last Updated
August 27, 2021
Sponsor
Denver Health and Hospital Authority
Collaborators
Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division, University of Colorado, Denver, Rocky Mountain Poison and Drug Center
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1. Study Identification

Unique Protocol Identification Number
NCT02911961
Brief Title
APAP-CYS Protein Adduct Concentrations in Patients With Liver-Directed Therapy Intended to Treat Hepatic Tumors
Official Title
Serum Acetaminophen-Cysteine (APAP-CYS) Adduct Concentrations in Subjects Expected to Develop Aminotransferase Elevations With Liver-Directed Therapy Intended to Treat Hepatic Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Withdrawn
Why Stopped
Due to lack of enrollment and organizational desire to focus recruitment efforts on other studies.
Study Start Date
August 2021 (Anticipated)
Primary Completion Date
August 2021 (Anticipated)
Study Completion Date
August 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Denver Health and Hospital Authority
Collaborators
Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division, University of Colorado, Denver, Rocky Mountain Poison and Drug Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acetaminophen Exposure

7. Study Design

Primary Purpose
Screening
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Acetaminophen
Arm Type
Experimental
Arm Description
Subjects will take extra strength acetaminophen (4g/day) for the three days prior to the embolization procedure.
Arm Title
Observational - No Acetaminophen
Arm Type
No Intervention
Arm Description
Subjects will take no acetaminophen containing products prior to the embolization procedure.
Intervention Type
Drug
Intervention Name(s)
Acetaminophen
Other Intervention Name(s)
Tylenol
Intervention Description
1 gram acetaminophen 4 times a day with at least 6 hour intervals between doses for the 3 days prior to the embolization procedure.
Primary Outcome Measure Information:
Title
APAP-CYS Concentrations Over Time - Acetaminophen Group
Description
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 Outcome Measure Information:
Title
APAP-CYS Concentrations Over Time - Non-Acetaminophen Group
Description
To determine if subjects who report no exposure to acetaminophen prior to the procedure have detectable APAP-CYS concentrations
Time Frame
2 years
Title
Relationship between APAP-CYS and other biochemical markers of liver function
Description
To evaluate the relationship between APAP-CYS concentrations with aspartate aminotransferase (AST), alanine aminotransferase (ALT), and miRNA activity
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: Moderate: Hemoglobin 8-9.5 g/dL 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kennon Heard, MD, PhD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado Denver
City
Denver
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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