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

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ClinicalTrials.gov Identifier: NCT02911961
Recruitment Status : Recruiting
First Posted : September 23, 2016
Last Update Posted : December 10, 2019
Sponsor:
Collaborators:
Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division
University of Colorado, Denver
Rocky Mountain Poison and Drug Center
Information provided by (Responsible Party):
Kennon Heard, Denver Health and Hospital Authority

Study Description
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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.

Condition or disease Intervention/treatment Phase
Acetaminophen Exposure Drug: Acetaminophen Phase 4

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Screening
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
Estimated Study Start Date : January 1, 2020
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Liver Cancer

Arms and Interventions
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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 Name: Tylenol
No Intervention: Observational - No Acetaminophen
Subjects will take no acetaminophen containing products prior to the embolization procedure.


Outcome Measures
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Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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. 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


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

    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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02911961


Contacts
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Contact: Clinical Research Coordinator 303-389-1800 Clinical.Trials@rmpdc.org

Locations
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United States, Colorado
University of Colorado Denver Recruiting
Denver, Colorado, United States, 80045
Contact: Clinical Research Coordinator    303-389-1800    Clinical.Trials@rmpdc.org   
Sponsors and Collaborators
Denver Health and Hospital Authority
Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division
University of Colorado, Denver
Rocky Mountain Poison and Drug Center
Investigators
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Principal Investigator: Kennon Heard, MD, PhD University of Colorado, Denver
More Information
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Responsible Party: Kennon Heard, Principal Investigator, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier: NCT02911961    
Other Study ID Numbers: 16-0031
First Posted: September 23, 2016    Key Record Dates
Last Update Posted: December 10, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Liver Diseases
Acetaminophen
 Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics