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

Denver Health and Hospital Authority

Status and phase

Withdrawn

Phase 4

Conditions

Acetaminophen Exposure

Treatments

Drug: Acetaminophen

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT02911961

16-0031

Details and patient eligibility

About

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.

Full 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.

Sex

All

Ages

21 to 80 years old

Volunteers

No 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