Aminotransferase Trends During Prolonged Acetaminophen Dosing

This study has been completed.
Sponsor:
Collaborator:
McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.
Information provided by (Responsible Party):
Kennon Heard, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier:
NCT00743093
First received: August 26, 2008
Last updated: September 6, 2013
Last verified: September 2013

August 26, 2008
September 6, 2013
August 2008
August 2011   (final data collection date for primary outcome measure)
The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations. [ Time Frame: serial samples for 16-40 days ] [ Designated as safety issue: Yes ]
ALT was measured on Day 0 and 16 for all study participants. Subjects with an elevated ALT at Day 16 continued dosing with study drug and continued to have their ALT measured every three days until the ALT elevation resolved or until Day 40. Persistent ALT elevation was defined as any subject with an unresolved ALT elevation at study Day 40.
alanine aminotransferase (ALT) [ Time Frame: serial samples over 17-42 days ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00743093 on ClinicalTrials.gov Archive Site
The Proportion of Subjects With Detectable Serum Acetaminophen-cysteine Adduct (APAP-cys) Concentrations 1, 2, and 3 Days After Starting the Maximal Recommended Dosing of Acetaminophen (4 g/Day). [ Time Frame: Days 1-3 ] [ Designated as safety issue: No ]
acetaminophen-protein adducts [ Time Frame: serial samples for 16-42 days ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Aminotransferase Trends During Prolonged Acetaminophen Dosing
Aminotransferase Trends During Prolonged Therapeutic Acetaminophen Dosing

The objective of this study is to monitor liver function tests (blood levels of an indicator of liver function) of healthy people taking the maximum labeled daily dose of acetaminophen compared to people taking placebo for 16 to 40 days. Those people that continue to have normal liver tests after 16 days will have completed their part of the study. People that develop abnormal liver function tests will continue taking acetaminophen or placebo, and have their liver tests monitored closely for up to an additional 24 days. This is to (1) make sure these tests return to normal and (2) determine when these tests return to normal while still taking acetaminophen or placebo. If at any time the liver tests indicate anything more than a minor increase, you would be immediately told to stop taking the study drug.

Secondary objective is to determine the proportion of subjects that have detectable acetaminophen-protein adducts after daily dosing.

Acetaminophen use is common and many consumers take 4g/day for longer than 4 days. The use of 4g/day of acetaminophen for more than 4 days causes an asymptomatic ALT elevation in some people. This elevation most likely resolves while continuing treatment, but it is possible that some individuals may go on to develop clinical liver injury. By carefully following healthy subjects who are taking the maximal daily dose of acetaminophen, we can safely determine if the ALT elevation resolves or progresses to clinical liver injury. If a subject develops clinical liver injury we can intervene before irreversible injury occurs.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
  • Drug Toxicity
  • Healthy
  • Drug: acetaminophen
    500 mg caplets; 2 caplets (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days.
    Other Name: tylenol
  • Drug: placebo
    placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days
    Other Name: placebo
  • Experimental: acetaminophen
    acetaminophen, 4 grams/day (1 gram every 4 hours for 4 doses)
    Intervention: Drug: acetaminophen
  • Placebo Comparator: placebo
    placebo for acetaminophen 4 grams/day (2 caplets every 4 hours for 4 doses)
    Intervention: Drug: placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
398
August 2011
August 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • age 18 or older

Exclusion Criteria:

  1. History of acetaminophen ingestion on any of the four days preceding study enrollment
  2. Measurable serum acetaminophen level at time of enrollment
  3. Viral markers of Hepatitis B or C, or viral markers of Hepatitis A with an ALT level greater than ULN during screening laboratory testing
  4. Serum ALT or AST level greater than ULN at Screening or Day 0
  5. Total bilirubin level greater than ULN at Screening or Day 0
  6. INR level greater than ULN at Screening
  7. Alkaline phosphatase level greater than ULN at Screening
  8. Platelet count less than 125 10^9/L at Screening
  9. Known cholelithiasis
  10. Positive pregnancy test at Screening (female participants only)
  11. History of consuming more than an average of 3 alcohol containing drinks daily over the preceding 2 weeks
  12. History of consuming 3 or more alcohol containing drinks on any given day during the 2 weeks prior to study enrollment
  13. New prescription medication started within the previous 30 days
  14. Currently taking isoniazid
  15. Currently taking warfarin
  16. Currently adheres to a fasting type diet as determined by self report
  17. Currently has anorexia nervosa as determined by self report
  18. Participant is clinically intoxicated, psychiatrically impaired or unable to give informed consent for any reason
  19. Known hypersensitivity or allergy to acetaminophen
Both
18 Years and older
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00743093
COMIRB #06-1265
Yes
Kennon Heard, Denver Health and Hospital Authority
Denver Health and Hospital Authority
McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.
Principal Investigator: Kennon Heard, MD Denver Health/Rocky Mountain Poison & Drug Center
Denver Health and Hospital Authority
September 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP