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Aminotransferase Trends During Prolonged Acetaminophen Dosing

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00743093
Recruitment Status : Completed
First Posted : August 28, 2008
Results First Posted : July 25, 2013
Last Update Posted : September 18, 2013
Information provided by (Responsible Party):

Study Description
Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Drug Toxicity Healthy Drug: acetaminophen Drug: placebo Phase 4

Detailed Description:
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.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 398 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Official Title: Aminotransferase Trends During Prolonged Therapeutic Acetaminophen Dosing
Study Start Date : August 2008
Primary Completion Date : August 2011
Study Completion Date : August 2011

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: acetaminophen
acetaminophen, 4 grams/day (1 gram every 4 hours for 4 doses)
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
Placebo Comparator: placebo
placebo for acetaminophen 4 grams/day (2 caplets every 4 hours for 4 doses)
Drug: placebo
placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days

Outcome Measures

Primary Outcome Measures :
  1. 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 ]
    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.

Secondary Outcome Measures :
  1. 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 ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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
Contacts and Locations

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): NCT00743093

United States, Colorado
University of Colorado Health Sciences Center - GCRC
Aurora, Colorado, United States, 80045
Denver Health Rocky Mountain Poison and Drug Center
Denver, Colorado, United States, 80204
Sponsors and Collaborators
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
More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Kennon Heard, Fellowship Director, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier: NCT00743093     History of Changes
Other Study ID Numbers: COMIRB #06-1265
First Posted: August 28, 2008    Key Record Dates
Results First Posted: July 25, 2013
Last Update Posted: September 18, 2013
Last Verified: September 2013

Keywords provided by Kennon Heard, Denver Health and Hospital Authority:
protein adducts
drug safety
alanine aminotransferase
Alanine Amino Transferase

Additional relevant MeSH terms:
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs