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Aminotransferase Trends During Prolonged Acetaminophen Dosing

Information source: Denver Health and Hospital Authority
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Drug Toxicity; Healthy

Intervention: acetaminophen (Drug); placebo (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: Denver Health and Hospital Authority

Official(s) and/or principal investigator(s):
Kennon Heard, MD, Principal Investigator, Affiliation: Denver Health/Rocky Mountain Poison & Drug Center


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.

Clinical Details

Official title: Aminotransferase Trends During Prolonged Therapeutic Acetaminophen Dosing

Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Primary outcome: The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations.

Secondary outcome: 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).

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.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


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

Locations and Contacts

University of Colorado Health Sciences Center - GCRC, Aurora, Colorado 80045, United States

Denver Health Rocky Mountain Poison and Drug Center, Denver, Colorado 80204, United States

Additional Information

Related publications:

Drug Induced Liver Injury Network, U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for Industry Drug Induced Liver Injury: Premarketing Clinical Evaluation [Web Page]. 2007 Oct; Accessed 2008 Jan 17. Available at: http://www.fda.gov/cder/guidance/index.htm.

Case JP, Baliunas AJ, Block JA. Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled comparison trial with diclofenac sodium. Arch Intern Med. 2003 Jan 27;163(2):169-78.

Davern TJ 2nd, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, Lalani E, Munoz S, Shakil AO, Lee WM; Acute Liver Failure Study Group. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology. 2006 Mar;130(3):687-94. Erratum in: Gastroenterology. 2006 May;130(6):1933.

García Rodríguez LA, González-Pérez A. Long-term use of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. BMC Med. 2005 Nov 29;3:17.

Golden HE, Moskowitz RW, Minic M. Analgesic efficacy and safety of nonprescription doses of naproxen sodium compared with acetaminophen in the treatment of osteoarthritis of the knee. Am J Ther. 2004 Mar-Apr;11(2):85-94.

Starting date: August 2008
Last updated: September 6, 2013

Page last updated: August 23, 2015

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