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.

Study Overview

• Status: Completed
• Conditions: Healthy; Drug Toxicity
• Intervention / Treatment: Drug: acetaminophen; Drug: placebo

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 Type: Interventional
• Enrollment (Actual): 398
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations.	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.	serial samples for 16-40 days

Secondary Outcome Measures

Outcome Measure	Time Frame
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).	Days 1-3

Collaborators and Investigators

• Sponsor: Denver Health and Hospital Authority
• Collaborators: McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.
• Investigators: Principal Investigator: Kennon Heard, MD, Denver Health/Rocky Mountain Poison & Drug Center

Publications and helpful links

General 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. doi: 10.1053/j.gastro.2006.01.033. Erratum In: Gastroenterology. 2006 May;130(6):1933.
• Garcia Rodriguez LA, Gonzalez-Perez 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. doi: 10.1186/1741-7015-3-17.
• 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. doi: 10.1097/00045391-200403000-00002.
• Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC. A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration. BMC Pharmacol Toxicol. 2014 Jul 22;15:39. doi: 10.1186/2050-6511-15-39.

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: August 26, 2008
• First Submitted That Met QC Criteria: August 27, 2008
• First Posted (Estimate): August 28, 2008

Study Record Updates

• Last Update Posted (Estimate): September 18, 2013
• Last Update Submitted That Met QC Criteria: September 6, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Keywords: acetaminophen; protein adducts; drug safety; alanine aminotransferase; Alanine Amino Transferase
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Drug-Related Side Effects and Adverse Reactions; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: COMIRB #06-1265