Aminotransferase Trends During Prolonged Acetaminophen Dosing

NCT00743093 | Completed Phase 4 Results DMC

• 1 other identifier: COMIRB #06-1265
• Study Type: interventional
• Target: 398
• Locations: 1 country
• Sites: 2

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.

Conditions

Drug Toxicity; Healthy

Keywords

acetaminophen; protein adducts; drug safety; alanine aminotransferase; Alanine Amino Transferase

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (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).

  Days 1-3

Study Arms (2)

acetaminophen

EXPERIMENTAL

acetaminophen, 4 grams/day (1 gram every 4 hours for 4 doses)

Drug: acetaminophen

placebo

PLACEBO COMPARATOR

placebo for acetaminophen 4 grams/day (2 caplets every 4 hours for 4 doses)

Drug: placebo

Interventions

acetaminophen DRUG

500 mg caplets; 2 caplets (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days.

Also known as: tylenol

acetaminophen

placebo DRUG

placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days

placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• age 18 or older

You may not qualify if:

• History of acetaminophen ingestion on any of the four days preceding study enrollment
• Measurable serum acetaminophen level at time of enrollment
• Viral markers of Hepatitis B or C, or viral markers of Hepatitis A with an ALT level greater than ULN during screening laboratory testing
• Serum ALT or AST level greater than ULN at Screening or Day 0
• Total bilirubin level greater than ULN at Screening or Day 0
• INR level greater than ULN at Screening
• Alkaline phosphatase level greater than ULN at Screening
• Platelet count less than 125 10\^9/L at Screening
• Known cholelithiasis
• Positive pregnancy test at Screening (female participants only)
• History of consuming more than an average of 3 alcohol containing drinks daily over the preceding 2 weeks
• History of consuming 3 or more alcohol containing drinks on any given day during the 2 weeks prior to study enrollment
• New prescription medication started within the previous 30 days
• Currently taking isoniazid
• Currently taking warfarin

Sponsors & Collaborators

• Denver Health and Hospital Authority: lead
• McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.: collaborator

Study Sites (2)

University of Colorado Health Sciences Center - GCRC

Aurora, Colorado, 80045, United States

Location

Denver Health Rocky Mountain Poison and Drug Center

Denver, Colorado, 80204, United States

Location

Related Publications (6)

• 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.

  BACKGROUND

• 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. doi: 10.1001/archinte.163.2.169.

  PMID: 12546607 BACKGROUND

• 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.

  PMID: 16530510 BACKGROUND

• 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.

  PMID: 16316472 BACKGROUND

• 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.

  PMID: 14999359 BACKGROUND

• 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.

  PMID: 25047090 DERIVED

MeSH Terms

Conditions

Drug-Related Side Effects and Adverse Reactions

Interventions

Acetaminophen

Condition Hierarchy (Ancestors)

Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Limitations and Caveats

This study was limited to healthy volunteers. The ingestion of each dose of study drug and use of other medications was self-reported.

Results Point of Contact

• Title: Jody Green, PhD
• Organization: Denver Heatlh Rocky Mountain Poison and Drug Center

jody.green@rmpdc.org

303-389-1246

Study Officials

• Kennon Heard, MD

  Denver Health/Rocky Mountain Poison & Drug Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Fellowship Director

Study Record Dates

• First Submitted: August 26, 2008
• First Posted: August 28, 2008
• Study Start: August 1, 2008
• Primary Completion: August 1, 2011
• Study Completion: August 1, 2011
• Last Updated: September 18, 2013
• Results First Posted: July 25, 2013

Record last verified: 2013-09

Locations

US (2)