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Aminotransferase Trends During Prolonged Acetaminophen Dosing

NCT ID: NCT00743093

Last Updated: 2013-09-18

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

398 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-08-31

Study Completion Date

2011-08-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Drug Toxicity Healthy

Keywords

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acetaminophen protein adducts drug safety alanine aminotransferase Alanine Amino Transferase

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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acetaminophen

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

Group Type EXPERIMENTAL

acetaminophen

Intervention Type DRUG

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

placebo

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

Group Type PLACEBO_COMPARATOR

placebo

Intervention Type DRUG

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

Interventions

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acetaminophen

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

Intervention Type DRUG

placebo

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

Intervention Type DRUG

Other Intervention Names

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tylenol

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.

INDUSTRY

Sponsor Role collaborator

Denver Health and Hospital Authority

OTHER

Sponsor Role lead

Responsible Party

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Kennon Heard

Fellowship Director

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Kennon Heard, MD

Role: PRINCIPAL_INVESTIGATOR

Denver Health/Rocky Mountain Poison & Drug Center

Locations

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University of Colorado Health Sciences Center - GCRC

Aurora, Colorado, United States

Site Status

Denver Health Rocky Mountain Poison and Drug Center

Denver, Colorado, United States

Site Status

Countries

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United States

References

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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.

Reference Type 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.

Reference Type BACKGROUND
PMID: 12546607 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 16530510 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 16316472 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 14999359 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25047090 (View on PubMed)

Other Identifiers

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COMIRB #06-1265

Identifier Type: -

Identifier Source: org_study_id