Aminotransferase Trends During Prolonged Acetaminophen Dosing

This study has been completed.
Sponsor:
Collaborator:
McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.
Information provided by (Responsible Party):
Kennon Heard, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier:
NCT00743093
First received: August 26, 2008
Last updated: September 6, 2013
Last verified: September 2013
  Purpose

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 Intervention Phase
Drug Toxicity
Healthy
Drug: acetaminophen
Drug: placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Official Title: Aminotransferase Trends During Prolonged Therapeutic Acetaminophen Dosing

Resource links provided by NLM:


Further study details as provided by Denver Health and Hospital Authority:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    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:
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 398
Study Start Date: August 2008
Study Completion Date: August 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Other Name: 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00743093

Locations
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.
Investigators
Principal Investigator: Kennon Heard, MD Denver Health/Rocky Mountain Poison & Drug Center
  More Information

Publications:
Additional 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
Study First Received: August 26, 2008
Results First Received: March 18, 2013
Last Updated: September 6, 2013
Health Authority: United States: Food and Drug Administration

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

Additional relevant MeSH terms:
Acetaminophen
Analgesics
Analgesics, Non-Narcotic
Antipyretics
Central Nervous System Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014