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Aminotransferase Trends During Prolonged Acetaminophen Dosing

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ClinicalTrials.gov Identifier: NCT00743093
Recruitment Status : Completed
First Posted : August 28, 2008
Results First Posted : July 25, 2013
Last Update Posted : September 18, 2013
Sponsor:
Collaborator:
McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.
Information provided by (Responsible Party):
Kennon Heard, Denver Health and Hospital Authority

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Conditions Drug Toxicity
Healthy
Interventions Drug: acetaminophen
Drug: placebo
Enrollment 398
Recruitment Details Recruitment took place from August 2008 through August 2011 in the Denver Metro area. Healthy volunteers were recruited from the community through the use of approved advertisements.
Pre-assignment Details 398 subjects were consented for the study. Of these, 122 were excluded for not meeting full eligibility criteria. 276 eligible subjects were assigned to treatment groups, of which 252 completed all study requirements.
Arm/Group Title Acetaminophen Arm Placebo Arm
Hide Arm/Group Description

acetaminophen

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

placebo

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

Period Title: Base Study Period
Started 224 52
Completed 205 47
Not Completed 19 5
Period Title: Extended Dosing Period
Started 51 [1] 1 [1]
Completed 48 1
Not Completed 3 0
[1]
Subjects not meeting stopping criteria after base continued into the extended dosing.
Arm/Group Title Acetaminophen Arm Placebo Arm Total
Hide Arm/Group Description acetaminophen 500 mg placebo Total of all reporting groups
Overall Number of Baseline Participants 224 52 276
Hide Baseline Analysis Population Description
Baseline characteristics were collected on all subjects at screening and included: race, ethnicity, gender, age, weight, and height. The number of participants included in the analysis (276) is based on the safety population, which includes any subject that took at least one dose of study medication.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 224 participants 52 participants 276 participants
<=18 years
1
   0.4%
0
   0.0%
1
   0.4%
Between 18 and 65 years
221
  98.7%
52
 100.0%
273
  98.9%
>=65 years
2
   0.9%
0
   0.0%
2
   0.7%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 224 participants 52 participants 276 participants
36.3  (12.16) 35.8  (12.50) 36.2  (12.21)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 224 participants 52 participants 276 participants
Female
163
  72.8%
39
  75.0%
202
  73.2%
Male
61
  27.2%
13
  25.0%
74
  26.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 224 participants 52 participants 276 participants
224 52 276
1.Primary Outcome
Title The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations.
Hide Description 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.
Time Frame serial samples for 16-40 days
Hide Outcome Measure Data
Hide Analysis Population Description
The total number of subjects completing the trial was used for analysis. Subjects who withdrew early were not included.
Arm/Group Title Acetaminophen Arm Placebo Arm
Hide Arm/Group Description:

acetaminophen

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

placebo

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

Overall Number of Participants Analyzed 205 47
Measure Type: Number
Unit of Measure: participants
Subjects without persisitent ALT elevation 204 47
Subjects with persistent ALT elevation 1 0
2.Secondary Outcome
Title 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).
Hide Description [Not Specified]
Time Frame Days 1-3
Hide Outcome Measure Data
Hide Analysis Population Description
A subset of the safety population was monitored for early detection of APAP-cys. This subset of subjects had APAP-cys measured at Days 1, 2, and 3 in addition to other protocol defined timepoints.
Arm/Group Title Acetaminophen Arm Placebo Arm
Hide Arm/Group Description:

acetaminophen

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

placebo

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

Overall Number of Participants Analyzed 64 15
Measure Type: Number
Unit of Measure: participants
Day 1-No. Subjects with Detectable APAP-cys 7 1
Day 2-No. Subjects with Detectable APAP-cys 57 1
Day 3-No. Subjects with Detectable APAP-cys 59 1
Time Frame Adverse events were collected starting at the time of consent through study completion.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Acetaminophen Arm Placebo Arm
Hide Arm/Group Description

acetaminophen

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

placebo

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

All-Cause Mortality
Acetaminophen Arm Placebo Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Acetaminophen Arm Placebo Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   0/224 (0.00%)   0/52 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Acetaminophen Arm Placebo Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   147/224 (65.63%)   25/52 (48.08%) 
Ear and labyrinth disorders     
Ear and labyrinth disorders  1  3/224 (1.34%)  0/52 (0.00%) 
Eye disorders     
Eye disorders  1  2/224 (0.89%)  0/52 (0.00%) 
Gastrointestinal disorders     
Gastrointestinal Disorders  1  70/224 (31.25%)  10/52 (19.23%) 
General disorders     
General disorders and administration site conditions  1  23/224 (10.27%)  3/52 (5.77%) 
Infections and infestations     
Infections and infestations  1  14/224 (6.25%)  2/52 (3.85%) 
Injury, poisoning and procedural complications     
Injury, poisoning and procedural complications  1  10/224 (4.46%)  2/52 (3.85%) 
Metabolism and nutrition disorders     
Metabolism and nutrition disorders  1  3/224 (1.34%)  1/52 (1.92%) 
Musculoskeletal and connective tissue disorders     
Muskuloskeletal and connective tissue disorders  1  26/224 (11.61%)  5/52 (9.62%) 
Nervous system disorders     
Nervous system disorders  1  42/224 (18.75%)  11/52 (21.15%) 
Psychiatric disorders     
Psychiatric disorders  1  6/224 (2.68%)  1/52 (1.92%) 
Renal and urinary disorders     
Renal and urinary disorders  1  0/224 (0.00%)  1/52 (1.92%) 
Reproductive system and breast disorders     
Reproductive system and breast disorders  1  5/224 (2.23%)  1/52 (1.92%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory, thoracic and mediastinal disorders  1  23/224 (10.27%)  5/52 (9.62%) 
Skin and subcutaneous tissue disorders     
Skin and subcutaneous tissue disorders  1  9/224 (4.02%)  0/52 (0.00%) 
Vascular disorders     
Vascular disorders  1  9/224 (4.02%)  1/52 (1.92%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
This study was limited to healthy volunteers. The ingestion of each dose of study drug and use of other medications was self-reported.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Jody Green, PhD
Organization: Denver Heatlh Rocky Mountain Poison and Drug Center
Phone: 303-389-1246
EMail: jody.green@rmpdc.org
Layout table for additonal information
Responsible Party: Kennon Heard, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier: NCT00743093     History of Changes
Other Study ID Numbers: COMIRB #06-1265
First Submitted: August 26, 2008
First Posted: August 28, 2008
Results First Submitted: March 18, 2013
Results First Posted: July 25, 2013
Last Update Posted: September 18, 2013