Drug Toxicity, Healthy
Conditions
Keywords
acetaminophen, protein adducts, drug safety, alanine aminotransferase, Alanine Amino Transferase
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.
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.
Interventions
DRUGacetaminophen
500 mg caplets; 2 caplets (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days.
DRUGplacebo
placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days
Sponsors
McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.
Denver Health and Hospital Authority
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations. | serial samples for 16-40 days | 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
| 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 |
Countries
United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Acetaminophen Arm acetaminophen 500 mg | 224 |
| Placebo Arm placebo | 52 |
| Total | 276 |
Baseline characteristics
| Characteristic | Placebo Arm | Acetaminophen Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 52 Participants | 221 Participants | 273 Participants |
| Age Continuous | 35.8 years STANDARD_DEVIATION 12.5 | 36.3 years STANDARD_DEVIATION 12.16 | 36.2 years STANDARD_DEVIATION 12.21 |
| Region of Enrollment United States | 52 participants | 224 participants | 276 participants |
| Sex: Female, Male Female | 39 Participants | 163 Participants | 202 Participants |
| Sex: Female, Male Male | 13 Participants | 61 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 147 / 224 | 25 / 52 |
| serious Total, serious adverse events | 0 / 224 | 0 / 52 |
Outcome results
Primary
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.
Time frame: serial samples for 16-40 days
Population: The total number of subjects completing the trial was used for analysis. Subjects who withdrew early were not included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acetaminophen Arm | The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations. | Subjects without persisitent ALT elevation | 204 participants |
| Acetaminophen Arm | The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations. | Subjects with persistent ALT elevation | 1 participants |
| Placebo Arm | The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations. | Subjects without persisitent ALT elevation | 47 participants |
| Placebo Arm | The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations. | Subjects with persistent ALT elevation | 0 participants |
Secondary
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acetaminophen Arm | 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). | Day 1-No. Subjects with Detectable APAP-cys | 7 participants |
| Acetaminophen Arm | 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). | Day 2-No. Subjects with Detectable APAP-cys | 57 participants |
| Acetaminophen Arm | 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). | Day 3-No. Subjects with Detectable APAP-cys | 59 participants |
| Placebo Arm | 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). | Day 1-No. Subjects with Detectable APAP-cys | 1 participants |
| Placebo Arm | 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). | Day 2-No. Subjects with Detectable APAP-cys | 1 participants |
| Placebo Arm | 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). | Day 3-No. Subjects with Detectable APAP-cys | 1 participants |