Aminotransferase Trends During Prolonged Acetaminophen Dosing

Study Overview
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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.

Official Title
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Aminotransferase Trends During Prolonged Therapeutic Acetaminophen Dosing

Conditions
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Drug Toxicity, Healthy

Intervention / Treatment
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* Drug: acetaminophen
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 or older Exclusion Criteria: 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 Currently adheres to a fasting type diet as determined by self report Currently has anorexia nervosa as determined by self report Participant is clinically intoxicated, psychiatrically impaired or unable to give informed consent for any reason Known hypersensitivity or allergy to acetaminophen

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: acetaminophen<br>acetaminophen, 4 grams/day (1 gram every 4 hours for 4 doses) | Drug: acetaminophen<br>* 500 mg caplets; 2 caplets (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days.<br>* Other names: tylenol;|
| Placebo Comparator: placebo<br>placebo for acetaminophen 4 grams/day (2 caplets every 4 hours for 4 doses) | Drug: placebo<br>* placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acetaminophen, protein adducts, drug safety, alanine aminotransferase, Alanine Amino Transferase