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| ID | Type | Description | Link |
|---|---|---|---|
| UL1RR025758 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Harvard University | OTHER |
| National Center for Research Resources (NCRR) | NIH |
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The purpose of this study is to determine whether excipients in the liquid formulation of acetaminophen prevent the formation of the toxic metabolites of acetaminophen.
Acetaminophen (APAP) poisoning is the most frequent cause of acute hepatic failure in the United States. Toxicity requires cytochrome P-450 bioactivation of APAP. Children are less susceptible to APAP toxicity; the current theory is that they have different metabolism than adults. However, children's liquid preparations of APAP contain excipients which have been shown to inhibit APAP bioactivation in vitro and in rodents. Children tend to ingest liquid preparations, which could potentially explain their decreased susceptibility instead of an intrinsically different metabolism. Further, our review of Poison Center epidemiologic data shows that liquid preparations are less toxic in adults. Our hypothesis is that excipients in liquid preparations inhibit the bioactivation of APAP. The design is a pharmacokinetic cross-over study in humans. Healthy adult subjects will be recruited for administration of therapeutic doses of APAP in capsule and liquid formulations. Plasma via a heplock will be collected at serial time points up to 8 hours and assayed for APAP and its metabolites. After a washout period, subjects will receive the same dose of APAP in the alternate preparation. The pattern of metabolites, indicating the activity of the bioactivating enzymes, will be compared. A significant difference in P-450 metabolites will support the hypothesis and provide preliminary data for studies in patients who have ingested potentially toxic doses of APAP. Ultimately, this work could support development of novel antidotal therapy for APAP overdose.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Acetaminophen solid formulation | Placebo Comparator | Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation. |
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| Acetaminophen liquid formulation | Active Comparator | Subjects in this arm will receive a 15mg/kg dose of a liquid acetaminophen formulation. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acetaminophen liquid formulation | Drug | Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation. |
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| Measure | Description | Time Frame |
|---|---|---|
| Acetaminophen Metabolites | Area-under-curve from time zero to 8 hours for APAP-cysteinate metabolite. Serum was collected just prior to and at hours 1, 2, 4, 6, and 8 after administration of the APAP dose. | 8 hours |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Ganetsky, MD | Beth Israel Deaconess Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Harvard - Thorndike Clinical Research Center at Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23436315 | Derived | Ganetsky M, Bohlke M, Pereira L, Williams D, LeDuc B, Guatam S, Salhanick SD. Effect of excipients on acetaminophen metabolism and its implications for prevention of liver injury. J Clin Pharmacol. 2013 Apr;53(4):413-20. doi: 10.1002/jcph.24. Epub 2013 Feb 22. |
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Whether subjects received the solid or liquid preparation initially was randomly chosen.
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| ID | Title | Description |
|---|---|---|
| FG000 | Solid Acetaminophen First, Then Liquid Acetaminophen | Study participants randomized to receive solid formulation first. They received a 15mg/kg dose of a solid acetaminophen formulation for pharmacokinetic sampling on first study day, then had at least a 2 week washout period, then received a 15mg/kg dose of a liquid acetaminophen formulation for pharmacokinetic sampling on subsequent study day. |
| FG001 | Liquid Acetaminophen First, Then Solid Acetaminophen | Study participants randomized to receive liquid formulation first. They received a 15mg/kg dose of a liquid acetaminophen formulation for pharmacokinetic sampling on first study day, then had at least a 2 week washout period, then received a 15mg/kg dose of a solid acetaminophen formulation for pharmacokinetic sampling on subsequent study day. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Acetaminophen Dosing (1 Day) |
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| Washout (at Least 14 Days) |
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| Second Acetaminophen Dosing (1 Day) |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | All study participants received a 15mg/kg dose of a solid acetaminophen formulation and a 15mg/kg dose of a liquid acetaminophen formulation separated by at least a 2 week washout period. |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Acetaminophen Metabolites | Area-under-curve from time zero to 8 hours for APAP-cysteinate metabolite. Serum was collected just prior to and at hours 1, 2, 4, 6, and 8 after administration of the APAP dose. | Posted | Mean | Standard Error | mcg.hr/ml | 8 hours |
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Adverse even data was collected during the study period (first day of dosing, at least 2 week washout period, second day of dosing)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Solid Acetaminophen First, Then Liquid Acetaminophen | Participants in arm Solid Acetaminophen First: received a single 15mg/kg dose of a solid acetaminophen formulation first, and then a 15mg/kg dose of a liquid acetaminophen formulation after a 2 week washout period. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Michael Ganetsky, MD | BIDMC | 6177542323 | mganetsk@bidmc.harvard.edu |
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| Acetaminophen solid formulation | Drug | Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation. |
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| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Units | Counts |
|---|---|
| Participants |
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| 0 |
| 6 |
| 0 |
| 6 |
| EG001 | Liquid Acetaminophen First, Then Solid Acetaminophen | Participants in arm Liquid Acetaminophen First: received a single 15mg/kg dose of a liquid acetaminophen formulation, and then a 15mg/kg dose of a solid acetaminophen formulation after a 2 week washout period. | 0 | 9 | 0 | 9 |
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