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| Name | Class |
|---|---|
| McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| acetaminophen | Experimental | acetaminophen, 4 grams/day (1 gram every 4 hours for 4 doses) |
|
| placebo | Placebo Comparator | placebo for acetaminophen 4 grams/day (2 caplets every 4 hours for 4 doses) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| acetaminophen | Drug | 500 mg caplets; 2 caplets (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days. |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kennon Heard, MD | Denver Health/Rocky Mountain Poison & Drug Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado Health Sciences Center - GCRC | Aurora | Colorado | 80045 | United States | ||
| Denver Health Rocky Mountain Poison and Drug Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | Drug Induced Liver Injury Network, U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for Industry Drug Induced Liver Injury: Premarketing Clinical Evaluation [Web Page]. 2007 Oct; Accessed 2008 Jan 17. Available at: http://www.fda.gov/cder/guidance/index.htm. | ||
| 12546607 | Background | Case JP, Baliunas AJ, Block JA. Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled comparison trial with diclofenac sodium. Arch Intern Med. 2003 Jan 27;163(2):169-78. doi: 10.1001/archinte.163.2.169. | |
| 16530510 |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Acetaminophen Arm | acetaminophen acetaminophen : 500 mg caplets; 2 capsules (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days. |
| FG001 | Placebo Arm | placebo placebo : placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Base Study Period |
| |||||||||||||
| Extended Dosing Period |
|
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.
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| ID | Title | Description |
|---|---|---|
| BG000 | Acetaminophen Arm | acetaminophen 500 mg |
| BG001 | Placebo Arm | placebo |
| BG002 |
| Units | Counts |
|---|---|
| Participants |
|
| 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 | 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. | The total number of subjects completing the trial was used for analysis. Subjects who withdrew early were not included. | Posted | Number | participants | serial samples for 16-40 days |
|
Adverse events were collected starting at the time of consent through study completion.
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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 | Acetaminophen Arm | acetaminophen acetaminophen : 500 mg caplets; 2 capsules (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ear and labyrinth disorders | Ear and labyrinth disorders | MedDRA | Systematic Assessment |
This study was limited to healthy volunteers. The ingestion of each dose of study drug and use of other medications was self-reported.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jody Green, PhD | Denver Heatlh Rocky Mountain Poison and Drug Center | 303-389-1246 | jody.green@rmpdc.org |
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| ID | Term |
|---|---|
| D064420 | Drug-Related Side Effects and Adverse Reactions |
| ID | Term |
|---|---|
| D064419 | Chemically-Induced Disorders |
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| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 |
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| placebo | Drug | placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days |
|
| Denver |
| Colorado |
| 80204 |
| United States |
| Background |
| Davern TJ 2nd, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, Lalani E, Munoz S, Shakil AO, Lee WM; Acute Liver Failure Study Group. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology. 2006 Mar;130(3):687-94. doi: 10.1053/j.gastro.2006.01.033. |
| 16316472 | Background | Garcia Rodriguez LA, Gonzalez-Perez A. Long-term use of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. BMC Med. 2005 Nov 29;3:17. doi: 10.1186/1741-7015-3-17. |
| 14999359 | Background | Golden HE, Moskowitz RW, Minic M. Analgesic efficacy and safety of nonprescription doses of naproxen sodium compared with acetaminophen in the treatment of osteoarthritis of the knee. Am J Ther. 2004 Mar-Apr;11(2):85-94. doi: 10.1097/00045391-200403000-00002. |
| 25047090 | Derived | Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC. A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration. BMC Pharmacol Toxicol. 2014 Jul 22;15:39. doi: 10.1186/2050-6511-15-39. |
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|
| Total |
Total of all reporting groups |
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 |
| Placebo Arm |
placebo placebo : placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days |
|
|
| 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). | 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. | Posted | Number | participants | Days 1-3 |
|
|
|
| 0 |
| 224 |
| 147 |
| 224 |
| EG001 | Placebo Arm | placebo placebo : placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days | 0 | 52 | 25 | 52 |
| Eye disorders | Eye disorders | MedDRA | Systematic Assessment |
|
| Gastrointestinal Disorders | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| General disorders and administration site conditions | General disorders | MedDRA | Systematic Assessment |
|
| Infections and infestations | Infections and infestations | MedDRA | Systematic Assessment |
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| Injury, poisoning and procedural complications | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Metabolism and nutrition disorders | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Muskuloskeletal and connective tissue disorders | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Nervous system disorders | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Psychiatric disorders | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Renal and urinary disorders | Renal and urinary disorders | MedDRA | Systematic Assessment |
|
| Reproductive system and breast disorders | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Respiratory, thoracic and mediastinal disorders | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Skin and subcutaneous tissue disorders | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Vascular disorders | Vascular disorders | MedDRA | Systematic Assessment |
|
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| Aniline Compounds |
| D000588 | Amines |
| Day 3-No. Subjects with Detectable APAP-cys |
|