Drug ToxicityPhase 4NCT00743093

Aminotransferase Trends During Prolonged Acetaminophen Dosing

A Phase 4 study testing acetaminophen in people with Drug Toxicity and Healthy, run by Denver Health and Hospital Authority at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for: Drug Toxicity, Healthy
What is being tested?: acetaminophen
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 398 participants
Where: 2 sitesUnited States
Study dates: Aug 2008to Aug 2011
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

age 18 or older

Who cannot join

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

Show all 19Show fewer

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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

University of Colorado Health Sciences Center - GCRC
Aurora, Colorado, 80045
Denver Health Rocky Mountain Poison and Drug Center
Denver, Colorado, 80204

Other trials in United States

About this study

Official title: Aminotransferase Trends During Prolonged Therapeutic Acetaminophen Dosing

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.

Read the 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.

Conditions: Drug Toxicity, Healthy
Being tested: acetaminophen, placebo
Keywords: acetaminophen, protein adducts, drug safety, alanine aminotransferase, Alanine Amino Transferase
Medical subject headings: Drug-Related Side Effects and Adverse Reactions

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

acetaminophenDrug
Also called tylenol
500 mg caplets; 2 caplets (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days.
placeboDrug
placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days

Study groups in NCT00743093
Study group	Role	What they receive
acetaminophen	Experimental	acetaminophen, 4 grams/day (1 gram every 4 hours for 4 doses) Receives: Drug: acetaminophen
placebo	Placebo comparator	placebo for acetaminophen 4 grams/day (2 caplets every 4 hours for 4 doses) Receives: Drug: placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: serial samples for 16-40 days

Secondary outcomes (1)

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).
Measured: Days 1-3

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Aug 2008Aug 2011

First posted28 Aug 2008 (estimated)
Study startAug 2008
Primary completionAug 2011
Study completionAug 2011

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (6)Papers the sponsor has linked to this study.
Other trials for Drug ToxicityStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 398 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00743093
Sponsor's protocol ID: COMIRB #06-1265
Status last verified: Sep 2013
First submitted: 26 Aug 2008
Last updated: 18 Sep 2013
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
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.
PubMed 12546607
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.
PubMed 16530510
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.
PubMed 16316472
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.
PubMed 14999359
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.
PubMed 25047090

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 18 Sep 2013. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Aminotransferase Trends During Prolonged Therapeutic Acetaminophen Dosing
ClinicalTrials.gov ID: NCT00743093
Acronym / sponsor ID: COMIRB #06-1265
Conditions: Drug Toxicity, Healthy
Keywords: acetaminophen, protein adducts, drug safety, alanine aminotransferase, Alanine Amino Transferase
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 398 participants (actual)
Lead sponsor: Denver Health and Hospital AuthorityUniversity, hospital or other
Collaborators: McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.
Study start: Aug 2008
Primary completion: Aug 2011 (actual)
Study completion: Aug 2011 (actual)
First posted: 28 Aug 2008 (estimated)
Results: Posted 25 Jul 2013

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Secondary objective is to determine the proportion of subjects that have detectable acetaminophen-protein adducts after daily dosing.

Detailed description

Study design

Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
acetaminophen	Experimental	Drug: acetaminophenacetaminophen, 4 grams/day (1 gram every 4 hours for 4 doses)
placebo	Placebo comparator	Drug: placeboplacebo for acetaminophen 4 grams/day (2 caplets every 4 hours for 4 doses)

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (1 listed)

age 18 or older

Key exclusion criteria (19 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
acetaminophenAlso: tylenol500 mg caplets; 2 caplets (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days.	Drug	acetaminophen
placeboplacebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days	Drug	placebo

Primary outcome

The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations.
Time frame: 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.

1 secondary outcome

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

Results and safety

Results posted to the registry on 25 Jul 2013, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Acetaminophen Arm	224	205
Placebo Arm	52	47

Primary outcome: The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations.

Time frame: serial samples for 16-40 days. Number. Unit: participants

Measure	Acetaminophen Arm n = 205	Placebo Arm n = 47
Subjects without persisitent ALT elevation	204	47
Subjects with persistent ALT elevation	1	0

Population analysed: The total number of subjects completing the trial was used for analysis. Subjects who withdrew early were not included.

1 secondary outcome is reported in the full results.

Adverse events

Time frame: Adverse events were collected starting at the time of consent through study completion.. Other adverse events reported at 1% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Acetaminophen Arm	0 of 224 (0%)	147 of 224 (65.6%)	Not reported
Placebo Arm	0 of 52 (0%)	25 of 52 (48.1%)	Not reported

Limitations and caveats (from the sponsor): This study was limited to healthy volunteers. The ingestion of each dose of study drug and use of other medications was self-reported.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2013.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
BackgroundDrug 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.
Background: PubMed 12546607Case 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.
Background: PubMed 16530510Davern 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.
Background: PubMed 16316472Garcia 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.
Background: PubMed 14999359Golden 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.
Derived from this study: PubMed 25047090Heard 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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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Kennon Heard, MD principal investigator

Denver Health/Rocky Mountain Poison & Drug Center

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing acetaminophen in people with Drug Toxicity and Healthy, run by Denver Health and Hospital Authority at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Sep 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Jul 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations. (time frame: serial samples for 16-40 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00743093, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Sep 2013.