Trial Outcomes & Findings for Mechanisms of Action of Acetaminophen (NCT NCT00646906)

Last Updated: 2026-02-12

Results Overview

Thromboxan B2 is a stable metabolite of thromboxane A2. Thromboxane B2 formation during clotting of whole blood (37 degrees Celsius, 1 hour) is reflective of the capacity of platelets to form thromboxane A2. Serum Thromboxane B2 was measured by radio-immuno assay. The quantity of interest was percent change from start (8:00 am on day 1) to finish (8:00 am on last day) of each crossover period in serum thromboxane B2. This was calculated as: 100%\*(value at start of period minus value at end of period)/value at start of period.

Recruitment status

COMPLETED

Study phase

Target enrollment

55 participants

Primary outcome timeframe

7 days (Phase 1a and 1b), 4 days (Phase 2)

Results posted on

2026-02-12

Participant Flow

Phase 1a: 16 evaluable healthy individuals and 16 evaluable apparently healthy chronic smokers. Crossover design. Phase 1b: 8 evaluable healthy and non-smoking subjects. No crossover. Phase 2: 8 evaluable healthy and non-smoking subjects. Crossover design. Enrollment from 6/2/2004 to 8/14/2007

Participant milestones

Participant milestones
Measure	Phase 1a: Aspirin 81 mg / Acetaminophen 1000 mg Sequence 1 All subjects in this arm of the study termed "Phase 1a" (smokers (n=8) and non-smokers (n=8) will receive 81 mg aspirin at 8 am followed by 1000 mg acetaminophen at 10 am each day, for six days during the first crossover period ("Aspirin first"). During the second crossover period, beginning after a 2 week washout, the order will be reversed and the subjects will receive 1000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am each day, for six days ("Aspirin last"). The occurrence of the two crossover periods (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.	Phase 1a: Aspirin 81 mg / Acetaminophen 1000 mg Sequence 2 All subjects in this arm of the study termed "Phase 1a" (smokers (n=8) and non-smokers (n=8) will receive 1000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am each day, for six days during the first crossover period ("Aspirin last"). During the second crossover period, beginning after a 2 week washout, the order will be reversed and the subjects will receive 81 mg aspirin at 8 am followed by 1000 mg acetaminophen at 10 am each day, for six days ("Aspirin first"). The occurrence of the two crossover periods (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.	Phase 1a: Aspirin 81 mg / Acetaminophen 2000 mg Sequence 1 All subjects in this arm of the study termed "Phase 1a" (smokers (n=8) and non-smokers (n=8) will receive 81 mg aspirin at 8 am followed by 2000 mg acetaminophen at 10 am each day, for six days during the first crossover period ("Aspirin first"). During the second crossover period, beginning after a 2 week washout, the order will be reversed and the subjects will receive 2000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am each day, for six days ("Aspirin last"). The occurrence of the two crossover periods (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.	Phase 1a: Aspirin 81 mg / Acetaminophen 2000 mg Sequence 2 All subjects in this arm of the study termed "Phase 1a" (smokers (n=8) and non-smokers (n=8) will receive 2000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am each day, for six days during the first crossover period ("Aspirin last"). During the second crossover period, beginning after a 2 week washout, the order will be reversed and the subjects will receive 81 mg aspirin at 8 am followed by 2000 mg acetaminophen at 10 am each day, for six days ("Aspirin first"). The occurrence of the two crossover periods (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.	Phase 1b: Acetaminophen 1000mg Alone: 4 Days Eight healthy, non-smoking subjects will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM. Study assessments will be performed on day 1 and on day 6. Phase 1b is not a crossover design. Phase 1b will end after the first treatment period, which will be identical for all subjects.	Phase 2: Acetaminophen 4000 mg/d / Ibuprofen 800 mg/d In the first period of this arm of the crossover study termed "Phase 2", healthy non-smoking subjects will be administered acetaminophen (1000 mg) orally at 8 AM, 2 PM, 8 PM and 2 AM (4000 mg/d) for 3 days. The last dose will be administered on day four at 8 AM In the other crossover period, after a washout period of at least 14 days, the subjects will receive ibuprofen (200 mg) orally at 8 AM, 2 PM, 8 PM and 2 AM (800 mg/d) for 3 days. The last dose will be administered on day four at 8 AM. The treatment periods will be randomized by order.	Phase 2: Ibuprofen 800 mg/d / Acetaminophen 4000 mg/d In the first period of this arm of the crossover study termed "Phase 2", healthy non-smoking subjects will be administered ibuprofen (200 mg) orally at 8 AM, 2 PM, 8 PM and 2 AM (800 mg/d) for 3 days. The last dose will be administered on day four at 8 AM In the other crossover period, after a washout period of at least 14 days, the subjects will receive acetaminophen (1000 mg) orally at 8 AM, 2 PM, 8 PM and 2 AM (4000 mg/d) for 3 days. The last dose will be administered on day four at 8 AM. The treatment periods will be randomized by order.
Crossover Period 1 STARTED	9	9	10	9	8	5	5
Crossover Period 1 COMPLETED	8	9	10	9	8	4	5
Crossover Period 1 NOT COMPLETED	1	0	0	0	0	1	0
Washout (>/= 14 Days) STARTED	8	9	10	9	0	4	5
Washout (>/= 14 Days) COMPLETED	8	9	10	9	0	4	5
Washout (>/= 14 Days) NOT COMPLETED	0	0	0	0	0	0	0
Crossover Period 2 STARTED	8	9	10	9	0	4	5
Crossover Period 2 COMPLETED	8	8	8	8	0	4	4
Crossover Period 2 NOT COMPLETED	0	1	2	1	0	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase 1a: Aspirin 81 mg / Acetaminophen 1000 mg Sequence 1 All subjects in this arm of the study termed "Phase 1a" (smokers (n=8) and non-smokers (n=8) will receive 81 mg aspirin at 8 am followed by 1000 mg acetaminophen at 10 am each day, for six days during the first crossover period ("Aspirin first"). During the second crossover period, beginning after a 2 week washout, the order will be reversed and the subjects will receive 1000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am each day, for six days ("Aspirin last"). The occurrence of the two crossover periods (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.	Phase 1a: Aspirin 81 mg / Acetaminophen 1000 mg Sequence 2 All subjects in this arm of the study termed "Phase 1a" (smokers (n=8) and non-smokers (n=8) will receive 1000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am each day, for six days during the first crossover period ("Aspirin last"). During the second crossover period, beginning after a 2 week washout, the order will be reversed and the subjects will receive 81 mg aspirin at 8 am followed by 1000 mg acetaminophen at 10 am each day, for six days ("Aspirin first"). The occurrence of the two crossover periods (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.	Phase 1a: Aspirin 81 mg / Acetaminophen 2000 mg Sequence 1 All subjects in this arm of the study termed "Phase 1a" (smokers (n=8) and non-smokers (n=8) will receive 81 mg aspirin at 8 am followed by 2000 mg acetaminophen at 10 am each day, for six days during the first crossover period ("Aspirin first"). During the second crossover period, beginning after a 2 week washout, the order will be reversed and the subjects will receive 2000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am each day, for six days ("Aspirin last"). The occurrence of the two crossover periods (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.	Phase 1a: Aspirin 81 mg / Acetaminophen 2000 mg Sequence 2 All subjects in this arm of the study termed "Phase 1a" (smokers (n=8) and non-smokers (n=8) will receive 2000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am each day, for six days during the first crossover period ("Aspirin last"). During the second crossover period, beginning after a 2 week washout, the order will be reversed and the subjects will receive 81 mg aspirin at 8 am followed by 2000 mg acetaminophen at 10 am each day, for six days ("Aspirin first"). The occurrence of the two crossover periods (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.	Phase 2: Acetaminophen 4000 mg/d / Ibuprofen 800 mg/d In the first period of this arm of the crossover study termed "Phase 2", healthy non-smoking subjects will be administered acetaminophen (1000 mg) orally at 8 AM, 2 PM, 8 PM and 2 AM (4000 mg/d) for 3 days. The last dose will be administered on day four at 8 AM In the other crossover period, after a washout period of at least 14 days, the subjects will receive ibuprofen (200 mg) orally at 8 AM, 2 PM, 8 PM and 2 AM (800 mg/d) for 3 days. The last dose will be administered on day four at 8 AM. The treatment periods will be randomized by order.	Phase 2: Ibuprofen 800 mg/d / Acetaminophen 4000 mg/d In the first period of this arm of the crossover study termed "Phase 2", healthy non-smoking subjects will be administered ibuprofen (200 mg) orally at 8 AM, 2 PM, 8 PM and 2 AM (800 mg/d) for 3 days. The last dose will be administered on day four at 8 AM In the other crossover period, after a washout period of at least 14 days, the subjects will receive acetaminophen (1000 mg) orally at 8 AM, 2 PM, 8 PM and 2 AM (4000 mg/d) for 3 days. The last dose will be administered on day four at 8 AM. The treatment periods will be randomized by order.
Crossover Period 1 Withdrawal by Subject	1	0	0	0	1	0
Crossover Period 2 Withdrawal by Subject	0	1	2	1	0	0
Crossover Period 2 Physician Decision	0	0	0	0	0	1

Baseline Characteristics

Mechanisms of Action of Acetaminophen

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1a: Acetaminophen 1000mg / Aspirin n=16 Participants All subjects in this arm (smokers (n=8) and non-smokers (n=8) will receive 81 mg aspirin at approximately 8 am followed by 1000 mg acetaminophen at approximately 10 am during one treatment phase (see "Aspirin first" intervention). During the other treatment phase, beginning after a 2 week washout, the order will be reversed and the subjects will receive 1000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am (see "Aspirin last" intervention). The occurrence of the two study phases (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender. Aspirin first: Subjects will receive 81 mg aspirin at approximately 8 am followed by 1000 or 2000 mg acetaminophen at approximately 10 am during this intervention phase. Aspirin last: Subjects will receive 1000 or 2000 mg acetaminophen at approximately 8am followed by 81 mg aspirin at approximately 10 am during this intervention phase.	Phase 1a: Acetaminophen 2000mg / Aspirin n=16 Participants All subjects in this arm (smokers (n=8) and non-smoking volunteers (n=8)) will receive 81 mg aspirin at approximately 8 am followed by 2000 mg acetaminophen at approximately 10 am during one treatment phase (see "Aspirin first" intervention). During the other treatment phase, beginning after a 2 week washout, the order will be reversed and the subjects will receive 2000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am (see "Aspirin last" intervention). The occurrence of the two study phases (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender. Aspirin first: Subjects will receive 81 mg aspirin at approximately 8 am followed by 1000 or 2000 mg acetaminophen at approximately 10 am during this intervention phase. Aspirin last: Subjects will receive 1000 or 2000 mg acetaminophen at approximately 8am followed by 81 mg aspirin at approximately 10 am during this intervention phase.	Phase 1b: Acetaminophen 1000 mg Alone n=8 Participants Eight male and non-pregnant female subjects who are healthy and non-smoking will be recruited. They will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM (see "Acetaminophen 1000 mg/d" intervention). Study assessments will be performed on day 1 and on day 6. Acetaminophen 1000 mg/d: They will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM.	Phase 2: Acetaminophen vs. Ibuprofen n=8 Participants Eight male and non-pregnant female subjects who are healthy and non-smoking will be recruited. In one treatment period of this cross-over study acetaminophen (1000 mg p.o.) will be administered orally at 8 AM, 2 PM, 8 PM and 2 AM for 3 days (see "Acetaminophen 4000 mg/d" intervention). The last dose will be administered on day four at 8 AM In the other treatment period, after a washout period of at least 14 days, the subjects will receive ibuprofen (200 mg) orally at at 8 AM, 2 PM, 8 PM and 2 AM for 3 days (see "Ibuprofen 800 mg/d" intervention). The last dose will be administered on day four at 8 AM. Acetaminophen 4000 mg/d: Acetaminophen (1000 mg p.o.) orally at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. The last dose will be administered on day four at 8 AM. Ibuprofen 800 mg/d: Ibuprofen (200 mg) orally at at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. The last dose will be administered on day four at 8 AM.	Total n=48 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=47 Participants	0 Participants n=55 Participants	0 Participants n=102 Participants	0 Participants n=1267 Participants	0 Participants n=50 Participants
Age, Categorical Between 18 and 65 years	16 Participants n=47 Participants	16 Participants n=55 Participants	8 Participants n=102 Participants	8 Participants n=1267 Participants	48 Participants n=50 Participants
Age, Categorical >=65 years	0 Participants n=47 Participants	0 Participants n=55 Participants	0 Participants n=102 Participants	0 Participants n=1267 Participants	0 Participants n=50 Participants
Age, Continuous	35.3 years STANDARD_DEVIATION 11.4 • n=47 Participants	37.6 years STANDARD_DEVIATION 11.2 • n=55 Participants	31.8 years STANDARD_DEVIATION 7.1 • n=102 Participants	30.9 years STANDARD_DEVIATION 8.3 • n=1267 Participants	33.9 years STANDARD_DEVIATION 9.5 • n=50 Participants
Sex: Female, Male Female	8 Participants n=47 Participants	8 Participants n=55 Participants	3 Participants n=102 Participants	4 Participants n=1267 Participants	23 Participants n=50 Participants
Sex: Female, Male Male	8 Participants n=47 Participants	8 Participants n=55 Participants	5 Participants n=102 Participants	4 Participants n=1267 Participants	25 Participants n=50 Participants
Region of Enrollment United States	16 participants n=47 Participants	16 participants n=55 Participants	8 participants n=102 Participants	8 participants n=1267 Participants	48 participants n=50 Participants

PRIMARY outcome

Timeframe: 7 days (Phase 1a and 1b), 4 days (Phase 2)

Outcome measures

Outcome measures
Measure	Phase 1a: Acetaminophen 1000 mg / Aspirin First n=16 Participants 81 mg aspirin at 8 am followed by 1000 mg acetaminophen at 10 am.	Phase 1a: Acetaminophen 1000 mg / Aspirin Last n=16 Participants 1000 mg acetaminophen at 8am followed by 81 mg aspirin at 10 am.	Phase 1a: Acetaminophen 2000 mg / Aspirin First n=16 Participants 81 mg aspirin at 8 am followed by 2000 mg acetaminophen at 10 am.	Phase 1a: Acetaminophen 2000 mg / Aspirin Last n=16 Participants 2000 mg acetaminophen at 8am followed by 81 mg aspirin at 10 am.	Phase 1b: Acetaminophen 1000 mg/d n=8 Participants Eight male and non-pregnant female subjects who are healthy and non-smoking will be recruited. They will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM (see "Acetaminophen 1000 mg/d" intervention). Study assessments will be performed on day 1 and on day 6. Acetaminophen 1000 mg/d: They will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM.	Phase 2: Acetaminophen 4000 mg/d n=8 Participants Acetaminophen (1000 mg p.o.) orally at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. Last dose on day four at 8 AM.	Phase 2: Ibuprofen 800 mg/d n=8 Participants Ibuprofen (200 mg) orally at at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. Last dose on day four at 8 AM.
Percent Change in Serum Thromboxane B2	97.0 Percent inhibition of baseline Standard Deviation 4.7	97.4 Percent inhibition of baseline Standard Deviation 3.6	98.3 Percent inhibition of baseline Standard Deviation 1.0	96.7 Percent inhibition of baseline Standard Deviation 2.6	-6.5 Percent inhibition of baseline Standard Deviation 59.7	21.9 Percent inhibition of baseline Standard Deviation 19.7	62.6 Percent inhibition of baseline Standard Deviation 32.2

SECONDARY outcome

Timeframe: 7 days (only Phase 1a)

Platelet aggregation was induced by 500 micro molar arachidonic acid using a Chronolog aggregometer. The quantity of interest was percent change from start (8:00 am on day 1) to finish (8:00 am on last day) of each crossover period in platelet aggregation. This was calculated as: 100%\*(value at start of period minus value at end of period)/value at start of period.

Outcome measures

Outcome measures
Measure	Phase 1a: Acetaminophen 1000 mg / Aspirin First n=16 Participants 81 mg aspirin at 8 am followed by 1000 mg acetaminophen at 10 am.	Phase 1a: Acetaminophen 1000 mg / Aspirin Last n=16 Participants 1000 mg acetaminophen at 8am followed by 81 mg aspirin at 10 am.	Phase 1a: Acetaminophen 2000 mg / Aspirin First n=16 Participants 81 mg aspirin at 8 am followed by 2000 mg acetaminophen at 10 am.	Phase 1a: Acetaminophen 2000 mg / Aspirin Last n=16 Participants 2000 mg acetaminophen at 8am followed by 81 mg aspirin at 10 am.	Phase 1b: Acetaminophen 1000 mg/d Eight male and non-pregnant female subjects who are healthy and non-smoking will be recruited. They will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM (see "Acetaminophen 1000 mg/d" intervention). Study assessments will be performed on day 1 and on day 6. Acetaminophen 1000 mg/d: They will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM.	Phase 2: Acetaminophen 4000 mg/d Acetaminophen (1000 mg p.o.) orally at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. Last dose on day four at 8 AM.	Phase 2: Ibuprofen 800 mg/d Ibuprofen (200 mg) orally at at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. Last dose on day four at 8 AM.
Percent Change in Arachidonic Acid Induced Platelet Aggregation	93 Percent inhibition of baseline Standard Deviation 6	93 Percent inhibition of baseline Standard Deviation 6	95 Percent inhibition of baseline Standard Deviation 4	90 Percent inhibition of baseline Standard Deviation 16	—	—	—

Adverse Events

Phase 1a: Acetaminophen 1000mg / Aspirin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Phase 1a: Acetaminophen 2000mg / Aspirin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Phase 1b: Acetaminophen 1000 mg Alone

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Phase 2: Acetaminophen vs. Ibuprofen

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Tilo Grosser, MD

University of Pennsylvania

Phone: 215-573-7600

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place