Trial Outcomes & Findings for Drug Interactions Between Morphine and Orally or IV Administered Acetaminophen (NCT NCT02848729)

Last Updated: 2020-02-05

Results Overview

The area under the plasma drug concentration-time curve (AUC) is an estimate of how much drug remains available for the body to use, within a certain amount of time after the drug is administered. AUC6 is reported for each of the 6-hour dosing periods of acetaminophen before (hours -6 to 0), during (hours 0-6 and 6-12) and after (hours 12-18) morphine co-administration for each route of acetaminophen administration

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

50 participants

Primary outcome timeframe

hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration

Results posted on

2020-02-05

Participant Flow

Participant milestones

Participant milestones
Measure	Oral Acetaminophen Treatment A = 4 repeat doses of 1,000 mg oral acetaminophen (2 x 500 mg tablets) and an intravenous (IV) infusion of saline every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6.	IV Acetaminophen Treatment B = 4 repeat doses of IV acetaminophen (1,000 mg/100 mL) and 2 placebo tablets every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6.
Overall Study STARTED	27	23
Overall Study Per Protocol Population	11	11
Overall Study Safety Population	27	23
Overall Study COMPLETED	11	12
Overall Study NOT COMPLETED	16	11

Reasons for withdrawal

Reasons for withdrawal
Measure	Oral Acetaminophen Treatment A = 4 repeat doses of 1,000 mg oral acetaminophen (2 x 500 mg tablets) and an intravenous (IV) infusion of saline every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6.	IV Acetaminophen Treatment B = 4 repeat doses of IV acetaminophen (1,000 mg/100 mL) and 2 placebo tablets every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6.
Overall Study Withdrawal by Subject	1	0
Overall Study Emesis	15	11

Baseline Characteristics

Drug Interactions Between Morphine and Orally or IV Administered Acetaminophen

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	IV Acetaminophen n=11 Participants Treatment B = 4 repeat doses of IV acetaminophen (1,000 mg/100 mL) and 2 placebo tablets every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6.	Total n=22 Participants Total of all reporting groups	Oral Acetaminophen n=11 Participants Treatment A = 4 repeat doses of 1,000 mg oral acetaminophen (2 x 500 mg tablets) and an IV infusion of saline every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6.
Age, Continuous	32.5 years STANDARD_DEVIATION 11.25 • n=107 Participants	32.8 years STANDARD_DEVIATION 10.31 • n=206 Participants	33.1 years STANDARD_DEVIATION 9.82 • n=99 Participants
Sex: Female, Male Female	1 Participants n=107 Participants	1 Participants n=206 Participants	0 Participants n=99 Participants
Sex: Female, Male Male	10 Participants n=107 Participants	21 Participants n=206 Participants	11 Participants n=99 Participants
Race/Ethnicity, Customized White	9 Participants n=107 Participants	16 Participants n=206 Participants	7 Participants n=99 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=107 Participants	4 Participants n=206 Participants	2 Participants n=99 Participants
Race/Ethnicity, Customized Hispanic or Latino Ethnicity	6 Participants n=107 Participants	10 Participants n=206 Participants	4 Participants n=99 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	5 Participants n=107 Participants	12 Participants n=206 Participants	7 Participants n=99 Participants

PRIMARY outcome

Timeframe: hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration

Population: Per-protocol population, which is defined as the participants who received all study medication, provided all 33 blood samples within required time points and completed the study with no major protocol deviations.

Outcome measures

Outcome measures
Measure	First Dose - Before Morphine Co-administration n=11 Participants AUC6 for acetaminophen before morphine co-administration (hours -6 to -1)	Second Dose - During Morphine Co-administration n=11 Participants AUC6 for acetaminophen during morphine co-administration (hours 0 to 6)	Third Dose - During Morphine Co-administration n=11 Participants AUC6 for acetaminophen during morphine co-administration (hours 6 to 12)	Fourth Dose - After Morphine Co-administration n=11 Participants AUC6 for acetaminophen after morphine co-administration (hours 12 to 18)
Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen Treatment A: Oral Acetaminophen	31.00 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 5.11	28.51 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 5.96	25.31 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 11.59	52.38 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 13.48
Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen Treatment B: IV Acetaminophen	42.56 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 3.94	44.37 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 4.46	43.59 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 4.21	49.05 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 3.95

PRIMARY outcome

Timeframe: hours 0-18 during treatment with each mode of acetaminophen administration

AUC18 is reported for the 18-hour treatment period after first morphine co-administration, for each route of acetaminophen administration

Outcome measures

Outcome measures
Measure	First Dose - Before Morphine Co-administration n=11 Participants AUC6 for acetaminophen before morphine co-administration (hours -6 to -1)	Second Dose - During Morphine Co-administration AUC6 for acetaminophen during morphine co-administration (hours 0 to 6)	Third Dose - During Morphine Co-administration AUC6 for acetaminophen during morphine co-administration (hours 6 to 12)	Fourth Dose - After Morphine Co-administration AUC6 for acetaminophen after morphine co-administration (hours 12 to 18)
Area Under the Plasma Concentration-time Curve Over 18 Hours (AUC18) for Acetaminophen After First Morphine Co-administration Treatment A: Oral Acetaminophen	82.50 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 23.28	—	—	—
Area Under the Plasma Concentration-time Curve Over 18 Hours (AUC18) for Acetaminophen After First Morphine Co-administration Treatment B: IV Acetaminophen	63.58 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 6.74	—	—	—

PRIMARY outcome

Timeframe: hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration

Population: Per-protocol population

Following the administration of drugs, the plasma concentration generally reaches a single, well-defined peak which is the most drug that is available for the body to use (Cmax). Cmax is reported for the 6-hour dosing periods before (hours -6 to 0), during (hours 0-6 and 6-12), and after (hours 12-18) morphine co-administration for each route of acetaminophen administration.

Outcome measures

Outcome measures
Measure	First Dose - Before Morphine Co-administration n=11 Participants AUC6 for acetaminophen before morphine co-administration (hours -6 to -1)	Second Dose - During Morphine Co-administration n=11 Participants AUC6 for acetaminophen during morphine co-administration (hours 0 to 6)	Third Dose - During Morphine Co-administration n=11 Participants AUC6 for acetaminophen during morphine co-administration (hours 6 to 12)	Fourth Dose - After Morphine Co-administration n=11 Participants AUC6 for acetaminophen after morphine co-administration (hours 12 to 18)
Maximum Concentration (Cmax) of Acetaminophen Treatment A: Oral Acetaminophen	11.6 mcg/mL Standard Deviation 4.11	7.29 mcg/mL Standard Deviation 1.82	7.25 mcg/mL Standard Deviation 3.95	13.5 mcg/mL Standard Deviation 3.31
Maximum Concentration (Cmax) of Acetaminophen Treatment B: IV Acetaminophen	22.6 mcg/mL Standard Deviation 3.83	17.0 mcg/mL Standard Deviation 1.48	17.5 mcg/mL Standard Deviation 1.93	28.5 mcg/mL Standard Deviation 4.31

PRIMARY outcome

Timeframe: hours -6 to 0, 0-6, 6-12 and 12-18 during treatment with each mode of acetaminophen administration

Population: Per-protocol population

Following the administration of drugs, the time at which the plasma concentration reaches Cmax is called Tmax. Tmax is reported for the 6-hour dosing periods before (hours -6 to 0), during (hours 0-6 and 6-12) and after (hours 12-18) morphine co-administration for each route of acetaminophen administration.

Outcome measures

Outcome measures
Measure	First Dose - Before Morphine Co-administration n=11 Participants AUC6 for acetaminophen before morphine co-administration (hours -6 to -1)	Second Dose - During Morphine Co-administration n=11 Participants AUC6 for acetaminophen during morphine co-administration (hours 0 to 6)	Third Dose - During Morphine Co-administration n=11 Participants AUC6 for acetaminophen during morphine co-administration (hours 6 to 12)	Fourth Dose - After Morphine Co-administration n=11 Participants AUC6 for acetaminophen after morphine co-administration (hours 12 to 18)
Time to Maximum Concentration (Tmax) of Acetaminophen Oral Acetaminophen	1.48 hours Interval 0.75 to 2.02	1.64 hours Interval 0.5 to 3.0	3.26 hours Interval 0.5 to 5.85	2.84 hours Interval 1.17 to 4.02
Time to Maximum Concentration (Tmax) of Acetaminophen IV Acetaminophen	0.25 hours Interval 0.25 to 0.27	0.50 hours Interval 0.5 to 0.5	0.51 hours Interval 0.5 to 0.57	0.25 hours Interval 0.25 to 0.28

Adverse Events

Oral Acetaminophen

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

IV Acetaminophen

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Medical Information Call Center

Mallinckrodt Pharmaceuticals

Phone: 800-556-3314

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	First Dose - Before Morphine Co-administration n=11 Participants AUC6 for acetaminophen before morphine co-administration (hours -6 to -1)	Second Dose - During Morphine Co-administration n=11 Participants AUC6 for acetaminophen during morphine co-administration (hours 0 to 6)	Third Dose - During Morphine Co-administration n=11 Participants AUC6 for acetaminophen during morphine co-administration (hours 6 to 12)	Fourth Dose - After Morphine Co-administration n=11 Participants AUC6 for acetaminophen after morphine co-administration (hours 12 to 18)
Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen Treatment A: Oral Acetaminophen	31.00 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 5.11	28.51 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 5.96	25.31 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 11.59	52.38 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 13.48
Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen Treatment B: IV Acetaminophen	42.56 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 3.94	44.37 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 4.46	43.59 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 4.21	49.05 hourmicrogram per milliliter (hmcg/mL) Standard Deviation 3.95

Measure	Oral Acetaminophen n=27 participants at risk Treatment A = 4 repeat doses of 1,000 mg oral acetaminophen (2 x 500 mg tablets) and an IV infusion of saline every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6.	IV Acetaminophen n=23 participants at risk Treatment B = 4 repeat doses of IV acetaminophen (1,000 mg/100 mL) and 2 placebo tablets every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6.
Gastrointestinal disorders Vomiting	55.6% 15/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	47.8% 11/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Gastrointestinal disorders Nausea	44.4% 12/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	43.5% 10/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Gastrointestinal disorders Abdominal discomfort	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Gastrointestinal disorders Abdominal pain	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Gastrointestinal disorders Salivary hypersecretion	0.00% 0/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	4.3% 1/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Nervous system disorders Dizziness	14.8% 4/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	17.4% 4/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Nervous system disorders Somnolence	14.8% 4/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	4.3% 1/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Nervous system disorders Headache	7.4% 2/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	8.7% 2/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Nervous system disorders Paraesthesia	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	8.7% 2/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
General disorders Asthenia	7.4% 2/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
General disorders Catheter site pain	7.4% 2/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
General disorders Chills	0.00% 0/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	4.3% 1/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
General disorders Fatigue	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
General disorders Feeling abnormal	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
General disorders Feeling hot	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
General disorders Feeling of relaxation	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
General disorders Infusion site pruritus	0.00% 0/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	4.3% 1/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Psychiatric disorders Euphoric mood	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	13.0% 3/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Psychiatric disorders Irritability	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Skin and subcutaneous tissue disorders Pruritus	7.4% 2/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	8.7% 2/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Skin and subcutaneous tissue disorders Pruritus generalised	0.00% 0/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	4.3% 1/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.
Renal and urinary disorders Micturition disorder	3.7% 1/27 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.	0.00% 0/23 • From start of the study to the end of study (approximately 2 weeks, including wash-out period) The safety analysis set, defined as all participants who received study drug, was used for the adverse events module.