Trial Outcomes & Findings for Aminotransferase Trends During Prolonged Acetaminophen Dosing (NCT NCT00743093)

Last Updated: 2013-09-18

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

398 participants

Primary outcome timeframe

serial samples for 16-40 days

Results posted on

2013-09-18

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.	Placebo Arm placebo placebo : placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days
Base Study Period STARTED	224	52
Base Study Period COMPLETED	205	47
Base Study Period NOT COMPLETED	19	5
Extended Dosing Period STARTED	51	1
Extended Dosing Period COMPLETED	48	1
Extended Dosing Period NOT COMPLETED	3	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Aminotransferase Trends During Prolonged Acetaminophen Dosing

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Acetaminophen Arm n=224 Participants acetaminophen 500 mg	Placebo Arm n=52 Participants placebo	Total n=276 Participants Total of all reporting groups
Age, Categorical <=18 years	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	221 Participants n=5 Participants	52 Participants n=7 Participants	273 Participants n=5 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Age Continuous	36.3 years STANDARD_DEVIATION 12.16 • n=5 Participants	35.8 years STANDARD_DEVIATION 12.50 • n=7 Participants	36.2 years STANDARD_DEVIATION 12.21 • n=5 Participants
Sex: Female, Male Female	163 Participants n=5 Participants	39 Participants n=7 Participants	202 Participants n=5 Participants
Sex: Female, Male Male	61 Participants n=5 Participants	13 Participants n=7 Participants	74 Participants n=5 Participants
Region of Enrollment United States	224 participants n=5 Participants	52 participants n=7 Participants	276 participants n=5 Participants

PRIMARY outcome

Timeframe: serial samples for 16-40 days

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

Outcome measures

Outcome measures
Measure	Acetaminophen Arm n=205 Participants acetaminophen acetaminophen : 500 mg caplets; 2 capsules (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days.	Placebo Arm n=47 Participants placebo placebo : placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days
The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations. Subjects without persisitent ALT elevation	204 participants	47 participants
The Proportion of Subjects Treated With Long-term Acetaminophen (4 g/Day) That Develops Persistent ALT Elevations. Subjects with persistent ALT elevation	1 participants	0 participants

SECONDARY outcome

Timeframe: Days 1-3

Population: 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.

Outcome measures

Outcome measures
Measure	Acetaminophen Arm n=64 Participants acetaminophen acetaminophen : 500 mg caplets; 2 capsules (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days.	Placebo Arm n=15 Participants placebo placebo : placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days
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). Day 1-No. Subjects with Detectable APAP-cys	7 participants	1 participants
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). Day 2-No. Subjects with Detectable APAP-cys	57 participants	1 participants
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). Day 3-No. Subjects with Detectable APAP-cys	59 participants	1 participants

Adverse Events

Acetaminophen Arm

Serious events: 0 serious events

Other events: 147 other events

Deaths: 0 deaths

Placebo Arm

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Jody Green, PhD

Denver Heatlh Rocky Mountain Poison and Drug Center

Phone: 303-389-1246

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Acetaminophen Arm n=224 participants at risk acetaminophen acetaminophen : 500 mg caplets; 2 capsules (1 g)/dose; 4 doses (4 g)/day, 4 hours apart for 16 to 40 days.	Placebo Arm n=52 participants at risk placebo placebo : placebo caplets, 2 caplets per dose, 4 doses per day, 4 hours apart for 16 to 40 days
Ear and labyrinth disorders Ear and labyrinth disorders	1.3% 3/224 • Adverse events were collected starting at the time of consent through study completion.	0.00% 0/52 • Adverse events were collected starting at the time of consent through study completion.
Eye disorders Eye disorders	0.89% 2/224 • Adverse events were collected starting at the time of consent through study completion.	0.00% 0/52 • Adverse events were collected starting at the time of consent through study completion.
Gastrointestinal disorders Gastrointestinal Disorders	31.2% 70/224 • Adverse events were collected starting at the time of consent through study completion.	19.2% 10/52 • Adverse events were collected starting at the time of consent through study completion.
General disorders General disorders and administration site conditions	10.3% 23/224 • Adverse events were collected starting at the time of consent through study completion.	5.8% 3/52 • Adverse events were collected starting at the time of consent through study completion.
Infections and infestations Infections and infestations	6.2% 14/224 • Adverse events were collected starting at the time of consent through study completion.	3.8% 2/52 • Adverse events were collected starting at the time of consent through study completion.
Injury, poisoning and procedural complications Injury, poisoning and procedural complications	4.5% 10/224 • Adverse events were collected starting at the time of consent through study completion.	3.8% 2/52 • Adverse events were collected starting at the time of consent through study completion.
Metabolism and nutrition disorders Metabolism and nutrition disorders	1.3% 3/224 • Adverse events were collected starting at the time of consent through study completion.	1.9% 1/52 • Adverse events were collected starting at the time of consent through study completion.
Musculoskeletal and connective tissue disorders Muskuloskeletal and connective tissue disorders	11.6% 26/224 • Adverse events were collected starting at the time of consent through study completion.	9.6% 5/52 • Adverse events were collected starting at the time of consent through study completion.
Nervous system disorders Nervous system disorders	18.8% 42/224 • Adverse events were collected starting at the time of consent through study completion.	21.2% 11/52 • Adverse events were collected starting at the time of consent through study completion.
Psychiatric disorders Psychiatric disorders	2.7% 6/224 • Adverse events were collected starting at the time of consent through study completion.	1.9% 1/52 • Adverse events were collected starting at the time of consent through study completion.
Renal and urinary disorders Renal and urinary disorders	0.00% 0/224 • Adverse events were collected starting at the time of consent through study completion.	1.9% 1/52 • Adverse events were collected starting at the time of consent through study completion.
Reproductive system and breast disorders Reproductive system and breast disorders	2.2% 5/224 • Adverse events were collected starting at the time of consent through study completion.	1.9% 1/52 • Adverse events were collected starting at the time of consent through study completion.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders	10.3% 23/224 • Adverse events were collected starting at the time of consent through study completion.	9.6% 5/52 • Adverse events were collected starting at the time of consent through study completion.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders	4.0% 9/224 • Adverse events were collected starting at the time of consent through study completion.	0.00% 0/52 • Adverse events were collected starting at the time of consent through study completion.
Vascular disorders Vascular disorders	4.0% 9/224 • Adverse events were collected starting at the time of consent through study completion.	1.9% 1/52 • Adverse events were collected starting at the time of consent through study completion.