Clinical, Pharmacological and Molecular Effects of IV and Oral Acetaminophen in Adults With aSAH (aSAH)

• ClinicalTrials.gov Identifier: NCT02549716
• Recruitment Status: Terminated
• First Posted: September 15, 2015
• Results First Posted: April 10, 2019
• Last Update Posted: April 10, 2019
• Sponsor: Milton S. Hershey Medical Center
• Information provided by (Responsible Party): Sprague W Hazard III, Milton S. Hershey Medical Center

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Conditions: Subarachnoid Hemorrhage; Stroke
• Interventions: Drug: IV acetaminophen; Drug: Oral acetaminophen; Drug: Oral placebo; Drug: IV placebo
• Enrollment: 3

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	IV Acetaminophen + Oral Placebo	Oral Acetaminophen + IV Placebo
Arm/Group Description	Patients in this group will receive IV acetaminophen and an oral placebo. The IV formulation will be given using the FDA approved OFIRMEV which comes in a single glass bottle at a concentration of 1000mg/100ml (10mg/ml) containing a total of 1 gram of acetaminophen. IV acetaminophen: Patients in this group will receive IV acetaminophen and an oral placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. Oral placebo: Patients who receive IV acetaminophen will also receive an oral placebo with their IV treatments (every 6 hours for a 14 day period).	Patients in this group will receive oral acetaminophen and a saline solution placebo through their IV. The enteral formulation will be in the standard tablet form of 500mg per pill. Patients will receive two pills, or 1 gram of acetaminophen. Oral acetaminophen: Patients in this group will receive oral acetaminophen and an IV saline solution placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. IV placebo: Patients who receive oral acetaminophen will also receive a saline solution placebo at the same time that they receive the oral acetaminophen treatment (every 6 hours for 14 days).
Period Title: Overall Study
Started	1	2
Completed	1	2
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		IV Acetaminophen + Oral Placebo	Oral Acetaminophen + IV Placebo	Total
Arm/Group Description		Patients in this group will receive IV acetaminophen and an oral placebo. The IV formulation will be given using the FDA approved OFIRMEV which comes in a single glass bottle at a concentration of 1000mg/100ml (10mg/ml) containing a total of 1 gram of acetaminophen. IV acetaminophen: Patients in this group will receive IV acetaminophen and an oral placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. Oral placebo: Patients who receive IV acetaminophen will also receive an oral placebo with their IV treatments (every 6 hours for a 14 day period).	Patients in this group will receive oral acetaminophen and a saline solution placebo through their IV. The enteral formulation will be in the standard tablet form of 500mg per pill. Patients will receive two pills, or 1 gram of acetaminophen. Oral acetaminophen: Patients in this group will receive oral acetaminophen and an IV saline solution placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. IV placebo: Patients who receive oral acetaminophen will also receive a saline solution placebo at the same time that they receive the oral acetaminophen treatment (every 6 hours for 14 days).	Total of all reporting groups
Overall Number of Baseline Participants		1	2	3
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Full Range); Unit of measure: Years
	Number Analyzed	1 participants	2 participants	3 participants
		37; (37 to 37)	45; (45 to 46)	42.6; (37 to 46)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1 participants	2 participants	3 participants
	Female	1 100.0%	2 100.0%	3 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1 participants	2 participants	3 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	1 100.0%	2 100.0%	3 100.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	1 participants	2 participants	3 participants
		1	2	3

Outcome Measures

1. Primary Outcome

Title	Bioavailability of Acetaminophen in Cerebral Spinal Fluid (CSF) and Blood
Description	Patients in both IV and PO groups will have samples taken from their Cerebral Spinal Fluid (CSF) and blood at the above times after acetaminophen is administered for the first time. They will then have additional samples taken every 24 hours following the time of first drug administration for 14 days. Patients will also have a sample collected every 35 hours (1 hour before the 6th loading dose) to determine the steady state level of acetaminophen.
Time Frame	Time = 0, 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after first drug administration

Outcome Measure Data

Analysis Population Description

Outcome measure was not analyzed because study was terminated early.

Arm/Group Title	IV Acetaminophen + Oral Placebo	Oral Acetaminophen + IV Placebo
Arm/Group Description:	Patients in this group will receive IV acetaminophen and an oral placebo. The IV formulation will be given using the FDA approved OFIRMEV which comes in a single glass bottle at a concentration of 1000mg/100ml (10mg/ml) containing a total of 1 gram of acetaminophen. IV acetaminophen: Patients in this group will receive IV acetaminophen and an oral placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. Oral placebo: Patients who receive IV acetaminophen will also receive an oral placebo with their IV treatments (every 6 hours for a 14 day period).	Patients in this group will receive oral acetaminophen and a saline solution placebo through their IV. The enteral formulation will be in the standard tablet form of 500mg per pill. Patients will receive two pills, or 1 gram of acetaminophen. Oral acetaminophen: Patients in this group will receive oral acetaminophen and an IV saline solution placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. IV placebo: Patients who receive oral acetaminophen will also receive a saline solution placebo at the same time that they receive the oral acetaminophen treatment (every 6 hours for 14 days).
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

2. Secondary Outcome

Title	Concentrations of Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Thromboxane A-2 (TXA-2) in Cerebral Spinal Fluid (CSF) and Blood
Description	Patients in both IV and PO groups will have samples taken from their Cerebral Spinal Fluid (CSF) and blood at the above times after acetaminophen is administered for the first time. They will then have additional samples taken every 24 hours following the time of first drug administration for 14 days. These samples will be examined to determine concentrations of Interleukin-1 (IL-1), Interleukin-6 (IL-6), and thromboxane A-2 (TXA-2) in both the Cerebral Spinal Fluid (CSF) and blood. This will enable the team to determine if route of entry of acetaminophen plays a significant role in the level of inflammatory markers in critically ill patients.
Time Frame	Time = 0, 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after first drug administration. Additionally, every 24 hours after time t=0 for 14 days (14 additional samples from both blood and CSF).

Outcome Measure Data

Analysis Population Description

Outcome measure was not analyzed because study was terminated early

Arm/Group Title	IV Acetaminophen + Oral Placebo	Oral Acetaminophen + IV Placebo
Arm/Group Description:	Patients in this group will receive IV acetaminophen and an oral placebo. The IV formulation will be given using the FDA approved OFIRMEV which comes in a single glass bottle at a concentration of 1000mg/100ml (10mg/ml) containing a total of 1 gram of acetaminophen. IV acetaminophen: Patients in this group will receive IV acetaminophen and an oral placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. Oral placebo: Patients who receive IV acetaminophen will also receive an oral placebo with their IV treatments (every 6 hours for a 14 day period).	Patients in this group will receive oral acetaminophen and a saline solution placebo through their IV. The enteral formulation will be in the standard tablet form of 500mg per pill. Patients will receive two pills, or 1 gram of acetaminophen. Oral acetaminophen: Patients in this group will receive oral acetaminophen and an IV saline solution placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. IV placebo: Patients who receive oral acetaminophen will also receive a saline solution placebo at the same time that they receive the oral acetaminophen treatment (every 6 hours for 14 days).
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

3. Secondary Outcome

Title	Number of Febrile Periods
Description	Patients in both IV and PO groups will have their temperatures taken at the times listed. This will help determine if route of entry of acetaminophen plays a significant role in the number of febrile periods.
Time Frame	Time = 0, 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after first drug administration. Additionally, every 24 hours after time t=0 for 14 days (14 additional samples from both blood and CSF).

Outcome Measure Data

Analysis Population Description

Outcome measure was not analyzed because study was terminated early

Arm/Group Title	IV Acetaminophen + Oral Placebo	Oral Acetaminophen + IV Placebo
Arm/Group Description:	Patients in this group will receive IV acetaminophen and an oral placebo. The IV formulation will be given using the FDA approved OFIRMEV which comes in a single glass bottle at a concentration of 1000mg/100ml (10mg/ml) containing a total of 1 gram of acetaminophen. IV acetaminophen: Patients in this group will receive IV acetaminophen and an oral placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. Oral placebo: Patients who receive IV acetaminophen will also receive an oral placebo with their IV treatments (every 6 hours for a 14 day period).	Patients in this group will receive oral acetaminophen and a saline solution placebo through their IV. The enteral formulation will be in the standard tablet form of 500mg per pill. Patients will receive two pills, or 1 gram of acetaminophen. Oral acetaminophen: Patients in this group will receive oral acetaminophen and an IV saline solution placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. IV placebo: Patients who receive oral acetaminophen will also receive a saline solution placebo at the same time that they receive the oral acetaminophen treatment (every 6 hours for 14 days).
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

4. Secondary Outcome

Title	Incidence of Vasospasm
Description	The investigators will measure the incidence of vasospasm in patients with subarachnoid hemorrhage (SAH) who receive 1g Q6 of IV acetaminophen starting on post-bleed day 0 and continuing for 14 consecutive days (typical vasospasm window). Clinical vasospasm will be defined as the presence of new focal neurological deficits (motor or speech deficits) that developed after subarachnoid hemorrhage (SAH), a decrease in the Glasgow Coma Score (GCS) of 2 or more points for >6hrs, a new cerebral infarction unrelated to post-treatment (coiling or clipping) complications, re-bleed, progressive hydrocephalus, electrolyte or metabolic disturbance, or infection. The incidence of clinical vasospasm will be identified in the patients Electronic Medical Record (EMR) after the 14 day period.
Time Frame	Days 0-14 following diagnosis with subarachnoid hemorrhage.

Outcome Measure Data

Analysis Population Description

Outcome measure was not analyzed because study was terminated early.

Arm/Group Title	IV Acetaminophen + Oral Placebo	Oral Acetaminophen + IV Placebo
Arm/Group Description:	Patients in this group will receive IV acetaminophen and an oral placebo. The IV formulation will be given using the FDA approved OFIRMEV which comes in a single glass bottle at a concentration of 1000mg/100ml (10mg/ml) containing a total of 1 gram of acetaminophen. IV acetaminophen: Patients in this group will receive IV acetaminophen and an oral placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. Oral placebo: Patients who receive IV acetaminophen will also receive an oral placebo with their IV treatments (every 6 hours for a 14 day period).	Patients in this group will receive oral acetaminophen and a saline solution placebo through their IV. The enteral formulation will be in the standard tablet form of 500mg per pill. Patients will receive two pills, or 1 gram of acetaminophen. Oral acetaminophen: Patients in this group will receive oral acetaminophen and an IV saline solution placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. IV placebo: Patients who receive oral acetaminophen will also receive a saline solution placebo at the same time that they receive the oral acetaminophen treatment (every 6 hours for 14 days).
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	2 weeks (14 days)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	IV Acetaminophen + Oral Placebo		Oral Acetaminophen + IV Placebo
Arm/Group Description	Patients in this group will receive IV acetaminophen and an oral placebo. The IV formulation will be given using the FDA approved OFIRMEV which comes in a single glass bottle at a concentration of 1000mg/100ml (10mg/ml) containing a total of 1 gram of acetaminophen. IV acetaminophen: Patients in this group will receive IV acetaminophen and an oral placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. Oral placebo: Patients who receive IV acetaminophen will also receive an oral placebo with their IV treatments (every 6 hours for a 14 day period).		Patients in this group will receive oral acetaminophen and a saline solution placebo through their IV. The enteral formulation will be in the standard tablet form of 500mg per pill. Patients will receive two pills, or 1 gram of acetaminophen. Oral acetaminophen: Patients in this group will receive oral acetaminophen and an IV saline solution placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. IV placebo: Patients who receive oral acetaminophen will also receive a saline solution placebo at the same time that they receive the oral acetaminophen treatment (every 6 hours for 14 days).
All-Cause Mortality
	IV Acetaminophen + Oral Placebo		Oral Acetaminophen + IV Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/1 (0.00%)		0/2 (0.00%)
Serious Adverse Events
	IV Acetaminophen + Oral Placebo		Oral Acetaminophen + IV Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0.00%)		0/2 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	IV Acetaminophen + Oral Placebo		Oral Acetaminophen + IV Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0.00%)		1/2 (50.00%)
Hepatobiliary disorders
Elevated Liver Function Tests † [1]	0/1 (0.00%)	0	1/2 (50.00%)	1
† Indicates events were collected by systematic assessment; [1] A participant was had an elevation in liver function tests that were greater than three times the admission values and led to withdrawal from the study

Limitations and Caveats

Study was terminated early

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Sprague W. Hazard III, M.D.
• Organization: Milton S. Hershey Medical Center
• Phone: 717-531-0003 ext 311253
• EMail: shazard@pennstatehealth.psu.edu

• Responsible Party: Sprague W Hazard III, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT02549716 History of Changes
• Other Study ID Numbers: IRBSTUDY00002767
• First Submitted: July 1, 2015
• First Posted: September 15, 2015
• Results First Submitted: February 28, 2019
• Results First Posted: April 10, 2019
• Last Update Posted: April 10, 2019