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

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ClinicalTrials.gov Identifier: NCT02549716
Recruitment Status : Recruiting
First Posted : September 15, 2015
Last Update Posted : August 3, 2017
Sponsor:
Information provided by (Responsible Party):
Sprague W Hazard III, Milton S. Hershey Medical Center

Brief Summary:
This study compares the bioavailability of IV and PO acetaminophen in both blood and the cerebrospinal fluid (CSF) of patients following subarachnoid hemorrhage. The study will also compare the temperature and levels of inflammatory cytokines in both blood and CSF of patients treated with IV and PO acetaminophen.

Condition or disease Intervention/treatment Phase
Subarachnoid Hemorrhage Stroke Drug: IV acetaminophen Drug: Oral acetaminophen Drug: Oral placebo Drug: IV placebo Phase 4

Detailed Description:
In individuals diagnosed with subarachnoid hemorrhage (SAH), fevers have been shown to have detrimental micro and macroscopic effects on the brain that can ultimately cause secondary brain injury. The anti-pyretic effects of oral acetaminophen have been studied in critically ill patients but no study has been able to compare these effects to the IV form of acetaminophen also known as OFIRMEV. The investigators wish to explore the notion that IV acetaminophen will be more effective than enteral acetaminophen in reducing the incidence of non-infectious fevers in critically ill patients. In addition, the investigators propose to study the levels of inflammatory cytokines after administration of IV or enteral acetaminophen, as well as, determine the incidence of vasospasm in SAH patients treated with IV acetaminophen. Currently, external ventricular drain (EVD) placement is the "standard of care" in patients who present with SAH and altered mental status/coma. The presence of an EVD allows for continuous sampling and removal of cerebral spinal fluid (CSF) as necessary to alleviate dangerous elevations in intracranial pressure. This clinical scenario allows for a unique, continuous outlet to access the CSF, without placing patients at risk, and without further invasive procedures (i.e. repeated spinal taps). These samples of CSF can be assayed for levels of acetaminophen, as well as inflammatory markers of fever which include interleukin-1 (IL-1), interleukin-6 (IL-6), and thromboxane-2 (TXA-2), in patients selected to be given enteral or IV acetaminophen.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Clinical, Pharmacological and Molecular Effects of Intravenous and Oral Acetaminophen in Adults With Aneurysmal Sub-Arachnoid Hemorrhage
Actual Study Start Date : January 5, 2017
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : June 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

Arm Intervention/treatment
Experimental: IV acetaminophen + oral placebo
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.
Drug: 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.
Other Names:
  • Ofirmev
  • IV paracetamol

Drug: 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).
Other Name: placebo

Experimental: Oral acetaminophen + IV placebo
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.
Drug: 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.
Other Names:
  • Tylenol
  • paracetamol

Drug: 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).
Other Name: placebo, saline solution




Primary Outcome Measures :
  1. Bioavailability of Acetaminophen in CSF and blood [ Time Frame: Time = 0, 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after first drug administration ]
    Patients in both IV and PO groups will have samples taken from their 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.


Secondary Outcome Measures :
  1. Concentrations of IL-1, IL-6, and TXA-2 in CSF and blood [ 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). ]
    Patients in both IV and PO groups will have samples taken from their 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 IL-1, IL-6, and TXA-2 in both the 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.

  2. 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). ]
    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.

  3. Incidence of vasospasm [ Time Frame: Days 0-14 following diagnosis with subarachnoid hemorrhage. ]
    The investigators will measure the incidence of vasospasm in patients with 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 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 EMR after the 14 day period.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of subarachnoid hemorrhage (must be confirmed by CT, CTA, lumbar puncture, or MRI).
  • Fisher Grade between 1-3 (subarachnoid blood without signs of intraventricular hemorrhage or parenchymal extension).
  • Placement of an external ventricular drain.
  • Adults aged 18-100 years.

Exclusion Criteria:

  • Anyone under the age of 18 or over the age of 100.
  • Adult patients with subarachnoid hemorrhage with interventricular hemorrhage or parenchymal extension (Fisher Grade 4).
  • Contraindication to acetaminophen such as a known hypersensitivity, severe hepatic impairment, or severe active liver disease.
  • Severe renal impairment (creatinine clearance ≤ 30 mL/min).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02549716


Contacts
Contact: Sprague W Hazard, MD 717-531-0003 ext 311253 shazard@hmc.psu.edu

Locations
United States, Pennsylvania
Penn State Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033
Contact: Will Hazard, MD    717-531-8521    shazard@hmc.psu.edu   
Sponsors and Collaborators
Milton S. Hershey Medical Center
Investigators
Principal Investigator: Sprague W Hazard, MD "Penn State College of Medicine, Penn State Milton S. Hershey Medical Center

Responsible Party: Sprague W Hazard III, Assistant Professor of Anesthesiology, Milton S. Hershey Medical Center
ClinicalTrials.gov Identifier: NCT02549716     History of Changes
Other Study ID Numbers: IRBSTUDY00002767
First Posted: September 15, 2015    Key Record Dates
Last Update Posted: August 3, 2017
Last Verified: August 2017

Keywords provided by Sprague W Hazard III, Milton S. Hershey Medical Center:
Acetaminophen
interleukin-6
interleukin-1
thromboxane A2

Additional relevant MeSH terms:
Hemorrhage
Subarachnoid Hemorrhage
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pharmaceutical Solutions
Acetaminophen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics