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Acetaminophen in aSAH to Inhibit Lipid Peroxidation and Cerebral Vasospasm

Primary Purpose

Aneurysmal Subarachnoid Hemorrhage, Cerebral Vasospasm

Status
Active
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Placebos for acetaminophen and N-acetylcysteine
APAP 1 gm every 6 hours and N-acetylcysteine placebo
NAC IV infusion at 0.5 gm hourly and APAP placebo
APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Sponsored by
Vanderbilt University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aneurysmal Subarachnoid Hemorrhage focused on measuring Lipid, Peroxidation, N-Acetylcysteine, Acetaminophen, Vasospasm

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Ages ≥ 20
  • Fisher Grade III or III + IV SAH based upon admitting CT scan
  • Aneurysm secured by either clipping or coiling within 72 hours of SAH
  • Intracranial aneurysm confirmed by angiography or CTA
  • Presence of ventriculostomy for external ventricular drainage (EVD) prior to randomization

Exclusion Criteria:

  • Consent unobtainable
  • Enrollment in another interventional study
  • Patient is pregnant or lactating
  • Known co-morbidities that could affect outcome of this study
  • Contraindication to CTA
  • Serum creatinine > 1.4
  • Documented allergy to iodinated contrast that cannot be adequately treated with premedication
  • Documented allergy and/or intolerance to ApAP
  • Baseline liver disease
  • History of recent alcohol abuse with documented ALT or AST above normal laboratory values
  • Documented history of both malnutrition and decreased serum albumin below normal lab values
  • Documented abnormal platelet count below normal lab values
  • Documented abnormal PT or PTT above normal lab values
  • History or evidence of active asthma
  • Documented allergy and/or intolerance to N-acetylcysteine
  • Currently taking phenytoin, carbamazepine, or phenobarbital
  • Currently taking isoniazid (INH, Lanzid, Nydrazid)
  • Severe life-threatening complications resulting from standard aneurysm treatments that will likely prevent completion of the study
  • Patient unsuitable for the study, in the opinion of the investigator(s)

Sites / Locations

  • Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Placebo Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Placebos for acetaminophen and N-acetylcysteine

Acetaminophen and N-acetylcysteine placebo

N-acetylcysteine and acetaminophen

Acetaminophen 1 Gram and N-acetylcysteine

Acetaminophen 1.5 Gram and N-acetylcysteine

Arm Description

Placebos for acetaminophen and N-acetylcysteine

Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo

N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo

Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly

Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly

Outcomes

Primary Outcome Measures

The study is to determine whether APAP, NAC, and APAP with NAC will inhibit lipid peroxidation in (aSAH), utilizing F2-IsoPs as biomarkers for lipid peroxidation. The effect on the F2-IsoPs will be the primary study endpoint.

Secondary Outcome Measures

To determine whether APAP and APAP with NAC will inhibit vasospasm and brain ischemia in aSAH, as assessed by CTA w/perfusion imaging or MRI and diffusion weighted images.

Full Information

First Posted
December 26, 2007
Last Updated
October 17, 2022
Sponsor
Vanderbilt University Medical Center
Collaborators
National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS)
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1. Study Identification

Unique Protocol Identification Number
NCT00585559
Brief Title
Acetaminophen in aSAH to Inhibit Lipid Peroxidation and Cerebral Vasospasm
Official Title
Inhibition of Lipid Peroxidation and Cerebral Vasospasm by an Acetaminophen-Based Regimen in Patients With Aneurysmal Subarachnoid Hemorrhage
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 2007 (undefined)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University Medical Center
Collaborators
National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The objective of this study is to determine whether acetaminophen (APAP), N-acetylcysteine (NAC), and APAP in combination with NAC will inhibit lipid peroxidation in aneurysmal subarachnoid hemorrhage (aSAH), utilizing F2-IsoPs as biomarkers for lipid peroxidation.
Detailed Description
Aneurysmal subarachnoid hemorrhage (aSAH) is an often devastating form of stroke with high morbidity and mortality despite advances in surgical management. Approximately 30,000 patients annually suffer aSAH in the U.S. For patients who survive the initial subarachnoid hemorrhage, delayed cerebral vasospasm occurring from days 4-14 is the greatest cause of neurological disability and death. A growing body of evidence incriminates hemoprotein-catalyzed lipid peroxidation as the mediator of the vasospasm. Hemoglobin released from lysed red cells in the subarachnoid space becomes oxidized, in which state it acts as a pseudoperoxidase and generates the protein radicals that induce lipid peroxidation. F2-isoprostanes formed by this lipid peroxidation are highly potent constrictors of cerebral arterioles. We have demonstrated a more than 5 fold mean increase in F2-isoprostanes in the cerebrospinal fluid of patients with aSAH; this increase is maximal at the time of delayed vasospasm, and the level of increase is a function of the severity of the aSAH. We hypothesize that such vasoconstrictors are major contributors to the vasospasm produced by the hemoproteins, hemoglobin and myoglobin, in diseases in which they are released from their cellular confines. We have discovered that acetaminophen (APAP) is a potent inhibitor of hemoprotein-catalyzed lipid peroxidation with an IC50 for hemoglobin of 15 uM, which is in the range of plasma levels resulting from therapeutic doses of the drug in humans. Acetaminophen acts by reducing the ferryl-oxo radical form of the heme, and thereby prevents formation of the hemoprotein radical that initiates lipid peroxidation. To assess proof of concept in vivo, we determined the effect of acetaminophen in a rat model of rhabdomyolysis in which renal failure results from intense vasospasm. Acetaminophen blocked lipid peroxidation in this model, and prevented the renal failure with a dose that produced plasma levels in the therapeutic range for humans. We also have demonstrated that N-acetylcysteine (NAC) will inhibit hemoprotein-catalyzed lipid peroxidation. Moreover, NAC administration increases the levels of glutathione in vivo, and glutathione is a co-substrate for the glutathione peroxidases that can reduce the levels of peroxides in the environment of the aSAH . This is important as acetaminophen is most potent in inhibiting hemoprotein-catalyzed lipid peroxidation when peroxide concentrations are low. This concerted evidence is the basis for a hypothesis that NAC will augment the efficacy of acetaminophen as an inhibitor of hemoprotein-catalyzed lipid peroxidation in aSAH. These finding provide the rationale for a pilot study seeking proof of the concept that acetaminophen-based regimens can inhibit lipid peroxidation in patients with subarachnoid hemorrhage. Lipid peroxidation will be determined by analysis of F2-isoprostanes in cerebrospinal fluid. If such inhibition is seen, that then would provide a basis for a larger multi-center investigation to assess the effect on clinical endpoints. This pilot study will determine whether APAP, NAC, and APAP in combination with NAC will inhibit lipid peroxidation in aneurysmal subarachnoid hemorrhage.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aneurysmal Subarachnoid Hemorrhage, Cerebral Vasospasm
Keywords
Lipid, Peroxidation, N-Acetylcysteine, Acetaminophen, Vasospasm

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Placebos for acetaminophen and N-acetylcysteine
Arm Type
Placebo Comparator
Arm Description
Placebos for acetaminophen and N-acetylcysteine
Arm Title
Acetaminophen and N-acetylcysteine placebo
Arm Type
Active Comparator
Arm Description
Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo
Arm Title
N-acetylcysteine and acetaminophen
Arm Type
Active Comparator
Arm Description
N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo
Arm Title
Acetaminophen 1 Gram and N-acetylcysteine
Arm Type
Active Comparator
Arm Description
Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
Arm Title
Acetaminophen 1.5 Gram and N-acetylcysteine
Arm Type
Active Comparator
Arm Description
Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
Intervention Type
Drug
Intervention Name(s)
Placebos for acetaminophen and N-acetylcysteine
Intervention Description
Placebos for acetaminophen and N-acetylcysteine
Intervention Type
Drug
Intervention Name(s)
APAP 1 gm every 6 hours and N-acetylcysteine placebo
Intervention Description
Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo
Intervention Type
Drug
Intervention Name(s)
NAC IV infusion at 0.5 gm hourly and APAP placebo
Intervention Description
N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo
Intervention Type
Drug
Intervention Name(s)
APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Intervention Description
Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
Intervention Type
Drug
Intervention Name(s)
APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Intervention Description
Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
Primary Outcome Measure Information:
Title
The study is to determine whether APAP, NAC, and APAP with NAC will inhibit lipid peroxidation in (aSAH), utilizing F2-IsoPs as biomarkers for lipid peroxidation. The effect on the F2-IsoPs will be the primary study endpoint.
Time Frame
21 days
Secondary Outcome Measure Information:
Title
To determine whether APAP and APAP with NAC will inhibit vasospasm and brain ischemia in aSAH, as assessed by CTA w/perfusion imaging or MRI and diffusion weighted images.
Time Frame
8 +/- days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Ages ≥ 20 Fisher Grade III or III + IV SAH based upon admitting CT scan Aneurysm secured by either clipping or coiling within 72 hours of SAH Intracranial aneurysm confirmed by angiography or CTA Presence of ventriculostomy for external ventricular drainage (EVD) prior to randomization Exclusion Criteria: Consent unobtainable Enrollment in another interventional study Patient is pregnant or lactating Known co-morbidities that could affect outcome of this study Contraindication to CTA Serum creatinine > 1.4 Documented allergy to iodinated contrast that cannot be adequately treated with premedication Documented allergy and/or intolerance to ApAP Baseline liver disease History of recent alcohol abuse with documented ALT or AST above normal laboratory values Documented history of both malnutrition and decreased serum albumin below normal lab values Documented abnormal platelet count below normal lab values Documented abnormal PT or PTT above normal lab values History or evidence of active asthma Documented allergy and/or intolerance to N-acetylcysteine Currently taking phenytoin, carbamazepine, or phenobarbital Currently taking isoniazid (INH, Lanzid, Nydrazid) Severe life-threatening complications resulting from standard aneurysm treatments that will likely prevent completion of the study Patient unsuitable for the study, in the opinion of the investigator(s)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthew Fusco, MD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Acetaminophen in aSAH to Inhibit Lipid Peroxidation and Cerebral Vasospasm

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