Acetaminophen in aSAH to Inhibit Lipid Peroxidation and Cerebral Vasospasm

NCT ID: NCT00585559

Last Updated: 2025-04-18

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-04-30
• Study Completion Date: 2023-10-26

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.

Conditions

Aneurysmal Subarachnoid Hemorrhage; Cerebral Vasospasm

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebos for acetaminophen and N-acetylcysteine

Placebos for acetaminophen and N-acetylcysteine

Group Type: PLACEBO_COMPARATOR

Placebos for acetaminophen and N-acetylcysteine

Intervention Type: DRUG

Placebos for acetaminophen and N-acetylcysteine

Acetaminophen and N-acetylcysteine placebo

Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo

Group Type: ACTIVE_COMPARATOR

APAP 1 gm every 6 hours and N-acetylcysteine placebo

Intervention Type: DRUG

Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo

N-acetylcysteine and acetaminophen

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

Group Type: ACTIVE_COMPARATOR

NAC IV infusion at 0.5 gm hourly and APAP placebo

Intervention Type: DRUG

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

Acetaminophen 1 Gram and N-acetylcysteine

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

Group Type: ACTIVE_COMPARATOR

APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly

Intervention Type: DRUG

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

Acetaminophen 1.5 Gram and N-acetylcysteine

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

Group Type: ACTIVE_COMPARATOR

APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly

Intervention Type: DRUG

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

Interventions

Placebos for acetaminophen and N-acetylcysteine

Placebos for acetaminophen and N-acetylcysteine

Intervention Type: DRUG

APAP 1 gm every 6 hours and N-acetylcysteine placebo

Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo

Intervention Type: DRUG

NAC IV infusion at 0.5 gm hourly and APAP placebo

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

Intervention Type: DRUG

APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly

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

Intervention Type: DRUG

APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly

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

Intervention Type: DRUG

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)

• Minimum Eligible Age: 20 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of General Medical Sciences (NIGMS)

NIH

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Matthew Fusco

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Matthew Fusco, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NIH P50 GM015431

Identifier Type: -

Identifier Source: org_study_id

VUMCIRB060556

Identifier Type: -

Identifier Source: secondary_id

P50GM015431

Identifier Type: NIH

Identifier Source: secondary_id

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