TerminatedNCT00585559Updated Apr 18, 2025Results posted

Acetaminophen in aSAH to Inhibit Lipid Peroxidation and Cerebral Vasospasm

A Phase 3 interventional study of Placebos for acetaminophen and N-acetylcysteine and APAP 1 gm every 6 hours and N-acetylcysteine placebo in Aneurysmal Subarachnoid Hemorrhage and Cerebral Vasospasm, sponsored by Vanderbilt University Medical Center. Terminated at 1 site in United States. Open to participants aged 20 Years and older. Per ClinicalTrials.gov, last updated 2025-04-18.

Sponsored by Vanderbilt University Medical Center · Phase 3, Interventional, and Treatment

Phase: Phase 3
Study type: Interventional
Enrollment: 44
Allocation: Randomized
Ages: 20 Years and older
Sex: All

Study 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.

Read the 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 studied

Aneurysmal Subarachnoid Hemorrhage
Cerebral Vasospasm

Browse trials for

Keywords

Lipid
Peroxidation
N-Acetylcysteine
Acetaminophen
Vasospasm

In context

Subarachnoid Hemorrhage

509 studies on the registry are indexed under Subarachnoid Hemorrhage; 124 are open to participants now.

This study's enrollment of 44 is below the median of 52 across 263 interventional studies indexed under Subarachnoid Hemorrhage.

Browse Subarachnoid Hemorrhage studies →

Lead sponsor

Vanderbilt University Medical Center is the lead sponsor of 824 studies on the registry; 164 are open to participants now.

Of its 122 completed or terminated interventional studies of FDA-regulated products, 91 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 20 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

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

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)

Study design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 44 participants (actual)

Study arms

Placebo comparator
Placebos for acetaminophen and N-acetylcysteine
Placebos for acetaminophen and N-acetylcysteine
Drug: Placebos for acetaminophen and N-acetylcysteine
Active comparator
Acetaminophen and N-acetylcysteine placebo
Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo
Drug: APAP 1 gm every 6 hours and N-acetylcysteine placebo
Active comparator
N-acetylcysteine and acetaminophen
N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo
Drug: NAC IV infusion at 0.5 gm hourly and APAP placebo
Active comparator
Acetaminophen 1 Gram and N-acetylcysteine
Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
Drug: APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Active comparator
Acetaminophen 1.5 Gram and N-acetylcysteine
Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
Drug: APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly

Interventions

DrugPlacebos for acetaminophen and N-acetylcysteine
Placebos for acetaminophen and N-acetylcysteine
DrugAPAP 1 gm every 6 hours and N-acetylcysteine placebo
Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo
DrugNAC IV infusion at 0.5 gm hourly and APAP placebo
N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo
DrugAPAP 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
DrugAPAP 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

What researchers measure

Primary outcomes

Number of Patients With Vasospasm Based on Magnetic Resonance Angiography (MRA)
Presence of vasospasm measured Magnetic Resonance Angiography (MRA). MRA measures the degree of arterial narrowing, with a higher score indicating more severe vasospasm. An MRA score of 84% sensitivity and 72% specificity is indicative of vasospasm.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
Number of Patients With Vasospasm Based on Computed Tomographic Angiography (CTA)
Presence of vasospasm measured by Computed Tomographic Angiography (CTA). CTA scores range from 0 (no vasospasm) to 34, where a score of 10 or more is indicative of vasospasm.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
National Institutes of Health Stroke Scale (NIHSS) Score
The scale measures the severity of symptoms associated with patient's stroke. It assesses the severity of impairments related to stroke. The impairments are graded on a 3-4 point scale with scores that range from 0-42. Patients with a higher score have a more severe impairment, and patients with a lower score have a less severe impairment.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
Modified Rankin Scale (MRS) Score
The modified Rankin Scale (mRS) is used for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The 7 point ordinal scale ranges from No symptoms (0) to Death (6), with higher scores representing worse outcome.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
Glasgow Outcome Scale (GOS) Score
The Glasgow Outcome Scale (GOS) is a scale used to assess recovery of participants with brain damage. The scale has 5 categories: Death (1), Persistent vegetative state (2), Severe disability (3), Moderate disability (4), Good recovery (5).
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
The Barthel Index Score
The Barthel index measures the extent to which someone can function independently during basic activities of daily living. Scores range from (from 0 to 100), 0 meaning disability and 100 meaning independence, therefore, higher score, better outcome.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event

Results

Posted Apr 18, 2025

Limitations and caveats

The original trial had multiple stops and starts in enrollment due to PI relocation and funding gaps. This prolonged the patient enrollment periods. Further, the original PI unexpectedly passed away quite suddenly at which point the data management and supervision of the trial reporting passed to its current reporting physician.

Participant flow

Participant flow — Overall Study
Milestone	N-acetylcysteine IV Infusion at 0.5 gm Hourly	Placebo for N-acetylcysteine IV Infusion at 0.5 gm Hourly	Acetaminophen Plus N-acetylcysteine Infusion
Started	16	17	11
Completed	16	17	11
Not completed	0	0	0

Outcome measures

PrimaryNumber of Patients With Vasospasm Based on Magnetic Resonance Angiography (MRA)

Presence of vasospasm measured Magnetic Resonance Angiography (MRA). MRA measures the degree of arterial narrowing, with a higher score indicating more severe vasospasm. An MRA score of 84% sensitivity and 72% specificity is indicative of vasospasm.

Time frame:: 8 Days post subarachnoid hemorrhage (SAH) event