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Safety Study of Sildenafil in Treatment of Cerebral Aneurysm Vasospasm

Primary Purpose

Cerebral Vasospasm, Subarachnoid Hemorrhage

Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Sildenafil citrate
Sponsored by
University of Nebraska
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Cerebral Vasospasm focused on measuring Cerebral Vasospasm, Vasospasm, Subarachnoid Hemorrhage, Sildenafil citrate, Aneurysm, Intracranial aneurysm

Eligibility Criteria

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

Inclusion Criteria:

  • Subarachnoid Hemorrhage (Fisher Grade 3)
  • Cerebral Aneurysm documented by CTA/MRA/Cerebral Angiogram
  • Enrollment within 48 hours of symptom onset

Exclusion Criteria:

  • Hypersensitivity to Sildenafil
  • Pregnancy
  • Age less than 19 years
  • Concurrent use of nitrates or alpha-blockers
  • Aneurysm related to an arteriovenous malformation
  • Delayed enrollment past 48 hours
  • Subarachnoid hemorrhage that is not Fisher Grade 3

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Sildenafil Treatment of Cerebral Aneurysm Vasospasm

    Arm Description

    Trial Arm (single arm study)

    Outcomes

    Primary Outcome Measures

    Onset of cerebral vasospasm
    Onset of cerebral vasospasm, defined as transcranial Doppler velocity exceeding 120 cm/sec.

    Secondary Outcome Measures

    Long-term participant functional outcome
    Long-term outcome as measured by the Glasgow Outcome Scale: 1 (Dead) to 8 (Upper Good Recovery)
    Long-term participant activities of daily living outc
    Long-term outcome as measured by the Barthel Index: 0 - 100 (0-20 total dependency, 21-60 severe dependency, 61-90 moderate dependency, 100 no dependency

    Full Information

    First Posted
    March 26, 2009
    Last Updated
    August 11, 2023
    Sponsor
    University of Nebraska
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00871065
    Brief Title
    Safety Study of Sildenafil in Treatment of Cerebral Aneurysm Vasospasm
    Official Title
    Safety and Efficacy Trial of Sildenafil Citrate in Attenuation of Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    PI decision
    Study Start Date
    July 2008 (Anticipated)
    Primary Completion Date
    February 25, 2009 (Actual)
    Study Completion Date
    February 25, 2009 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    University of Nebraska

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Rupture of a cerebral aneurysm is a serious medical condition that may result in permanent disability or even death just related to the aneurysm rupture itself. Patients who undergo successful surgical treatment of their aneurysm will rarely experience problems related to that specific aneurysm in the future. However, blood that is on the surface of the brain from the initial aneurysm rupture is very irritating to other blood vessels that it comes in contact with. When these blood vessels become irritated, they spasm and become narrower. This narrowing restricts blood flow through the vessel, and if severe can result in a stroke that is caused by inadequate blood flow through the vessel. Depending on location and severity, this condition of vessel spasm (cerebral vasospasm) may result in permanent disability or death. Treatment to prevent cerebral vasospasm decreases the risk of stroke. This research is trying to see if a medication that is FDA approved for the treatment of lung disease and sexual dysfunction can be used to prevent and/or treat cerebral vasospasm.
    Detailed Description
    When a cerebral aneurysm ruptures, the surface of the brain and its blood vessels are covered with clotted blood. This condition is called subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage secondary to rupture of a cerebral aneurysm is a medical condition associated with a high morbidity and mortality; approximately 10-15% of patients die before reaching medical care, and overall mortality is approximately 45%. Of those that survive, 30% suffer permanent disability graded as moderate to severe, and two-thirds of survivors never return to the same quality of life as they had prior to their hemorrhage. A large number of patients (30-70%) who are able to make it to the hospital and have successful treatment of their aneurysm will develop delayed cerebral vasospasm that is related to the blood clot from their initial aneurysm rupture. Of patients that survive their initial aneurysm rupture, vasospasm results in an additional 7% mortality and another 7% of severe disabilities secondary to ischemic strokes from severe spasm of cerebral arteries. The pathogenesis of cerebral vasospasm has been a topic of significant research. The occurrence and severity are directly related to the volume of hemorrhage and the thickness of the blood clot encasing the arteries. Arterial vasospasm and impaired vasodilation are delayed processes that have a gradual onset, typically starting no earlier than 3 days post-hemorrhage and clinically resolving within 12 days of the initial aneurysm rupture. Breakdown of the clotted subarachnoid blood impairs the normal vasodilator and constrictor mechanisms of the cerebral arteries by altering the levels of several molecules including nitric oxide (NO), a vasodilator. Nitric oxide is normally produced by vascular endothelial cells and leads to vasodilation by stimulating the enzyme soluble guanylate cyclase. This enzyme catalyzes the production of cyclic guanosine monophosphate (cGMP), which is responsible for vasodilation through both direct and indirect actions. Selective deactivation of cGMP is accomplished by the enzyme phosphodiesterase subtype V (PDE-V). Studies have revealed elevated levels of PDE-V and diminished levels of cGMP in animals with experimentally induced SAH, while levels of nitric oxide synthase remain stable after hemorrhage. This prior research points toward SAH causing an enhancement in PDE-V activity, subsequently decreasing cGMP levels and impairing normal vasodilation. Papaverine, a nonselective phosphodiesterase inhibitor, is beneficial and selectively used for treatment of active vasospasm. Its use is limited by its short duration of action, and its nonspecific nature results in systemic vasodilation and subsequent hypotension. Sildenafil citrate, a selective PDE-V inhibitor, has been shown to enhance the reactivity of the cerebral vasculature in normal healthy adults and has been shown to decrease the severity of vasospasm in animals with experimentally induced SAH. These effects have been noted with minimal effects on systemic hemodynamics. Given that sildenafil citrate has safely demonstrated the expected clinical effect of cerebral arterial dilation in normal healthy humans as well as animals with and without induced SAH, the aim of this study is to determine if this medicine shows efficacy in humans with SAH secondary to ruptured aneurysm.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Cerebral Vasospasm, Subarachnoid Hemorrhage
    Keywords
    Cerebral Vasospasm, Vasospasm, Subarachnoid Hemorrhage, Sildenafil citrate, Aneurysm, Intracranial aneurysm

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Sildenafil Treatment of Cerebral Aneurysm Vasospasm
    Arm Type
    Experimental
    Arm Description
    Trial Arm (single arm study)
    Intervention Type
    Drug
    Intervention Name(s)
    Sildenafil citrate
    Other Intervention Name(s)
    Viagra, Revatio
    Intervention Description
    20 mg tablet orally every 8 hours until Day 14 post-hemorrhage
    Primary Outcome Measure Information:
    Title
    Onset of cerebral vasospasm
    Description
    Onset of cerebral vasospasm, defined as transcranial Doppler velocity exceeding 120 cm/sec.
    Time Frame
    Daily measurements for 12 days
    Secondary Outcome Measure Information:
    Title
    Long-term participant functional outcome
    Description
    Long-term outcome as measured by the Glasgow Outcome Scale: 1 (Dead) to 8 (Upper Good Recovery)
    Time Frame
    6 months
    Title
    Long-term participant activities of daily living outc
    Description
    Long-term outcome as measured by the Barthel Index: 0 - 100 (0-20 total dependency, 21-60 severe dependency, 61-90 moderate dependency, 100 no dependency
    Time Frame
    6 months

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    19 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Subarachnoid Hemorrhage (Fisher Grade 3) Cerebral Aneurysm documented by computed tomography angiography (CTA)/magnetic resonance angiography (MRA)/Cerebral Angiogram Enrollment within 48 hours of symptom onset Exclusion Criteria: Hypersensitivity to Sildenafil Pregnancy Age less than 19 years Concurrent use of nitrates or alpha-blockers Aneurysm related to an arteriovenous malformation Delayed enrollment past 48 hours Subarachnoid hemorrhage that is not Fisher Grade 3
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    William E Thorell, MD
    Organizational Affiliation
    University of Nebraska
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Guy A Music, MD
    Organizational Affiliation
    University of Nebraska
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Learn more about this trial

    Safety Study of Sildenafil in Treatment of Cerebral Aneurysm Vasospasm

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