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Withdrawn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
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
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
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Withdrawn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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