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Safety Study of Sildenafil in Treatment of Cerebral Aneurysm Vasospasm

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00871065
Recruitment Status : Withdrawn (PI decision)
First Posted : March 30, 2009
Last Update Posted : May 16, 2017
Information provided by (Responsible Party):
University of Nebraska

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.

Condition or disease Intervention/treatment Phase
Cerebral Vasospasm Subarachnoid Hemorrhage Drug: Sildenafil citrate Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Safety and Efficacy Trial of Sildenafil Citrate in Attenuation of Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage
Study Start Date : July 2009
Estimated Primary Completion Date : July 2010
Estimated Study Completion Date : January 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Aneurysms Bleeding

Arm Intervention/treatment
Experimental: A
Trial Arm (single arm study)
Drug: Sildenafil citrate
20 mg tablet orally every 8 hours until Day 14 post-hemorrhage
Other Names:
  • Viagra
  • Revatio

Primary Outcome Measures :
  1. Onset of cerebral vasospasm, defined as transcranial Doppler velocity exceeding 120 cm/sec. [ Time Frame: Daily measurements for 12 days ]

Secondary Outcome Measures :
  1. Longterm outcome as measured by the Glasgow Outcome Scale and Barthel Index assessments [ Time Frame: 6 months ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00871065

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United States, Nebraska
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198-2035
Sponsors and Collaborators
University of Nebraska
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Principal Investigator: William E Thorell, M.D. University of Nebraska
Study Director: Guy A Music, M.D. University of Nebraska

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Responsible Party: University of Nebraska Identifier: NCT00871065     History of Changes
Other Study ID Numbers: 165-08-FB
First Posted: March 30, 2009    Key Record Dates
Last Update Posted: May 16, 2017
Last Verified: May 2017
Keywords provided by University of Nebraska:
Cerebral Vasospasm
Subarachnoid Hemorrhage
Sildenafil citrate
Intracranial aneurysm
Additional relevant MeSH terms:
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Subarachnoid Hemorrhage
Vasospasm, Intracranial
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Sildenafil Citrate
Citric Acid
Sodium Citrate
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Urological Agents