Safety Study of Sildenafil in Treatment of Cerebral Aneurysm Vasospasm

This study has been withdrawn prior to enrollment.
(PI decision)
Sponsor:
Information provided by:
University of Nebraska
ClinicalTrials.gov Identifier:
NCT00871065
First received: March 26, 2009
Last updated: NA
Last verified: March 2009
History: No changes posted
  Purpose

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 Intervention Phase
Cerebral Vasospasm
Subarachnoid Hemorrhage
Drug: Sildenafil citrate
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Safety and Efficacy Trial of Sildenafil Citrate in Attenuation of Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage

Resource links provided by NLM:


Further study details as provided by University of Nebraska:

Primary Outcome Measures:
  • Onset of cerebral vasospasm, defined as transcranial Doppler velocity exceeding 120 cm/sec. [ Time Frame: Daily measurements for 12 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Longterm outcome as measured by the Glasgow Outcome Scale and Barthel Index assessments [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 45
Study Start Date: July 2009
Estimated Study Completion Date: January 2011
Estimated Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00871065

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

No publications provided

Responsible Party: William Thorell, M.D., Assistant Professor of Neurosurgery, University of Nebraska Medical Center
ClinicalTrials.gov Identifier: NCT00871065     History of Changes
Other Study ID Numbers: 165-08-FB
Study First Received: March 26, 2009
Last Updated: March 26, 2009
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Nebraska:
Cerebral Vasospasm
Vasospasm
Subarachnoid Hemorrhage
Sildenafil citrate
Aneurysm
Intracranial aneurysm

Additional relevant MeSH terms:
Aneurysm
Intracranial Aneurysm
Brain Diseases
Hemorrhage
Subarachnoid Hemorrhage
Vasospasm, Intracranial
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Central Nervous System Diseases
Nervous System Diseases
Intracranial Arterial Diseases
Citric Acid
Sildenafil
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Chelating Agents
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Cardiovascular Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 14, 2014