Clinical Trial Details
— Status: Withdrawn
Administrative data
NCT number |
NCT00871065 |
Other study ID # |
0165-08-FB |
Secondary ID |
|
Status |
Withdrawn |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
July 2008 |
Est. completion date |
February 25, 2009 |
Study information
Verified date |
August 2023 |
Source |
University of Nebraska |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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.
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.