Clinical trial NCT03028298: Sildenafil for DCI
Official title: Sildenafil for the Treatment of Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Subarachnoid Hemorrhage
Cerebral Vasospasm
Lead sponsor: University of Mississippi Medical Center
Sponsor class: OTHER
First posted: 2017-01-23
Enrollment: 24
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomly assigned to either low dose sildenafil (20mg oral and 10mg intravenous) or high dose sildenafil (60mg oral and 30 mg intravenous)
Primary purpose: TREATMENT

Brief summary: Each year, approximately 30,000 people in the United States suffer an intra-cranial hemorrhage due to aneurysmal rupture. Of those surviving the initial event, up to 40% will go on to have further neurological injury secondary to stroke (delayed cerebral ischemia) caused by constriction of blood vessels (i.e. vasospasm). Previous studies have shown that the medication sildenafil, given intravenously, improves vasospasm, but has an associated degree of hypotension. The degree of hypotension was well within safety thresholds for these patients.

Sildenafil is a medication that strongly inhibits the protein phosphodiesterase-V (PDE-V). The hypothesis for this study is that oral sildenafil will also improve vasospasm, but does not result in as much hypotension. Specifically, the investigators look to show that comparable doses of oral sildenafil produces the same degree of PDE-V inhibition as an intravenous dose while the degree of hypotension is reduced. Additionally, using measurements of cerebral blood flow regulation acquired using transcranial Doppler ultrasound, the investigators look to show that oral sildenafil produces the same degree of improvement in vasospasm and blood flow regulation.


Eligibility criteria: Inclusion Criteria:

1. Age \>= 21
2. Onset of symptoms within 72 hours from presentation
3. Subarachnoid hemorrhage from ruptured cerebral aneurysm
4. Cerebral vasospasm diagnosed on transcranial doppler, CT angiography, or digital subtraction angiography

Exclusion Criteria:

1. Pregnancy
2. Subarachnoid hemorrhage secondary to traumatic or mycotic aneurysm
3. Pre-ictal sildenafil therapy (last dose within 1 week of presentation)
4. Contraindications to sildenafil therapy (i.e. use of nitrates, left ventricular outflow obstruction, impaired autonomic blood pressure control)

Primary outcomes:
measure: Change from baseline in mean arterial blood pressure
timeFrame: baseline and 2 hours post-dose
measure: Area under the plasma concentration versus time curve (AUC) of sildenafil
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 20, and 24 hours post-dose
Secondary outcomes:
measure: Area under the cerebral spinal fluid concentration versus time curve (AUC) of sildenafil
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 20, and 24 hours post-dose
measure: Change from baseline in cerebral autoregulation
timeFrame: baseline and 2 hours post-dose
Other outcomes:
Locations:
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
Study officials:
affiliation: University of Mississippi Medical Center
name: Chad W Washington, MS, MD, MPHS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Washington CW, Derdeyn CP, Dhar R, Arias EJ, Chicoine MR, Cross DT, Dacey RG Jr, Han BH, Moran CJ, Rich KM, Vellimana AK, Zipfel GJ. A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage. J Neurosurg. 2016 Feb;124(2):318-27. doi: 10.3171/2015.2.JNS142752. Epub 2015 Aug 28.
citation: Dhar R, Washington C, Diringer M, Zazulia A, Jafri H, Derdeyn C, Zipfel G. Acute Effect of Intravenous Sildenafil on Cerebral Blood Flow in Patients with Vasospasm After Subarachnoid Hemorrhage. Neurocrit Care. 2016 Oct;25(2):201-4. doi: 10.1007/s12028-016-0243-0.