Sildenafil for DCI

Sildenafil for the Treatment of Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Subarachnoid Hemorrhage; Cerebral Vasospasm
• Intervention / Treatment: Drug: Low dose sildenafil citrate; Drug: High dose sildenafil citrate

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose sildenafil; Twelve patients with cerebral vasospasm following aneurysmal subarachnoid hemorrhage will be assigned to low dose sildenafil citrate and will receive a 20mg oral dose and a subsequent 10mg intravenous dose of sildenafil citrate.	Drug: Low dose sildenafil citrate
Experimental: High dose sildenafil; Twelve patients with cerebral vasospasm following aneurysmal subarachnoid hemorrhage will be assigned to high dose sildenafil citrate and will receive a 60mg oral dose and a subsequent 30mg intravenous dose of sildenafil citrate.	Drug: High dose sildenafil citrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in mean arterial blood pressure	baseline and 2 hours post-dose
Area under the plasma concentration versus time curve (AUC) of sildenafil	0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 20, and 24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Area under the cerebral spinal fluid concentration versus time curve (AUC) of sildenafil	0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 20, and 24 hours post-dose
Change from baseline in cerebral autoregulation	baseline and 2 hours post-dose

Collaborators and Investigators

• Sponsor: University of Mississippi Medical Center
• Investigators: Principal Investigator: Chad W Washington, MS, MD, MPHS, University of Mississippi Medical Center

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): July 1, 2023

Study Registration Dates

• First Submitted: January 13, 2017
• First Submitted That Met QC Criteria: January 19, 2017
• First Posted (Estimate): January 23, 2017

Study Record Updates

• Last Update Posted (Actual): June 8, 2021
• Last Update Submitted That Met QC Criteria: June 5, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage; Vasospasm, Intracranial; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Anticoagulants; Phosphodiesterase Inhibitors; Chelating Agents; Sequestering Agents; Phosphodiesterase 5 Inhibitors; Calcium Chelating Agents; Sildenafil Citrate; Citric Acid; Sodium Citrate
• Other Study ID Numbers: 2016-0134

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No