Official Title: “Phase 1 Study of Sildenafil (Viagra) Treatment of Subacute Ischemic Stroke”

Stroke is the third leading cause of death in the United States and the leading cause of serious long-term disability. Approximately 50% of the 750,000 people affected by stroke each year have residual physical impairment. Treatment options for recovery are limited at this time. Sildenafil (Viagra) has demonstrated the capability of significantly improving recovery in several animal experiments of stroke. This study is aiming to establish the safety of treatment with sildenafil in people with stroke with the ultimate aim of testing its usefulness to improve recovery.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety Study

Study Primary Completion Date: December 2010

Stroke is the third leading cause of death and the leading cause of serious longterm disability in the United States. Approximately 15-30% of stroke survivors are permanently disabled. Twenty eight percent of stroke patients are under age 65 which results in a loss of work income. While many restorative therapies are touted as promising for the treatment of ischemic stroke, to date none are approved for this purpose. Sildenafil (Viagra®), a phosphodiesterase type 5 inhibitor, has been shown to reduce mortality and improve the functional outcomes of young and aged rats when administered 24 hours and 7 days after stroke onset. Such results are encouraging and warrant further investigation in human stroke.

The specific aims of this study are to assess the safety of treating ischemic stroke patients with sildenafil (Viagra®) and to evaluate their outcomes at day 90. This will be a phase I dose-escalation study with cohort sizes of 12 patients (depending on the occurrence of serious adverse events). A total enrollment of 72 patients is planned. Patients who are between 4 and 7 days from stroke onset will receive 25, 50, 75, 100, 125, or 150 mg daily of sildenafil for a period of 14 days. Evaluation of potential toxicity will be monitored throughout the course of treatment and during a formal visit at day 16 after initiation of treatment. Evaluation of potential toxicity will be monitored throughout the course of treatment. Follow-up visits will take place at days 30, 60, and 90. Plasma and serum monitoring of vascular endothelial growth factor (VEGF) will be made prior to treatment, at days 7, 16, 30, 60, and 90. Measurements of NIHSS scores, Rankin scores, and Barthel indices will be made at days 30, 60, and 90. Patients will also be assessed for color vision changes and sexual function during day 16 and day 90 visits.

There will be every other day phone calls to patients while on treatment. The primary outcome measure will be death, recurrent stroke, myocardial infarction, and neurological worsening during treatment. Exploratory analysis will include functional outcomes on neurological scales and changes in VEGF levels in relation to clinical outcome.

The long-term objective is to identify a safe and easily administered treatment that improves functional outcome in patients with ischemic stroke.

Intervention(s) in this Clinical Trial

• Drug: Sildenafil (Viagra)
  • Dose escalation (one of the following): 25 mg daily for weeks, 50 mg daily for 2 weeks, 75 mg daily for 2 weeks, 50 mg twice daily for two weeks, 50 mg AM and 75 mg PM for 2 weeks, 75 mg twice daily for 2 weeks.
• Drug: Sildenafil
  • Dose escalation

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Sildenafil
  • Open label safety evaluation

Primary Measures

• The maximum tolerated dose and toxicity profile of sildenafil treatment in patients with subacute ischemic stroke.
  • Time Frame: 2 weeks
    Safety Issue?: Yes

Secondary Measures

• The estimated efficacy of sildenafil in comparison with concurrent patients not enrolled in the study (otherwise eligible but decline participation).
  • Time Frame: 3 months
    Safety Issue?: No

Inclusion Criteria:

• Patients with ischemic stroke between 4 and 7 days after symptom onset.
• Patients age 18-80.
• NIHSS score of 5-21 prior to treatment (within each cohort, there will be no more than 4 patients with NIHSS <9 and no fewer than 4 patients with NIHSS > 11).
• Signed IRB-approved informed consent by patient or authorized representative.

Exclusion Criteria:

• General
• Participation in another study with an investigational drug or device.
• Women known to be pregnant, lactating, or of childbearing potential with a positive urine beta-HCG.
• Patients who cannot receive oral medications.
• Patients using sildenafil or other phosphodiesterase inhibitors within the previous 7 days of stroke.
• Safety Related
• Unstable angina.
• Myocardial infarction within 3 months.
• Current use of nitrate agents.
• Current use of alpha-channel antagonists.
• Current use of medications that inhibit the cytochrome p450 3A4 system. These medications include: amiodarone, aprepitant, bosentan, cimetidine, cisapride, clarithromycin, delavirdine, diltiazem, efavirenz, erythromycin, fluconazole, fluvoxamine, grapefruit juice, imatinib, itraconazole, ketoconazole,loratadine, mibefradil, mifepristone (RU-486), niacin, nefazodone, quinidine, quinine, ritonavir, saquinavir, tacrolimus, verapamil, voriconazole.
• St. John's Wort and phenytoin (inducers of cytochrome P450 3A4)
• Baseline systolic blood pressure less than 100 mmHg.
• Penile deformities.
• Creatinine > 1.5.
• Abnormal liver function studies.
• Patients with a previous history of sudden monocular vision loss Potentially
• Interfering with Outcomes Assessment
• Prior history of dementia.
• Patients without fixed address or those deemed unlikely to present for follow-up by the investigator.
• Patients whose life expectancy is less than 90 days.
• Pre-stroke modified Rankin score >2.
• Glucose greater than or equal to 400 mg/dL at presentation.
• Other serious illness (e.g., severe hepatic, cardiac, or renal failure; acute myocardial infarction; or a complex disease that may confound treatment assessment).
• Previous stroke or TIA within 30 days.
• Allergy or hypersensitivity to sildenafil or other phosphodiesterase inhibitors.
• History of sudden monocular visual disturbance
• History of sudden unilateral hearing problem Imaging Related
• Evidence of primary intraparenchymal hemorrhage on initial neuroimaging study.
• Neuroimaging evidence of nonvascular cause for the neurological symptoms.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Henry Ford Health System

Overall Clinical Trial Officials and Contacts

Brian Silver, MD Principal Investigator Henry Ford Hospital  

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00452582

Study ID Number: HF-N-1

ClinicalTrials.gov Identifier: NCT00452582

Health Authority: United States: Food and Drug Administration

Public information page regarding the study