Sildenafil (Viagra) Treatment of Subacute Ischemic Stroke
Phase 1 Study of Sildenafil (Viagra) Treatment of Subacute Ischemic Stroke
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Stroke is the third leading cause of death and the leading cause of serious long-term 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 120 patients is planned. Patients who are between 4 and 7 days from stroke onset will receive 25, 50, 75, 100, 125, 150, 175, and 200 mg daily of sildenafil for a period of 14 days. Of the 120 patients, 24 will be randomly selected to receive standard treatment but will not receive sildenafil. All patients and physicians will be aware of treatment assignment. Evaluation of potential toxicity will be monitored throughout the course of treatment and during a formal visit at day 16 after initiation of treatment. Plasma 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, and myocardial infarction during treatment. Exploratory analysis will include functional outcomes as measured on the 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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Michigan
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Detroit, Michigan, United States, 48202
- Henry Ford Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients with ischemic stroke between 4 and 7 days after symptom onset.
- Patients age 18-80 years old.
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Sildenafil
Orally administered sildenafil in addition to usual care.
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Dose escalation (one of the following): 25 mg daily for 2 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, 75 mg in AM and 100 mg in PM for 2 weeks, 100 mg twice daily for 2 weeks.
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Active Comparator: Usual post-stroke care
Usual post-stroke treatment including physical, occupational, and speech therapy.
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Physical therapy, occupational therapy, speech therapy
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
The maximum tolerated dose and toxicity profile of sildenafil treatment in patients with subacute ischemic stroke.
Time Frame: 2 weeks
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2 weeks
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
The estimated efficacy of sildenafil in comparison with concurrent patients randomized assigned to usual care.
Time Frame: 3 months
|
3 months
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Brian Silver, MD, Henry Ford Hospital
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Necrosis
- Cardiovascular Diseases
- Vascular Diseases
- Cerebrovascular Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Brain Ischemia
- Infarction
- Brain Infarction
- Stroke
- Ischemic Stroke
- Ischemia
- Cerebral Infarction
- Molecular Mechanisms of Pharmacological Action
- Vasodilator Agents
- Urological Agents
- Enzyme Inhibitors
- Phosphodiesterase Inhibitors
- Phosphodiesterase 5 Inhibitors
- Sildenafil Citrate
Other Study ID Numbers
- HF-N-1
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