Sildenafil and Stroke Recovery

This is a small, pilot randomized clinical trial of administering sildenafil citrate to individuals within 10 days of ischemic stroke who have motor impairment and who are undergoing inpatient rehabilitation compared to placebo. The primary outcome is motor recovery at one and three months.

Study Overview

• Status: Terminated
• Conditions: Stroke
• Intervention / Treatment: Drug: Placebo; Drug: sildenafil citrate

Detailed Description

Individuals who are within 4-10 days post ischemic stroke with arm hemiparesis or hemiplegia who are admitted to inpatient rehabilitation are randomized to receive either sildenafil citrate (25 mg once per day) or placebo for 14 days. These individuals receive usual rehabilitation and medical care. Primary outcomes are motor skills and walking speed at one and three months.

If willing and able, participants undergo an MRI to measure the integrity of the white matter pathways in the motor system using diffusion tensor imaging. Repeat MRIs are obtained at one and three months. The investigators will examine if such white matter integrity predicts response to the drug and if the drug facilitates changes in white matter.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. between 4 and 9 days post-ischemic stroke;
2. admitted to inpatient rehabilitation;
3. cognitively able to provide consent or assent;
4. were living independently in the community prior to their stroke.

Exclusion Criteria:

1. hemorrhagic stroke or subarachnoid hemorrhage;
2. other neurological or psychiatric conditions deemed by the investigator to impair participation;
3. no previous stroke on same side of brain unless that stroke was cerebellar
4. moribound or not expected to live 6 months;
5. contraindications to taking sildenafil in pill or syrup form;
6. other medical conditions that would limit ability to participate in the study, specifically a) currently taking the P450 enzyme inhibitors (erythromycin, ketoconazole, itraconazole, saquinavir), b) currently taking the protease inhibitor ritonavir, c) currently taking nitrates or have a history of requiring nitrates treatment, d) have left ventricular outflow obstruction (i.e., aortic stenosis, idiopathic hypertrophic subaortic stenosis as confirmed by review of standard of care echo received before admission to rehabilitation), e) have severely impaired autonomic control of blood pressure, f) have previous history of symptomatic hypotension, g) have severely impaired hepatic function, h) is pregnant or become pregnant during the course of the study, i) Any medical condition which, in the opinion of the investigator, may compromise compliance with the objectives and/or procedures of the protocol.

7. scores > 50 on the upper extremity section of the Fugl-Meyer or no walking/gait impairment

   For the MRI portion of the study only:

8. contraindication to MRI: ferrous metal in body, lead included body art, claustrophobia, pacemaker
9. allergic to or had previous reaction to gadolinium

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Drug; Sildenafil citrate 25mg once per day for 14 days starting day 5-9 post stroke while undergoing usual rehabilitation	Drug: sildenafil citrate; Other Names: Viagra
Placebo Comparator: control; placebo capsule once per day for 14 days starting day 5-9 post stroke while undergoing usual rehabilitation	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fugl-Meyer Motor Assessment	An assessment of upper extremity and lower extremity motor impairment	change from baseline at 1 month
Fugl-Meyer Assessment	An assessment of upper extremity and lower extremity motor impairment	change from baseline at 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
10 meter walk	an assessment of usual gait speed	change from baseline at one month
Wolf Motor Function Test	An assessment of motor function	baseline, one month, three months
Motor Activity Log	A self-report of paretic arm (frequency and perceived ability) use in every day activities	one month
Stroke Impact Scale	A self-report measure of the impact of stroke on the individual for body functions, activities, and participation	one month
10 meter walk	an assessment of usual gait speed	change from baseline at 3 months
Wolf Motor Function Test	An assessment of motor function	change from baseline at 3 months
Motor Activity Log	A self-report of paretic arm (frequency and perceived ability) use in every day	3 months
Stroke Impact Scale	A self-report measure of the impact of stroke on the individual for body	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with unsafe Blood pressure change	blood pressure reductions or increases while taking the drug/placebo	one month
number of participants with cardiovascular side effects	cardiovascular events, such as heart attack, angina pectoris, heart failure	one month
number of participants with visual side effects	new abnormal color vision, light sensitivity, blurred vision or other visual side effects	one month
number of participants with auditory or vestibular side effects	new loss of hearing, tinnitus, dizziness	one month

Collaborators and Investigators

• Sponsor: University of Utah

Publications and helpful links

General Publications

• Silver B, McCarthy S, Lu M, Mitsias P, Russman AN, Katramados A, Morris DC, Lewandowski CA, Chopp M. Sildenafil treatment of subacute ischemic stroke: a safety study at 25-mg daily for 2 weeks. J Stroke Cerebrovasc Dis. 2009 Sep-Oct;18(5):381-3. doi: 10.1016/j.jstrokecerebrovasdis.2009.01.007.
• Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, Zhang L, Chopp M. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke. 2002 Nov;33(11):2675-80. doi: 10.1161/01.str.0000034399.95249.59.
• Li L, Jiang Q, Zhang L, Ding G, Gang Zhang Z, Li Q, Ewing JR, Lu M, Panda S, Ledbetter KA, Whitton PA, Chopp M. Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke. Brain Res. 2007 Feb 9;1132(1):185-92. doi: 10.1016/j.brainres.2006.10.098. Epub 2006 Dec 26.
• Ding G, Jiang Q, Li L, Zhang L, Zhang ZG, Ledbetter KA, Panda S, Davarani SP, Athiraman H, Li Q, Ewing JR, Chopp M. Magnetic resonance imaging investigation of axonal remodeling and angiogenesis after embolic stroke in sildenafil-treated rats. J Cereb Blood Flow Metab. 2008 Aug;28(8):1440-8. doi: 10.1038/jcbfm.2008.33. Epub 2008 Apr 16.
• Zhang RL, Chopp M, Roberts C, Wei M, Wang X, Liu X, Lu M, Zhang ZG. Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse. PLoS One. 2012;7(10):e48141. doi: 10.1371/journal.pone.0048141. Epub 2012 Oct 31.
• Zhang L, Zhang RL, Wang Y, Zhang C, Zhang ZG, Meng H, Chopp M. Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke. 2005 Apr;36(4):847-52. doi: 10.1161/01.STR.0000158923.19956.73. Epub 2005 Mar 3.
• Ding G, Jiang Q, Li L, Zhang L, Zhang ZG, Ledbetter KA, Gollapalli L, Panda S, Li Q, Ewing JR, Chopp M. Angiogenesis detected after embolic stroke in rat brain using magnetic resonance T2*WI. Stroke. 2008 May;39(5):1563-8. doi: 10.1161/STROKEAHA.107.502146. Epub 2008 Mar 20.
• Ding G, Jiang Q, Li L, Zhang L, Zhang Z, Lu M, Li Q, Gu S, Ewing J, Chopp M. Longitudinal magnetic resonance imaging of sildenafil treatment of embolic stroke in aged rats. Stroke. 2011 Dec;42(12):3537-41. doi: 10.1161/STROKEAHA.111.622092. Epub 2011 Sep 8.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: December 7, 2015
• First Submitted That Met QC Criteria: December 9, 2015
• First Posted (Estimate): December 11, 2015

Study Record Updates

• Last Update Posted (Estimate): January 5, 2017
• Last Update Submitted That Met QC Criteria: January 3, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: stroke; rehabilitation; motor skills; sildenafil citrate; White matter
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: 53515

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided