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E-Selectin Nasal Instillation to Prevent Secondary Stroke

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ClinicalTrials.gov Identifier: NCT00069069
Recruitment Status : Not yet recruiting
First Posted : September 15, 2003
Last Update Posted : October 19, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:

This study will determine the maximum safe dose of the experimental drug E-selectin that can be given to stroke patients. E-selectin causes white blood cells called lymphocytes to change so that they prevent clots from forming in the vessels that supply blood to the brain. The drug has been shown to be effective in animal models of stroke. This study will look at the safety of using this experimental drug in nasal instillation form in patients who have had a stroke or transient ischemic attack (TIA).

Patients 45 years of age or older who have had a recent stroke or TIA (30 to 120 days before entering the study) due to a clot forming in a vessel that supplies blood to the brain may be eligible for this study. They must be taking at least one medication to prevent clots, such as coumadin, aspirin, ticlopidine, or others. Candidates will be screened with a physical and neurological examination, blood and urine tests, electrocardiogram (EKG), echocardiogram (ultrasound test of the heart), and magnetic resonance imaging (MRI) of the brain.

Participants will be randomly assigned to receive E-selectin at a dose level of 5, 15, or 50 micrograms or a placebo (nasal drops with no active ingredient). They will instill a small, carefully premeasured amount (one dose) of fluid in their nose every other day for 10 days (total of 5 doses). This course of treatment will be repeated two times at 3-week intervals. Patients will be followed at 1 month and 3 months with a neurologic examination and blood and urine tests. They will be contacted by phone, fax, or email in between these two visits.

Condition or disease Intervention/treatment Phase
Ischemic Attack, Transient Transient Drug: Intransal instillation of E-selectin Phase 1

Detailed Description:

In the United States, stroke is the third leading cause of death and the leading cause of disability. Despite the use of antithrombotic drugs for the secondary prevention of stroke, 10% of patients who experience a cerebral ischemic event will go on to have a stroke within 90 days (Claiborne Johnston et al. 2003). The development of new treatment strategies for the secondary prevention of stroke is an important issue for modern medicine. There is increasing evidence that inflammation at the sites of endothelial activation plays an important role in the pathogenesis of stroke. Control of molecular inflammation at the sites of endothelial activation can be achieved by induction of mucosal tolerance. The induction of mucosal tolerance with repeated low-dose intranasal administration of antigen causes a shift of immune response from proinflamatory T helper type 1(T(H)1) effects to anti-inflammatory immunmomodulatory regulatory T cell (Treg) or T helper type 2 (T(H)2) effects at the sites of inflammation. E-selectin is an adhesion molecule expressed only on activated endothelium in response to proinflammatory cytokines.

Objective. The goals of the study are: (a) to test whether repeated administration of low-dose intranasal E-selectin is safe and tolerable and (b) to test whether it can induce mucosal tolerance to this compound causing a shift of immune response from TH1 to TH2 type with production of Treg cells.

Study Population. The study population will include 3-50 patients (depending on dose escalation events) plus 0-8 replacement patients (depending on the number of drop outs) with recent (>30 and <120 days) occurrence of any type or location of stroke documented by CT or MRI. The final number of patients will be determined by a dose escalation plan described below that may stop early in the accrual process should adverse events arise. Since patients will be required to make serial visits to the NIH clinical center, a functional recovery score of 0-2 on the modified Rankin Scale (i.e. 0 = no symptoms at all; 2 = slight disability: unable to carry out all previous activities, but able to look after own affairs without assistance) is required for inclusion in this study.

Study Design. This is a single center, Phase 1, open label, dose escalation trial assessing safety profile of four doses of intranasal recombinant human E-selectin.

Outcome Measures. The primary goal of this study is to define the maximum tolerated dose of intranasal instillation of recombinant human E-selection as described I the Study Medications and Drug Administration section. The secondary goal is to determine doses that generate Treg cells or induce immune deviation from TH1 to TH2 type response. The tertiary goals are to determine the presence or absence of antibody to human E-selectin, P- selectin, and L-selectin and the level of endothelial activation markers including von Willebrand factor, soluble E-selectin, VCAM-1, and Thrombomodulin.

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Induction of Mucosal Tolerance to Human E-Selectin for the Secondary Prevention of Stroke
Study Start Date : October 1, 2003
Estimated Primary Completion Date : November 20, 2025
Estimated Study Completion Date : November 20, 2025

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: 1
single center, Phase 1, open label, dose escalation trial assessing safety profile of four doses of intranasal recombinant human E-selectin
Drug: Intransal instillation of E-selectin
Intranasal recombinant human E-selectin

Outcome Measures

Primary Outcome Measures :
  1. To define the MTD for intranasal instillation of recombinant human E-selectin. [ Time Frame: One year ]

Secondary Outcome Measures :
  1. Immune deviation from TH1 to TH2 type response with generation of Treg cells. [ Time Frame: One year ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   45 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

    1. Occurrence of any type or location of stroke (acute ischemic or primary hemorrhagic stroke) at least 31 days, but not more than 120 days prior to enrollment confirmed by brain imaging (CT or MRI).
    2. Age equal to or greater than 45 years.
    3. Modified Rankin Score of 0-2 (functionally independent) at the time of study enrollment and determined to be clinically and neurologically stable by the enrolling investigator.


Patients with any of the following conditions will not be eligible for participation in this study:

  1. Intracranial or extracranial dissection, Moyamoya disease, vasculitis, radiation-induced vasculopathy, fibromuscular dysplasia, venous thrombosis.
  2. Current treatment with Immunosuppressive medication including: prednisone, cyclophosphamide, cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, anti-CD3 moab (Othoclone OKT3), takrolimus (FK506), sirolimus, anti-IL2r moab (simulect, zenapax), etanercept, infliximab, lenercept, thymoglobulin; thalidomide.
  3. Known active autoimmune diseases (RA, LE, MS, Myasthenia Gravis, etc.).
  4. Active cancer or lymphoproliferative diseases. (except for basal cell carcinoma)
  5. Thrombocytopenia (platelets less than 100,000).
  6. HIV or other known immunodeficiencies.
  7. Recent major surgery performed within one month of study enrollment.
  8. Active systemic infections, or severe focal or upper respiratory infections (URI).
  9. Alcohol or substance abuse.
  10. Dementia or psychiatric problems (determined by examination, mini-mental status test) that prevents the patient from providing informed consent or following an outpatient program reliably.
  11. Pregnancy (urine pregnancy test will be given to women of childbearing potential).
  12. Severe rhinopathy or sinusitis.
  13. Continuing use of any other over the counter, prescribed or recreational intranasal drug.
  14. History of NCI grade 3 epistaxis within 1 month.
  15. Exposure to an investigational drug within the 30 days prior to screening for this study.
  16. Planned surgery (e.g. carotid or cardiac surgery) or endovascular intervention during the study period until study variables have returned to baseline to prevent attributions of surgical complications to E-selectin tolerization.
  17. Patients who are not eligible for or unable to tolerate a brain MRI prior to the start of study drug.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00069069

Contact: John M Hallenbeck, M.D. (301) 496-6231 hallenbj@ninds.nih.gov

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
Principal Investigator: John M Hallenbeck, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
More Information

Additional Information:
Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier: NCT00069069     History of Changes
Other Study ID Numbers: 030293
First Posted: September 15, 2003    Key Record Dates
Last Update Posted: October 19, 2017
Last Verified: March 23, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):

Additional relevant MeSH terms:
Ischemic Attack, Transient
Brain Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases