E-Selectin Nasal Instillation to Prevent Secondary Stroke

July 3, 2018 updated by: National Institute of Neurological Disorders and Stroke (NINDS)

Induction of Mucosal Tolerance to Human E-Selectin for the Secondary Prevention of Stroke

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

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 Type

Interventional

Phase

  • Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • INCLUSION CRITERIA:

    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.

EXCLUSION CRITERIA:

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To define the MTD for intranasal instillation of recombinant human E-selectin.
Time Frame: One year
One year

Secondary Outcome Measures

Outcome Measure
Time Frame
Immune deviation from TH1 to TH2 type response with generation of Treg cells.
Time Frame: One year
One year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

  • Principal Investigator: John M Hallenbeck, M.D., National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2003

Primary Completion (Actual)

May 9, 2018

Study Completion (Actual)

May 9, 2018

Study Registration Dates

First Submitted

July 12, 2006

First Submitted That Met QC Criteria

September 12, 2003

First Posted (Estimate)

September 15, 2003

Study Record Updates

Last Update Posted (Actual)

July 5, 2018

Last Update Submitted That Met QC Criteria

July 3, 2018

Last Verified

May 9, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 030293
  • 03-N-0293

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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