E-Selectin Nasal Instillation to Prevent Secondary Stroke

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.

- 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.