Objectives: Recombinant human interferon beta-1a (IFN-Beta1a) is an FDA approved treatment for patients with relapsing remitting multiple sclerosis, in whom the safety profile is well characterized. The actions of IFN-Beta1a to inhibit pro-inflammatory cytokines and prevent blood brain barrier disruption suggest a therapeutic potential in ischemic stroke, and recent experimental evidence supports that effect. This study will be the first clinical trial exposure of patients with acute stroke to IFN-Beta1a. The purpose of this study is to investigate the safety of IFN-Beta1a (Rebif(Registered Trademark)) in patients with acute ischemic stroke. Study Population: Patients age 18-85 years with probable or definite acute ischemic cerebrovascular syndrome within 24 hours of onset will be studied. Design: This is a randomized double-blind placebo-controlled sequential dose escalation, phase 1 trial. Five dose cohorts of 5 patients (4:1 active: placebo) will be studied at 11 mcg, 22 mcg, 44 mcg, 66 mcg and 88 mcg administered daily for 7 days. The first dose will be administered intravenously and subsequent doses will be administered subcutaneously. Patients will be pre-medicated to prevent fevers, a common complication of interferon treatment, since fever may worsen stroke outcome. Patients will be monitored for adverse events and neurological outcomes up to 28 days from onset of treatment. Data will be reviewed in an ongoing fashion by a data safety monitoring board (DSMB). Dose escalation will be continuous unless drug-related toxicity reaches a predetermined level of one dose-limiting adverse event (1 of 4 treated) within a dose cohort, in which case a second cohort of 5 patients (4:1) will be treated at that dose. The study will be terminated at a dose level at which 2 of 4 or 3 of 8 patients on active treatment have a severe dose limiting toxicity or when all planned dose cohorts have been completed. Outcome Measures: Expected, common toxicities with IFN-Beta1a treatment are flu-like symptoms (e.g., fevers, myalgias, headaches, fatigue) and injection site reactions. With long term administration liver function abnormalities and leukopenia may occur and these will also be monitored. Toxicity will be graded according to the NCI criteria as well as study specific criteria defined in section 7a. Dose limiting toxicities will be considered any serious adverse event or grade 3 toxicity judged to be probably or definitely related to study medication or grade 4 or 5 toxicity judged to be possibly, probably or definitely related to study medication or any of the predefined study specific criteria. Serum levels of IFN-Beta1a and serum markers of IFN-Beta1a activity will be measured to characterize the pharmacokinetics and pharmacodynamics of IFN-Beta 1a in acute stroke patients.
- INCLUSION CRITERIA: Adult male or female patients with confirmed acute ischemic stroke, presenting within 24 hours of symptom onset and meeting inclusion criteria at each of the study sites will be assessed for possible enrollment into the study. 1. New focal neurologic deficit consistent with acute cerebral ischemia. 2. Age greater than or equal to 18 and less than or equal to 85. 3. Premorbid modified Rankin score 0-2 (functionally independent). 4. Signed informed consent obtained from the patient or patient's legally authorized representative. 5. Initiation of study drug within 24 hours of symptom onset. EXCLUSION CRITERIA: 1. Acute intracerebral hemorrhage. 2. Major surgery planned within 30 days of symptom onset. 3. Treatment with IV tPA or other recanalization therapy for current event. 4. Pre-existing medical, neurological or psychiatric disease that would confound the outcome evaluations. 5. Women known to be pregnant, lactating or having a positive or indeterminate pregnancy test. 6. Coma or altered level of consciousness (score of 1 or more on LOC items of NIHSS score). 7. Hemodynamic instability. 8. Current participation in another experimental treatment protocol. 9. Inadequate liver function, defined by a total bilirubin, AST or ALT or alkaline phosphatase greater than 2 times the upper limit of normal values. 10. Renal impairment with serum creatinine greater than 2.0 mg/dl. 11. NIHSS greater than 18. 12. Prior use of interferon. 13. Active major infection. 14. Allergy to human serum albumin, mannitol. 15. Seizure disorder or seizure at onset of stroke. 16. Severe depressive disorder and/or suicidal ideation. 17. Significant leukopenia (white blood cell count less than 0.5 times the lower limit of normal) within 7 days prior to symptom onset.