Neuroprotection With Statin Therapy for Acute Recovery Trial Phase 2

This is a phase 2 randomized, blinded and controlled safety study in patients with ischemic
stroke. The time window for enrollment will be within 0-24 hours of symptom onset. For
patients who are found with the stroke on awakening, it will be assumed that the stroke
occurred the last time that the patient was known to be normal. All patients will be
identified by the stroke acute care team in the emergency room of the participating centers,
or in some cases, on the floor services of the hospital (i.e., for patients with stroke
occurring in hospital). If preliminary data indicate that the patient meets eligibility
criteria the patient (or legally authorized representative) will be approached about
participation in the study, and consent obtained. Surrogate consent will be allowed at
centers at which this is permitted according to regulations. Patients who are consented
through a surrogate and subsequently regain capacity, will be approached and reconsented to
continue in the study.

The intervention chosen for this trial is either (1) placebo for patients not taking a
statin at the time of admission OR lovastatin 80 mg in place of their regular statin for
patients taking a statin (atorvastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin,
lovastatin) at time of enrolment VERSUS (2) oral lovastatin at dosage of 640 mg daily for 3
days. The time of first dose will be considered time 0. Patients will be administered the
total daily dose in four daily divided doses (i.e., QID schedule). After the initial 3 days
of acute dosage, all patients will receive statin therapy at the discretion of their
treating physician.

Inclusion Criteria:

1. Age >18

2. Satisfies the criteria for ischemic stroke: acute focal neurological deficit of
likely ischemic vascular origin.

3. Patient or legally authorized representative has provided written informed consent
prior to study entry. Patient who regains capacity provides his/her written consent
to remain in the study.

4. Patient can receive the first treatment dose within 0-24 hours of stroke onset. For
patients found with stroke on awakening, it will be assumed that the stroke occurred
the last time that the patient was known to be normal.

5. Patient has pretreatment brain CT scan compatible with ischemic stroke and excludes
hemorrhagic and non-vascular etiologies of symptoms.

6. Patients taking statins at time of stroke may be included.

7. Patients receiving standard dose intravenous tPA or mechanical interventional
procedures may be enrolled.

Exclusion Criteria:

1. Brain imaging study shows a lesion other than ischemic stroke that could explain
patient's symptoms (intracranial or subarachnoid hemorrhage, arteriovenous
malformation, aneurysm, multiple sclerosis, tumor, abscess or other). Asymptomatic
meningiomas are allowed.

2. Mild stroke, defined as NIH Stroke Scale <2.

3. Weight < 50 kg.

4. Patient is comatose, regardless of etiology (> 4 points on the first three items of
the NIHSS).

5. History of intolerance or allergic reaction to any statins (myotoxicity, hepatic
dysfunction, rash, etc.)

6. Use of drugs within past 30 days that utilize the cytochrome CYP3A pathway
(cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, nefazodone,
posaconazole, voriconazole, dronedarone, diltiazem, colchicine and ranolazine).

7. Use of drugs within past 30 days that increase risk of myotoxicity with statins
(gemfibrozil, other fibrates, niacin, amiodarone, verapamil).

8. Baseline major electrolyte disturbances (sodium <125 or >150, potassium <3.0 or
>5.5).

9. Recent major trauma (<3 months).

10. Hypothermia (body temperature < 96F).

11. Baseline hypoxia (defined as oxygen saturation <92% on room air).

12. History of likely or proven systemic viral infection within 30 days.

13. Known HIV infection or use of protease inhibitors.

14. Endocarditis likely as cause of stroke.

15. Mitochondrial disorder likely as cause of stroke.

16. Pregnancy or lactation.

17. History of rhabdomyolysis, myopathy, or other severe muscle disease.

18. History of hepatitis, decompensated liver disease (ascites, bleeding varices or
encephalopathy), or liver failure.

19. Liver function tests (ALT, AST) > 2 X upper limit of normal.

20. Unstable cardiovascular (includes uncontrolled hypertension), pulmonary,
gastrointestinal, hepatic or musculoskeletal disease.

21. Patient has evidence of severe congestive heart failure or has history of end-stage
cardiovascular disease (e.g. CHF NYHA Class III or IV or unstable angina).

22. Abnormal ECG showing: Hemodynamically significant arrhythmia or frequent PVCs
(>5/minute) (controlled atrial arrhythmia will not be an exclusion); evidence of
acute myocardial infarction; Mobitz Type II 2nd degree AV block or 3rd degree AV
block; ventricular tachycardia or ventricular fibrillation.

23. Significant renal insufficiency, indicated by serum creatinine >2.0 mg/dl.

24. Hypoglycemia (glucose < 60 mg/dl) or diabetic ketoacidosis unresponsive to therapy.

25. Any of these hematologic abnormalities: WBC <3.0 x 103/mm3; Platelet count
<50,000/mm3

26. Received an investigational drug within 30 days.

27. Severe behavioral or social problems that may interfere with the conduct of clinical
study procedures.

28. Patient unlikely, in the investigator's opinion, to complete the study and return for
follow-up visits for any reason.