Neuroprotection With Statin Therapy for Acute Recovery Trial Phase 2
Neuroprotection With Statin Therapy for Acute Recovery Trial Phase 2
This trial will be a phase 2 randomized safety study in which ischemic stroke patients will
 be randomly assigned within 24 hours of symptom onset to placebo or standard dose lovastatin
 versus short-term high-dose lovastatin 640 mg per day for 3 days. The primary outcome of this
 Phase 2 study will be musculoskeletal and hepatic toxicity, defined by clinical and
 laboratory criteria, with a 3-month follow-up period (± 1 week). Secondary outcomes will
 include neurological outcome (National Institute of Health (NIH) Stroke Scale), functional
 outcomes (Barthel Index), and handicap (modified Rankin scores). Effects on inflammatory
 markers and lipid levels will also be assessed.
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.