The Safety and Efficacy Study of High Dose Atorvastatin After Thrombolytic Treatment in Acute Ischemic Stroke
The Safety and Efficacy Study of High Dose Atorvastatin After Thrombolytic Treatment in Acute Ischemic Stroke
Emerging studies have shown that statin treatment has pleiotropic non-cholesterol-dependent
 effects in the setting of ischemic stroke.

 Recombinant tissue plasminogen activator (rt-PA) is the only proven effective pharmaceutical
 treatment for hyper-acute management of ischemic stroke, in spite of the deleterious
 side-effects such as hemorrhagic transformation and reperfusion injury. These harmful impacts
 can be counteracted with proper neuro-protective therapy. In fact, the simultaneous use of an
 effective neuro-protective agent was proved to reduce the comorbid vascular injury of rt-PA.
 In experimental research, high dose of atorvastatin combined with rt-PA can significantly
 reduce infarct volume and improve the neurologic deficits. Previous studies showed that fewer
 than 40% ischemic stroke patients established early reperfusion after intravenous
 thrombolysis, while high dose of atorvastatin was revealed to favor the maintenance of
 cerebral vascular patency and integrity, most likely by reducing thrombosis secondary to
 rt-PA administration. Moreover, it was suggested that statin can sufficiently improve the
 restoration and remodeling of neurovascular unit in cerebral cortex.

 Investigators thus design this study to prospectively investigate whether high dose of
 atorvastatin prescribed within 24 hours after IV-thrombolysis will have a synergic effect to
 improve neurological outcome in acute ischemic stroke patients. Moreover, investigators
 deemed it necessary to non-invasively monitor neuronal and vascular morphological changes in
 brain as an indication of functional improvement. In the investigation centers, investigators
 have developed and implemented novel multimodality MR imaging which can dynamically monitor
 neurovascular remodeling. Therefore, it is worthwhile to evaluate these MRI measurements for
 early prediction of neurovascular reorganization with long term functional recovery in
 thrombolytic stroke patients administrated with high dose of atorvastatin.

 The primary target of this study is to prospectively investigate whether high dose of
 atorvastatin (80mg) administrated within 24 hours after IV-thrombolysis will have a synergic
 effect to improve neurological outcome in acute stroke patients, versus moderate dose.
Study design It is a bi-center, randomized, open-label prospective study. Investigators will
 enroll the ischemic stroke patients who received IV-thrombolysis with rt-PA. Those who meet
 inclusion criteria will be randomized either to the high dose group (atorvastatin 80mg) or
 the moderate dose group (atorvastatin 20mg) within 24 hours after IVT. The initial dose of
 atorvastatin will last at least 2 weeks, and then be adjusted according to the stroke risk
 stratification and tolerance. All patients will be followed at 0, 1 month, 3 months, 6
 months, and 12 months, and evaluated the neurological deficits and some patients will be
 randomly assigned to perform multimodality MRI scan. Other standard secondary prevention of
 stroke and life-style guidance will be provided according to 2014 AHA/ASA stroke secondary
 prevention guidelines. All patients will be followed up in stroke prevention clinic or on
 phone by trained investigators.

 Study Endpoints Primary endpoint The percentage of patients with mRS (modified Rankin Score)
 equivalent to or less than 2 between high dose groups and moderate dose groups at 90 days.

 Secondary endpoints NIHSS score at 7 day, 1 month mRS at 6,12 month Inflammation biomarkers
 at 6 month Imaging outcomes include the neuronal and vascular morphological changes indicated
 by multi-model imaging.

 Safety and tolerability will be evaluated by recording the incidence and severity of adverse
 events, abnormal physical examination findings, and abnormal laboratory values through the
 study. Especially monitoring the patients who have any the following events:

 Hemorrhagic complications including intracranial, digestive tract. New stroke or TIA Death
 from all-cause death, stroke events or cardiovascular events The patients having muscle
 symptoms such as myalgia, fatigue, weakness, creatinine kinase values 10 times the upper
 limit of normal, or rhabdomyolysis, and having persistent elevation in alanine
 aminotransferase (ALT), aspartate aminotransferase (AST), or both (defined as two consecutive
 measurements obtained 4 to 10 days apart that is more than three times the upper limit of the
 normal range).
Inclusion Criteria:

 1. Men or women ≧18 years of age

 2. Able and willing to comply with study requirements

 3. Signed informed consent by patient self or legally authorized representatives.

 4. Baseline mRS before this stroke onset less than 2

 5. Receive IV rt-PA thrombolysis with a final diagnosis of ischemic stroke

 6. Liver transaminases (ALT and/or AST) ≤ 2 x upper limit of normal (ULN) with no active
 liver disease and creatine kinase (CK) ≤ 2 x ULN at screen visit.

 Exclusion Criteria:

 1. History of mental instability, drug/alcohol abuse within the past 5 years, or major
 psychiatric illness not adequately controlled and stable on pharmacotherapy

 2. Patients who have been treated with any other investigational drug within 3 months of
 enrollment

 3. Impaired renal function ( serum creatinine ≧1.5 mg/dL) or nephrotic syndrome

 4. Patients hypersensitive or have allergic response to HMG-CoA reductase inhibitors

 5. Metastatic neoplasm at the onset or the follow-up

 6. Prohibited concomitant therapies, e.g.:

 ① Medications that are potent inhibitors of CYP3A4, including cyclosporine, systemic
 itraconazole or ketoconazole, erythromycin or clarithromycin, nefazodone, verapamil
 and human immunodeficiency virus (HIV) protease inhibitors.

 ②Oral corticosteroids unless used as replacement therapy for pituitary/adrenal disease

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

 8. Any condition or situation which, in the opinion of the investigator, might pose a
 risk to the patient or confound the results of the study