Neuroprotection With Statin Therapy for Acute Recovery Trial Phase 2

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase 2 Safety Study in Which Ischemic Stroke Patients Will be Randomized Within 24 Hours of Symptom Onset to Placebo or Oral Lovastatin 640 mg Per Day for 3 Days.

Conditions
-----------------
Stroke, Rhabdomyolysis, Jaundice

Intervention / Treatment
-----------------
* Drug: Low Dose Lovastatin
* Other: Placebo
* Drug: High Dose Lovastatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >18 Satisfies the criteria for ischemic stroke: acute focal neurological deficit of likely ischemic vascular origin. 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. 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. Patient has pretreatment brain CT scan compatible with ischemic stroke and excludes hemorrhagic and non-vascular etiologies of symptoms. Patients taking statins at time of stroke may be included. Patients receiving standard dose intravenous tPA or mechanical interventional procedures may be enrolled. Exclusion Criteria: 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. Mild stroke, defined as NIH Stroke Scale <2. Weight < 50 kg. Patient is comatose, regardless of etiology (> 4 points on the first three items of the NIHSS). History of intolerance or allergic reaction to any statins (myotoxicity, hepatic dysfunction, rash, etc.) 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). Use of drugs within past 30 days that increase risk of myotoxicity with statins (gemfibrozil, other fibrates, niacin, amiodarone, verapamil). Baseline major electrolyte disturbances (sodium <125 or >150, potassium <3.0 or >5.5). Recent major trauma (<3 months). Hypothermia (body temperature < 96F). Baseline hypoxia (defined as oxygen saturation <92% on room air). History of likely or proven systemic viral infection within 30 days. Known HIV infection or use of protease inhibitors. Endocarditis likely as cause of stroke. Mitochondrial disorder likely as cause of stroke. Pregnancy or lactation. History of rhabdomyolysis, myopathy, or other severe muscle disease. History of hepatitis, decompensated liver disease (ascites, bleeding varices or encephalopathy), or liver failure. Liver function tests (ALT, AST) > 2 X upper limit of normal. Unstable cardiovascular (includes uncontrolled hypertension), pulmonary, gastrointestinal, hepatic or musculoskeletal disease. 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). 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. Significant renal insufficiency, indicated by serum creatinine >2.0 mg/dl. Hypoglycemia (glucose < 60 mg/dl) or diabetic ketoacidosis unresponsive to therapy. Any of these hematologic abnormalities: WBC <3.0 x 103/mm3; Platelet count <50,000/mm3 Received an investigational drug within 30 days. Severe behavioral or social problems that may interfere with the conduct of clinical study procedures. Patient unlikely, in the investigator's opinion, to complete the study and return for follow-up visits for any reason.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose Lovastatin<br>High dose lovastatin (640 mg daily for three days) will be administered orally | Drug: High Dose Lovastatin<br>* 640 mg daily for 3 days<br>* Other names: Mevacor;|
| Active Comparator: Low Dose Lovastatin<br>Lovastatin 80 mg daily for three days will be administered orally to patients who were taking statin therapy at the time of enrolment | Drug: Low Dose Lovastatin<br>* 80 mg daily for 3 days<br>* Other names: Mevacor;|
| Placebo Comparator: Placebo<br>Placebo will be administered orally to patients who were NOT taking statin therapy at the time of enrolment | Other: Placebo<br>* Placebo for 3 days<br>* Other names: microcrystalline cellulose;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase in Liver Function Tests (LFTs) | Primary safety outcome: the development of clinical or laboratory evidence of major hepatic toxicity within 7 days of treatment onset or the development of clinical or laboratory evidence of rhabdomyolysis within 7 days of treatment onset. The primary safety outcome will be defined as: Liver toxicity: LFT increase at any time point > 3X upper limit of normal or development of jaundice, otherwise unexplained coagulopathy, or other clinical evidence of hepatitis or liver failure; or Muscle toxicity: An increase in CK (Creatine Kinase) at any time point > 10 X upper limit of normal, or clinical evidence of muscle pain or weakness not related to the stroke and associated with CK > 5 X upper limit of normal. | 90 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Score on NIH Stroke Scale | Measure of neurological outcomes. | 90 days | 
| Barthel Index Score | Measure of functional outcomes. | 90 days | 
| Modified Rankin scores | Measure of handicap. | 90 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stroke, Rhabdomyolysis, Jaundice