Stroke Trials Registry

Neu-START
Neuroprotection with Statin Therapy for Acute Recovery Trial [SPOTRIAS]

Principal Investigator
Mitchell S Elkind, MD, MS

PI Address
Mitchell S Elkind, MD, MS
Columbia University
New York, NY

Contact Address
Tania E. Corporan, MD
Columbia University Medical Center
New York, NY 10032

Ph: 212-305-7755

Contact Email
tcorporan@neuro.columbia.edu

Sponsor

Trial Phase:	Phase I
Study Size Actual:	33
Study Size Planned:	33
Centers Actual:	2
Centers Planned:	2
Max Time from onset:	24 Hours
Min Age:	18
Follow-up Duration:	1 Months
ISRCTN#	NCT00243880

Status:
Published in 2009.

Purpose:
To determine whether lovastatin in increasing doses can be administered safely following acute ischemic stroke.

Interventions:

Lovastatin
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor; lowers cholesterol

Location(s):
New York.

Year Started: 2006

Year Finished: 2009

Year Presented: 2008

Year Published: 2009

Design:
Single-center, non-randomized, dose-escalation and dose-finding study.

Inclusion Criteria
Patients who satisfy the criteria for ischemic stroke: acute focal neurological deficit of likely ischemic vascular origin. Patient has pretreatment brain CT scan compatible with ischemic stroke.

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; patient had a stroke (ischemic or hemorrhagic) with residual deficit within 1 month prior to treatment; mild stroke, defined as NIH Stroke Scale <2; patient has received or is expected to receive intravenous rt-PA within 3 hours or intra-arterial rt-PA within 6 hours of stroke onset, according to our institutional standard of care; receipt of intravenous rt-PA after 3 hours or intra-arterial rt-PA after 6 hours post-stroke onset; seizure at presentation or within two weeks prior to stroke; 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, azithromycin, clarithromycin, nefazodone); 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 < 96 degrees Fahrenheit); 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) > 2X upper limit of normal; unstable cardiovascular (includes uncontrolled hypertension), pulmonary, gastrointestinal, hepatic or musculoskeletal disease within one month (30 days) prior to treatment (by reported history); patient has evidence of 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), significant hyperglycemia (glucose > 400 mg/dl) or diabetic ketoacidosis; any of these hematologic abnormalities: Hb <10 g/dl; 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 Involvement:
Escalating dosage levels of short-term high-dose oral lovastatin (1, 3, 6, 8 and 10 mg/kg per day for 3 days). Dose-toxicity model is calibrated such that the method will eventually select a dose that causes 7% to 13% dose-limiting toxicity.

Primary Outcome:
Musculoskeletal and hepatic toxicity, defined by clinical and laboratory criteria, with a one-month follow-up period.

Secondary Outcome:
Other clinical and laboratory data, including platelet effects and pharmacokinetic parameters, will also be assessed.

Results:
We enrolled 33 patients (16 men/17 women, age range 23-82 years). Three patients were treated at 1 mg/kg, 10 at 3 mg/kg, 12 at 6 mg/kg, and 8 at 8 mg/kg. Thirty of the 33 patients (90.9%) completed at least 11 of 12 doses. Two patients at the 6-mg/kg dose level experienced transient mild elevations in transaminases without clinical sequelae. After an initial dose reduction, the dose was re-escalated to 8 mg/kg, and no further patients reached safety outcomes. No clinical liver disease, myopathy, or creatine phosphokinase elevations occurred. The final model-based toxicity at 8 mg/kg was 13%; no patient was treated at 10 mg/kg. In conclusion, Lovastatin at doses above those currently approved by the Food and Drug Administration is feasible for 3 days after an acute ischemic stroke and the maximum tolerated dose is estimated to be 8 mg/kg/day. Further randomized studies are warranted to confirm its safety and to demonstrate its efficacy in improving functional outcomes after stroke.

Source of Information:
Presented at the 2007 International Stroke Conference [February 2007].
ClinicalTrials.gov
Abstract presented at the AHA International Stroke Conference, New Orleans, Feb. 2008.

Web Links and Publications:

High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART).
Cerebrovasc Dis 2009;28(3):266-75

The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke.
Int J Stroke 2008 Aug;3(3):210-8

Columbia University

Neu-START
ClinicalTrials.gov

This information last updated on: 9/28/2009

Reviewed on: 09/16/2009.

UID: 743