Neuroprotection With Statin Therapy for Acute Recovery Trial (Neu-START) (Neu-START)

SPOTRIAS: Neuroprotection With Statin Therapy for Acute Recovery Trial

The purpose of this dose escalation study is to evaluate the use of lovastatin for the treatment of acute ischemic stroke.

Study Overview

• Status: Completed
• Conditions: Stroke
• Intervention / Treatment: Drug: lovastatin

Detailed Description

The Neuroprotection with Statin Therapy for Acute Recovery Trial (Neu-START) is part of the Specialized Program on Translational Research in Acute Stroke (SPOTRIAS). The overall goals of SPOTRIAS are to enhance delivery of acute stroke patient care with a focus on high-risk, disadvantaged populations, train acute stroke translational researchers, and conduct 3 innovative acute stroke projects.

Neu-START will enroll 33 patients with acute ischemic stroke presenting within 24 hours of onset. In the trial, investigators will treat the patients within 24 hours of symptom onset with short term high-dose lovastatin at escalating dosage. The escalating dosage levels will be 1, 3, 6, 8, and 10 mg/kg per day for 3 days. Lovastatin is in a class of drugs called statins, used for lowering cholesterol and preventing cardiovascular disease. Patients will be followed for 30 days for clinical and laboratory outcome events.

The goals of this trial are to determine if lovastatin in increasing doses from 1 mg/kg to 10 mg/kg daily for 3 days beginning 24 hours after acute ischemic stroke can be administered safely, and to assess the pharmacokinetics of lovastatin administered at high doses.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 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.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: lovastatin; lovastatin at escalating dosages: 1 mg/kg/day, 3 mg/kg/day, 6 mg/kg/day, 8 mg/kg/day, 10 mg/kg/day	Drug: lovastatin; investigators will treat the patients within 24 hours of symptom onset with short term high-dose lovastatin at escalating dosage. The escalating dosage levels will be 1, 3, 6, 8, and 10 mg/kg per day for 3 days.; Other Names: Mevacor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety through 30 days defined as absence of liver or muscle-related toxicity on days 1, 2, 3, 5, 7, and 30.	Devt of clinical or laboratory evidence of major hepatic or muscle toxicity. Either: (1) liver toxicity: liver function test increase, devt jaundice, unexplained coagulopathy, or other clinical evidence of hepatitis or liver failure; or (2) muscle toxicity: increase in creatine phosphokinase (CK) at any time point	30 days

Secondary Outcome Measures

Outcome Measure	Time Frame
pharmacokinetic measurements made on days 1, 3, 4, and 5.	5 days

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Mitchell Elkind, MD, MS, Columbia University; Principal Investigator: Ji Chong, MD, Columbia University

Publications and helpful links

General Publications

• Elkind MS, Sacco RL, MacArthur RB, Fink DJ, Peerschke E, Andrews H, Neils G, Stillman J, Corporan T, Leifer D, Cheung K. 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. doi: 10.1111/j.1747-4949.2008.00200.x.
• Elkind MS, Sacco RL, Macarthur RB, Peerschke E, Neils G, Andrews H, Stillman J, Corporan T, Leifer D, Liu R, Cheung K. 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. doi: 10.1159/000228709. Epub 2009 Jul 16.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): May 1, 2008

Study Registration Dates

• First Submitted: October 24, 2005
• First Submitted That Met QC Criteria: October 24, 2005
• First Posted (Estimate): October 25, 2005

Study Record Updates

• Last Update Posted (Estimate): May 9, 2016
• Last Update Submitted That Met QC Criteria: May 5, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: acute ischemic stroke; neuroprotection; SPOTRIAS; statin; lovastatin
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; L 647318; Dihydromevinolin
• Other Study ID Numbers: AAAA5855; R01NS049060 (Other Grant/Funding Number: NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED