Neuroprotection With Statin Therapy for Acute Recovery Trial Phase 2 (NeuSTART2)

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.

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.

Study Overview

• Status: Completed
• Conditions: Stroke; Jaundice; Rhabdomyolysis
• Intervention / Treatment: Drug: High Dose Lovastatin; Drug: Low Dose Lovastatin; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 164
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90024
      • University of California, Los Angeles Stroke Network
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women'S Hospital
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Hospital of the University of Pennsylvania

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:

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

Collaborators and Investigators

• Sponsor: Mitchell S Elkind
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Mitchell S Elkind, MD, MS, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2009
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: October 30, 2013
• First Submitted That Met QC Criteria: October 30, 2013
• First Posted (Estimate): November 6, 2013

Study Record Updates

• Last Update Posted (Actual): July 24, 2017
• Last Update Submitted That Met QC Criteria: July 20, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Stroke; Jaundice; Rhabdomyolysis
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Musculoskeletal Diseases; Muscular Diseases; Skin Manifestations; Hyperbilirubinemia; Stroke; Jaundice; Rhabdomyolysis; 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: AAAD9004; 2P50NS049060 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No