Clinical trial NCT00836355: Enoxaparin and/or Minocycline in Acute Stroke
Official title: Pilot Study of Treatment With Intravenous Enoxaparin and/or Oral Minocycline to Limit Infarct Size After Ischemic Stroke
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Acute Ischemic Stroke
Keywords: stroke
magnetic resonance imaging
enoxaparin
minocycline
NIH stroke scale
modified Rankin scale
neuroprotection
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: James N. Kirby Foundation
First posted: 2009-02-04
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate whether enoxaparin, minocycline, or both medications in combination may help in recovery from acute stroke.

Enoxaparin (brand name Lovenox®) is a medication approved for use in humans to prevent and to treat blood clots in deep veins in certain specific medical situations. Minocycline (brand name Minocin®) is a tetracycline antibiotic approved to treat a number of bacterial infections in humans. The investigators are studying these medications in acute human stroke because they have each been separately shown to reduce the amount of injured brain tissue in rats made to have acute ischemic stroke experimentally. In a human trial comparing minocycline with placebo (a sugar pill) acute ischemic stroke patients who took minocycline had better recovery after 1 week, 1 month and 3 months than patients who took placebo.

Detailed description: Enoxaparin is a low molecular weight heparin (average molecular weight 4,500 daltons, vs. 12,000 to 15,000 daltons for unfractionated heparin) administered subcutaneously and intravenously. It is a marketed drug FDA-approved in various clinical situations for: the prevention and treatment of deep vein thrombosis; and in the treatment of acute myocardial infarction. Minocycline is an orally administered antibiotic of the tetracycline class. It is a marketed drug FDA-approved for the treatment of various bacterial and rickettsial infections. Both medications have been found to be neuroprotective in experimental stroke models. Minocycline has shown promise in a human acute stroke study.

This study is designed to investigate two logistically simple treatment regimens, singly or in combination, employing these medications for acute ischemic stroke:

1. pulsed intravenous (iv) administration of enoxaparin initiated within 6 hours and completed by 24 hours after stroke onset; and
2. oral minocycline treatment once daily for five days.

The goal of treatment is neuroprotection: the limitation of the loss of brain tissue that follows ischemic stroke.

Eligibility criteria: There are two Study Sections: A and B

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Study Section A Inclusion Criteria:

1. acute ischemic stroke in an adult in-patient who can complete screening and begin study treatment within 6 hours of stroke onset (onset time defined as the last time the patient was known to be at his/her usual level of functioning)
2. patient not a candidate for rTPA treatment because treatment cannot be started within the required 3 hours after stroke onset, or because rTPA treatment is refused.

Study Section A Exclusion Criteria:

1. intracranial hemorrhage;
2. subfalcine, transtentorial, or foramen magnum herniation on CT or MRI scan of the brain;
3. history of hypersensitivity or intolerance to or toxicity from enoxaparin, other heparinoids, heparin, minocycline, or other tetracyclines;
4. weight 125lbs or less;
5. active bleeding;
6. thrombolytic treatment or major surgery in the previous 24 hours;
7. anticipated need for treatment with coumarin, or a low-molecular weight heparin other than enoxaparin, or unfractionated heparin before 36 hours after stroke onset (but see deep venous thrombosis prophylaxis, below);
8. INR above the normal range;
9. known coagulopathy;
10. platelet count \<100,000/mm3 (if the count drops below 100,000 while on enoxaparin, the medication will be stopped)
11. pregnancy or lactation;
12. undergoing dialysis; severe renal impairment (creatinine clearance known or estimated to be \<30ml/min);
13. mean arterial BP (taken to be 1/3 of the difference in mm Hg between diastolic BP and systolic BP, added to the diastolic BP) of 130 mm Hg or greater; (if the mean arterial BP is 130 mm Hg or greater but can be reduced by treatment to \< 130 mm Hg, with systolic BP in the 150 169 mm Hg range, the patient may be entered).

Patients in Study Section A will be randomly assigned to one of the four treatment arms: enoxaparin, minocycline, enoxaparin and minocycline, or no intervention.

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Study Section B Inclusion Criteria:

1. acute ischemic stroke in an adult in-patient who can complete screening and begin study treatment within 24 hours of stroke onset (onset time defined as the last time the patient was known to be at his/her usual level of functioning;)
2. patient does not qualify for, or declines to participate in, Study Section A.

Study Section B Exclusion Criteria:

1. acute primary intracranial hemorrhage;
2. subfalcine, transtentorial, or foramen magnum herniation on CT or MRI scan of the brain;
3. pregnancy or lactation.

Patients in Study Section B will be randomly assigned to one of TWO treatment arms: minocycline, or no intervention.

Primary outcomes:
measure: Indices of Salvaged Ischemic Penumbra and of Final Infarct Volume Based on Quantitative Volumetric Analyses of Pre- and Post-treatment Perfusion-weighted and Diffusion-weighted Brain MR Imaging
timeFrame: Within approximately 7 days of stroke onset
Secondary outcomes:
measure: NIH Stroke Scale Scores
timeFrame: Baseline and after approximately one week
measure: Modified Rankin Scale Score
timeFrame: Baseline, and approximately one week and 3 months later
Other outcomes:
Locations:
city: New York
country: United States
facility: Bellevue Hospital Center
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
Study officials:
affiliation: Department of Neurology; New York University School of Medicine
name: Saran Jonas, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Neurology; New York University School of Medicine
name: Giacinto Grieco, M.D.
role: STUDY_DIRECTOR
References:
citation: Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology. 2007 Oct 2;69(14):1404-10. doi: 10.1212/01.wnl.0000277487.04281.db.
citation: Mary V, Wahl F, Uzan A, Stutzmann JM. Enoxaparin in experimental stroke: neuroprotection and therapeutic window of opportunity. Stroke. 2001 Apr;32(4):993-9. doi: 10.1161/01.str.32.4.993.
citation: Quartermain D, Li Y, Jonas S. Enoxaparin, a low molecular weight heparin decreases infarct size and improves sensorimotor function in a rat model of focal cerebral ischemia. Neurosci Lett. 2000 Jul 14;288(2):155-8. doi: 10.1016/s0304-3940(00)01223-4.
citation: Quartermain D, Li YS, Jonas S. The low molecular weight heparin enoxaparin reduces infarct size in a rat model of temporary focal ischemia. Cerebrovasc Dis. 2003;16(4):346-55. doi: 10.1159/000072556.
citation: Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, Hill WD, Feuerstein G, Hess DC. Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. BMC Neurol. 2004 Apr 26;4:7. doi: 10.1186/1471-2377-4-7.
citation: Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13496-500. doi: 10.1073/pnas.96.23.13496.
citation: Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, Weinstein PR, Liu J. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke. 2007 Jan;38(1):146-52. doi: 10.1161/01.STR.0000251791.64910.cd. Epub 2006 Nov 22.