Use of Minocycline in Intracerebral Hemorrhage

Study Overview
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Brief Summary
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To date, no neuroprotective drugs have demonstrated clinical efficacy in intracerebral hemorrhage (ICH). This study will use intravenous (IV) minocycline in ICH to evaluate for (1) safety/ tolerability and (2) evaluate for clinical efficacy

Detailed Description
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Intracerebral hemorrhage (ICH) remains a devastating neurological disorder with high mortality and poor prognosis with unchanged mortality rates (53-59%). Acute treatment options for ICH remain supportive with no available effective drug or surgical therapy. All trials so far have failed to improve clinical outcome in randomized, double-blinded trials. However, one area of interest has been maintaining the integrity of the blood-brain-barrier (BBB) and preventing the growth of vasogenic edema. Matrix metalloproteinases (MMP) are a family of ubiquitous zinc-dependent endopeptidase enzymes whose primary function is the digestion of collagen type IV, laminin, and fibronectin for the purpose of remodeling extracellular basal lamina. Elevated MMP-9 as a pathological process associated with larger hematoma volume, larger perihematomal edema, and poorer clinical outcome in intracerebral hemorrhage is well documented in animal models and patients. One particular MMP-9 inhibitor gaining usage in cerebrovascular disease is minocycline. Normally FDA-approved for bacterial infection and acne vulgaris, minocycline has also been found to be both a safe and effective treatment in ischemic stroke; its potential role as a neuroprotectant in ischemic stroke is currently being tested in a large, randomized, double-blinded trial. Minocycline's beneficial role as a neuroprotectant may also extend to ICH. By inhibiting MMP-9, minocycline may decrease BBB permeability, resulting in less perihematomal edema and decreased mass effect. Although numerous animal ICH models support minocycline's role as an inhibitor of MMP-9 and neuroprotectant, its use has never been studied in humans with ICH.

Official Title
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Minocycline and Matrix Metalloproteinase Inhibition in Acute Intracerebral Hemorrhage: A Pilot Trial

Conditions
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Intracerebral Hemorrhage

Intervention / Treatment
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* Drug: Minocycline
* Other: normal saline infusion


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 18-80 yo Acute neurological deficit with corresponding ICH noted on head CT Glasgow Coma Scale (GCS) > 8 Onset of symptoms within 12 hrs < 30 ml of blood noted on initial CTH (30 ml hematoma volume is a noted independent marker between good and poor clinical outcome) ICH score < 3 English/ Spanish speaking Exclusion Criteria: Allergy to tetracycline and tetracycline analogues Pregnancy or suspected pregnancy Hepatic and/or renal insufficiency (LFTs 3x greater than upper limit of normal; creatinine > 2 mg/dL) Thrombocytopenia (plt count < 75,000) History of intolerance to minocycline Baseline modified Rankin score > 1 Stuporous or comatose (GCS < 8) Presence of concomitant serious illness that would confound study, including serious psychiatric disease or prior suicide attempts.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>normal saline infusion | Other: normal saline infusion<br> <br> |
| Experimental: minocycline<br>intravenous minocycline | Drug: Minocycline<br>* high-dose, intravenous minocycline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with Treatment-related Adverse Effects | Treatment-related adverse effects as noted by package insert: fever, nausea, vomiting, C-diff, hepatic toxicity, dermatitis, anaphylaxis, renal injury) | day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Volume (ml) of Perihematomal Edema | Volumetric analysis (ml) computed from computed tomography head | Change from baseline perihematomal edema volume to chronic (day 5-11) perihematomal edema volume | 
| modified Rankin score | modified Rankin score (points ranging from 0 to 6) | day 90 | 
| Barthel Index | Barthel Index score (points ranging from 0 to 100) | day 90 | 
| National Institutes of Health Stroke Scale Score | National Institutes of Health Stroke Scale Score (points ranging from 0 to 42) | day 90 | 
| Glasgow Coma Score | Glasgow Coma Score (points ranging from 3 to 15) | day 90 |