Use of Minocycline in Intracerebral Hemorrhage

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

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

Study Overview

• Status: Completed
• Conditions: Intracerebral Hemorrhage
• Intervention / Treatment: Other: normal saline infusion; Drug: Minocycline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Age 18-80 yo
2. Acute neurological deficit with corresponding ICH noted on head CT
3. Glasgow Coma Scale (GCS) > 8
4. Onset of symptoms within 12 hrs
5. < 30 ml of blood noted on initial CTH (30 ml hematoma volume is a noted independent marker between good and poor clinical outcome)
6. ICH score < 3
7. English/ Spanish speaking

Exclusion Criteria:

1. Allergy to tetracycline and tetracycline analogues
2. Pregnancy or suspected pregnancy
3. Hepatic and/or renal insufficiency (LFTs 3x greater than upper limit of normal; creatinine > 2 mg/dL)
4. Thrombocytopenia (plt count < 75,000)
5. History of intolerance to minocycline
6. Baseline modified Rankin score > 1
7. Stuporous or comatose (GCS < 8)
8. Presence of concomitant serious illness that would confound study, including serious psychiatric disease or prior suicide attempts.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; normal saline infusion	Other: normal saline infusion
Experimental: minocycline; intravenous minocycline	Drug: Minocycline; high-dose, intravenous minocycline

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Tennessee
• Collaborators: University of Southern California

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2013
• Primary Completion (Actual): November 30, 2016
• Study Completion (Actual): November 30, 2016

Study Registration Dates

• First Submitted: January 25, 2017
• First Submitted That Met QC Criteria: January 30, 2017
• First Posted (Estimate): February 2, 2017

Study Record Updates

• Last Update Posted (Estimate): February 2, 2017
• Last Update Submitted That Met QC Criteria: January 30, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage; Anti-Infective Agents; Anti-Bacterial Agents; Minocycline
• Other Study ID Numbers: MITCH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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