Clinical Stroke Research at MCG

Current Projects
1) Minocycline to Improve Neurologic Outcome (MINO)
Principal Investigator: David C. Hess, M.D.
Funding Source: NIH/NINDS 5R01NS055728-02
Year Started: 2007
Summary: Minocycline is a safe and well-tolerated antibiotic with excellent blood-brain barrier penetration. Recent evidence demonstrates that minocycline is a promising neuroprotective agent and is effective in animal models of global and focal ischemia. Minocycline has anti-inflammatory and anti-apoptotic effects and also inhibits the matrix metalloproteinases. Moreover, minocycline is neuroprotective in a rodent model of temporary focal ischemia at serum concentrations that are likely to be achievable in humans. MINO is a phase 1 clinical trial of intravenous minocycline in acute ischemic stroke. This study will enroll 60 patients within 6 hours of symptom onset at 3 centers around the country with the goal of determining the maximally tolerated dose of minocycline for acute ischemic stroke within 4 predefined dose tiers.

MINO in the news!
(For the Scientist Live article, click here)
(For the Augusta Chronicle article, click here)

2) Matrix Metalloproteinases Predict Poor Outcome in Acute Stroke
Principal Investigator: Jeffrey A. Switzer, D.O.
Sub-Investigator: Adviye Ergul, M.D., Ph.D.
Funding Source: MCG Intramural Grant Programs--Scientist Training Program
Year Started: 2006
Summary: Patients with diabetes mellitus are at particular risk for death and poor outcome from stroke. This may be attributable to pathologic remodeling of the cerebrovasculature in diabetics, resulting in amplified breakdown of the BBB in response to cerebral infarction or primary hemorrhage. Recent findings have demonstrated augmented cerebrovascular remodeling in an experimental model of Type 2 diabetes mellitus. These changes are characterized by increased cerebrovascular matrix metalloprotease activities, which are proposed to mediate BBB breakdown leading to edema and hemorrhage formation in stroke. This study will test the hypothesis that elevated serum MMP-2 and -9 activities are associated with worsened outcome in diabetic AIS and sICH patients and serve as a prognostic marker. Eighty ischemic stroke patients and 32 patients with intracerebral hemorrhage will be enrolled within 12 hours of symptom onset. Blood samples will be collected and clinical scales measured upon enrollment, at 24 and 48 hours, discharge and 3 months.

3) Targeting Fibrinolytic Inhibitors to Enhance Recanalization in Acute Stroke
Principal Investigator: Jeffrey A. Switzer, D.O.
Sub-investigator: Irina Sazonova, Ph.D.
Funding Source: Departmental
Year Started: 2008
Summary: This study will test the hypothesis that high levels of endogenous fibrinolytic inhibitors, particularly alpha2-antiplasmin, inhibit recanalization following intravenous rt-PA administration for acute ischemic stroke and reduce the odds of a favorable outcome. Subjects will have blood samples collected prior to rt-PA administration and at three months. Recanalization and clinical outcomes will be assessed.

 

Recently Completed Projects
1) Prevention Regimen For Effectively avoiding Second Strokes (PROFESS)
Local Principal Investigator: Fenwick T. Nichols, III, M.D.
Funding Source: Boerhinger-Ingelheim
Year Started: 2003
Year Completed: 2007
Summary: Randomized clinical trial comparing the efficacy and safety of Aggrenox® (25 mg aspirin/200 mg extended-release dipyridamole) with Clopidogrel (Plavix®), and Micardis® (telmisartan) with placebo in the presence of background anti-hypertensive treatment in the prevention of recurrent stroke.

PROFESS in the news! (click here)

2) Glucose Regulation in Acute Stroke Patients Trial (GRASP)
Local Principal Investigator: Christiana E. Hall, M.D.
Funding Source: NIH/NINDS
Year Started: 2005
Year Completed: 2007
Summary: Recent data suggest that glucose-insulin-potassium infusion (GIK) in acute myocardial infarction results in an improved survival of patients, especially in patients undergoing reperfusion therapy. GRASP was a phase 1 clinical trial assessing the feasibility and safety of glucose/insulin/potassium infusion in acute ischemic stroke patients. Patients were randomly assigned to tight glucose control (target 70 – 110 mg/dL), loose glucose control (70 – 200 mg/dL), or usual care.

3) Recombinant Factor VIIa in Acute Intracerebral Haemorrhage (FAST)
Local Principal Investigator: Christiana E. Hall, M.D.
Funding Source: Novo Nordisk
Year Started: 2005 Year
Completed: 2007
Summary: FAST was a multi-center randomized clinical trial to determine if the treatment of Recombinant Factor VIIa in patients with acute intracerebral bleeding will help more patients recover without severe permanent disability by reducing further intracerebral bleeding. Patients were randomized to one of three treatment arms: placebo, and rFVIIa 20 or 80 mcg/kg administered no more than 4 hours after symptom onset, and no more than 1 hour after baseline CT scan.

FAST in the news! (click here)

Seminal Projects
1) Stroke Prevention Trial in Sickle Cell Anemia (STOP)
Principal Investigator: Robert J. Adams, M.D.
Funding Source: NIH/NHLBI 1U10HL052193
Year Started: 1994
Year Completed:
1999 Summary: To enter the study, children with sickle cell anemia and no history of stroke had to have undergone two transcranial Doppler studies that showed that the time-averaged mean blood-flow velocity in the internal carotid or middle cerebral artery was 200 cm per second or higher. The patients were randomly assigned to receive standard care or transfusions to reduce the hemoglobin S concentration to less than 30 percent of the total hemoglobin concentration. The incidence of stroke (cerebral infarction or intracranial hemorrhage) was compared between the two groups. A total of 130 children (mean [±SD] age, 8.3±3.3 years) were enrolled; 63 were randomly assigned to receive transfusions, and 67 to receive standard care. At base line, the transfusion group had a slightly lower mean hemoglobin concentration (7.2 vs. 7.6 g per deciliter, P=0.001) and hematocrit (20.4 vs. 21.7 percent, P=0.002). Ten patients dropped out of the transfusion group, and two patients crossed over from the standard-care group to the transfusion group. There were 10 cerebral infarctions and 1 intracerebral hematoma in the standard-care group, as compared with 1 infarction in the transfusion group — a 92 percent difference in the risk of stroke (P<0.001). This result led to the early termination of the trial. This trial demonstrated that transfusion greatly reduces the risk of a first stroke in children with sickle cell anemia who have abnormal results on transcranial Doppler ultrasonography.

2) Stroke Prevention Trial in Sickle Cell Anemia 2 (STOP 2)
Principal Investigator: Robert J. Adams, M.D.
Funding Source: NIH/NHLBI 2U01HL052193
Year Started: 1999
Year Completed: 2004
Summary: We studied children with sickle cell disease who had a high risk of stroke on the basis of a transcranial Doppler screening examination and who had received transfusions for 30 months or longer, during which time the Doppler readings became normal. The children were randomly assigned to continued transfusion or no continued transfusion. Children with severe stenotic lesions on cerebral magnetic resonance angiography were excluded. The composite primary end point was stroke or reversion to a result on Doppler examination indicative of a high risk of stroke. The study was stopped after 79 children of a planned enrollment of 100 underwent randomization. Among the 41 children in the transfusion-halted group, high-risk Doppler results developed in 14 and stroke in 2 others within a mean (±SD) of 4.5±2.6 months (range, 2.1 to 10.1) of the last transfusion. Neither of these events of the composite end point occurred in the 38 children who continued to receive transfusions. The average of the last two transcranial Doppler results before transfusion was started was the only predictor of the composite end point (P=0.05). This trial demonstrated that discontinuation of transfusion for the prevention of stroke in children with sickle cell disease results in a high rate of reversion to abnormal blood-flow velocities on Doppler studies and stroke.