1. Stroke Research 2016 Jeanne Carroll, RN, BA, CCRC 2 Ivorine Yu, PhD 1 Fen-Lei Chang, MD, PhD 1,2,3 1 Indiana University School of Medicine – Fort Wayne 2 Parkview Neuroscience and Stanley Wissman Stroke Center 3 Fort Wayne Neurology May 18, 2016 1 Disclosures: FC: Genentech, Biogen, Boehringer-Ingelheim and AstraZeneca: Principal Investigator for clinical trials

2. Neuroprotection Overcoming Failure of Translational Research from Bench to Bedside More than 1000 peer-reviewed publications on successful neuroprotection against stroke neural damage in various stroke models, but none so far proven to be useful in human clinical trials. Proposed reasons –Difference of stroke in human and animal models –(Difference in immunological mechanisms between human and mice) –Heterogeneity of stroke in human –Lack of sensitivity of outcome measures in human stroke research –Lack of clinical relevance of basic research such as pre-treatment, early reperfusion, and unrealistic dosing Needs for combination treatment with efficacy on blocking multiple ischemic pathways 2

3. Indiana University School of Medicine – Fort Wayne Translational Stroke Research First animal stroke model focused on penumbra, not on ischemic core Clinically relevant time window after stroke onset MCA occlusion, brain slice, and cell culture models Combination Rx: –Lamotrigine –Lovastatin –Minocycline Translational research 3 S260-2 ISH-Il1b & IHC-HP1 R CPU (core) 40x

4. ComboRx Reduced Necrosis and Apoptosis of Cultured Hippocampal Neurons After OGD while Minocycyline reduced apoptosis, and Lovastatin and Lamotrigine reduced necrosis 4 necrosis apoptosis

5. ComboRx Reduced Necrosis and Apoptosis of Cultured Hippocampal Neurons After OGD while Minocycyline reduced apoptosis, and Lovastatin and Lamotrigine reduced necrosis 5

6. Model for Cardiac Arrest 6

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10. Acute Ischemic Stroke Model 10

11. Acute Ischemic Stroke Model 11

12. Acute Ischemic Stroke Model 12

13. Acute Ischemic Stroke Model 13

14. Acute Ischemic Stroke Model 14

15. Opportunity for Translational Research Safe – medications on the market with extensive experience Pre-clinical evidence of efficacy efficacy Making sense for patients and family members –Lovastatin: statin with proven neuro-protective benefits –Lamotrigine: anti- seizure medication to prevent seizures –Minocycline: antibiotics to prevent infection and fever 15

16. PRISMS Phase IIIb, double-blind study to evaluate Alteplase in patients with mild stroke Within 3 hours of stroke onset NIHSS < 5 and not clearly disabling Why? Many of these patients (around 30%) were significantly disabled upon evaluation at 3 months (mRS 2-6) 16

17. PRISMS So Why So Many People with Significant Disability After Initial Mild Deficits?? Stroke Progression from lost collaterals and/or increased thrombus Under-measured cognitive deficits by NIHSS Under-appreciated effect of deficits at time of presentation 17

18. SOCRATES Acute Stroke Or Transient IsChemic Attack TReated with Aspirin or Ticagrelor and Patient OutcomES Evaluate ASA vs Ticagrelor for patients with mild stroke (NIHSS < 5) or high risk TIA on vascular outcome including 1. Stroke 2. MI 3. Vascular death 18

19. SOCRATES Ticagrelor (Brilinta) is a platelet aggregation inhibitor Ticagrelor is more effective than clopidogrel to prevent CV death, MI, and stroke after acute coronary syndrome, The PLATO trial [Wallentin et al., N. Engl. J. Med. 2009, 361 (11): 1045–57] NIHSS < 5 ASA or Ticagrelor starts within 24 hours of stroke onset ** Study was completed, and failed to demonstrate better efficacy 19

20. Embolic Strokes of Undetermined Source: The Case for a New Clinical Construct 20 Hart et al., Lancet Neurology, 2014, 13, 429-438

21. Embolic Strokes of Undetermined Source (ESUS): The Case for a New Clinical Construct Cryptogenic: vague, negatively defined ESUS: non-lacunar strokes without an identified cardioembolic source or due to occlusive atherosclerosis Embolic sources – usually low risk –LV dysfunction –Mitral annular calcification –Patent foramen ovale –Left atrial stasis associated with atrial tachycardia –Non-stenotic atherosclerotic carotid plaques –Aortic arch atheroma 21

22. Embolic Strokes of Undetermined Source (ESUS): The Case for a New Clinical Construct Prior studies showed no benefit due to –Less well defined patient population –Coumadin with increased bleeding risk New clinical trial to include –ESUS platform –New generation oral anticoagulant –May provide a valid treatment options for this group of patients 22

23. PRIMARY OBJECTIVE: To assess the clinical effects of natalizumab versus placebo in acute ischemic stroke on clinical measures of functional independence and activities of daily living. STUDY TREATMENT: IV Natalizumab vs. Placebo up to 9 hrs from onset of stroke symptoms RATIONALE: Experimental and pathologic data suggest that peri-infarct inflammation contributes to secondary injury after brain ischemia and that blocking inflammation reduces the volume of brain infarction and improves clinical outcomes Natalizumab is a recombinant humanized monoclonal antibody that inhibits the transmigration of leukocytes into inflamed parenchymal tissue

24. Mild & Rapidly Improving Stroke Study PRIMARY OBJECTIVE: To clarify long-term outcomes of patients with mild and rapidly improving stroke and examine the association with tPA treatment STUDY TREATMENT: Observational study using patient questionnaires to measure long term patient outcomes RATIONALE: Mild and rapidly improving stroke symptoms are common presentations of acute stroke. The great majority of these pts are not treated with thrombolytics yet almost 1 in 3 are unable to return home or ambulate independently at discharge. MaRISS will describe the long-term outcomes with a battery of outcome measures and will elucidate predictors of poor outcome by analyzing stroke baseline characteristics and early fluctuations.

25. Penn Alliance for Therapeutic Hypothermia (PATH) Registry PRIMARY OBJECTIVE: To provide hospitals with the ability to benchmark and perform research around cardiac arrest care. STUDY TREATMENT: Comprehensive data abstraction on every cardiac arrest entering Parkview Regional Medical Center. All data entered will be exportable in real time and quarterly data summary reports will be available to all users. RATIONALE: With therapeutic hypothermia (TH) and more aggressive post-arrest interventions and monitoring becoming common, PATH addresses the need to track and assess many different aspects of cardiac arrest. The comprehensive data capture in PATH is ideal in terms of both quality improvement and research initiatives.

26. CAROTID REVASCULARIZATION & MEDICAL MANAGEMENT FOR ASYMPTOMATIC CAROTID STENOSIS PRIMARY OBJECTIVE: To test the primary hypothesis that intensive medical management (IMM) differs from Carotid Endarterectomy (CEA) + IMM and Carotid Artery Stenting (CAS) + IMM in preventing the primary endpoint of stroke or death in pts with high-grade asymptomatic carotid stenosis STUDY TREATMENTS: Two parallel Studies: CEA + IMM versus IMM Alone CAS + IMM versus IMM Alone RATIONALE: There have been substantial changes in MEDICAL management in the past two decades that may have substantially reduced the risk of stroke in asymptomatic carotid stenosis. CREST-2 is uniquely positioned to test the merits of CEA and CAS in the context of the latest intensive medical management treatment.

27. Thank You! Creating knowledge - Finding new treatment options Collaboration of –Parkview Neuroscience Service Line –Parkview Mirro Research and Innovation Center –Parkview Center on Aging and Health – Fall Prevention Clinic –Indiana University School of Medicine-Fort Wayne –Fort Wayne Neurology 27

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