1. Phase 2/3 study of intravenous thrombolysis and hypothermia for acute treatment of ischemic stroke (ICTuS 2/3) Patrick D. Lyden, MD, FAAN, FAHA Chairman, Neurology Louis and Carmen Warschaw Chair in Neurological Research

2. Wu&Grotta Lancet Neurol 2013; 12:275-84

3. 3 Mild hypothermia is protective Hypothermia is an effective neuroprotectant (Yenari—Stanford Stroke Center) 38C 33C

4. 101 studies 3353 animals

5. We conclude that in animal models of focal cerebral ischaemia, hypothermia improves outcome by about one-third under conditions that may be achievable for large numbers of patients with ischaemic stroke.

6. Neurons Hypothermia 33 o C vs 35 o C-24 hours- OGD 2 Hours

7. Intravascular Cooling in the Treatment of acute Stroke – Longer t-PA window ClinicalTrials.gov identifier: NCT00283088 ICTuS-L SPOTRIAS No. P50N5044148 7

8. ICTuS-L: Conclusions 8 Endovascular cooling can performed in awake patients after moderate to severe stroke Endovascular cooling can be combined with thrombolytic therapy Increased SAE Ratio with Hypothermia Increase risk of pneumonia with Hypothermia Pneumonia did not effect outcome at 90 days Hemmen et at Stroke 2010.

9. Accutrol TM Catheter and RTx Console

10. Thermoregulatory Control 10 Anesthesiology 1997; 86:1046-54

11. 1.Meperidine Bolus 1 mg/Kg before cooling (max 100mg) Slowly given over 10-15 min Infusion 25mg/hr (adjusted to sedation and shivering) If shivering, then: a. 10-25 mg IV bolus, PRN b. increase infusion by 5 mg/hr 2.Buspirone 30 mg p.o. after randomization 15 mg p.o. at hour 8 and 16 and 24 3.Skin warming Heating blanket – Medium setting Anti-shivering protocol

13. Treatment Times to Target in 26 Cooled Patients (PP) Lyden, Neurocrit Care, 16:413-420, 2012 13

14. Multivariate Model VariableEstimateP Time to Reach 34°C(Intercept)1258.14NS Age-25.80.051 Weight16.8<0.05 Gender67.9NS Meperidine-0.5<0.05 Shivering33.3NS Lyden, Neurocrit Care, 16:413-420, 2012

15. Multivariable Analysis VariableEstimateP AUC under 34°C (Intercept)3774.7150<0.01 R 2 =0.51, p<0.01 Age-5.3761NS BSA-1718.9852<0.001 Meperidine0.4721<0.05 Shivering * * -18.2924<0.05 AUC under 35°C (Intercept)6980.7695<0.01 R 2 =0.54, p<0.01 Age1.232NS BSA-3407.079<0.001 Meperidine1.0799<0.05 Shivering * * -37.249<0.05

16. Conclusions From ICTuS L Exploratory Analyses Time to reach target is a function of age, weight, and shivering control Maintaining hypothermia depends on weight, and to a lesser extent on shivering control

17. Pneumonia has been reduced in ICTuS 2 Vigilant surveillance Preventive measures Early empiric antibiotics “Permissive Hypothermia”

18. Implications from ICTuS L and ICTuS 2 Permissive hypothermia In Ictus 3, patients will be cooled as quickly as possible. The target reached early will be the target for the 24 hour cooling period.

19. Methods and Protocol International Journal of Stroke 9.1 (2014): 117-125. Effect size 7% Power 80% Alpha 0.05

20. PurposeTo determine whether the combination of thrombolysis and hypothermia is superior to thrombolysis alone for the treatment of acute ischemic stroke. DesignProspective, randomized, single-blind, multi- center Phase 2/3 study OutcomeFavorable outcome defined as a 90 day Modified Rankin score of 0 or 1

21. Age 22 to 82 IV rt-PA <3 hours NIHSS 7 – 20/24 Pre-stroke mRS 0-1 No posterior circulation strokes No I/A at this time Inclusion/Exclusion

22. Enrollment/Recruitment Update 112 Subjects enrolled to date!  16 sites actively recruiting (1 in Europe)  13 sites in start up phase

23. Transition Plan if we enter StrokeNET End ICTuS 2 when SPOTRIAS funding ends. Begin ICTuS 3 upon entering StrokeNET We will have about 200 patients by May 2015 First Interim (futility/efficacy) planned for 400 patients Second Interim at 800 DSMB could ask for a Third Interim at 1200

24. Eliminate saline bolus and simplify protocol Add sites – Canada, Australia, Europe Propose to StrokeNET Status Report

25. Questions

26. Back Up Slides