1. Protocol Nichol McBee, MPH, CCRP BIOS Coordinating Center Johns Hopkins University

3. Protocol Overview

4. Schedule of Events

5. Registration/Screening Diagnostic CT Blood pressure control Pregnancy test Toxicology screen Lab assessments Concomitant treatments NIHSS Barthel Index (historic) Modified Rankin scale (historic)

6. Early Notification is Important ICH in the ED!

7. Diagnostic CT Within 24 hours of symptom onset Time 0 CT or CTA ICH > 30 cc Infratentorial hemorrhage – Brainstem involvement or third nerve palsy No underlying pathology

8. Blood Pressure Control SBP < 180 mmHg 6 hours Long-term goal: MAP < 100 or 140/80

9. Pregnancy Test Urine or serum Prior to consent: Review if done standard of care Post consent: Order if not done per standard of care Pregnancy during follow-up

10. Toxicology Screen Cocaine, barbiturates, etc Contributor(s) to the bleed As close to presentation to ED as possible Standard of care? Data collection only

11. Lab Assessments Screening: – Plt count – INR – Pregnancy test (if applicable) Once prior to randomization: – Plasma plasminogen activity – Fibrinogen Daily through day 6: – WBC – Hct – Plt count – aPTT – INR

12. Concomitant Treatments Concomitant medications Concomitant procedures

13. NIHSS ED presentation Certified examiner Day 7, 30, 180, and 365

14. Barthel Index Screening: historical Level of functioning prior to symptom onset Comparison of scores at days 30, 90, 180, 270, and 365

15. Modified Rankin Scale Screening: historical 0-1 Level of functioning prior to symptom onset Comparison of scores at days 30, 90, 180, 270, and 365

16. Medical history/review of systems MRI/MRA (or CTA) Post Consent Screening Informed consent Stability CT Blood pressure control Pregnancy test Toxicology screen Lab assessments Concomitant treatments NIHSS Modified Rankin Scale

17. Inclusion Criteria ICH ≥ 30 mL on dCT GCS ≤ 14 or a NIHSS ≥ 6 ICH stability Symptom onset < 24 h prior to dCT MIS 12-72h post dCT 1 st dose up to 76h post dCT SBP < 180 mmHg Historical mRS 0 or 1 Age ≥ 18 and ≤ 80

18. Exclusion Criteria Infratentorial hemorrhage Intraventricular hemorrhage requiring EVD Thalamic bleeds with midbrain extension Irreversible impaired brain stem function Underlying pathology Unstable mass or evolving intracranial compartment syndrome

19. Exclusion Criteria (cont.) Coagulopathy Long-term anti-coagulation required Dabigatran use Systemic bleeding Pregnancy Allergy/sensitivity to rt-PA Prior enrollment Other interventional trial Survival to d365 is not expected

20. Exclusion Criteria (cont.) Concurrent illness Mechanical heart valve Known risk for embolization Investigator judgment Active drug or alcohol use or dependence that would interfere with follow-up Unstable patient who needs specific intervention No consent

21. Randomization Only after I/E criteria satisfied and informed consent signed Adaptive design Timelines

22. Post-Randomization/Pre-Surgery Lab assessments Concomitant treatments NIHSS Barthel Index Modified Rankin Scale MRI/MRA

23. Day 1 (Day of Randomization) Medical management Image-guided catheter placement + aspiration Post catheter placement CT Review of systems (post surgery) rt-PA administration Daily CT Vital signs Neurocheck Lab assessments Concomitant treatments

24. Medical Management ICP management Neurological status Cardiovascular management Respiratory care Nutritional support DVT and PE prophylaxis Withdrawal of care

25. MIS Procedure Credentialed neurosurgeon Trajectory determination Surgical Center review Antibiotic therapy Catheter placement Post catheter placement CT Stabilization period Catheter adjustment/replacement

26. Review of Systems Post Surgery Neurological status 3 hours post MIS Clinical worsening or improvement

27. DOSING Who – Certified investigator or designee What – 1.0mg/1.0mL of Cathflo followed by 3.0 mL of flush Where – At the bedside – Into the clot system

28. DOSING When – 1 st dose no sooner than 12 hours and no later than 76 hours post Diagnostic CT scan and after stability is confirmed. – Every 8 hours for up to 9 doses How – Sterile field – Monitor vital signs

29. DOSING ELIGIBILITY Daily CT scans Catheter tract stability Dosing endpoints

30. Days 2 and 3 (Post Randomization) rt-PA administration Daily CT Vital signs Neurocheck Lab assessments Concomitant treatments

31. DAILY SAFETY LABS Serum – White blood cell count – Hematocrit – Platelet count – INR – PT – aPTT – Plasminogen – Fibrinogen – D-dimer

32. Days 4-6 (Post Randomization) Daily CT (day 4) CT 24h post catheter removal Vital signs Neurocheck Lab assessments Concomitant treatments

33. Day 7 (Post Randomization) MRI NIHSS

34. Follow-up (Post Symptom Onset) Day 30 ± 7 days Day 90 ± 7 days Day 180 ± 14 days Day 270 ± 14 days Day 365 ± 14 days Daily CT ScanX† Concomitant treatmentsSOC NIHSSSOC Barthel IndexXXXXX Modified Rankin ScaleXXXXX Stroke Impact ScaleXXXXX GOS-E ScaleXXXXX Mini-Mental ExamX X X Euro-Quol-5D ScaleXXXXX PBSIX X X Personal Health Utility Assessment Interview X

35. RESOURCE UTILIZATION ICU stay Hospital stay Time at home

36. CONCOMITANT MEDICATIONS 7 days prior to symptom onset Acute treatment phase Follow-up phase Required interventions Prohibited interventions Precautionary interventions

37. AE & SAE REPORTING All AEs and SAEs through day 7 All SAEs and neurological AEs through day 365 SAEs must be reported using the EDC system – No paper worksheet!

38. FINAL VISIT Day 365 follow-up visit CT scan Outcome Scales Record new AE/SAE or procedures – Neurosurgical procedures Confirm ongoing or document resolution of previously recorded events