PI and Coordinator Webinar May 22, 2018 Enrollment 55 patients - PowerPoint Presentation

PI and Coordinator Webinar May 22, 2018

Enrollment 55 patients consented 22 eligible for randomization (40%) 13 randomized Randomization by month: Feb: 0 Mar: 2 Apr: 8 May: 3

Top enrolling sites Site Consented Randomized University of Cincinnati Medical Center 6 3 Memorial Hermann Texas Medical Center 5 2 Northwestern University 4 0 University of Iowa 4 1 University of Florida -Health Shands 3 1 UPMC Presbyterian Hospital 3 1 Intercoastal Medical Group Sarasota 3 1 OSU Wexner Medical Center 2 1

Enrolling sites Site Consented Randomized Brigham and Women’s Hospital 2 0 Mercy Health Saint Mary’s 2 1 Harborview Medical Center 2 0 NYP Columbia 2 0 NYP Weill Cornell 2 0 Hospital of the University of Pennsylvania 2 1 University of Minnesota Medical Center 1 0 Hennepin County Medical Center 1 0

Enrolling sites Site Consented Randomized Oregon Health and Science University 1 0 Christiana 1 0 Spectrum Health Hospitals 1 0 Vanderbilt 1 0 LAC + USC Medical Center 1 0 United Hospital, St. Paul 1 0 Maimonides Medical Center 1 0 Medstar Washington 1 0

Enrolling sites Site Consented Randomized Montefiore Medical Center 1 0 University of Nebraska 1 0 Mercy St. Vincent Medical Center 1 1

Site startup 99 completed trial agreements 85 CIRB submissions 63 CIRB approvals 54 readiness calls 52 sites released to enroll

Protocol trial agreements Many trial agreements are still pending Site PI should manage this actively: I dentify responsible parties C heck in with them regularly T his makes a big difference Seek support from institutional/departmental leadership We are happy to help however we can!

Regulatory updates/reminders Additional documents posted in webdcu in preparation for changes in submission process and document tracking Webinar to discuss the changes in regulatory submission process and WebDCU ™ updates to be held in June. Date TBD Site Names-Should be consistent on all submission documents and should include where the subject will be consented and where follow-up will occur. CVs-should include the current site affiliation and be signed/dated

Local site context form

Local site context form

Local Site Context Form

NAVIGATE ESUS trial Double-blinded randomized trial of rivaroxaban ( Xarelto ) vs. aspirin 7,213 subjects enrolled at 459 centers in 31 countries: Imaging-confirmed non-lacunar ischemic stroke 7 days to 6 months prior <50% stenosis of cervical vessels No major-risk cardioembolic source (<6 min/day of AF allowed) Required testing: Echo, 20 hours of heart-rhythm monitoring, extracranial vessel imaging Rivaroxaban 15 mg daily vs. aspirin 100 mg daily

Why did NAVIGATE ESUS find no benefit? Theory 1: Study agent Theory 2: Anticoagulation works only for AF, valves, very low EF Theory 3: ESUS is heterogeneous and requires personalized therapy Theory 4: Others?

Higher intracranial bleeding risk in NAVIGATE 0.5%/ yr higher risk of symptomatic intracranial hemorrhage with rivaroxaban compared to aspirin arm Possible reasons: Inherent risk of NOACs Specific to rivaroxaban Timing of randomization Concomitant low-dose aspirin No increased ICH risk in AVERROES

POINT trial Double-blinded randomized trial of aspirin vs. aspirin/clopidogrel 4,881 subjects enrolled at 269 sites in 10 countries: Minor stroke (NIHSS ≤3) or high-risk TIA (ABDC 2 score ≥4) in prior 12 hours Excluded if thrombolysis/thrombectomy, anticoagulation, carotid surgery Required testing: Echo, 20 hours of heart-rhythm monitoring, extracranial vessel imaging Treatment arm 1: Aspirin (50-325 mg daily) + placebo Treatment arm 2: Aspirin + clopidogrel (600-mg load + 75 mg daily)

Introduction of reversal agent (Andexanet alfa (trade name AndexXa ))

Lab Core Update Shipment Attachment submissions Review shipment before sending BioBank and subject consent

Identifying eligible patients Experience at University of Cincinnati

Frequently asked questions Q= Our echo lab does provide us the “LA dimension” measurement.  Is that the same as the “Left atrial end systolic antero -posterior diameter” that is listed on Form 505 of the CRF?  A= “LA dimension” is too generic a description for us to be able to say what it corresponds to. Chances are that it is what we are looking for, because that is the way LA is commonly measured; however, I would confirm that this is the case with the echo lab for your first patient, and if they confirm it you can safely assume that this is what it will be in all patients from that point forward.

FAQs (continued) Q= Is petechial hemorrhagic transformation noted on the follow-up imaging exclude a subject from ARCADIA? A= No, this is not exclusionary, but you would need to wait 14 days to randomize and re-evaluate the subject eligibility status to ensure they still meet criteria.

FAQs (continued) Q= Are all of the labs listed on the CRF required for the subject to be enrolled? What if the patient did not have some of these? A= The Creatinine and CBC are required for randomization. We do require the eligibility form to be entered prior to randomization. If Eligibility Q16 Creatinine and/or Q19 Hemoglobin is left blank, the Protocol Violation is triggered on the eligibility form and randomization will be blocked. The other labs are considered standard of care for stroke but if they are not done you will just get a rule violation on the lab form, but the subject can be enrolled.

FAQs (Continued) Q= We have a patient with a history of cervical spine stenosis who has had spinal surgery in the past. In the consent form it states in the risk section that apixaban can cause a serious blood clot if a patient has a history of spinal surgery. I am not seeing this as an exclusion criteria in the protocol though. Can we enroll this patient? A= The consent language is related to the risks of undergoing a spinal puncture (lumbar puncture) or spinal anesthesia. The language is taken straight from the FDA label, which says that if you are about to have a spinal puncture (lumbar puncture) or spinal anesthesia, then having had prior spine surgery or a spine problem might increase your risk of bleeding . So having a history of spine problems or spine surgery isn’t an exclusion. But if this patient ends up being consented and randomized, you should just make sure to warn them that they should not agree to any kind of spinal puncture or spinal anesthesia unless they are sure the doctor knows they may be taking apixaban . Typically, if they really need the spinal puncture, the doctors would stop study drug for a few days beforehand.

FAQs (Continued) Q= On imaging of a potential subject, there was a short cut off in a distal branch of the anterior cerebral artery. We think this cutoff was due to an embolic phenomenon. If this is the case would the patient be eligible based on this imaging? A=   Yes. It is a clinical judgment whether you think that a patient’s vessel cutoff is due to embolism or to underlying atherosclerosis. Embolism frequently causes abrupt vessel cutoff, so vessel cutoff itself should not preclude enrolment. Follow-up imaging may help distinguish these possibilities as recanalization may occur, but this is not required by the study. The presence of fixed stenosis of 50-99% in the territory of the vessel is more indicative of underlying atherosclerosis, and should be exclusionary per ESUS criteria.

Determining eligibility for consent Can consent as soon as standard-of-care tests are completed As early as 24 hours after admission after echo, ECG, imaging, telemetry, etc Standard-of-care tests must be from after stroke onset B ut please let us know if there is an otherwise eligible patient who doesn’t have this (e.g., had a recent echo or vascular imaging and team does not want to repeat) Miscellaneous Hemorrhagic conversion is NOT an exclusion (though would delay timing of randomization) Large-vessel occlusion is NOT an exclusion if it is not atherosclerotic

Hotline 24-hour telephone hotline Please use it for any urgent questions Eligibility, randomization, unblinding, etc 1-833-427-2234 (1-877-4AR-CADI ): useful to save in your cell phone The hotline automatically calls the four PIs in succession Please let it ring And call back if no luck—one of us will pick up!

Maintaining confidentiality Remove ALL identifiers (name, DOB, MRN, etc ) from ECGs and safety packets before uploading to WebDCU . If you are unsure if something is an identifier (e.g. “Account Number”) go ahead and remove it. Identifiers are sometimes still visible when manually removed. Preferred de-identification method is electronic removal using Adobe Acrobat or other PDF editor

Source Documents A ‘source’ is the original documentation of a piece of information/data point. The sources for all data collected in this study must be available for monitoring purposes. Source for much of the ARCADIA data already exists in the subject’s medical record b/c data is from standard of care procedures. Procedures performed for study purposes (e.g. vital signs at follow up visits, drug adherence, etc ) are not typically documented in the medical record, but source documentation is still required. Paper CRFs can be used as source documents if this will be where data is first recorded. eCRFs can also be source documents if data is directly entered into the eCRF . If an eCRF is source, this should be noted in the ‘General Comments’ field. An eCRF is NOT source if data is first documented elsewhere (EMR, paper worksheet, etc ) and then transcribed to the eCRF .

Next steps Please complete trial agreements and CIRB submissions Actively screen Send us feedback—we will make changes as needed to make this trial successful! Next webinar : June 26 at 2 PM ET