PI and Coordinator Webinar April 23, 2019

Site startup 118 sites released to enroll 70 sites with at least one randomization 110 sites with at least one consent

Enrollment 827 patients consented 198 randomized

Top enrolling sites – by # randomized Consented United 10 31 Cincinnati 25 OHSU 9 Iowa 28 Memorial Hermann 7 20 Penn 6 19 UF Shands 18 MUSC 5 21 UPMC 4 22 Intercoastal

Top enrolling sites – by randomization rate Randomized/Month Consented/Month United 0.86 2.7 OHSU 0.78 Iowa 0.71 2.2 Cincinnati 0.68 1.7 Memorial Hermann 0.52 1.5 Emory 3.1 McLaren Flint 0.8 Penn 0.47 UF Shands 0.46 1.4 Barnes Jewish 0.45 1.6

Summary of enrollment webinar Formal system for screening Reminders/in-service for treating team Familiarity with etiological subtype classification Rapid access to site PI (especially for ? ESUS) Investigators available to accompany coordinators

Summary of enrollment webinar Treating physician to intro/recommend study Good communication with PCP/cardiologist Site PI centrally involved in inpatient/outpatient transition

ARCADIA Protocol Amendment 4.0 changes *The CIRB approved ARCADIA Protocol Amendment 4 only pertains to the StrokeNet sites (not VA) Summary of the changes: Increase the number of potential sites to 200 Mild mitral stenosis is no longer an exclusion (moderate-severe is an exclusion ) Provide procedure for obtaining written informed consent from a surrogate/LAR via fax. Allow for tests that establish ESUS to be done up to 3 months prior to index stroke.

ARCADIA Protocol Amendment 4.0 changes e. Provides a plan and approved screening letter and phone script for contacting potential patients by phone f. Allows more flexibility to do follow-up visits by phone or using other HIPAA compliant telehealth technology g. Clarifies that study drug must be stopped if an investigator identifies an event that could be a possible primary outcome. (stroke)

Screening potential subjects -letter and phone call If a potential subject was not introduced to the trial by a treating physician who asked for permission for ARCADIA investigators or coordinators to approach the patient, the steps below must be followed in sequence before a patient can be called about ARCADIA: 1. A waiver of HIPAA authorization must be in place to screen medical records to identify potentially eligible subjects. 2. Permission to approach the patient must be obtained from the potential subject’s primary care physician or neurologist. 3. Recruitment materials must be mailed to the potential subject, along with instructions to return a postcard or make a telephone call indicating that they do not wish to participate. 4. If the potential subject does not indicate refusal to participate, the study team may call them about the study after the time indicated in the instructions. 5. Sites must submit a detailed plan to the CIRB for approval before starting to call patients in this manner.

Allowing for follow-up visits by phone or telemedicine This change was made to allow for flexibility in the follow-up improve retention. It is not intended to replace all in person follow-up visits. Sites will need to determine what your local policy is on shipping study medication. Is your pharmacy permitted to mail medications? If not, can the coordinator mail them? How will your site cover the shipping costs? How will you do study drug accountability? Will you ask subjects to mail the old bottles back? Will subjects save the old bottles and bring them when they come back? Are home visits an option at your site?

Process for site approvals of Amendment 4 NCC staff (Emily Stinson and Jen Golan) will be editing each site ICF and submitting these for your site to the CIRB Once these are approved by the CIRB you will receive your approval letter and new ICFs. The approval letter and the new ICFs will need to be uploaded to WebDCU. If you have translated consents, these will be submitted to the translation company on your behalf. If your local IRB needs to review/acknowledge the new protocol and ICF please let us know if this needs to be done before you can use the new ICF.

FAQs Question: Large-vessel occlusion, downstream infarct, not much evidence of athero. Can the patient be enrolled? Answer: Yes No

FAQs Question: Large-vessel occlusion, downstream infarct, not much evidence of athero. Can the patient be enrolled? Answer: Yes. If occlusion thought to be embolic, okay to enroll. These can be hard to distinguish so just trust your gut!

FAQs Question: 50-year-old patient, no vascular risk factors, has a PFO, plan for closure. Can the patient be enrolled? Answer: Yes No

FAQs Question: 50-year-old patient, no vascular risk factors, has a PFO, plan for closure. Can the patient be enrolled? Answer: Yes—technically. But do you really think it is ESUS? Why close the PFO then?

FAQs Question: Patient >80 years old had repeat creatinine a few days after randomization and value went up substantially to >1.5. What to do? Answer: Wait until next follow-up to switch study drug kit. Contact us to arrange a new dose-adjusted study drug kit immediately.

FAQs Question: Patient >80 years old had repeat creatinine a few days after randomization and value went up substantially to >1.5. What to do? Answer: Contact us to arrange a new dose-adjusted study drug kit immediately.

FAQs Question: No 12-lead ECG available, just rhythm strips. OK to use that to establish ESUS? Answer: Yes. No.

FAQs Question: No 12-lead ECG available, just rhythm strips. OK to use that to establish ESUS? Answer: Yes. The rationale is to exclude AF and a rhythm strip is fine to establish ESUS. But we do need a post-stroke 12-lead ECG to determine eligibility for randomization.

FAQs Question: A patient had a first stroke 6 months ago on aspirin, then another on apixaban, now with a third stroke. All strokes were ESUS. Eligible? Answer: Yes. No.

FAQs Question: A patient had a first stroke 6 months ago on aspirin, then another on apixaban, now with a third stroke. All strokes were ESUS. Eligible? Answer: Yes. No exclusion for strokes before the index stroke.

FAQs Question: A potentially eligible patient had a fall at the time of his stroke. He has a 1” scalp hematoma without a deep incision or active external bleeding, and the head CT does not show any intracranial bleeding. OK to enroll? Answer: Yes. No.

FAQs Question: A potentially eligible patient had a fall at the time of his stroke. He has a 1” scalp hematoma without a deep incision or active external bleeding, and the head CT does not show any intracranial bleeding. OK to enroll? Answer: Yes. This sounds like minor trauma.

FAQs Question: A patient has a weakly positive APLS screen and no other apparent stroke mechanism. Treating physicians do not feel this was the cause of stroke. OK to enroll? Answer: Yes. No.

FAQs Question: A patient has a weakly positive APLS screen and no other apparent stroke mechanism. Treating physicians do not feel this was the cause of stroke. OK to enroll? Answer: Yes. It sounds like ESUS.

FAQs Question: A patient had a run of SVT on their post-stroke Holter monitoring. No evidence of afib or aflutter. OK to enroll? Answer: Yes. No.

FAQs Question: A patient had a run of SVT on their post-stroke Holter monitoring. No evidence of afib or aflutter. OK to enroll? Answer: Yes. SVT is not an exclusion.

FAQs Question: If a patient on study drug has another stroke, and emergency unblinding reveals they are on apixaban, can they receive Andexxa and then IV TPA? Answer: Yes. No. It is complicated.

FAQs Question: If a patient on study drug has another stroke, and emergency unblinding reveals they are on apixaban, can they receive Andexxa and then IV TPA? Answer: It is complicated. Decisions about whether and how to treat with tPA are left to the treating physicians and are not mandated by the study protocol. We will provide emergency unblinding and the rest is in the treating physician’s hands.

FAQs Question: If a patient on study drug has another stroke, and emergency unblinding reveals they are on apixaban, can they receive Andexxa and then IV TPA? Answer: Based on expert opinion and consensus statements, we advise that IV tPA is okay if the patient is found to be on apixaban and has not taken study drug in 48 hours; if they have taken study drug within 48 hours, we do not recommend reversing and then giving tPA. These are just recommendations and it is ultimately up to the treating physician.

We are on the right track! These post hoc data are supportive of our hypothesis Secondary analyses must be approached with caution A prospective trial is needed to prove this hypothesis and change practice It is up to you!

Feel free to reach out! 24-hour telephone hotline Please use it for any urgent questions Eligibility, randomization, unblinding, etc 1-877-427-2234 (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! Please email arcadia@ucmail.uc.edu with non-urgent questions