PI and Coordinator Webinar August 27, 2019

Milestones crossed! >1000 patients consented >25% (n=275) of target randomized Canadian Stroke Consortium approved participation in ARCADIA Abstracts submitted to ISC 2020 Next DSMB meeting Sept 3, 2019 Julius Caesar's crossing the Rubicon river was an event in January 49 BC that precipitated the Roman Civil War, which ultimately led to Caesar becoming dictator and the rise of the imperial era of Rome. 

Site startup: update 125 -> 131 sites released to enroll 121 sites currently active Approx 30 more US sites being onboarded Approx 30 Canadian sites being onboarded 114 -> 116 sites with at least one consent 76 -> 86 sites with at least one randomization

Enrollment 1047 -> 1133 patients consented 254 -> 287 randomized Increase of 86 in past month 254 -> 287 randomized Increase of 33 in past month Overall 0.18 patients randomized/site/month (0.19 among those SITES released to enroll) Overall 287/1133 patients consented  25.3% randomized 41 -> 35 Eligible not yet randomized

Top enrolling sites – by # randomized Consented Proportion United 13 39 0.33 Cincinnati 11 33 OHSU 9 34 0.26 Iowa 37 0.24 Mayo 8 22 0.36 Memorial Hermann 20 0.40 Penn 24 Intercoastal 28 0.29 U Kentucky 26 0.31 UF Shands 7 19 0.37 Univ Minnesota 0.32

Top enrolling sites – by randomization rate Randomized/Month Date released to enroll Univ Mississippi 1.23 May 20, 2019 North Shore UH 0.97 June 25, 2019 United 0.82 May 1, 2018 OSF St Francis, Peoria 0.66 Jul 12, 2019 Emory 0.59 Oct 23, 2018 U Kentucky Jul 11, 2018 Cincinnati 0.58 Jan 29, 2018 OHSU 0.57 May 3, 2018 Mayo Saint Mary’s 0.56 Jun 21, 2018 Iowa 0.53 Apr 2, 2018

New randomizers since July 23, 2019 North Shore (2) Banner University MC-Tucson, AZ OSF St Francis, Peoria Good Samaritan, San Jose Chandler Regional, AZ (2) St. Louis University

Demographics of randomized patients (July 15, 2019)   N % All patients 253 100.0 Age 68.1 + 11.0 yrs Gender Male 121 47.83 Female 132 52.17 Ethnicity Hispanic or Latino 19 7.51 Not Hispanic or Latino 233 92.09 Unknown / Not reported 1 0.40 Race Asian Black or African American 60 23.72 Native Hawaiian or Other Pacific Islander White 190 75.10

Severe strokes or hemorrhagic transformation of the index stroke Days from stroke onset to randomization   Randomized subjects Severe strokes or hemorrhagic transformation of the index stroke Other Days from stroke onset to randomization N 253 28 225 Mean 52.2 + 36.3 51.4 + 31.9 52.3 + 36.8 Median 42.0 40.5 43.0 Range 3-120 6-117

Cautions Withdrawal of consent before randomization 7.4% after randomization 6.7% Adherence: By 9 months, ~12-14% of doses missed

ARCADIA Coordinator Hero Daniel Hernandez from Intercoastal Medical Group in Sarasota Florida Screens without assumptions and seeks confirmation even in difficult cases – his screening is focused on whether subjects are eligible rather than assuming odd medical conditions screens a subject out Although we try to randomize as soon as possible within protocol guidelines, bringing the willing subjects from consent to randomization is not always easy or simple Even though they have signed consent, we need to keep in touch with them to confirm they still wish to continue in the trial and be randomized for the study drug. Re-scheduling subjects who wish to participate once, twice and beyond to make the process easier for the subjects Sometimes it takes leaving various messages, calling the contacts the subject provided, and even sending letters. Hence 20 consented subjects at the site and every eligible subject has been randomized! Our coordinator hero seeks confirmation and never gives up if the subject is willing to participate, then he finds a way to get to the randomization goal line! Thank you, Daniel H. and Dr. Mauricio Concha along with the whole Intercoastal team for being part of the success of the ARCADIA trial!

DCU Slides - Faria

F514 Study Drug Usage and Adherence Remind subjects to never throw away study drug Remind subjects to bring their pill bottles in before each follow-up visit. Ask subjects not to combine pills across visits. If the subject forgets their bottles, please call them to get the pill count over the phone when possible. Please leave a note in general comments that the pill count was conducted over the phone. Ask the subject to keep their pills and return them at the next visit to confirm the pill counts are correct. When completing F514, if the subject did not return their pills the same day the new drug kit was dispensed, please enter the date the new kit was dispensed for the Q04 & Q11 ‘Date pills returned’ questions, as these dates are used to calculate adherence. If pills were not returned, please leave the pill count questions blank and respond to the warnings. Do not enter ‘0’ for the pill count unless an empty bottle is returned.

General WebDCUTM Data Entry Reminders Please complete all required CRFs for a visit within 5 days of the visit taking place. Note: Do not open the F104 Adverse Event CRF unless you need to report an AE. If you accidentally click the form, please notify me so our programmer can ‘clean’ the form. DCRs/queries should be addressed within 5 days of generation. Please remember to respond to any open rule violations. Click the blue pencil icon underneath the rule violation to type a response. Entering a response will allow you to save and submit the CRF. Please double check you are in the correct subject’s binder/adding the correct visit before entering data. If you receive an error message or anything seems wrong please contact the NDMC for assistance. If an error has been reported, please wait till you receive confirmation that the issue has been resolved before attempting to enter data or proceed with the task that generated the initial error message.

Who to Contact? Srikala Appana at NDMC appana@musc.edu When to contact: If you have WebDCU-related DOA/regulatory database questions, Informed Consent Remote Monitoring questions, or Site Monitoring questions Faria Khattak at NDMC khattak@musc.edu When to contact: Any other WebDCU-related or CRF-related questions Patty Hutto at NDMC huttoja@musc.edu When to contact: Any other WebDCU-related or CRF-related questions NOTE: Please refer to the Data Collection Guidelines posted in [Project Documents] under [Toolbox] in WebDCUTM, or email Faria or Patty for CRF related questions

Quick survey: Practice patterns of ARCADIA investigators If not enrolling in ARCADIA, what dose of aspirin would you routinely put patients on? A) 50 mg B) 81 mg C) 162 mg D) 325 mg E) Other

Quick survey: Practice patterns of ARCADIA investigators When I use aspirin and clopidogrel after minor stroke, I continue treatment for: A) 1 week B) 2 weeks C) 30 days D) 90 days E) I do not use aspirin and clopidogrel for these patients

FAQs Q: We have a potential patient who had an aortic valve replacement done back in 2016. Is the patient eligible for enrolment? Answer (vote): A) Yes B) No C) It depends .

FAQs Q: We have a potential patient who had an aortic valve replacement done back in 2016. Is the patient eligible for enrolment? Answer: A) Yes B) No C) It depends .

FAQs The patient had a bovine aortic valve replacement done back in 2016. - A bioprosthetic valve is not an exclusion. It’s not just valve replacement but that these will lead patients to be put on prohibited medication for a period of time and that will exclude them. If the patient satisfies the other inclusion/exclusion criteria and the team is okay with randomizing to anticoagulation or antiplatelets, it’s okay to consent this patient. Are all valve replacement patients excluded or just those in the last 4 weeks? -The inclusion item that mentions 4 weeks is: “myocardial infarction within the last 4 weeks.”   The inclusion criteria state: “No major-risk cardioembolic source of embolism, including AF, intracardiac thrombus, mechanical prosthetic cardiac valve, atrial myxoma or other cardiac tumors, moderate or severe mitral stenosis, myocardial infarction within the last 4 weeks, left ventricular ejection fraction <30%, valvular vegetations, or infective endocarditis).” If uncertain, reach out to PIs or ARCADIA email.

FAQs Question: Our subject qualified for randomization, but we are waiting until she is discharged from rehab before randomizing her.  However, she was just admitted to a different hospital from rehab for lethargy and abnormal lab values (potassium of 6.0 and creatinine of 3.21).  Do I need to track these as AE’s?  Answer (vote): Yes No It depends

FAQs Questions: Our subject qualified for randomization, but we are waiting until she is discharged from rehab before randomizing her.  However, she was just admitted to a different hospital from rehab for lethargy and abnormal lab values (potassium of 6.0 and creatinine of 3.21).  Do I need to track these as AE’s?  Or do we only track AE’s after a patient has been randomized? Answer: No. We complete an adverse event report when these occur after randomization.   Question: Can we still randomize this subject? Answer (vote): Yes, now Not now, maybe later. Never

FAQ Questions: Our subject qualified for randomization, but we are waiting until she is discharged from rehab before randomizing her.  However, she was just admitted to a different hospital from rehab for lethargy and abnormal lab values (potassium of 6.0 and creatinine of 3.21).  Do I need to track these as AE’s?  Or do we only track AE’s after a patient has been randomized? Answer: No. We complete an adverse event report when these occur after randomization.   Can we still randomize this subject? Answer: Not now, maybe later. -The subject is not currently eligible for randomization with a creatine level of ≥2.5 mg/dL. -However, they can be randomized if, within 120-day randomization window, the patient’s creatinine level falls below the exclusion criteria of serum creatinine ≥2.5 mg/dL AND the PI expects the creatinine level to remain within eligibility parameters during the course of the trial. -If randomized and the creatinine level reaches is ≥2.5 mg/dL at any point, the study drug will need to be stopped until such time that the creatinine is documented to be <2.5 mg/dL, at which time study drug can be resumed. Subjects should continue to be followed as part of the study during such study drug interruption(s). (see MOP)

FAQ Question: Is having an implantable loop recorder exclusionary FAQ Question: Is having an implantable loop recorder exclusionary? Answer (vote): Yes. No.

FAQ Question: Is having an implantable loop recorder exclusionary FAQ Question: Is having an implantable loop recorder exclusionary? Answer: No. Having an implantable loop recorder is not exclusionary for ARCADIA subjects. Of course, this device may show afib at some point. If it happens after consent and before randomization, then you will not be able to randomize this subject and will need to close them out after revising the F101 (inclusion/exclusion criteria). If it happens after randomization, then it’s an SAE and you will need to stop the study drug right away so that the patient can be treated with open label medication as per their clinical team.

FAQ A site was referred a patient to the clinic from an outside hospital who had a frontal cortical infarction, but no echocardiogram was performed during his stroke hospitalization.  She is arranging to have one done outpatient.  Would this patient still be eligible for enrollment in ARCADIA although he did not have an echo at time of index event? Answer (vote): Yes. No.

FAQ A site was referred a patient to the clinic from an outside hospital who had a frontal cortical infarction, but no echocardiogram was performed during his stroke hospitalization.  She is arranging to have one done outpatient.  Would this patient still be eligible for enrollment in ARCADIA although he did not have an echo at time of index event? Answer: Yes. Definitely eligible, as long as echo is after the stroke, it doesn’t have to be immediately after.

FAQ If a patient has apical akinesis or other cardiac wall motion abnormalities such as inferolateral akinesis (or both in combination), would the patient still be eligible for ARCADIA? Answer (vote): Yes No.

FAQ If a patient has apical akinesis or other cardiac wall motion abnormalities such as inferolateral akinesis (or both in combination), would the patient still be eligible for ARCADIA? Answer: Yes If the primary neurologist is not planning empiric anticoagulation specifically for this and is not convinced this was the mechanism of stroke, then patient is eligible. Apical akinesis alone would not exclude the patient, as long as no thrombus there. Although apical akinesis is a high-risk cardioembolic source per TOAST criteria, it’s not defined as such in the ESUS paper by Hart at el 2014. PI judgment is essential!

FAQ Question: Is a patient with Hypoplastic Left Vertebral Artery, most likely congenital, eligible for enrollment? Answer (vote): Yes. No.

FAQ Question: Is a patient with Hypoplastic Left Vertebral Artery, most likely congenital, eligible for enrollment? Answer: Yes. If the PI and treating physicians don’t believe that it’s the cause of the stroke, and the patient otherwise meets eligibility criteria, then it is okay to enroll.

FAQ A potential participant wanted to know about the ingredients in the ARCADIA study drugs. He asked if the placebo capsules contain lactose? Answer: Yes. BMS uses anhydrous lactose in the apixaban, aspirin, and all placebo tablets. Do we know all placebo drug ingredients? Answer: No. BMS does not provide ingredients on their placebos but will confirm if a specific ingredient of concern is in the placebo.

What is ESUS? If you have questions about complicated patients, or are unsure of the diagnosis of ESUS in any particular patient, please feel free to get in touch with Rebeca Aragon, Pam Plummer, the PIs, or email us at arcadia@ucmail.uc.edu.

Literature update Ntaios G et al. Carotid plaques and detection of atrial fibrillation in ESUS. Neurology 2019; 92:e2644-2652. Background: Substenotic plaque (i.e., carotid plaque <50%) may be a cause of ESUS. If so, then patients with ipsilateral substenotic plaque should be LESS LIKELY to have AF detected during follow-up. Hypothesis: Patients with ESUS with substenotic plaque are less likely to have AF detected during follow up.

Literature update Retrospective analysis 777 patients from 3 different registries (Lausanne, Athens, Larissa) Follow up 2642 patient-years (mean 3.4 years per patient) Primary outcome: detection of AF; no systematic monitoring for AF Ntaios G et al. Neurology 2019; 92:e2644-2652.

Literature update Retrospective analysis 777 patients from 3 different registries (Lausanne, Athens, Larissa) Follow up 2642 patient-years (mean 3.4 years per patient) Primary outcome: detection of AF; no systematic monitoring for AF Results: 38.6% of patients (n=341) had an ipsilateral substenotic plaque The detection rate was 8.5% in patients with substenotic plaque vs 19.0% in patients without substenotic plaque. After adjusting for other factors, presence of plaque associated with ~50 likelihood of detecting AF (adj HR 0.57, 95%CI 0.34-0.96). Ntaios G et al. Neurology 2019; 92:e2644-2652.

Ten-year cumulative probability of atrial fibrillation detection in embolic stroke of undetermined source patients with and without nonstenotic carotid plaques ipsilateral to the index stroke Ten-year cumulative probability of atrial fibrillation detection in embolic stroke of undetermined source patients with and without nonstenotic carotid plaques ipsilateral to the index stroke George Ntaios et al. Neurology 2019;92:e2644-e2652 © 2019 American Academy of Neurology

Literature update Potential implications: Limitations Substenotic plaque may be causally associated with ESUS The finding of substenotic plaque may be a reason to pursue more or less aggressive monitoring for AF (i.e., look less hard in those without the plaque) Patients with substentoic plaque may similarly be less likely to have atrial cardiopathy Limitations The incidence of AF detection is high even in those with substenotic plaque (~9% over 3 years). Study was retrospective No systematic monitoring for AF or uniform detection protocol (i.e., based on clinical detection) Patients did not have intracranial imaging for “pragmatic reasons”: may not have all had ESUS Ntaios G et al. Neurology 2019; 92:e2644-2652.

Open mike…

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