Innovative Features of the ADAPTABLE Trial

1. Innovative Features of the ADAPTABLE Trial Matthew T. Roe, MD, MHS ADAPTABLE Co-Principal Investigator Duke Clinical Research Institute October 6-8, 2015

2. ADAPTABLE Study DesignPatients with known ASCVD + ≥1 “Enrichment Factor” Identified through EHR screening and electronic patient contact by CDRNs/PPRNs (PPRN patients would need to connect through a CDRN to participate) Patients contacted electronically with trial information and e-consent via web portal Treatment assignment will be provided directly to patient • *Enrichment Factors • Age > 65 years • Creatinine> 1.5 mg/dL • Diabetes mellitus (type 1 or 2) • Known 3-vessel CAD • Current CVD or PAD • Known EF<50% by echo, cath, nuclear study • Current smoker ASA 81 mg QD ASA 325 mg QD Randomized Electronic Follow-Up: 3 vs 6 months Supplemented with EHR/CDM Data Queries Duration: Enrollment over 24 months; maximum follow up of 30 months Primary Endpoint: Composite of all-cause mortality, hospitalization for MI, or hospitalization for stroke Primary Safety Endpoint: Hospitalization for major bleeding

3. Main Objectives of the ADAPTABLE Trial • To compare the effectiveness and safety of two doses of aspirin (81 mg and 325 mg) in high-risk patients with coronary artery disease. • Primary Effectiveness Endpoint: Composite of all-cause mortality, hospitalization for MI, or hospitalization for stroke • Primary Safety Endpoint: Hospitalization for major bleeding • To compare the effects of aspirin in pre-defined key subgroups of patients • Age, Diabetes, Sex • Race, P2Y12 inhibitor Use • Chronic Kidney Disease • To develop and refine the infrastructure for PCORnet to conduct multiple comparative effectiveness trials in the future

4. Disrupting the NormTraditional Trials vs. ADAPTABLE Costs +++++ +

5. ADAPTABLE: Recruitment Approach • 5-9 CDRNs participate, 1 PPRN (HeH) • Total enrollment: 20,000 patients • Electronic, computable phenotype to be used to interrogate CDRN EHR data to facilitate widespread screening of large numbers of potentially eligible patients • Potential patients will be approached remotely through email and electronic outreach and will be directed to the web portal for electronic informed consent • Patient engagement through the ADAPTORS patient group to enhance and refine recruitment approaches

6. Computable Phenotype for CDRNs • At least one of the following: • Age > 65 years • Creatinine> 1.5 mg/dL • DiabetesMellitus • Known 3 vessel coronary artery disease • Current cerebrovascular disease and/or peripheral arterial disease • Known ejection fraction <50%, • Current smoker • History of CAD • Prior MI • OR • Prior angiogram showing significant CAD • OR • Prior Revascularization (PCI/CABG) Electronic Patient Outreach

7. Informed Consent and Randomization Screening of CDRN EHR data with computable phenotype Electronic outreach to potential patients with trial introduction and link to ADAPTABLE web portal • Web-Based, Electronic Informed Consent • Initial patient contact via web portal text and video consent options Developing a common consent form with selected local adaptations • Focused questions to confirm patient comprehension for informed consent and eligibility for randomization after consent Randomization and Aspirin dose assignment

8. Enabling and Testing Pragmatic Research: e-Data Collection and e-Follow-Up 30 N=20,000 • Web Portal Follow-Up • Randomized to 3 vs. 6 months contact • Patient Reported Hospitalizations • Medication use • Health outcomes ADAPTABLE Enrollee 18 24 12 6 Death Ascertainment National Death Index (NDI) & Social Security Database • PCORNetCoordinating Center Follow-Up • Via Common Data Model • Validated coding algorithms for endpoints Baseline Data

9. ADAPTABLE IRB Approach • Started with a common e-consent template for all CDRNs with injury language and local contacts customized • Concerns about meeting criteria for minimal risk shared by several IRBs so protocol modified to address concerns • Representatives from all CDRN IRBs discussed and further revised e-consent template to try to minimize local customization of the template • All CDRN IRBs will submit protocol and e-consent template simultaneously

10. Approach to Endpoint Ascertainment • Routine queries of the PCORnet CDM to capture and classify endpoints using validated coding algorithms • Hospitalizations will be identified via standardized, validated coding algorithms developed centrally and applied to the CDM • ADAPTABLE WEB portal will ask about possible endpoint events (hospitalizations for myocardial infarction, stroke, or major bleeding) during participant contacts (every 3-6 months) • Such information will provide additional confirmation for the CDM-generated hospitalization data that meet criteria for the endpoints specified • Death ascertainment via Social Security Administration (Medicare beneficiaries) and National Death Index

11. Validated Endpoint Coding Algorithms (1) • Efficacy Endpoints • Hospitalization for MI: ICD-9-CM diagnosis codes 410.x0-410.x1 in the principal or primary position. • Hospitalization for Ischemic Stroke: ICD-9-CM diagnosis codes 430.x, 431.x, 433.x1, 434.x1, 435.x, 436, and 362.3 in the principal or primary position. • Hospitalization for Hemorrhagic Stroke: ICD-9 diagnosis codes 431 and 432 in the principal or primary position. • Coronary Revascularization includes all coronary revascularization procedures (PCI/CABG) performed during the study. These will be identified using procedure codes 3610-3617, 3619, 0066, 3606, 3607, 3609.

12. Validated Endpoint Coding Algorithms (2) • Safety Endpoint • Major bleeding at any location will be ascertained using ICD-9-CM diagnosis codes for • a) intracranial bleeding • b) gastrointestinal bleeding • c) bleeding at another location or physician service code for GI hemorrhage (CPT code 43255 or ICD-9 procedure code 44.4x) • Major bleeding requires an above code plus a CPT code 36430 for any blood product transfusion during the same hospitalization

13. ADAPTABLE Innovations Summary • Innovative, pragmatic, randomized trial that will test the PCORnet infrastructure with several novel approaches • Clinical question about the optimal aspirin dose for the treatment of patients with chronic atherosclerotic cardiovascular disease will be addressed by leveraging these novel approaches for recruitment, data collection, and endpoint ascertainment • Patient engagement will be a key attribute of the trial and essential to meeting the trial objectives

14. Learn More www.YourURL.URL www.pcori.org info@pcori.org #PCORI2015

15. Questions?

16. Thank You! Matthew T. Roe, MD, MHS ADAPTABLE Co-Principal Investigator Duke Clinical Research Institute Durham, NC