A Prospective, Multicenter, Randomized, Open-label Trial to Compare Efficacy and Safety of Clopidogrel vs Ticagrelor in Stabilized Patients With Acute Myocardial Infarction After Percutaneous Coronary Intervention; TicAgrelor Versus CLOpidogrel in Stabilized Patients With Acute Myocardial Infarction: TALOS-AMI

1. Study design Pospective, multi-center, randomized, open trial
2. Study Objective To investigate the efficacy and safety of switching from ticagrelor to clopidogrel in stabilized patients with AMI with no adverse events during the first month after an index PCI
3. Study Drug Test drug: Clopidogrel Control drug: Ticagrelor
4. Study Disease Acute myocardial infarction: ST-segment elevation MI (STEMI) and non-ST-segment elevation MI (NSTEMI)
5. Study Population 2590 (loss to follow-up: 10 %) -Test group: 1295 -Control group: 1295
6. SAMPLE SIZE CALCULATIONS

The present study is designed to show non-inferiority for the treatment group with aspirin plus clopidogrel versus the control group with aspirin plus ticagrelor. The sample size is based on the combined occurrence rate of ischaemic and bleeding events between 1 and 12 months after AMI. According to the PLATO investigators, the event rate of the primary efficacy endpoint including CV death, MI or stroke was 5.28% in the ticagrelor group and 6.60% in the clopidogrel group between 1 and 12 months after the index event1. There were no reported data on the bleeding event rate associated with ticagrelor from 1 to 12 months after AMI, especially the BARC bleeding rate at the time of the present study design. Therefore, we assumed the event rate of BARC 2, 3 or 5 bleeding from the event rates of non-coronary artery bypass graft (CABG)-related PLATO major or minor bleeding because the content of BARC 2, 3 or 5 bleeding was conceptually quite similar with non-CABG-related PLATO major or minor bleeding. With regard to the assumption of the bleeding rate from 1 to 12 months after the index PCI, we calculated the expected bleeding rate using a proportional equation under the assumption that the occurrence ratio of non-CABG-related major bleeding of the first 30 days to that of after 30 days and the ratio of non- CABG-related major or minor bleeding of the first 30 days to that of after 30 days could be equal. Thus, for the event rate of BARC 2, 3 or 5 bleeding associated with ticagrelor from 1 to 12 months after AMI, the event rate was assumed from the event rates of non-CABG-related PLATO major or minor bleeding during a year of ticagrelor therapy (8.7%) and non-CABG-related major bleeding of the first 30 days (2.47%) and after 30 days (2.17%) in the PLATO trial. For the event rate of BARC 2, 3 or 5 bleeding associated with clopidogrel from 1 to 12 months after AMI, the event rate was assumed from the event rates of non- CABG-related PLATO major or minor bleeding during a year of clopidogrel therapy (7.0%) and non-CABG-related major bleeding of the first 30 days (2.21%) and after 30 days (1.65%) in the clopidogrel group of the PLATO trial7. After applying a proportional equation, we estimated that the BARC 2, 3 or 5 bleeding would be 4.07% in the ticagrelor group and 2.99% in the clopidogrel group. Thus, the expected event rate of the primary endpoint from 1 to 12 months after the index PCI was 9.35% (ischaemic event of 5.28% + bleeding event of 4.07%) in the ticagrelor group and 9.59% (ischaemic event of 6.6% + bleeding event of 2.99%) in the clopidogrel group. We chose the non-inferiority margin in accordance with clinical judgement and other relevant studies with a non-inferiority design for the present study design. The non-inferiority margin of two contemporary trials of antiplatelet treatment after PCI that were available up to that time was equivalent to a 40% increase in the expected event rate16,17. The steering committee decided that the non-inferiority margin in our study should be less than a 40% increase compared to the expected event rate of the control group. After considering clinically acceptable relevance and the feasibility of study recruitment, we finally selected the non-inferiority margin of 3.0%, which was equivalent to a 32% increase in the expected event rate. Sample size calculations (PASS 13; NCSS, LLC, Kaysville, UT, USA) were initially performed based on a one-sided α of 0.025 and a power of 80%. To achieve these goals, a total of 2,230 patients was needed. After considering a follow-up loss rate of 10%, there should be at least 1,644 per group and a total of 3,288 patients. However, while the study was actively underway, the government policy on investigator-initiated trials (ITTs) changed: it was decided not to allow national health insurance to charge for the medical care costs of participating patients in ITTs. Soon after, the government was forced to permit the application of national health insurance to ITTs on the condition that researchers should obtain approval for their studies by the head of the Health Insurance Review and Assessment service. However, during this turmoil, researchers' willingness to register patients had been compromised, and they could not register patients as planned within the period. Thus, the steering committee held an emergency meeting with data and safety monitoring board (DSMB) members and independent statisticians and decided to recalculate the sample size for the timely completion of the trial. In recalculating the sample size, we adopted a one-sided α of 0.05 instead of 0.025. According to the CONSORT statement of non-inferiority and equivalence in trials18, a one-sided α of 0.05 was acceptable for the non-inferiority clinical trials. Moreover, in the large-scale TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition Chronic Antiplatelet Treatment for ACS) trial (one of the famous CV drug trials similar to the TALOS-AMI trial), the researchers adopted a one-sided α of 0.05 for the sample size calculation4. Furthermore, of 110 CV non-inferiority trials published in JAMA, The Lancet or the New England Journal of Medicine from 1990 to 2016, a one-sided α was 0.05 in 66 trials19. Based on this external harsh environment and a review of the sample size calculation in previous large-scale randomised trials published in high-impact journals, we recalculated the sample size by using a one-sided α of 0.05, a power of 80% and a follow-up loss rate of 10%. As such, the sample size was reduced from 3,288 to 2,590 (1,295 patients in each group) 7. Study Design

1. Screening period

To conduct screening AMI patients based on the inclusion/exclusion criteria who (1) have been treated with ticagrelor+aspirin for at least 30±7 days after an index PCI, (2) received full explanation of the study details, (3) given informed consent To randomize eligible subjects within 30±7 days after AMI undergoing PCI with newer generation DES, and receiving aspirin and ticagrelor to the treatment and control groups in a 1:1 ratio.

2)Treatment period