Platelet Inhibition of Ticagrelor Versus Clopidogrel in Type 2 Diabetic Patients After Elective Percutaneous Coronary Intervention

A Randomized, Open-label, Active-controlled, Parallel-group Study to Investigate the Platelet Inhibition of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease and Type 2 Diabetes Mellitus After Recent Elective Percutaneous Coronary Intervention

This will be a single-center, randomized, open-label, active-controlled, parallel-group study to investigate the platelet inhibition of Ticagrelor versus Clopidogrel with acetylsalicylic acid (ASA) as background therapy in approximate 40 patients with stable coronary artery disease (SCAD) and type 2 diabetes mellitus (DM) after recent successful elective percutaneous coronary intervention (PCI) by evaluation of the P2Y12 reaction unit (PRU) by VerifyNow P2Y12 assay at 2-4 hours after the first study drug dose on treatment day 15±2.

The study will consist of a screening period, a 15±2 day treatment period, and a 7 day follow-up period. The screening period will be up to 7 days. Once each patient has signed the informed consent, the eligibility of the patient will be determined at screening, and laboratory assessments will be taken (Visit 1). During the treatment period, patients participating in the study will be randomized to receive either Ticagrelor with ASA, or Clopidogrel with ASA for 15±2 days. The final dose of study medication will be administered at the study site in the morning of day 15±2. Study visits at the beginning (Visit 2) and the end of the treatment period (Visit 4) will allow assessment of platelet function. At 7±1 days after Visit 2, a telephone visit (Visit 3) will be carried out for collection of information on concomitant medication, adverse events (including vascular events), and safety end point events. After the platelet function tests at Visit 4 are finished, patients in both groups will discontinue their study medication (end of treatment, EOT). A follow-up period will begin at 1 day after Visit 4 and continue for 7 days. During the follow-up period, patients in Ticagrelor group will take Clopidogrel 600 mg loading dose on the first day, followed by Clopidogrel 75 mg maintenance dose from the second day for 6 days; patients in Clopidogrel group will continue taking Clopidogrel 75 mg maintenance dose for 7 days. Both adverse events (including vascular events) and safety end point events will be collected at the safety visit (Visit 5), which will occur 7 days after Visit 4. The study will last approximately 4 weeks per patient. After the informed consents are signed by the patients, all adverse events (including vascular events), safety end point events and concomitant medications will be recorded at each visit.

Inclusion Criteria:

1. Provision of written informed consent (by patient or appropriate designee according to local regulations) prior to any study specific procedures.

2. Aged 18 years or older, male or female.

3. Documented stable coronary artery disease (CAD) fulfilling any of the following:

   • History of stable angina pectoris with angiographic evidence of CAD (diameter stenosis ≥ 50%) in major, i.e., left main, left anterior descending, left circumflex, and right coronary arteries.
   • History of previous myocardial infarction (MI)
   • History of coronary revascularization, i.e., percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG), not including the elective PCI during the index hospitalization

4. Documented history of type 2 diabetes mellitus.

5. At least 24 hours after but within 14 days of angiographically successful elective PCI without complications.

   • Post-procedural residual diameter stenosis of the treated lesions < 20% in patients with stent implantation or < 50% in those with balloon angioplasty
   • Post-procedural thrombolysis in myocardial infarction (TIMI) grade 3 flow in treated vessels

6. Negative cardiac troponin test before the index elective PCI.

7. Taking Clopidogrel 75 mg daily dose for at least 7 days or taking Clopidogrel 75 mg daily dose for less than 7 days but with 300 to 600 mg Clopidogrel loading dose before PCI.

8. Taking acetylsalicylic acid (ASA) 100 mg daily treatment for at least 7 days or taking ASA 100 mg daily dose for less than 7 days but with 300 mg ASA loading dose before PCI.

9. Females with childbearing potential (i.e., females who are not post-menopausal or surgically sterile) must:

   • have a negative urine or blood pregnancy test at enrolment and prior to randomization;
   • currently be using a hormonal contraceptive and agree to continue its use in addition to using double-barrier local contraception (i.e., intra-uterine device plus spermicidal and condom for male partner) from screening through study completion.

Exclusion Criteria:

1. Patients who had acute coronary syndrome (ACS) within 12 months of screening.

2. Occurrence of myocardial infarction (MI) related to index elective PCI (type 4a MI) or myocardial infarction related to stent thrombosis (type 4b MI) according to the Third Universal Definition of Myocardial Infarction.

3. Use of parenteral antithrombotic agents, e.g., glycoprotein IIb/IIIa inhibitors (GPIs), bivalirudin, unfractionated heparin, enoxaparin or fondaparinux within 24 hours of screening.

4. Use of any oral antithrombotic agents, with the exception of Clopidogrel and ASA, within 30 days of screening.

5. Any other indications (e.g., atrial fibrillation, prosthetic heart valve, venous thromboembolism, ventricular thrombosis, et al) for antithrombotic treatment other than ASA 100 mg daily, Clopidogrel and Ticagrelor during study period.

6. Concomitant therapy with moderate or strong cytochrome P-450 (CYP) 3A inhibitors, CYP 3A substrates with narrow therapeutic index, or strong CYP 3A inducers during study period.

7. Concomitant therapy with moderate or strong CYP 2C19 inhibitors, CYP 2C19 substrates with narrow therapeutic index, or strong CYP 2C19 inducers during study period.

8. Increased bleeding risk including:

   • recent (within 30 days of screening) gastrointestinal (GI) bleeding;
   • any history of intracranial, intraocular, retroperitoneal, or spinal bleeding;
   • recent (within 30 days of screening) major trauma or major surgery;
   • sustained uncontrolled hypertension (systolic blood pressure [SBP] > 180 mmHg or diastolic blood pressure [DBP] > 100 mmHg);
   • history of hemorrhagic disorders that can increase the risk of bleeding, e.g., haemophilia, von Willebrand's disease;
   • inability to discontinue required concomitant therapy with non-selective non-steroidal anti-inflammatory drugs (NSAIDs) at screening;
   • platelet count less than 100,000/mm3 or hemoglobin < 10 g/dL.

9. Contraindication or other reason that ASA, Clopidogrel, or Ticagrelor should not be administered (e.g., hypersensitivity, active bleeding [including active pathological bleeding], any bleeding tendency [coagulation defects], moderate and severe hepatic impairment, risk of bradycardia, chronic obstructive pulmonary disease, chronic or active asthma, hyperuricemia, gout, etc.).

10. History of intolerance to ASA, Clopidogrel or Ticagrelor.

11. Patients that are scheduled for CABG during the study period.

12. Patient requires dialysis or has a creatinine clearance (Clcr) < 30 mL/min as calculated by the Cockcroft-Gault equation: Clcr = (140 - Age) × WT / (72 × Scr) (× 0.85 for females), where WT is weight in kg, Scr is serum creatinine in mg/dL.

13. Any acute or chronic unstable conditions in the past 30 days or other conditions which, in the opinion of the investigator, may either put the patient at risk or influence the result of the study (e.g., active cancer, risk for non-compliance, risk for being lost to follow-up).

14. Participation in another investigational drug or device study within 30 days of screening.

15. Involvement in the planning and conduct of the study (applies to investigators, contract research organization staff, and study site staff).

16. History of drug addiction or alcohol abuse in the previous 2 years.

17. Recent (within 30 days of screening) blood donation.

18. Known pregnancy, breast-feeding, or intend to become pregnant during the study period.