Safety and Efficacy of Low-Dose Ticagrelor in Chinese Patients With NSTE-ACS

Non ST Segment Elevation Acute Coronary Syndrome Clinical Trial

Official title:

Safety and Efficacy of Low-Dose Ticagrelor in Chinese Patients With Non-ST-Elevation Acute Coronary Syndrome: A Randomized Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02415803
• Other study ID #: ACS-1
• Status: Recruiting
• Phase: Phase 3
• First received: March 26, 2015
• Last updated: April 9, 2015
• Start date: December 2014

Study information

• Verified date: December 2014
• Source: First Affiliated Hospital of Harbin Medical University
• Contact: Yue Li, MD
• Phone: 86-451-85555673
• Email: ly99ly[@]vip.163.com
• Is FDA regulated: No
• Health authority: China: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Ticagrelor is an oral, reversibly-binding, direct-acting P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Guideline recommendations on the use of dual antiplatelet therapy (DAPT) have been formulated that ticagrelor 90 mg twice daily plus aspirin in preference to clopidogrel 75mg daily plus aspirin for patients who have an ACS with or without ST-segment elevation. These recommendations are primarily based on large, randomized, Phase III clinical trials. However, few East Asian patients (or those of East Asian descent) have been included in these trials to assess the use of these drugs. In addition, a growing body of data supported that East Asian might have different adverse event profiles (thrombophilia and bleeding) and "therapeutic window" compared with white subjects. Furthermore, "East Asian paradox" phenomenon has been described that East Asian patients have a higher prevalence of platelet reactivity during DAPT, but an ischaemic event rate following PCI or ACS is similar or even lower than white patients. Therefore, the antiplatelet treatment strategy that is most appropriate for East Asian patients is increasingly urgent. Therefore, we performed the current study to observe the different effects of low-dose ticagrelor (45 mg twice daily), conventional-dose ticagrelor (90 mg twice daily) and clopidogrel (75mg once daily) on high platelet reactivity (HPR) and IPA, and investigated the safety and efficacy of low-dose ticagrelor further in Chinese patients with non-ST-elevation ACS (NSTE-ACS).

Description:

Ticagrelor is an oral, reversibly-binding, direct-acting P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Guideline recommendations on the use of dual antiplatelet therapy (DAPT) have been formulated that ticagrelor 90 mg twice daily plus aspirin in preference to clopidogrel 75mg daily plus aspirin for patients who have an ACS with or without ST-segment elevation. These recommendations are primarily based on large, randomized, Phase III clinical trials. However, few East Asian patients (or those of East Asian descent) have been included in these trials to assess the use of these drugs. In addition, a growing body of data supported that East Asian might have different adverse event profiles (thrombophilia and bleeding) and "therapeutic window" compared with white subjects. Furthermore, "East Asian paradox" phenomenon has been described that East Asian patients have a higher prevalence of platelet reactivity during DAPT, but an ischaemic event rate following PCI or ACS is similar or even lower than white patients. Therefore, the antiplatelet treatment strategy that is most appropriate for East Asian patients is increasingly urgent. In Korea and Japan, it has been reported that low doses of ticagrelor had a more potent inhibition of platelet aggregation (IPA) than clopidogrel (75 mg once daily) in healthy subjects and patients with stable coronary artery disease, respectively. But it is still not clear whether a low dose of ticagrelor is superior to clopidogrel in a large population of Chinese ACS patients. A recent study on pharmacokinetics and tolerability of ticagrelor has found that maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of ticagrelor (90 mg twice daily) and its active metabolite (AR-C124910XX) tended to be approximately 40% higher in healthy Chinese volunteers compared with Caucasian subjects. This data also suggested that a low dose of ticagrelor might be more appropriate for Chinese ACS patients. In view of a large diurnal variation with a single daily dose, a lower dose twice daily may be a better choice for Chinese patients. Therefore, we performed the current study to observe the different effects of low-dose ticagrelor (45 mg twice daily), conventional-dose ticagrelor (90 mg twice daily) and clopidogrel (75mg once daily) on high platelet reactivity (HPR) and IPA, and investigated the safety and efficacy of low-dose ticagrelor further in Chinese patients with non-ST-elevation ACS (NSTE-ACS).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• hospitalized for NSTE-ACS within the preceding 48 h

• have one of the following additional criteria:

1. ischemic symptoms at rest, lasting =10 minutes;

2. horizontal or down-sloping ST segment depression =0.1 mV;

3. cardiac troponin I (cTnI), marker associated with NSTE-ACS, local laboratory upper limit of normal values;

4. underwent percutaneous coronary intervention (PCI); (5) a history of myocardial infarction.

Exclusion Criteria:

• ST-elevation ACS;

• planned use of glycoprotein IIb/IIIa receptor inhibitors, adenosine diphosphate (ADP) receptor antagonists, or anticoagulant therapy during the study period;

• platelet count <100g/L;

• creatinine clearance rate < 30ml/min;

• diagnosed as respiratory or circulatory instability (cardiac shock, severe congestive heart failure NYHA II-IV or left ventricular ejection fraction < 40%);

• a history of bleeding tendency;

• aspirin, ticagrelor or clopidogrel allergies;

• diabetes.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Non ST Segment Elevation Acute Coronary Syndrome

Intervention

Drug:
• low-dose ticagrelor
90 mg loading dose, then 45 mg twice daily for 5 days
• conventional-dose ticagrelor
180 mg loading dose, then 90 mg twice daily for 5 days
• Clopidogrel
300 mg loading dose, then 75 mg once daily for 5 days

Locations

Country	Name	City	State
United States	VerifyNow	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
First Affiliated Hospital of Harbin Medical University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the differences in mean inhibition of platelet aggregation or inhibition ratio (%)	After overnight fasting, venous blood samples of all subjects were taken for pharmacodynamic measurements before dosing (baseline) and 12 hours after the last dose. VerifyNow P2Y12 (Accumetrics, SanDiego, CA), a whole-blood, cartridge-based and point-of-care turbidometric assay, was performed to test platelet aggregation at baseline and 12 hours after the last dose, and the results were reported in P2Y12 reaction units (PRU). With this assay, a higher PRU reflects greater adenosine-diphosphate-mediated platelet reactivity (PR). High-platelet reactivity (HPR) was defined as a PRU>208. Blood samples were placed in 3.2% sodium citrate (Greiner Bio-One Vacuette North America, Inc, Monroe, NC) for this assay. Additionally, inhibition of platelet aggregation (IPA) calculated by VerifyNow assays was similar to light transmittance aggregometry.	before dosing (baseline) and up to 12 hours after the last dose	Yes
Secondary	Number of bleeding events		throughout the study (from baseline to 12 hours after the last dose)	Yes
Secondary	Number of difficulty breathing events		throughout the study (from baseline to 12 hours after the last dose)	Yes
Secondary	number of ventricular pauses		throughout the study (from baseline to 12 hours after the last dose)	Yes
Secondary	number of myocardial infarction events		throughout the study (from baseline to 12 hours after the last dose)	Yes
Secondary	number of death events		throughout the study (from baseline to 12 hours after the last dose)	Yes
Secondary	number of stroke events		throughout the study (from baseline to 12 hours after the last dose)	Yes
Secondary	number of severe recurrent ischemia events		throughout the study (from baseline to 12 hours after the last dose)	Yes