Elsevier

American Heart Journal

Volume 152, Issue 4, October 2006, Pages 627-635
American Heart Journal

Trial Design
Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38)

https://doi.org/10.1016/j.ahj.2006.04.012Get rights and content

Background

Dual antiplatelet therapy with aspirin and clopidogrel is standard for prevention of thrombotic complications of percutaneous coronary intervention (PCI). Prasugrel is a thienopyridine that is more potent, more rapid in onset, and more consistent in inhibition of platelets than clopidogrel. TRITON-TIMI 38 is designed to compare prasugrel with clopidogrel in moderate to high-risk patients with acute coronary syndrome (ACS).

Study Design

TRITON-TIMI 38 is a phase 3, randomized, double-blind, parallel-group, multinational, clinical trial. Approximately 13 000 patients with moderate to high-risk ACS undergoing PCI (9500 unstable angina/non–ST-segment elevation myocardial infarction [MI], 3500 ST-segment elevation MI) will be randomized to prasugrel 60 mg loading dose followed by 10 mg daily or clopidogrel 300 mg loading dose followed by 75 mg daily for up to 15 months. The primary end point is the time of the first event of cardiovascular death, MI, or stroke. Analyses will be performed first in the unstable angina/non–ST-segment elevation MI cohort and, conditionally, on the whole ACS population. Major safety end points include TIMI major and minor bleeding unrelated to coronary artery bypass graft surgery.

Conclusions

TRITON-TIMI 38 is a phase 3 comparison of prasugrel versus clopidogrel in patients with moderate to high-risk ACS undergoing PCI. In addition, it is the first large-scale clinical events trial to assess whether a thienopyridine regimen that achieves a higher level of inhibition of platelet aggregation than the standard therapy results in an improvement in clinical outcomes.

Section snippets

Background

Dual antiplatelet therapy with aspirin and a thienopyridine is standard therapy for prevention of thrombotic complications of percutaneous coronary intervention (PCI).1, 2 Clopidogrel has largely replaced ticlopidine because of a better side-effect profile.3, 4 Studies have established the benefit of long-term clopidogrel for up to 1 year in subjects with an acute coronary syndrome (ACS), including those who undergo PCI.5, 6

Several important issues remain regarding this current standard. Most

Background on prasugrel

Prasugrel (CS-747, LY640315) is a thienopyridine that has been shown in preclinical studies to be more potent and rapid in onset than clopidogrel.15 Phase 1 studies in healthy human subjects showed greater inhibition of platelet aggregation (IPA) with a 60-mg dose of prasugrel than 300 mg of clopidogrel16 and repeat dosing with 10 mg of prasugrel compared with 75 mg of clopidogrel.17 There is also evidence that poor IPA response may be less frequent with an LD of 60 mg of prasugrel than 300 mg

Study objectives

The primary objective of TRITON-TIMI 38 is to test the hypothesis that prasugrel is superior to clopidogrel on a background of aspirin in the treatment of subjects with ACS who are to undergo PCI measured by the composite end point of cardiovascular (CV) death, nonfatal myocardial infarction (MI), or nonfatal stroke. Additional efficacy hypotheses include that prasugrel reduces the occurrence of (1) the primary composite at 30 or 90 days and (2) CV death, nonfatal MI, or urgent target vessel

Study design and population

TRITON-TIMI 38 is a randomized, double-blind, double-dummy, parallel-group, clinical trial with an active comparator (Figure 1). The study population includes subjects with moderate to high-risk ACS (Table I). Patients with unstable angina (UA) and non–ST-segment elevation MI (NSTEMI) and TIMI risk score21 of 3 or higher may be enrolled within 72 hours of symptom onset. Patients with ST-segment elevation MI (STEMI) may be enrolled either within 12 hours of the onset of symptoms (primary PCI) or

Treatment protocol and follow-up procedures

A loading dose of study medication is administered anytime after randomization until the completion of the PCI procedure (within 1 hour after the patient leaves the cardiac catheterization laboratory). Randomization may occur immediately after obtaining informed consent from patients with STEMI when primary PCI is planned. For patients with UA/NSTEMI or those enrolled post-STEMI, coronary angiography may reveal an anatomy that is not amenable to PCI, and therefore, randomization may occur only

Study closeout procedures

The analysis of the primary efficacy composite end point will include events occurring for each subject during the study period, defined as the day of randomization through the end of the study period (maximum 464 days, ie, 450+14 days), which is after randomization, as clarified hereinafter.

The completion date of the study will be determined by the executive committee as a specific date when the following are expected to be met: (1) 875 subjects with a primary end point in the UA/NSTEMI arm

Dosing regimens

The dosing regimen of prasugrel in TRITON-TIMI 38 is an LD of 60 mg and daily 10 mg of maintenance dose. These doses have been selected on the basis of nonclinical thrombosis models, nonclinical toxicology studies,22 dose escalation studies in healthy subjects,23 dose ranging versus clopidogrel in subjects with stable coronary artery disease,18 and the JUMBO-TIMI 26 study.20 These studies have demonstrated that prasugrel can achieve an increase in the inhibition of adenosine diphosphate–induced

Concomitant medications

All decisions regarding concomitant medications are left to the treating physician. It is recommended that long-term aspirin therapy be 75 to 162 mg. Patients may receive unfractionated heparin, low–molecular-weight heparin, any approved direct thrombin inhibitor, and/or GPIIb/IIIa receptor antagonist. Because of a lack of information regarding the safety of thienopyridines in combination with warfarin, blinded study drug is discontinued in patients requiring anticoagulation with warfarin, and

Study end points

The primary end point of the trial is the time of first occurrence of any element of the composite of CV death, nonfatal MI, or nonfatal stroke. Cardiovascular death is considered as any death with a demonstrable CV cause or any death that is not clearly attributable to a non-CV cause. Myocardial infarction must be distinct from the index event and is defined by symptoms suggestive of ischemia/infarction, electrocardiographic data, cardiac biomarker, or pathologic evidence of infarction

Determination of sample size

The study is designed to continue until 875 subjects with UA/NSTEMI reach one of the components of the primary end point. This provides 90% power to establish superiority relative to the primary composite end point of CV death, nonfatal MI, or nonfatal stroke in the UA/NSTEMI group. These calculations are based on the following assumptions: (1) 10.5% of subjects in the clopidogrel group will develop the primary end point within 1 year based on extrapolation from CURE and PCI CURE,5, 30, 31 (2)

Study organization

The TRITON-TIMI 38 trial is sponsored by Eli Lilly and Company (Indianapolis, IN) and Daiichi Sankyo Co. (Parsippany, NJ), and is coordinated by the TIMI Study Group. Quintiles Corporation serves as the contract research organization and provides data and site management services. The steering committee is responsible for the scientific content of the protocol, protocol implementation, results presentation, and written manuscripts. Trial operations are monitored and coordinated by the

Summary

TRITON-TIMI 38 is a phase 3, randomized, double-blind, double-dummy, parallel-group, clinical trial that assesses the efficacy and safety of prasugrel compared with that of clopidogrel in patients with an ACS undergoing PCI. This trial will provide important information regarding the safety and efficacy of prasugrel and whether this agent is superior to the current standard of care. Furthermore, this is the first large-scale clinical events trial that assesses whether a thienopyridine regimen

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    The TRITON-TIMI 38 trial is supported by Eli Lilly and Company, Indianapolis, IN, and Daiichi Sankyo Co., Parsippany, NJ.

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