Trial DesignThe Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA•CER) trial: study design and rationale
Section snippets
Platelet protease-activated receptors
Thrombin is the most potent platelet stimulator acting on the protease-activated receptors (PAR) by cleaving the N-terminal domain and unmasking a tethered ligand that activates the receptor (Figure 1).17, 18, 19 Protease-activated receptor 1 (PAR-1) is a high-affinity receptor for thrombin and is thought to be the key platelet thrombin receptor.18 Thus, it may potentially be an even more important target than TX A2 and P2Y12 pathways in both the acute and chronic coronary disease setting. In
The PAR-1 inhibitor SCH 530348
SCH 530348 is a nonprotein, small-molecule, high-affinity, orally active, competitive PAR-1 inhibitor.12, 23 Both the association and dissociation rates of SCH 530348 with the PAR-1 receptor are slow, yet the inhibition is reversible. Importantly, SCH 530348 has no effect on thrombin's capability to generate fibrin.
SCH 530348 inhibits, in a dose-dependent manner, thrombin receptor activating peptide (TRAP)–induced platelet aggregation. Of note, SCH 530348 does not affect collagen-induced
The TRA-PCI trial
SCH 530348 was tested in a large phase II clinical trial in 1030 subjects scheduled to undergo PCI or angiography with intention to perform PCI.25 Subjects were sequentially randomized to receive 10, 20, or 40 mg of SCH 530348 or placebo before angiography at least 1 hour before PCI. Subjects who actually had PCI were further randomized to 1 of 3 maintenance once-daily doses of SCH 530348 (0.5, 1, or 2.5 mg), or placebo for 60 days. The primary end point was the composite of TIMI major or minor
Design of the TRA•CER trial
The TRA•CER trial has been designed to examine the role of SCH 530348 in addition to current standard of care in the short- and long-term treatment of patients with NSTE ACS (Figure 2). The TRA•CER trial is a global, randomized, double-blind, placebo-controlled, balanced parallel-groups study of orally administered SCH 530348 in subjects with NSTE ACS. The study population is expected to consist of approximately 10 000 patients enrolled at about 800 sites in >35 countries worldwide.
Study objectives
The primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, MI, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. The key secondary objective of the study is to demonstrate that SCH 530348 will reduce the composite of cardiovascular death, MI, and stroke. Other secondary efficacy outcome measures include all-cause death and
Safety objectives
The specific safety objectives, in relative order of importance, will be the incidences of:
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The composite of moderate and severe bleeding events according to the GUSTO classification.
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Clinically significant bleeding, defined as TIMI major or TIMI minor bleeding, or bleeding that requires unplanned medical treatment, surgical treatment, or laboratory evaluation even if it does not meet the criteria for TIMI major or TIMI minor bleeding.
Inclusion and exclusion criteria
Inclusion and exclusion criteria are detailed in Table I.
Randomization and study drug administration
Eligible patients will be randomly assigned with 1:1 ratio to SCH 530348 or placebo. Randomized assignment will be stratified according to the use of or intent to use glycoprotein IIb/IIIa inhibitor at the time of randomization and the type of antithrombin used or anticipated to be used (direct thrombin inhibitor vs other antithrombin agents) at the time of randomization. Immediately after randomization and study drug assignment, subjects will receive a 40-mg loading dose of oral SCH 530348 or
Study procedures and follow-up
Clinical events, procedures, adverse events, concomitant medications, and safety laboratory evaluations will be collected during the baseline hospitalization and subsequent follow-up visits, which will be conducted at 30 days, 4 months, 8 months, 12 months, and every 6 months after the first year of follow-up for the entire duration of the study. The TRA•CER trial is an event-driven trial, and thus it will continue until a minimum of 2334 primary efficacy end point and 1457 key secondary
Statistical analysis
Based on data from the CURE trial, the estimated rates of the primary efficacy end point and key secondary end point at 1 year in the placebo group are 18% and 10%, respectively. The sample size is determined to provide adequate power to test the hypotheses of superiority for both the primary and key secondary efficacy end points. A total of 9400 subjects (4700 subjects per treatment group) will provide at least 98% power at a 2-sided significance level of .05 to detect a 15% relative risk
Interim analysis
One interim efficacy analysis will be performed when approximately 50% of the expected primary and 50% of the key secondary efficacy end points required for completion of the trial have occurred. Analyses will be based on the CEC-adjudicated events. The O'Brien-Fleming methodology will be implemented to preserve an overall type I error of 0.05.27 A nominal α level of .003 will be used for the interim analysis. The trial will not be stopped for efficacy unless both the primary and key secondary
Safety analyses
Safety analyses will include subjects who receive at least 1 dose of study treatment and will be performed according to treatment actually received. Inferential analysis with calculation of point of estimates and 95% CIs comparing SCH 530348 and placebo will be performed only for the 2 main safety objectives described above. For all the other safety measures, only descriptive statistics will be provided.
The TRA•CER biorepository
Serial blood samples and DNA samples will be collected from subjects included in the TRA•CER trial. RNA and plasma/serum samples will be collected at baseline, 30 days, and 1 year; plasma/serum samples will be also collected at the time of treatment completion. DNA, RNA, and plasma serum samples will be stored in a central biorepository and will be used for ancillary and exploratory analyses approved by the publications committee.
Study organization
The TRA•CER trial will be coordinated through a partnership of recognized academic research organizations (AROs) led by the Duke Clinical Research Institute (Figure 3).
The executive committee will be responsible for the scientific content of the study and the overall supervision of the study. The steering committee, comprising representatives from participating countries, will provide clinical guidance on study implementation, conduct of the study, and interpretation of results (Appendix A).
A
Discussion
The TRA•CER trial is a randomized clinical trial designed to assess whether the inhibition of platelet PAR-1 using the novel compound SCH 530348 will reduce the occurrence of ischemic complications in a large cohort of NSTE ACS patients with an acceptable safety profile.
The TRA program
The novel PAR-1 inhibitor, SCH 530348, will be evaluated in a clinical trial program comprising 2 large randomized clinical trials. In parallel with the TRA•CER trial, the TRA 2P-TIMI 50 trial is enrolling patients with a history of cardiovascular disease, with an expected population sample of 25,000 patients.28 The TRA•CER and TRA 2P trials share common database elements and identical definitions of end points. These features will facilitate the integration of the 2 data sets to perform
Rationale of patient selection in TRA•CER
All patients included in TRA•CER are required to have positive cardiac markers or significant ST-segment changes. We anticipate that cardiac troponins will play a major role in the identification of patients for the trial, given their universal use in modern care and their high sensitivity.29 Cardiac troponins are a powerful prognostic tool, correlate with the presence of coronary thrombosis, and are associated with increased benefit from aggressive antiplatelet therapies.30, 31, 32 Patients
End point selection and definition
The primary and key secondary TRA•CER end points are a composite of clinically relevant ischemic outcomes. The definition of recurrent MI in clinical trials—particularly early reinfarction and MI in the setting of PCI and CABG—is challenging and has not been consistent across past ACS clinical trials. The TRA•CER definition of MI incorporates, with some modifications, recent universal MI definitions.34 The data collection will ensure the possibility of using the template of different
Relevance of bleeding
Bleeding is associated with worse short- and long-term outcomes and presents uncertainties for appropriate management.8, 9, 10, 35 Therefore, efficacy of antithrombotic medications is now carefully weighed against the potential for bleeding risk. SCH 530348 development has been focusing on achieving efficacy without significantly adding on bleeding rates, with encouraging premises. First, the selective inhibition of the PAR-1 is thought to preserve key hemostatic platelet functions, such as von
Academic collaborative model
The cardiovascular clinical trial arena has become increasingly populated by numerous projects evaluating several new compounds in large cardiovascular populations, creating a competitive research landscape. Using a clinical trial registration Web site (http://www.clinicaltrials.gov), we have estimated that >100,000 patients will be included in ongoing clinical trials including ACS populations in the coming years. The currently inefficient research system struggles to handle such high volume,
The TRA•CER biorepository
The collection of serial blood samples in the TRA•CER endeavor represents one of the largest biorepository efforts and will create a unique platform for research aimed at improving clinical predictions of both short- and long-term outcomes and studying biological pathways involved in disease processes and drug effects.
The TRA•CER blood collection is specifically planned to study advanced biomarkers and take advantage of recent advances in technology allowing the rapid identification of DNA,
Conclusion
The TRA•CER trial will evaluate the novel platelet PAR-1 antagonist of SCH 530348 among patients with high-risk NSTE ACS in addition to modern standard of care. TRA•CER trial management will be based on a model of academic partnership. Finally, a large, serial, state-of-the-art blood collection effort is fully integrated within the trial.
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Clinical trial registration information: NCT00527943; http://www.clinicaltrials.gov/ct/show/NCT00527943.
Marc Cohen, MD, served as guest editor on this manuscript.
- a
See Appendix A for a complete listing of committee members.