Efficacy of Xience/promus versus Cypher in rEducing Late Loss after stENTing (EXCELLENT) trial: Study design and rationale of a Korean multicenter prospective randomized trial

Article Outline

• Abstract
• Methods
  • Study objectives and hypotheses
  • Study design
  • Study population
  • Endpoints
  • Statistical considerations
    • Sample size calculation
    • Statistical analyses
  • EXCELLENT substudies
  • Trial organization
    • Trial management, data coordination, and site monitoring
    • Committees
• Discussion
  • Comparison of LL prevention between EES and SES
  • Optimal duration of dual antiplatelet therapy after PCI
• Conclusion
• Acknowledgements
• Appendix A. 
• References
• Copyright

Background

The everolimus-eluting stent (EES) is a newly developed drug-eluting stent using the MULTILINK VISION stent platform combined with the drug everolimus contained in a polymer coating. Recently reported randomized trials have shown the noninferiority and subsequent superiority of the EES compared with the paclitaxel-eluting stent regarding in-stent late loss (LL) at 180 days. However, there have been no studies comparing head to head the EES with the sirolimus-eluting stent (SES), which has shown the least amount of LL among the previously released drug-eluting stent (DES).

In addition, adjunctive antiplatelet therapy is a critical factor in optimizing long-term DES safety. Despite the recommendation of the American Heart Association/American College of Cardiology to maintain 12 months of dual antiplatelet therapy, there have been no prospective randomized trials comparing the efficacy and safety of different durations.

Study Design

In the Efficacy of Xience/promus versus Cypher in rEducing Late Loss after stENTing (EXCELLENT) trial, approximately 1,400 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (EES vs SES) and the duration of dual antiplatelet therapy (6 vs 12 months). The primary end point is in-segment LL at 9 months for comparison of type of stent, and the coprimary end point is target vessel failure at 12 months for comparison of dual antiplatelet therapy duration.

Summary

The EXCELLENT trial is the largest study yet performed to directly compare the efficacy and safety of the EES versus the SES. In addition, this study will also address the issue of a 6- versus 12-month duration of dual antiplatelet therapy for post-percutaneous coronary intervention management.

The everolimus-eluting stent (EES) is a newly developed drug-eluting stent using the MULTILINK VISION stent platform combined with the drug everolimus contained in a polymer coating.¹ In the first-in-man SPIRIT First clinical trial, EES showed a significant benefit over the bare-metal Vision stent.² Compared with late loss of 0.85 ± 0.36 mm in the bare metal stent (BMS) arm, EES reduced late loss (LL) by 88% (0.10 ± 0.23 mm) at 6 months. The 6-month rate of major adverse cardiac events (MACE) was an acceptable 7.7%. In the SPIRIT II and III clinical trials, where the efficacy and safety of EES was compared against the paclitaxel-eluting stent (PES), another drug-eluting stent (DES), EES was shown to be noninferior and subsequently superior to PES with regard to in-stent LL at 180 days.³, ⁴ As for ischemia-driven target vessel failure (TVF), which was the secondary end point in the large-scale SPIRIT III pivotal trial, EES showed a lower rate of TVF (7.6% vs 9.7%) confirming the noninferiority of EES.

However, EES has not been compared against sirolimus-eluting stents (SESs), which have been shown to be the most efficacious drug-eluting stent regarding inhibition of neointima and LL.⁵, ⁶, ⁷, ⁸, ⁹ Both everolimus and sirolimus are macrocyclic lactones that target the mammalian target of rapamycin to reduce vascular smooth muscle proliferation after vessel injury and therefore, in principle, may show similar results after stenting in humans. However, the stent and polymer platform is not the same between the EES and SES, and the EES system has the thinnest stent + polymer thickness (88.6 μm) of all of the commercially available DES in Korea.

In addition, adjunctive antiplatelet therapy is also a critical factor in optimizing long-term DES safety.¹⁰, ¹¹ Despite the recommendation of the American Heart Association and the American College of Cardiology to maintain 12 months of dual antiplatelet therapy (DAT), these were not based on hard data from prospective randomized clinical trials but rather from a fury of reports emphasizing the dangers of DES-related stent thrombosis.¹² We do not have hard data as to whether 12 months of DAT has any safety benefit over a 6-month regimen of DAT.

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Methods 

Study objectives and hypotheses 

The primary objective of this study is to compare the efficacy and safety of coronary stenting with EES compared with SES in the treatment of coronary stenosis and to evaluate the efficacy and safety of a 6- versus 12-month duration of DAT. The working hypothesis of this trial is that EES is noninferior to SES in inhibiting neointimal growth at 9 months angiographically, and a 6-month duration of dual antiplatelet therapy is noninferior to a 12-month duration of DAT in preventing the occurrence of TVF defined as the composite of cardiac death, nonfatal myocardial infarction (MI), and target vessel revascularization (TVR).

Study design 

This is a prospective, randomized, open-label, 2 × 2 factorial designed multicenter trial to test whether EES is noninferior to SES in preventing LL and to test whether a 6-month duration of DAT is noninferior to a 12-month duration of DAT in preventing the occurrence of TVF. In total, approximately 1,400 patients will be enrolled at 17 centers in Korea. After enrollment and index PCI procedure, clinical follow-up will occur at 1, 3, 9, 12 months and yearly up to 5 years after intervention. The investigator may conduct follow-up as telephone contacts or office visits. An angiographic follow-up will be required at 9 months to determine late luminal loss. The trial algorithm is shown in Figure 1. This study is an investigator-initiated clinical trial with grant support from 3 sources: the Ministry of Health, Welfare, and Family Affairs of the Republic of Korea; Boston Scientific Korea (Seoul, Korea); and Abbott Korea Ltd (Seoul, Korea). Other than providing financial support, the companies were not involved with the protocol development or the study process, including site selection, management, and data collection and analysis. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents. The protocol of the trial has been registered at www.clinicaltrials.gov (NCT00698607).

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• Figure 1. 

  EXCELLENT trial algorithm. Target vessel failure defined as the composite of cardiac death, nonfatal MI, and TVR. TLR, Target lesion revascularization.

Study population 

Patients that are at least 18 years of age who show on coronary angiogram to have significant diameter stenosis by visual estimation on a native coronary artery and meet all of the inclusion and exclusion criteria (Table I) are eligible for this study. Those that agree to participate in the study and give written informed consent will be randomized 3:1 to either (a) EESs or (b) SESs, and 1:1 to either (a) 6-month clopidogrel therapy or (b) 12-month clopidogrel therapy (2 × 2 design). To assure that major factors that could contribute to the primary end point are evenly distributed among the groups, randomization will be stratified by enrolling sites, the presence of diabetes, and lesion length. All randomization is done via a Web-based online randomization system.

Table I. Enrollment criteria

General inclusion criteria

At least 18 years of age

Able to verbally confirm understandings of risks, benefits, and treatment alternatives of receiving the EES provides written informed consent before any study-related procedure

Significant coronary artery stenosis (>50% by visual estimate)

Evidence of myocardial ischemia (eg, stable, unstable angina, recent infarction, silent ischemia, positive functional study or a reversible changes in the electrocardiogram consistent with ischemia). In subjects with coronary artery stenosis >75%, evidence of myocardial ischemia does not have to be documented

Subjects must be an acceptable candidate for coronary artery bypass graft surgery

Angiographic inclusion criteria

Target lesion(s) located in a native coronary artery with visually estimated diameter of ≥2.25 and ≤4.25 mm

Target lesion(s)amenable for percutaneous coronary intervention

General exclusion criteria

Known hypersensitivity or contraindication to any of the following medications:

Heparin, aspirin, clopidogrel, sirolimus, everolimus, contrast media⁎

Systemic (intravenous) sirolimus, everolimus use within 12 m

Female of childbearing potential, unless a recent pregnancy test is negative, who possibly plans to become pregnant at any time after enrollment into this study

History of bleeding diathesis or known coagulopathy (including heparin-induced thrombocytopenia) or will refuse blood transfusions

Gastrointestinal or genitourinary bleeding within the prior 3 m or major surgery within 2 m

Current known current platelet count <100,000 cells/mm3 or Hgb <10 g/dL

An elective surgical procedure is planned that would necessitate interruption of clopidogrel during the first 12 m post enrollment

Noncardiac comorbid conditions are present with life expectancy <1 year or that may result in protocol noncompliance (per site investigator's medical judgment)

Patients who are actively participating in another drug or device investigational study, which have not completed the primary end point follow-up period

Patients who have received any stent implantation in the target vessel before enrollment

Patients with LVEF <25% or those with cardiogenic shock

Patients with MI within 72 h

Creatinine level >3.0 mg/dL or dependence on dialysis

Severe hepatic dysfunction (AST and ALT: 3 times upper normal reference values)

Angiographic exclusion criteria

Significant left main coronary artery stenosis

Target lesion(s) with ISR

Target lesion(s) with CTO

True bifurcation lesions requiring 2 stents

Hgb, Hemoglobin; LVEF, left ventricular ejection fraction; AST, aspartate aminotransferace; ALT, alanine aminotransferase.

Endpoints 

There are 2 primary end points in this study: first is in-segment LL at 9 months for comparison of stenting with EES versus SES and the other is TVF at 12 months for comparison of 6 months versus 12 months of clopidogrel therapy. The secondary study end points defined a priori are the following:

Statistical considerations 

To test the first hypothesis that EES is noninferior to SES in inhibiting neointimal growth at 9 months angiographically, we assumed the LL of EES to be 0.2 ± 0.41 mm and SES to be 0.2 ± 0.48 mm based on the QCA results from the SIRIUS, E-SIRIUS, C-SIRIUS, SIRTAX, and the SPIRIT II, III trials.³, ⁴, ⁵, ¹³, ¹⁴, ¹⁵ Using a noninferiority design with a noninferiority margin of 0.1 mm, type I error set at 0.05, statistical power set at 90%, sampling ratio of EES:SES at 3:1, and an estimated dropout rate of 20% (for 9-month follow-up angiography), we would need 1,233 patients (924 patients in the EES arm and 309 in the SES arm).

To test the second hypothesis that a 6-month duration of DAT is noninferior to a 12-month duration of DAT in preventing the occurrence of TVF, we assumed that the TVF rate at 1 year after drug-eluting stent implantation to be approximately 10%. Using a noninferiority design with a noninferiority margin of 4%, type I error set at 0.05, statistical power set at 80%, sampling ratio of 6-month clopidogrel/12-month clopidogrel at 1:1, and an estimated dropout rate of 5% (for 12-month clinical follow-up), we would need 685 patients in the 6-month clopidogrel arm and 685 patients in the 12-month clopidogrel arm (total 1,370 patients). Based on above calculations, we would need 1,372 patients (1,029 patients in the EES arm and 343 in the SES arm, 686 patients in the 6-month clopidogrel arm and 686 patients in the 12-month clopidogrel arm).

All primary and secondary end points will be analyzed both on an intention-to-treat basis (all patients analyzed as part of their assigned treatment group), per protocol basis (patients analyzed as part of their assigned treatment group only if they actually received their assigned treatment), and per treatment basis. The end points will also be analyzed both on a per-patient and per-lesion basis, whenever applicable. For patients receiving multivessel PCI, the lesion analyzed in the primary per patient analysis, will be determined randomly by a computer before QCA analysis. For intent-to-treat analysis, all patients who signed the written informed consent form and are randomized in the study will be included in the analysis sample, regardless of whether the correct treatment was administered or whether crossover occurred. For the per-protocol analysis, only enrolled patients who actually received the assigned treatment will be included in the analysis sample.

The primary end point of 9-month in-segment LL will be analyzed using a Student t test on an intention-to-treat and per- protocol basis. The null hypothesis will be evaluated using a noninferiority test. The coprimary end point of 12-month TVF will be analyzed by comparing the Kaplan-Meier event rates using the log-rank test on an intention-to-treat and per-protocol basis. The null hypothesis will be evaluated using a noninferiority statistic.

The primary as well as secondary end points will be analyzed in prespecified subgroups. These subgroups include patients with diabetes mellitus, long lesions, advanced age (age ≥70), renal dysfunction (calculated creatinine clearance ≤60 mL/min), and those receiving multivessel stenting.

EXCELLENT substudies 

There will be 2 main substudies, which will be analyzed at independent core laboratories. The long-term angiographic follow-up substudy will include at least 250 consecutive patients from selected centers that will undergo not only a 9-month angiographic follow-up but also a 2-year angiographic follow-up. Angiographic data from these patients will be analyzed with regard to LL to test the presence of any angiographic late catch-up in ‘limus’ DES. The IVUS substudy will consist of at least 250 consecutive patients from selected centers that will undergo IVUS at immediate postprocedure and at 9-month follow-up. Volumetric analysis will be performed including measurements of vessel, stent, lumen, persistent plaque, and intimal hyperplasia. Indices of remodeling, stent expansion, and stent-vessel wall apposition will also be analyzed between EES and SES. The issue of DES late catch-up will also be addressed with intravascular ultrasound at 2 years.

Trial organization 

The trial coordination and data management will be performed by the Medical Research Collaborating Center (MRCC) of Seoul National University Hospital. The MRCC is independent from any participating investigators. The MRCC will be responsible for the development of a Web-based randomization system, collection of case report form and data from individual sites, and final auditing. Site monitoring will be performed by dedicated research nurses from the Clinical Trials Center at Seoul National University Hospital. The designated trial monitors, at appropriate intervals, will review investigational data for accuracy and completeness and to ensure compliance with the protocol. They will review the documents of at least 30% of the patients enrolled from each participating center. This trial monitor will be able to inspect all documents and required records that are maintained by the individual investigator and site, including medical records (office, clinic, or hospital) for the subjects in this trial.

The trial was designed by the principal investigators and the executive committee. Besides the executive committee, the steering committee, data safety monitoring board, and the clinical event adjudication committee will be involved in the execution, administration, and supervision of the trial. The specific role and information regarding each of the committees appear in Appendix A (available online).

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Discussion 

Comparison of LL prevention between EES and SES 

The development of DES is considered as a giant leap in advancing the field of interventional cardiology. DES has significantly reduced the growth of neointima after stenting, which has been shown in multiple prospective randomized trials to reduce the need for repeat revascularizations.¹⁶ Nowadays, cardiac interventionists are able to tackle tougher and tougher lesions. The SES was the first DES approved for human use. Its efficacy and safety have been proven in numerous randomized prospective trials including the FIM, RAVEL, SIRIUS, E-SIRIUS, and SIRTAX trials.¹³, ¹⁴, ¹⁵, ¹⁷, ¹⁸

Everolimus-eluting stent is a recently developed second-generation DES, where the drug everolimus (Certican, Novartis, Basel, Switzerland) is coated onto the MultiLink Vision (Abbott Laboratories, Abbott Park, IL) stent platform using an acrylic and fluoro polymer.¹, ¹⁹ Recently reported randomized trials have shown the noninferiority and subsequent superiority of the EES compared with the PES regarding in-stent LL at 180 days.

In the first-in-man SPIRIT First clinical trial, EES showed a significant benefit over the bare-metal Vision stent.² Compared with LL of 0.85 ± 0.36 mm in the BMS arm, EES reduced LL by 88% (0.10 ± 0.23 mm). In addition, the clinical safety of EES was confirmed with a 6-month MACE rate of 7.7%. In the SPIRIT II clinical trial, which compared the efficacy and safety of the Xience V stent versus the Taxus Express2 stent, the primary end point was met showing a noninferiority of the Xience V compared with the Taxus Express2 regarding in-stent LL at 180 days.³ Actually, Xience V was superior to Taxus Express2 and reduced in-stent LL by 72% from a mean of 0.36 to 0.11 mm. In addition, analysis of other key clinical end points showed a lower rate of ischemia-driven MACE (2.7% vs 6.5% for Xience V vs Taxus Express2) and protocol-defined stent thrombosis (0.5% vs 1.3% for Xience V vs Taxus Express2). The lower rate of ischemia-driven MACE at 180 days was sustained through 1 year, and there were no new instances of late stent thrombosis in either group up to 1 year.

The SPIRIT III RCT was a prospective, 2:1 randomized, active-controlled, single-blinded, parallel, multicenter clinical evaluation of Xience V compared to Taxus in the treatment of up to 2 de novo lesions.⁴ This pivotal clinical trial was designed to demonstrate the noninferiority of Xience V compared with TAXUS. Patients were randomized 2:1 to Xience V or Taxus, and the primary end point was in-segment LL at 240 days. The results showed a mean in-segment LL of 0.14 mm for Xience V and 0.28 mm for Taxus (P < .001 for noninferiority, P = .0037 for superiority). The secondary end point, which was ischemia-driven TVF, was 7.6% for Xience V and 9.7% for Taxus, confirming the noninferiority of Xience V. Furthermore, the rate of definite and probable stent thrombosis was 1.1% and 0.6% for Xience V and Taxus, respectively.

Most of the previous data regarding the efficacy of the EES was derived from studies comparing EES with BMS or EES with PES. However, of the 3 commercially available DES in Korea (Cypher, Taxus, Endeavor), SES has shown the highest efficacy with regard to inhibition of late luminal loss. In addition to initial trials where patients and lesions were highly selected, LL with SES has been reported to be approximately 0.44, 0.19, 0.28, and 0.12 mm in tough real-world lesions such as in-stent restenosis (ISR) lesions,²⁰ in patients with diabetes,⁶ in chronic total occlusion (CTO) lesions,²¹ and in long lesions,¹⁵ respectively. Although CTO and ISR lesions will be excluded from this study, we will be able to obtain valuable results of EES in patients with diabetes and long lesions.

There have been no previous head-to-head comparisons between EES and SES. Both everolimus and sirolimus are macrocyclic lactones that target the mammalian target of rapamycin to reduce vascular smooth muscle proliferation after vessel injury and therefore in principle may show similar results after stenting in humans.²², ²³ Data from the EES arm in the SPIRIT III trial and the SES arm in the SIRIUS trial show similar rates of binary restenosis and LL (in-segment binary restenosis rate: 4.7% vs 4.3%; in-stent LL: 0.16 vs 0.15 mm for EES vs SES). However, the stent and polymer platform is not the same between the EES and SES, and it is reported that the EES system has the thinnest stent + polymer thickness (88.6 μm) of all of the previously Korea Food and Drug Administration-approved DES. In addition, there are no data available on the efficacy of the EES in broader lesion subsets than the selected lesions studied in the previous SPIRIT trials, such as long lesions (lesion length >28 mm), multivessel stenting, small vessels (reference diameter <2.5 mm), ostial lesions, so on.

In the EXCELLENT RCT, we plan to compare the efficacy of EES versus SES in preventing the formation of neointima. We will mandate a 9-month follow-up coronary angiogram to compare the late luminal loss between the 2 types of stents. Because we expect a 9-month angiographic follow up of >80%, this may impact reintervention rates due to the ‘oculostenotic relex.’ To reduce the chance of falsely high rates of repeat intervention, the investigators will adhere to a strict clinically driven revascularization protocol. In addition, all events will be independently and judiciously adjudicated by the clinical event adjudication committee.

Optimal duration of dual antiplatelet therapy after PCI 

The optimal duration of DAT after PCI using DES is unknown. Although the first generation of DES including SES and PES got approval from the US Food and Drug Administration with a recommendation of DAT of 3 and 6 months, respectively, it is recommended at present by the American College of Cardiology and American Heart Association that doctors prescribe clopidogrel for at least 12 months. These changes occurred due to fears of delayed healing and increased late stent thrombosis after DES implantation. In the BASKET LATE trial, which was a landmark analysis, investigators reported a significantly increased rate of death and MI in DES patients compared with patients with BMS after discontinuation of clopidogrel at 6 months.²⁴ Moreover, Camenzind et al,¹² in a meta-analysis of trials comparing SES with BMS, reported a higher incidence of cardiovascular death and MI in patients receiving SES after 1 year. In addition to these fears, longer duration of DAT has been advocated due to the benefit in preventing hard end points, shown in the PCI-CURE²⁵ and CREDO studies²⁶ during the BMS era.

Some investigators recommend an even longer duration of DAT for over 1 year (even lifelong). These claims are based on retrospective observational data showing that clopidogrel therapy beyond 1 year was an independent protective factor for death and MI at 2 years in patients who were event free at 12 months.²⁷ However, none of these recommendations have been based on sound prospective data or prospective randomized trials but rather on “expert” consensus. Actually, in the early studies of DES such as the SIRIUS and TAXUS trials, where the recommended duration of clopidogrel therapy was 3 and 6 months, respectively, DES did not show a significant increase in death or MI compared with BMS, suggesting that the 3- and 6-month dual antiplatelet therapy is sufficient. To the best of our knowledge, this trial will be the first trial in the DES era to specifically compare the efficacy and safety of 2 different durations of DAT, 6 versus 12 months. We hope to address one of the most commonly asked questions asked by cardiologist in the field of coronary intervention: “What is the optimal duration of clopidogrel treatment?” However, one limitation of the present trial is that it will be underpowered to answer any safety questions regarding dual antiplatelet therapy. To address the safety perspective of dual antiplatelet therapy, a mega-trial whose end point should be death and MI needs to be designed and would require several thousands of patients. In the future, we would welcome a multinational study to answer such a question.

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Conclusion 

No clinical trials to date have compared efficacy and safety of the newly developed EES with the SES. In addition, the optimal duration of DAT after DES implantation is still unclear. We hope to be able to address these issues in the EXCELLENT trial, a prospective, randomized, multicenter trial, which is enrolling approximately 1,400 patients with significant coronary artery stenosis undergoing percutaneous coronary intervention. This trial will determine whether the EES is noninferior to the SES in inhibiting neointima hyperplasia and preventing LL at 9 months and whether a 6-month duration of DAT is noninferior to a 12-month duration of DAT in preventing the occurrence of TVF, a composite of cardiac death, MI, and TVR.

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Acknowledgements 

The first two authors (KW Park and JH Yoon) contributed equally to this study.

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Appendix A. 

Executive committee

The Executive Committee will be composed of the study chairperson and selected members among the investigators. This committee is responsible for overseeing the administrative progress of the study and will approve the final trial design and protocol issued to the DSMB and the clinical sites. This committee will also be responsible for reviewing the final results, determining the methods of presentation and publication, and selecting the secondary projects and publications by members of the Steering Committee. The executive committee also holds the right to modify or stop the study prematurely based on recommendations from the DSMB.

Steering Committee

The Steering Committee will be composed of the principal investigators from the centers participating in this trial. The committee is responsible for the day-to-day administrative management of the trial and will meet on a regular base to monitor subject enrollment, clinical site progress, and protocol compliance. It will be the responsibility of the steering committee to provide assistance and education to individual sites and researchers to help with trial management, record keeping, and reporting requirements. The steering committee will prepare reports to be reviewed by the Executive Committee.

Data Safety Monitoring Board

The DSMB will be composed of general and interventional cardiologists and a biostatistician. The DSMB will function in accordance with applicable regulatory guidelines. The board members are independent and will not be participating in the trial. The DSMB committee will review the safety data from this study and make recommendations based on safety analyses of unanticipated device effects, serious adverse events, protocol deviation, device failures, and 30-day follow-up reports. The frequency of the DSMB meetings will be determined before study commencement. In addition, the DSMB may call a meeting at any time if there is reason to suspect that safety is an issue. The DSMB is responsible for making recommendations regarding any safety or compliance issues throughout the course of the study and may recommend to the Executive Committee to modify or stop the study. However, all final decisions regarding study modifications rest with the Executive Committee. All cumulative safety data will be reported to the DSMB and reviewed on an ongoing basis throughout enrollment and follow-up periods to ensure patient safety. Every effort will be made to allow the DSMB to conduct an unbiased review of patient safety information. Before the DSMB's first review of the data, the DSMB charter will be drafted. The DSMB will develop a consensus understanding of all trial end points and definitions used in the event adjudication process. All DSMB reports will remain strictly confidential but will be made available to the regulatory body upon request.

Clinical Event Adjudication Committee

The Clinical Events Adjudication Committee (CEAC) is composed of interventional and noninterventional cardiologists who are not participants in the study. The CEAC is charged with the development of specific criteria used for the categorization of clinical events and clinical end points in the study, which are based on protocol. At the onset of the trial, the CEAC will establish explicit rules outlining the minimum amount of data required and the algorithm followed to classify a clinical event. All members of the CEAC will be blinded to the primary results of the trial.

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