CENTER FOR DRUG EVALUATION ANDRESEARCH

APPLICATIONNUMBER:

22-307

MEDICAL REVIEW

Clinical ReviewKaren A. Hicks, M.D.NDA 22,307 N(OOO), N(OO I), N(002)Prasugrel

CLINICAL REVIEW

Application TypeSubmission Number

Submission Code

Letter DateStamp Date

PDUFA Goal Date

Reviewer NameReview Completion Date

Established Name(Proposed) Trade Name

Therapeutic ClassApplicant

Priority Designation

FormulationDosing Regimen

Indication

Intended Population

NDA22,307000N

December 26, 2007December26, 2007June 26, 2008

Karen A. Hicks, M.D.April 28, 2008

PrasugrelEffientP2Y12 ADP receptor inhibitorEli Lilly and Company

P

Oral60 mg loading dose then 10 mg/dReduction of atherothromboticevents and stent thrombosisAcute coronary syndromes

Clinical ReviewKaren A Hicks, M.D.NDA 22,307 N(OOO)Prasugrel

Table of Contents

1 Executive Summary 1

1.1 Recommendation on Regulatory Action 11.2 Recommendation on Postmarketing Actions 2

1..2.1 Risk Management Activity ; : 21.2.2 Required Phase 4 Commitments 2

1.3 Summary of Clinical Findings 21.3.1 BriefOverview ofClinical Prograrn 21.3.2 Efficacy 31.3.3 Safety : 41.3.4 Dosing Regimen and Administration 51.3.5 Drug-Drug Interactions 61.3.6 Special Populations 6

2 Introduction and Background 7

2.1 Product Information 72.2 Currently Available Treatment for Indications 72.3 Availability ofProposed Active Ingredient in the United States 82.4 Important Issues With Pharmacologically Related Products 82.5 Presubmission Regulatory Activity 82.6 Other Relevant Background Information N/A 8

3 Significant Findings from Other Review Disciplines 8

3.1 CMC (and Product Microbiology, ifApplicable) 83.2 Animal Pharmacology/Toxicology: 8

4 Data .Sources, Review Strategy, and Data Integrity 9

4.1 Sources ofClinical Data 94.2 Tables ofClinical Studies: 94.3 Review Strategy : 94.4 Data Quality and Integrity 94.5 Compliance with Good Clinical Practices 114.6 Financial Disclosures 11

5 Clinical Pharmacology 11

5.1 Pharmacokinetics 115.1.1 Salt to Base Conversion 125.1.2 Relationship Between Body Weight and Exposure 13

5.2 Pharmacodynamics 145.3 Exposure-Response Relationships 14

6 Integrated Review of Efficacy 15

6.1 Indication 156.1.1 Methods 156.1.2 General Discussion ofEndpoints 156.1.3 Study Design 156.1.4 Efficacy Findings : 196.1.5 Clinical Microbiology N/A .326.1.6 Efficacy Conclusions (Study TAAL) 32

7 Integrated Review of Safety _ ; 32

7.1 Methods and Findings 32

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Clinical ReviewKaren A. Hicks, M.D.NPA 22,307 N(OOO)Prasugrel

7.1.1 Deaths .337.1.2 Other Serious Adverse Events .357.1.3 Dropouts and Other Significant Adverse Events ..477.1.4 Common Adverse Events .497.1.5 Less Common Adverse Events .497.1.6 Laboratory Findings · 507.1.7 Vital Signs - .507.1.8 Electrocardiograms (ECGs) 507.1.9 Immunogenicity N/A .517.1.10 Hwnan Carcinogenicity (please see Section 7.1.2.2 for further details) , 517.1.11 Special Safety Studies N/A 517.1.12 Withdrawal Phenomena and/or Abuse Potential N/A .517.1.13 Human Reproduction and Pregnancy Data 517.1.14 Assessment of Effect on Growth N/A 517.1.15 Overdose Experience 517.1.16 Postmarketing Experience .51

7.2 Adequacy ofPatient Exposure and Safety Assessments : 517.2.1 Demographics : 537.2;2 Adequacy of Overall Clinical Experience 547.2.3 Adequacy ofSpecial Animal and/or In Vitro Testing 547.2.4 Adequacy ofRoutine Clinical Testing .547.2.5 Adequacy ofMetabolic, Clearance, and Interaction Workup 547.2.6 Adequacy ofEvaluation for Potential Adverse Events for Any New Drug and Particularly for Drugsin the Class Represented by the New Drug; Recommendations for Further Study : 557.2.7 Assessment ofQuality and Completeness ofData , .557.2.8 Additional Submissions, Including Safety Update .55

8 Additionlil Clinical Issues ...••.•....••••.•.••••••...••..•.•.••.••.....•••••_ _ _ 55

8.1 Conclusions 55

9 Appendices (Review Of Individual Study Reports) .._ _ _ _ "" __•...__ _..56

9.1 Study H7T-MC-TAAL (primary) (Clinical Study Report: "A Comparison ofCS-747 and Clopidogrelin Acute Coronary Syndrome Subjects Who are to Undergo Percutaneous Coronary InterventionITIMI 38")(Study Dates: November 5, 2004 - July 22,2007) (Date ofReport: November 28,2007) 56

9.1.1 Protocol, Amendment, and Post Hoc Changes : .569.1.2 Study Design 579.1.3 Study Population 579.1.4 Objectives 589.1.5 InclusionlExclusion Criteria 609.1.6 Study Plan 629.1.7 Schedule ofEvaluations and Procedures 659.1.8 Endpoints 689.1.9 Clinical Events Committee (CEC) 719.1.10 Statistical Considerations : 719.1.11 Results 76

9.2 Study H7T-MC-TABL(Clinical Study Report: "PRasugrel IN Comparison to Clopidogrel for InhibitionofPlatelet Activation and AggrEgation (PRINCIPLE) - TIM! 44") (Study Dates: August 24, 2006 - June 20,2007) (Date ofReport: October I, 2007) 106

9.2.1 Protocol, Amendment, and Post Hoc Changes 1069.2.2 Study Design 1069.2.3 Study Population 1069.2.4 Objectives 1069.2.5 InclusionlExclusion Criteria ~ 1079.2.6 Study Plan 108

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Clinical ReviewKaren A Hicks, M.D.NDA 22,307 N(OOO)Prasugrel

9.2.7 Schedule ofEvaluations and Procedures 1109.2.8 Endpoints 1129.2.9 Safety Measures 1139.2.10 Definitions 1139.2.11 Statistical Considerations ;.1159.2.12· Results , 1169.2.13 Surnmary(TABL) 135

9.3 Study H7T-MC-TAAH (Clinical Study Report: "A Double-Blind, Randomized, Multicenter, Dose-Ranging Trial ofCS-747 (LY640315) C.omparedWith Clopidogrel in Subjects Undergoing PercutaneousCoronary Intervention (Joint Utilization of Medications to Block Platelets Optimally) (JUMBO-TOO 26)")(Study Dates: April 15, 2003 - January 6, 2004) (Date ofReport: June 24, 2005) 136

9.3.1 Protocol, Amendment, and Post Hoc Changes 1369.3.2 Study Design 1369.3.3 Study Population 1369.3.4 Objectives 1369.3.5 InclusionlExclusion Criteria 1379.3.6 Study Plan 1389.3.7 Schedule ofEvaluations and Procedures 1399.3.8 Endpoints , 1419.3.9 Statistical Considerations ;1419.3.10 Results 143

9.4 Line-by-Line Labeling Review 145

10 References _ .._ 145

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Clinical ReviewKaren A. Hicks, M.D.NDA 22,307 N(OOO), N(OOI), N(002)Prasugrel

Table of Tables

Table 1. Sponsor's Analysis: Number and Percentage of Subjects Reaching the Composite Endpoint ofCV Death,Nonfatal MI or Nonfatal Stroke Using the Definition ofPeri-Procedural Myocardial Infarction Prior to ProtocolAmendment (CEC Adjudicated) (All Randomized Subjects) (TAAL) .3

. Table 2. Sponsor's Analysis: Number and Percentage ofSubjects Reaching the Composite Endpoint ofCV peath,Nonfatal MI, or Nonfatal Stroke Using the Expanded Definition (CEC Adjudicated) (All Randomized Subjects)(TAAL) 3Table 3. Sponsor's Analysis: CEC Adjudicated Non-CABG-Related Bleeding (1'AAL) ..4Table 4. Sponsor's Analysis: CEC-Adjudicated CABG-Related Bleeding Events Through Study End (Overall)(TAAL) 4Table 5. FDA Subgroup Analysis: Composite ofCardiovascular Death, Nonfatal Myocardial Infurction, orNonfatal Stroke at a Median of 12 Months ofFollow-Up by Age (1'AAL) 6Table 6. FDA Subgroup Analysis: Composite ofCardiovascular Death, Nonfatal Myocardial Infurction, or .Nonfatal Stroke at a Median of 12 Months ofFollow-up in Patients With and Without a Prior History ofTransientIschemic Attack/Cerebrovascular Accident (TAAL) , 7Table 7. Summary ofthe Pivotal Phase 3 and Phase 2 Studies ; 9Table 8. Sponsor's Analysis: Number and Percentage ofSubjects Reaching the Composite Endpoint ofCV Death,Nonfatal MI or Nonfatal Stroke Using the Definition ofPeri-Procedural Myocardial Infarction Prior to ProtocolAmendment (CEC Adjudicated) (All Randomized Subjects) (TAAL) , 19Table 9. Sponsor's Analysis: Number and Percentage ofSubjects Reaching the Composite Endpoint ofCV Death,Nonfatal MI, or Nonfatal Stroke Using the Expanded Definition ofPeri-Procedural Myocardial Infarction AfterProtocol Amendment (CEC Adjudicated) (All Randomized Subjects) (TAAL) 20Table 10. Sponsor's Analysis: Nonfatal MI (TAAL) ; 20Table II. Sponsor's Analysis: Summary ofNonfatal Myocardial Infarction 21Table 12. FDA Subgroup Analysis ofPriinary Endpoint by Age (Composite ofCV Death, Nonfatal MI, or NonfatalStroke) (TAAL) 22Table 13. FDA Subgroup Analysis ofPrimary Endpoint by Sex (Composite ofCV Death, Nonfatal MI, or NonfatalStroke) (1'AAL) 22Table 14. FDA Subgroup Analysis ofPrimary Endpoint by Ethnicity (Composite of CV Death, Nonfatal MI, or.Nonfatal Stroke) (1'AAL) ~ 23Table 15. FDA Subgroup Analysis of Primary Endpoint by Prior History ofTransient Ischemic Attack or Stroke(Composite ofCV Death, Nonfatal MI, or Nonfata1 Stroke) (TAAL) 23Table 16. FDA Subgroup Analysis ofPrimary Endpoint by Timing ofLoading Dose (Composite ofCV Death,Nonfatal MI, or Nonfatal Stroke) (TAAL) ; 24Table 17. FDA Subgroup Analysis ofPrimary Endpoint by Use ofProton Pump Inhibitors (Composite ofCVDeath, Nonfatal MI, or Nonfatal Stroke) (TAAL) 26Table 18. FDA Subgroup Analysis ofPrimary Endpoint by Weight (Composite ofCV Death, Nonfatal MI,orNonfatal Stroke) (TAAL) 26Table 19. Sponsor's Analysis: Number and Percentage ofSubjects Reaching the Secondary Composite Endpoints--CEC Adjudicated (All Randomized Subjects) (TAAL) 28Table 20. Sponsor's Analysis: Number and Percentage of Subjects Reaching Secondary and Other EfficacyEndpoints--CEC Adjudicated (All Randomized Subjects) (TAAL) 30Table 21. Sponsor's Analysis: Summary ofCEC-Adjudicated Deaths (All Randomized Subjects) (TAAL) 34Table 22. Sponsor's Analysis: CEC Adjudicated Non-CABG-Related Bleeding (1'AAL) 35Table 23. Sponsor's Analysis: CEC-Adjudicated CABG-Related Bleeding Events Through Study End (Overall)(1'AAL) , :..36Table 24. Sponsor's Analysis: Number and Percentage of Subjects with CABG-Related TIMI Major BleedingEvents Through Study End (CEC-Adjudicated) (All Treated Subjects) 36Table 25. Summary ofIntracranial Hemorrhages While at Risk (CEC Adjudicated) (All Treated All ACS Subjects)(TAAL) : .37Table 26. FDA Analysis: Number and Percentage ofSubjects with Bleeding Events (TAAL) 38Table 27. Number and Percentage of Subjects with Bleeding by Organ System (1'AAL) .39

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Clinical ReviewKaren A. Hicks, M.D.NDA 22,307 N(ODO)Prasugrel

Table 28. FDA Analysis: Relative Risk (95% CI) ofBleeding on Pmsugrel Compared to Clopidogrel (TAAL) .39Table 29. Relative Risk (95% CI) ofBleeding on Prasugrel Compared to Clopidogrel (TAAL) .40Table 30. Number ofNew First Cancers by Site and Treatment (TAAL) .43Table 31. Primary Reason for Premature Study Drug Discontinuation (All ACS) (TAAL) .48Table 32. Overview ofTreatment-Emergent Adverse Events Through Study End (All ACS Population) (TAAL) ..48Table 33. QTIRT Analysis: The Point Estimates and the 90% Cis Corresponding to the Largest Upper Bounds forPmsugrel 80 mg and the Largest Lower Bounds for Moxifloxacin (H7t~EW~TAAP) 51Table 34. Exposure to Prasugrel (by Days) in Subjects with Atherosclerosis in the Primary and Secondary SafetyDatabases 52Table 35. Pmsugrel Exposure in Clinical Pharmacology Studies 53Table 36. Demographics and Baseline Characteristics (All Randomized All ACS Subjects) (TAAL) 53Table 37. TIMI Hemorrhage Criteria" 60Table 38. TIMI Risk Score for UAINSTEMI 61Table 39. New York Heart Association Congestive Heart Failure (NYHA CHF) Classifications 61Table 40. Study Schedule for Study H7T-MC-TAAL 66Table 41. Interim Analyses by the Data Monitoring Committee 74Table 42. Calculation ofTIMI RISK SCORE for Subjects with UAINSTEMI or STEMI 75·Table 43. Sponsor's Analysis: Summary ofProtocol Violations Identified from the Clinical Database (TAAL) 77Table 44. Sponsor's Analysis: Number ofProtocol Violations Identified by Site Monitoring (TAAL) 77Table 45. Sponsor's Analysis: Subject Disposition (All Randomized Subjects) (TAAL) 79Table 46. Sponsor's Analysis: Kaplan-Meier Estimates for the Incidence ofWithdrawal of Consent or Lost-to-Follow-Up (TAAL) 80Table 47. Demographics and Baseline Characteristics (TAAL) 81Table 48. Index Procedure (All Randomized Subjects) (TAAL) 93Table 49. Duration oUoIlow-Up (All Randomized Subjects) (TAAL) 96Table 50. Number and Percentage of Subjects Reaching the Composite Endpoint ofCV Death, Nonfatal MI, orNonfatal Stroke--CEC Adjudicated (All Randomized Subjects) (TAAL) 96Table 51. FDA Subgroup Analyses ofPrimary Endpoint (TAAL) 98Table 52. Study Schedule Protocol PRINCIPLE - TIMI44 111Table 53. TIMI Hemorrhage Criteria (TAAL) ...................•.....................................................................................114Table 54. Protocol Violations (TABL) ~ 116Table 55. Demographic and Baseline Characteristics (TABL) 120Table 56. Sponsor's Analysis: IPA by LTA with 20~ ADP 6 Hours post LD (Acute Phase Population) (TABL)................................................................................................................................................................................... 121Table 57. Sponsor's Analysis: IPA to 20 J1M ADP at 14 ± 2 days (Chronic Phase Population) (TABL) 122Table 58. Sponsor's Analysis: IPA to 20~ ADP at 30 min, 2 hours, 18 to 24 hours Following Loading Dose ofStudy Drug 122Table 59. Sponsor's Analysis: Inhibition ofPlatelet Aggregation with 5~ Adenosine Diphosphate (Acute PhasePopulation) (TABL) , 123Table 60. Sponsor's Analysis: Maximum Platelet Aggregation to 20 11M ADP at 30 minutes, 2 hours, 6 hours and18 to 24 hours following Loading Dose ofStudy Drug (Acute Phase Population) (TABL) 124Table 61. Sponsor's Analysis: Maximal Platelet Aggregation to 5 11M Adenosine Disphosphate (Acute PhasePopulation) (TABL) 125Table 62. Sponsor's Analysis: VerifyNow™ P2Yu Percent Inhibition Data 126Table 63. Sponsor's Analysis: Thienopyridine Hyporesponsiveness to 20 11M ADP After LD and During MD 127Table 64. Sponsor's Analysis: VASP Platelet Reactivity Index (PRI %) Throughout Study 128Table 65. Sponsor's Analysis: Clinical Efficacy Measures Occurring at any Time During the Study (On-TreatmentPopulation) (TABL) 130Table 66. Exposure to Study Medication (On Treatment Population) (TABL) 131Table 67. Sponsor's Analysis: Non-CABG-Related TIMI Clinically Significant Bleeding Events up to Day 15 Visit(Number and Percentage ofSubjects) (On-Treatment Population) (TABL) 131

. Table 68. Sponsor's Analysis: Overview ofAdverse Events (Number and Percentage of Subjects) (On-TreatmentPopulation) (TABL) 133

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Clinical ReviewKaren A. Hicks, M.D.NDA 22,307 N(OOO)Prasugrel

Table 69. Sponsor's Analysis: Serious Adverse Events by System Organ Class and Preferred Term (Nwnber andPercentage ofSubjects) (All Randomized Subjects) 134Table 70. Treatlnent Regimen (TAAH) ~ , 138Table 71. Study Schedule (TAAH) 140Table 72. TIMI Hemorrhage Criteria 141Table 73. Subject Demographics and Baseline Characteristics (Evaluable Set) , 144

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Clinical ReviewKaren A. Hicks, M.D.NDA 22,307 N(OOO), N(OOI), N(002)Prasugrel

Table ofFigures

Figure I. Kaplan-Meier (K-M) Incidence Plot for All New Solid Cancers Diagnosed After 7 Days in TRITON :.5Figure 2. Clearance ofR-138727 Increases with Increase in body weight... 13Figure 3. Increased Exposures ofR-138727 with Decreased Body Weight (TAAL) 13Figure 4. Risk for TIMI Major Bleeding is Higher in Patients with Body Weight < 60 kg 14Figure 5. Simulation (N=2000) of the Proposed 5 mg Maintenance Dose in Patients with Body Weight < 60 kg«CL = 123 x (WT/85)o.798 ; Between-subject variability (%CV) = 24%) (Study TABR) 14Figure 6. Study H7T-MC-TAAL Study Design 16Figure 7. Study HIT-MC-TAAL Treatment Plan 17Figure 8. Enrollment of Subjects (TAAL): 18Figure 9. Kaplan-Meier Estimate ofthe Incidence of the Composite Endpoint of Cardiovascular Death, NonfatalMI, or Nonfatal Stroke (CEC Adjudicated) (All Randomized UNNSTEMI Subjects) (TAAL) 21Figure 10. Incidence ofCardiovascular Death, Nonfatal MI, or Nonfatal Stroke (TAAL) Based on Timing ofLoading Dose 25Figure II. Timing ofLoading Dose and Effect on Primary Endpoint (TAAL) 25Figure 12. FDA Analysis: Kaplan-Meier Plot for Any Bleeding Event (Day 0 to 360) (TAAL) .40Figure 13. FDA Analysis: Kaplan-Meier Plot for Any Bleeding Event (Day 0 to 30) (TAAL) .41Figure 14. FDA Analysis: Kaplan-Meier Plot for Serious Bleeding Events (Day 0 to 360) .41Figure 15. Kaplan-Meier Plot for Serious Bleeding Events (Day 0 to 30) .42Figure 16. Kaplan-Meier Plot for Gastrointestinal Bleeding Events (Day 0 to 360) .42Figure 17. Kaplan-Meier Plot for Gastrointestinal Bleeding (Day 0 to 90) .43Figure 18. Kaplan-Meier (K-M) Incidence Plot for All New Solid Cancers Diagnosed After 7 Days in TRITON 44Figure 19. Kaplan-Meier Incidence Plot for All New Solid Cancers in Women After 7 Days .45Figure 20. Kaplan-Meier Incidence Plot for All New Solid Cancers in Men After 7 Days .45Figure 21. Kaplan-Meier Incidence Plot for New Gastrointestinal/Genitourinary Cancers Diagnosed After 7 Days inTRITON ; 46Figure 22. Kaplan-Meier Incidence Plot for New Non-Gastrointestinal/Genitourinary Cancers Diagnosed After 7Days in TRITON 46Figure 23. Study H7T-MC-TAAL Study Design 63Figure 24. Study H7T-MC-TAAL Treatment Plan 64Figure 25. Evaluate the Superiority ofPrasugrel Compared to Clopidogrel at a One-Sided Alpha Level of0.025 inUNNSTEMI Cohort Relative to 73Figure 26. Enrollment ofSubjects (TAAL) 78Figure 27. Hazard Ratio and 95% Confidence Interval for the Composite Endpoint ofCV Death, Nonfatal MI, orNonfatal Stroke--CEC Adjudicated (All Randomized UNNSTEMI Subjects) (TAAL) 97Figure 28. Study Design (protocol HIT-MC-TABL) 109Figure 29. Schedule ofEvaluations and Procedures (Protocol H7T-MC-TABL) 110Figure 30. Subject Disposition (TABL) 118Figure 31. Study Populations (TABL) 119Figure 32. H7T-MC-TAAH Study Design 139Figure 33. Subject Disposition (All Randomized Set) (TAAH) 143Figure 34. Significant (TIM! non-CABG Major + Minor) Bleeding at 30-Day Visit (%) 144Figure 35. MACE (Death + MI + Stroke +CTVT + Recurrent Ischemia) at 30~Day Visit (%) (TAAH) 145

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Clinical ReviewKaren A. Hicks; M.D.NDA 22,307 N(OOO), N(OOI), N(002)Prasugrel

Abbreviations

ABT=AlI But TAAL studiesACS=acute coronary syndromesACT=activated clotting timeADP=adenosine diphosphateAE=adverse eventAfib=atrial fibrillationAfl=atrial flutterALT=alanine aminotransaminaseARB=angiotensin receptor blockersARC=Academic Research ConsortiumASA= aspirinAST=aspartate aminotransaminaseAUC=area under the curveBMS=bare metal stentBP=blood pressureBUN=blood urea nitrogenCABG=coronary artery bypass graft surgeryCAD=coronary artery diseaseCBC=complete blood countCEC=Clinical Endpoints CommitteeCHF=congestive heart failureCI=confidence intervalCffi=Clinical Investigator's BrochureCIE=cardiac ischemic eventsCK=creatine kinaseCK-MB=creatine kinase-myocardial bands

.Completion ofthe PCI procedure=defined as 60 minutes after the subject leaves the cardiac catheterizationlaboratory

C0X2=cyclooxygenase-2CRF=Case report formCRO=Contract research organizationCS-747=prasugrelCT=computed tomographyCURE=The Clopidogrel in Unstable angina to prevent Recurrent Events StudyC"=cardiovascularC"A=cerebrovascular accidentDBP=diastolic blood pressureDES=dnig eluting stentDM=diabetes mellitusDMC=Data Monitoring CommitteeECG=electrocardiogramEnd ofStudy (Trial)=End ofstudy (trial) is the date of the last visit shown in the study schedule

of the last subject active in the studyGP=glycoprotein .H2=histamine 2 receptorHct=hematocritHDL=high density lipoproteinHgb=hemoglobinHMG Co-A=3 hydroxy-3-methylglutaryl coenzyme AHTN=hypertension·

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Clinical ReviewKaren A. HickS, M.D.Nl)A 22,307 N(OOO)Prasugrel

HR=heart rateICH=intracranial hemorrhageINR=Intemational Nonnalized RatioIndex procedure=PCI during the initial hospitalizationIPA=inhibition ofplatelet aggregationIRBIERB=Institutional.review board/ethical review boardITT=intent-to-treatIVRS=Interactive Voice Response SystemJUMBO=The Joint Utilization ofMedications to Block Platelets Optimally studyLBBB=left bundle branch blockLD=loading doseMACE=major adverse cardiovascular eventsMD=maintenance doseMI=myocardial infarctionMPA=maximum platelet aggregationMRI=magnetic resonance imagingNtA=not applicableNE=not evaluatedNQWMI=non-Q-wave myocardial infarctionNSAIDS=nonsteroidal anti-inflammatory drugsNSTEMI=non-ST-segment elevation myocardial infarctionNYHA CHF=New York Heart Association Congestive Heart FailurePCI=percutaneous coronary interventionPPI=proton pump inhibitorsQD=once dailyQwMI=Q-wave myocardial infarctionRBC=red blood cellsSAE=serious adverse eventSAP=Statistical Analysis PlanSBP=systolic blood pressureSGOT=serurn glutamic oxaloacetic transaminasesSGPT=serurn glutamic pyruvic transaminasesSOC=system organ classSTEMI=ST-segment elevation myocardIal infarctionTAAL=Study H7T-MC-TAAL. A Comparison ofCS-747 and Clopidogrel in Acute Coronary

Syndrome Subjects Who Are To Undergo Percutaneous Coronary Intervention/fIMI-38TEAE=Treatment-emergent adverse event. Any untoward medical occurrence that either occurs

or worsens at any time after treatment baseline and which does not necessarily have tohave a causal relationship with this treatment.

TESAE=treatment emergent serious adverse eventTIA=transient ischemic attackTlMl=The TIMI StudyGroup. Named for a series of national clinical studies know as the TIMI

(Thrombolysis in Myocardial Infarction) studies launched in 1984 by Brigham andWomen's Hospital

TVR=target vessel revascularizationUA=unstable anginaUAlNSTEMI=unstable angina and non-ST-segment elevation myocardial infarctionULN=upper limit ofnonnal .US=United States ofAmericaUTVR=urgennarget vessel revascularizationVfib=ventricular fibrillationWBC= white blood cells

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