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

Table 51. FDA Subgroup Analyses of Primary Endpoint (TAAL)

Sube:roup Analysis of Primary endpointUAINSTEMI STEMI AlIACSPrasugrel Clopidogrel DR Prasugrel Clopidogrel HR Prasugrel Clopidogrel HR(N=5044) (N=S030) 95%CI (N=1769) (N=1765) 9S%CI (N=6813) (N=679S) 95%CI

P-value P-value P-valueAe:e (yr)

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

Suberoup Analysis of Primary endpointUA/NSTEMI STEMI AUACSPrasugrel Clopidogrel HR Prasugrel Clopidogrel HR Prasugrel Clopidogrel HR(N=S044) (N=S030) 9S0/0CI (N=1769) (N=176S) 9S0/0CI (N=6813) (N=679S) 9S0/0CI

P-value P-value P-value

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

Sub2roup Analysis of Primary endpointUAINSTEMI STEMI AIlACSPrasugrel Clopldogrel HR Prasugrel Clopidogrel HR Prasugrel Clopidogrel HR(N=5044) (N=5030) 95%CI (N=1769) (N=1765) 95%CI (N=6813) (N=6795) 95%CI

P-value P-value P-valueEthnicityCaucasian

N 4575 4569 0.80 1688 1105 0.80 6263 6274 0.80n 414 511 0.70,0.91 167 209 0.65,0.98 581 720 0.72,0.89

% 9.05 11.18 0.0011 9.89 12.26 0.0242 9.28 11.48

Clinical ReviewKaren A. Hicks, M.D.NDA 22,307 N(OOO)Prasugre1

Subl!roup Analvsis of Primary endpointUAINSTEMI· STEMI AllACSPrasugrel Clopidogrel HR Prasugrel Clopidogrel HR Prasugrel Clopidogrel HR(N=5044) (N=5030) 95%CI (N=1769) (N=1765) 9S%CI (N=6813) . (N=679S) 9S%CI

P-value P-value P-valueWeieht(kl!)

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

Subl!:roup Analysis of Primary endpointUAINSTEMI STEMI AllACSPrasugrel Clopidogrel HR Prasugrel Clopidogrel DR Prasugrel Clopidogrel HR(N=5044) (N=5030) 95%CI (N=1769) (N=1765) 95%CI (N=6813) (N=679S) 9S%CI

P-value P-value P-valueUse of GPIIbllIIainhibitors prior to and durin!"! PCIYes N 1764 1768 0.82 924 953 0.73 2688 2721 0.79

n 172 208 0.67, 1.01 91 125 0.56,0.96 263 333 0.67,0.93% 9.75 11.77 0.0939 9.85 13.12 0.Q18 9.78 12.24 0.0047

No N 3280 3262 0.82 845 812 0.87 4125 4074 0.83n 297 357 0.70,0.96 83 91 0.65,1.18 . 380 448 0.72,0.95

% 9.06 10.94 0.0089 9.82 11.21 0.3987 9.21 11.00 0.0058

FemaleYes N 433 486 0.88 198 205 0.68 631 691 0.80

n 41 52 0.58,1.32 22 32 0.39,1.17 63 84 0.58,1.12% 9.47 10.70 11.11 15.61 9.98 12.16 0.2178

No N 892 913 0.92 182 214 0.94 1074 1127 0.92n 96 107 0.70,1.21 19 24 0.52,1.72 115 131 0.72,1.18

% 10.76 11.72 10.44 11.21 10.71 11.62 0.4771MaleYes N 1331 1282 0.80 726 748 0.75 2057 2030 0.78

n 131 156 0.64, 1.01 69 93 0.55,1.03 200 249 0.65,0.94% 9.84 12.17 9.50 12.43 9.72 12.27 0.Q108

No N 2388 2349 0.78 663 598 0.86 3051 2947 0.80n 201 250 0.65,0.94 64 67 0.61, 1.21 265 317 0.68,0.94% 8.42 10.64 9.65 11.20 8.69 10.76 0.0054

Use of GPIIblIIIa inhibitors up to cath labYes N 366 353 0.85 171 199 0.69 537 552 0.80

n 37 42 0.54,1.31 14 23 0.36,0.34 51 65 0.55,1.15% 10.11 11.90 0.5441 8.19 11.56 0.2663 9.50 11.78 0.2769

No N 4678 4677 0.82 1598 1566 0.80 6276 6243 0.81n 435 523 0.72,0.93 160 193 0.65,0.99 592 716 0.73,0.91

% 9.23 11.18 0.0023 10.01 12.32 0.0348 9.43 11.47 0.0002

102

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

Sub2roup Analysis of Primary endpointUAINSTEMI STEMI AUACSPrasugrel Clopidogrel HR Prasugrel Clopidogrel HR Prasugrel Clopidogrel HR(N=5044) (N=5030) 95% CI (N=1769) (N=1765) 95%CI (N=6813) (N=6795) 95%CI

P-value P-value P-valueFemaleYes N 84 92 0.13 33 48 0.33 117 140 0.80

n 10 10 0.47,2.70 2 8 0.07,1.57 12 18 0.38,1.65% 11.90 10.87 0.5974 6.06 16.67 0.1476 10.26 12.86 0.6710

No N 1241 1307 0.89 347 371 0.86 1588 1678 0.88n 127 149 0.70,1.13 39 48 0.56,1.31 166 197 0.72,1.09% 10.23 11.40 0.4138 11.24 12.94 0.4076 10.45 11.74 0.2214

MaleYes N 282 261 0.77 138 151 0.86 420 412 0.80

n 27 32 0.46,1.28 '12 15 0.41,1.85 39 47 0.53,1.23% 9.57 12.26 0.3268 8.70 9.93 0.6897 9.29 11.41 0.3241

No N 3437 3370 0.79 1251 1195 0.79 4688 4565 0.79n 305 374 0.68,0.92 121 145 0.62, 1.0 426 519 0.70,0.90% 8.87 11.10 0.0022 9.67 12.13 0.0533 9.09 11.37 0.0003

Use of GPIIblIIIa inhibitors UP to cath lab and cath only (no PCI)Yes' N 3 9

n 0 1% - 11.11

No N 87 83n 7 5% 8.05 6.02

103

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

Sub2roUD Analvsis or Primary endpointUA/NSTEMI STEMI AllACSPras~grel Clopidogrel HR Prasugrel Clopidogrel HR Prasugrel Clopidogrel HR(N=S044) (N=S030) 9S0f0CI (N=1769) (N=176S) 9S0f0CI (N=6813) (N-679S) 9S0f0CI

P-value P-value P-valueTimin!! of Loadin2 Dose0-2 hrs prior 1078 1045 0.85 432 440 0.90 1510 1485 0.86toPCI 103 117 0.65, Lll 52 59 0.62, 1.30 155 176 0.70,1.08

0.3212 0.5843 0.23402-6 hrs prior 61 67 0.9191 9 7 . .70 74 0.90to PCI 4 5 1 I 5 6 0.28,2.95

0.89276-12 hrs 16 9 0.84 4 1 - 20 10 0.46prior to PCI 3 2 0,14,5.08 0 1 3 3 0.09,2.30

0.8530 0.32632:12 hrs prior 102 84 1.01 10 5 - 112 89 1.01to PCI 15 12 0.47,2.16 1 1 16 13 0-.47,2.16

0.9651 0.8358DuringPCI 3660 3671 0.82 1221 1213 0.75 4881 4884 0.80

329 400 0.71,0.95 110 143 0.59,0.97 439 543 0.71,0.910.0081 0.0209 0.0005

PostPCI 48 47 0.30 15 21 - 63 68 0.435 14 0.11,0.84 2 2 7 16 0.18, 1.04

0.0145 0.0391Use of any statinYes N 4859 4878 0.82 1717 1698 0.83 6576 6576 0.82

n 446 543 0.72,0.93 164 194 0.67,1.02 610 737 0.74,0.91% 9.18 lLl3 0.002 9.55 11.43 0.0653 9.28 11.21 0.0002

No N 185 152 0.88 52 67 0.54 237 219 0.69n 23 22 0.49,1.57 10 22 0.26, Ll4 33 44 0.44,1.08

% 12.43 14.47 0.7254 19.23 32.84 0.0787 13.92 20.09 0.1124

104

....•

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

Subl!rouD Analvsis of Primary endpointUAINSTEMI STEMI AIIACSPrasugrel Clopidogrel HR' Prasugrel Clopidogrel HR Prasugrel Clopidogrel . HR(N=5044) (N=5030) 95%CI (N=1769) (N=1765) 95%CI (N=6813) (N=6795) 95%CI

P,-value P-value P-valueUse of proton pump inhibitorYes N 2474 2463 0.83 916 882 0.80 3390 3345 0.82

n 262 310 0.70,0.98 103 122 0.62,1.05 365 432 0.72,0.95% 10.59 12.59 0.0319 11.24 13.83 0.0857 10.77 12.91 0.0056

No N 2570 2567 0.81 853 883 0.77 3423 3450 0.80n 207 255 0.67,0.97 71 94 0.57,1.05 278 349 0.68,0.93% 8.05 9.93 0.0248 8.32 10.65 0.0986 8.12 10.12 0.0046

DiabetesYes N 1246 1226 0.70 330 344 0.71 1576 1570 0.70

n 135 184 0.56,0.88 45 64 0.49,1.04 180 248 0.58,0.85% 10.84 15.01 0.0018 13.64 18.61 0.0610 11.42 15.80 0.0002

No N 3798 3804 0.87 1439 1421 0.83 5237 5225 0.86n 334 381 0.76, 1.01 129 152 0.66,1.05 463 533 0.76,0.98% 8.79 10.02 0.0856 8.96 10.70 0.1174 8.84 10.20 0.0193

Analysis by ( uouan Liu. M.D.. M.S.. Biometrics. FDA

105

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

9.2 Study H7T-MC-TABL(Clinical Study Report: "PRasugrel IN Comparison to ~lopidogrelforInhibition of Platelet Activation and AggrEgation (pRINCIPLE) - TIMI 44'') (Study Dates:August 24, 2006 - June 20, 2007) (Date of Report: October 1, 2007)

9.2.1 Protocol, Amendment, and Post Hoc Changes

The study description was based on the original protocol dated February 28, 2006 and Protocol Amendment (a)dated May 11,2006. Protocol Amendment (a) was completed prior to enrollment of subjects in the study andincluded the following changes: .1. The 15 minute sampling times were excluded for the following Phase 1 Platelet Function Measures:

a. IPA to 20 flM ADPb. IPA to 5 flM ADPc. Maximum platelet aggregation to 20 flM ADPd. Maximum platelet aggregation to 5 flM ADPe.Final extent ofplatelet aggregation (at 6 minutes after ADP addition) to 5 or 20 I!M ADP

2. Under "Myonecrosis Measures," troponin I was changed to troponin.

9.2.2 Study Design

This was a multicenter, randomized, parallel, double-blind, double-dummy, cross-over, active comparator-controlledstudy in subjects undergoing elective cardiac catheterization with planned percutaneous coronary intervention (pCI)with coronary stenting. The study had two phases. Phase 1 included study drug loading dose, cardiaccatheterization, PCI (if indicated), and daily maintenance dose for 14 ± 2 days in subjects undergoing PCI. In Phase2, subjects were crossed over to the alternative daily maintenance dose for an additional 14 ± 2 days.

9.2.3 Study Population

The study population included subjects undergoing cardiac catheterization with planned elective PCI with coronarystenting.

9.2.4 Objectives

Primary Objectives:The primary objectives of the study were• . to compare the inhibition ofplatelet aggregation (IPA) to 20 flM adenosine disphosphate (ADP) measured at 6

hours (± 30 minutes) after prasugrel60 mg loading dose versus clopidogrel600 mg loading dose (LD) insubjects in the "on treatment population" who did not receive a GPlIbIIIIa inhibitor

• to compare the IPA to 20 flM ADP measured after 14 ± 2 days ofprasugrellO mg daily maintenance doseversus the IPA after 14 ± 2 days ofclopidogrel150 mg daily maintenance dose (MD) in the "on treatmentpopulation" who have received PCI (this includes subjects receiving clopidogrel and prasugrel in either orderduring the crossover phase)

Secondary Objectives:The secondary objectives of the study were .• to measure the iDhibition ofplatelet aggregation to 20 JlM ADP measured at approximately 2 hours after

prasugrel60 mg loading dose versus clopidogre1600 mg loading dose in subjects in the "on treatmentpopulation" who did not receive a GPIIblIIIa inhibitor

• to compare overall safety and tolerability ofprasligrel60 mg LD and 10 mg daily MDversus clopidogrel600mg LD and 150 mg daily MD after 14 ± 2 days in treated subjects who have received PeI. Safety measures

106

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

inClude, but are not limited to, the following: non-CABG-associated TIMI Major Bleeding, non-CABG relatedTIMI life-threatening bleeding, and non-CABG-related TIMI Minor Bleeding.

• to compare overall safety and tolerability of the following dosing regimens: prasugrel60 mg LD and 10 mgdaily MD for 14 ± 2 days with crossover to clopidogrel 150 mg daily MD for 14 ± 2 days versus clopidogrel600 mg LD and 150 mg daily MD for 14:1: 2 days in treated subjects who have received PCI. Safety measuresinclude but are not limited to the following: -Non-CABG-associated TIMI Major Bleeding, non-CABG-related .TIMI life-threatening bleeding, and non-CABG-related TIMI Minor Bleeding.

• to compare prasugrel (60 mg LD, 10 mg MD) versus clopidogrel (600 mg LD, 150 mg MD) in the occurrenceofMajor Adverse Cardiac Events (MACE) after 14 ± 2 days in treated subjects who have received PCI.

• to compare prasugrel versus clopidogrel on additional measures ofplatelet inhibition including, but not limitedto, thienopyridine hyporesponsiveness, vasodilator-stimulated phosphoprotein (IIASP), biomarkers ofinflammation, and biomarkers ofplatelet activation

• to compare prasugrel (60 mg LD, 10 mg MD) "ersus clopidogrel (600 mg LD, 150 mg MD) in measures ofmyonecrosis [creatine kinase-MB isoforms (CK-MB), troponin)

9.2.5· InclusionlExclusion Criteria

Inclusion Criteria (Reproduced from Sponsor, page 879)Subjects are eligible to be entered in the study if they meet the following criteria only:1. Subjects ::: 18 years ofage undergoing cardiac catheterization with planned percutaneous coronary intervention

(ifcoronary anatomy is suitable) for an indication ofchest pain +/or anginal equivalent felt by the treatingphysician to be related to coronary ischemia

2. At least one ofthe following (a through c)a. Functional study (exercise, or pharmacologic) within the past 8 weeks consistent with ischemia as

manifested by at least one of the following: .i. a reversible defect on nuclear imaging

ii. a reversible wall-motion abnormality byechocardiographyiii. horizontal or down-sloping ST-depressions> 1 mm on electrocardiogram (ECG) (ifno

imaging· performedb. Prior coronary revascularization. (pCI or coronary artery bypass grafting (CABG»c. A cardiac catheterization with at least one coronary artery lesion amenable to PCI (not yet performed)

within 14 days prior to enrollment

Exclusion Criteria (Reproduced from Sponsor, page 879)Subjects cannot be entered and will be excluded from the study ifthey meet any of the following criteria:

Cardiovascular Exclusion Criterial. Known creatine kinase-myocardial bands (CK-MB) or cardiac troponin greater than the upper limit ofnormal

(ULN) at the time ofscreening2. Have a planned PCI procedure as initial treatment for an acute myocardial infarction (MI) (STEMI or

NSTEMI), or aplanned PCI within 48 hours of fibrinolytic therapy for STEMI3. Have cardiogenic shock at the time ofscreening (systolic blood pressure < 90 mm Hg associated with clinical

evidence ofend-organ hypoperfusion, or subjects requiring vasopressors to maintain systolic blood pressureover 90 mm Hg and associated with clinical evidence of end-organ hypoperfusion)

4. Have refractory ventricular arrhythmias5. Have New York Heart Association (NYHA) Class IV congestive heart failure (CHF)

Bleeding Risk Exclusion Criteria6. Have active internal bleeding or history ofbleeding diathesis7. Have clinical findings, in the judgment ofthe investigator, associated with an increased risk ofbleeding

107