Institute of Medicine Workshop:Transforming Clinical Research in the United States

Investigator, TIMI Study GroupAssociate Physician, Cardiovascular Division, BWH

Assistant Professor of Medicine, Harvard Medical School

Marc S. Sabatine, MD, MPHMarc S. Sabatine, MD, MPH

October 7, 2009

Thrombolysis in Myocardial Infarction (TIMI) Study Group

Disclosure Statement

The TIMI Study Group received research grant support from: Accumetrics, Amgen,

AstraZeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol-Myers Squibb, CV

Therapeutics, Eli Lilly and Company, GlaxoSmithKline, Inotek Pharmaceuticals,

Integrated Therapeutics, Merck & Co., Millennium Pharmaceuticals, Novartis

Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, sanofi-

aventis, Schering-Plough Research Institute.

Astra Zeneca (research grant, scientific advisory boards)

Bristol-Myers-Squibb (honoraria, scientific advisory boards)

Eli Lilly & Daiichi-Sankyo (honoraria)

Eisai (research grant)

sanofi-aventis (research grant, honoraria, scientific advisory boards)

Schering-Plough (research grant support)

Description

3

The Thrombolysis in Myocardial Infarction (TIMI) Study

Group is an Academic Research Organization (ARO)

devoted to conducting clinical trials to improve outcomes

in patients with cardiovascular disease.

The group is headquartered at

Brigham and Women’s Hospital & Harvard Medical School

Boston, MA

Trials to Date

• Phase I to Phase IV studies

• Initial trials NHLBI-funded, now trials industry-funded

• NIH grant support for ancillary studies

• 30 to 25,000 subjects

• Trial Status– 45 completed trials

– 6 ongoing trials

– 7 trials in various stages of planning

4

Current Staff

• Physician Staff– Eugene Braunwald, MD – Study Chairman

– 12 Staff Cardiologists

– 3 Senior Cardiology Fellows (2-year research fellowships)

– Rotating BWH Research Residents

• Operational Staff– Carolyn McCabe, BS – Director

– 8 Project Directors & Managers

– Research Assistants, etc.

• Biostatistical Core– Charles Contant, PhD – Director

– Programmers

5

Services

• Academic Leadership

• Project Management

• Biostatistics

• Site Management

• Medical Hotline

• Regulatory Services

• Safety Reporting

• Clinical Events Committee

6

Academic Leadership (1)

• Review the Compound– Pharmacokinetics & Pharmacodynamics

– Animal & Phase I Data

• Refine Scientific Question– Unmet clinical need

– Potential utility of compound

– Current and evolving concomitant treatments

• Initiation of study– Investigator-initiated

– Industry-initiated

7

Clopidogrel in STEMI

15.0

21.7

0

5

10

15

20

25

Oc

clu

de

d A

rte

ry o

r D

ea

th/M

I (

%)

PlaceboPlaceboClopidogrelClopidogrel

n=1752 n=1739

36%Odds Reduction

P<0.0001

36%Odds Reduction

P<0.0001

Sabatine MS et al. NEJM 2005;352:1179

days

CV

Death

, M

I, U

rgen

t R

evasc (

%)

CV

Death

, M

I, U

rgen

t R

evasc (

%)

05

10

15

0 5 10 15 20 25 30

PlaceboPlacebo

ClopidogrelClopidogrel

Odds Ratio 0.80Odds Ratio 0.80

(95% CI 0.65(95% CI 0.65--0.97)0.97)

P=0.026P=0.026

20%20%20%

Angiographic Clinical

0

20

40

60

80

100

120

0

10

20

30

40

5 µM ADP-induced Platelet Aggregation Death/ACS/CVA by 6 mo

Days

1 2 3 4 5 6

Baselin

e (

%)

Quartiles of response

Q1

Q2

Q3

Q4

Clop resist 40

6.7

0 0

Perc

en

t

P = 0.007

Q1 Q2 Q3 Q4

Matetzky S et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004;109:3064-3067.

Clopidogrel Response Variability andClopidogrel Response Variability and

Increased Risk of Ischemic Events Increased Risk of Ischemic Events Primary PCI for STEMI (N = 60)Primary PCI for STEMI (N = 60)

Prasugrel: more potent and predictable Prasugrel: more potent and predictable

platelet inhibitionplatelet inhibition

--20.020.0

0.00.0

20.020.0

40.040.0

60.060.0

80.080.0

100.0100.0

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

ati

on

(%

)In

hib

itio

n o

f P

late

let

Ag

gre

gati

on

(%

)

Response to PrasugrelResponse to PrasugrelResponse to ClopidogrelResponse to Clopidogrel

Clopidogrel Responder

Clopidogrel Non-responder

*Responder = ≥25% IPA at 4 and 24 h

Inte

rpati

en

tV

ari

ab

ilit

y

Inte

rpati

en

tV

ari

ab

ilit

y

Brandt JT et al. Am Heart J. 2007;153:66.e9-e16.

11

Prasugrel: Phase II EfficacyPrasugrel: Phase II Efficacy

4.0%

5.7%

7.0%6.5%

7.9%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

Clop Pras 40/7.5 60/10 60/15

P= NS

20/254 37/650 14/199 13/200 10/251R/N

RR=0.72 [0.4,1.2]

P = 0.23

Prasugrel LD/MDTreatment Group

Wiviott SD Circulation 2005

MI at

30 d

ays

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81

(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32

(1.03-1.68)P=0.03

Prasugrel

Clopidogrel1.8

2.4

13,608 Patients with ACS and Planned PCI Randomized to Prasugrel (60/10) vs. Clopidogrel (300/75)

CV Death / MI / Stroke

TIMI Major Non-CABG Bleeds

Wiviott SD et al. NEJM 2007;357:2001-15

7/2009

PROVE IT PROVE IT –– TIMI 22TIMI 22

00 33 1818 2121 2424 2727 303066 99 1212 1515

Death

or

Majo

r C

V E

ven

ts (

%)

Months of Follow-up

Pravastatin 40 mgPravastatin 40 mg(avg achieved LDL = 95 mg/dl)(avg achieved LDL = 95 mg/dl)

Atorvastatin 80 mgAtorvastatin 80 mg(avg achieved LDL = 62 mg/dl)(avg achieved LDL = 62 mg/dl)

16% RR16% RR

(P = 0.005)(P = 0.005)

3030

2525

2020

1515

1010

55

00

Cannon et al. NEJM 2003; 350: 1495

Circulation 2004;110:227-239

Academic Leadership (2)

• Develop Study Design– Study population

– Timing of intervention

– Control arm

– Background therapy

– Endpoint(s) and timing of ascertainment

– Statistical analysis plan

• Develop Key Trial Documents– Protocol

– Case Report Form

– Clinical Events Committee (CEC) Charter

– Data Safety and Monitoring Board (DSMB) Charter

14

Academic Leadership (3)

• Study Startup– Country & site selection

• Applicability to U.S.

• Acceptability to other countries

• Cost

– Steering Committee of National Lead Investigators

– Investigator Training

15

U.S. Enrollment

59

13

83

71

1 411

30

512

0

10

20

30

40

50

60

70

80

90

9B 17 18 22 25 28 36 38 42 46

TIMI Study Group Trial

En

roll

me

nt

fro

m U

.S.

(%)

3491324113,6086560349120,5064162222015,0783002N

Ranolaz.

vs. pbo

NSTE-ACS

Prasugrel

vs. clopi

ACS

Phase II:

OTAM

vs. UFH

NSTE-ACS

INV

vs. CONS

NSTE-ACS

Atorva

vs. Prava

Post

ACS

ENOX

vs. UFH

STEMI

w/ lytic

Clopi

vs. pbo

STEMI

w/ lytic

Phase II:

Rivarox.

vs. pbo

nPA

vs. TPA

Hirudin

vs. Heparin

Intervent.

Post

ACS

STEMI

w/ lytic

STEMI

w/ lytic

Population

K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke)

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,521

8,628

8,362

8,460

8,124

Days after randomisation

6,743

6,743

5,096

5,161

4,047

4,147

0 60 120 180 240 300 360

12

1110

9

87

65

432

10

13

Cu

mu

lati

ve i

ncid

en

ce (

%)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Wallentin L et al. NEJM 2009;361:1045-57.

Academic Leadership (4)

• Monitor Study Progress– Enrollment

– Changes in medical landscape

– Aggregate event rates (efficacy & safety)

– Retention

• Lead Study Analysis– Data analysis

– Separate copy of the database

– Rapidly move to presentation of data at scientific meeting

– Drafting of primary manuscript and subsequent analyses

18

CV

death

, M

I o

r str

oke

Days

CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

PPI Use & Thienopyridines

O’Donoghue M et al. Lancet 2009.

Clinical Events Committee

• Physician Staff– Stephen D. Wiviott, MD – Director

– Board-certified cardiologists, neurologists, oncologists, endocrinologists, hepatologists

– Seamless integration with eCRF

• Adjudicate Key Endpoints– Efficacy & Safety, including non-cardiovascular events

– 2 Independent reviewers with 3rd as needed

– Consistent application of definitions

– High-level of granularity

20

Cum

ula

tive Incid

ence (

%)

3.4

0.40.1

6.4

0

2.5

0.30

4.8

0.10

1

2

3

4

5

6

7

8

Type 1 Type 2 Type 3 Type 4 Type 5

Universal MI Classification

CLOPIDOGREL

PRASUGREL

29%↓↓↓↓

18%↓↓↓↓

24%↓↓↓↓

-- --0.0015 0.53p <0.0001

1.7

4b 4b

0.8

4a

4a

Spont. Secondary SCD PCI-related Peri-CABG

Efficacy Analysis byEfficacy Analysis by

Universal MI ClassificationUniversal MI Classification

Core Labs – Biomarker

• Laboratory– David A. Morrow, MD, MPH - Director

– 2000 sq ft CLIA-accredited lab with state-of-the-art equipment

• Samples– Baseline

– Follow-up

• Analytes– Existing protein biomarkers

– Discovery using proteomics & metabolomics

• Analysis– Independent risk prediction

– Guiding therapy22

Troponin levels in NSTE-ACS

11.7

3.4 3.7

6

7.5

0

1

2

3

4

5

6

7

8

0 to <0.4 0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0 >9.0

Cardiac Troponin I

Mo

rtali

ty a

t 42 d

ays (

%)

831 174 148 134 50 67

Antman et al. NEJM 1996; 335: 1342

P<0.001

χχχχ2 for trend

N=1404

TIMI IIIBTIMI IIIB

14.5

24.2

16.914.3

0

5

10

15

20

25

30

TnT - TnT +

D/M

I/A

CS

at

6 m

os

(%)

CONS INV

Troponin T: Treatment Interaction

TnT cut point = 0.01 ng/ml (54% of Pts TnT +)

OR=0.52OR=0.52p<0.001p<0.001

p=NSp=NS

N= 414 396 463 495

InteractionInteractionP<0.001P<0.001

Cannon NEJM 2001; 344: 1879

17.6

21.8 22.6 22.6

26.4

0

5

10

15

20

25

30

Q1 Q2 Q3 Q4 Q5

MV Model: age, index MV Model: age, index dxdx, prior MI, DM, renal, Rx arm, 30d LDL, 30d CRP, prior MI, DM, renal, Rx arm, 30d LDL, 30d CRP

AdjAdj HR = 1.33 HR = 1.33

(1.01(1.01--1.74)1.74)

Ev

en

t R

ate

(%

)E

ve

nt

Ra

te (

%)

P trend = 0.002P trend = 0.002

654 649 657 654 651

Lp-PLA2 Levels and Risk ofMajor Adverse CV Events

O’Donoghue M et al., Circulation 2006;113:1745

26

Hypothesis Targeting Lp-PLA2 a Key Player in Atherosclerosis

Lumen

Intima

native LDL

carrier of Lp-PLA2

Oxidized LDL

substrate for Lp-PLA2

Sustained

Inflammation

Necrotic Core

Expansion

Leukocyte

Darapladib(Lp-PLA2 inhibitor)

Atheroma

Lp-PLA2

Lp-PLA2

Macphee, Biochem J 1999; Zalewski and Macphee. ATVB. 2005; Shi Atherosclerosis 2007; Kolodgie, ATVB 2006

Core Labs – Pharmacogenetics

• Laboratory– Marc S. Sabatine, MD, MPH - Director

– Multiple core genotyping laboratories at Harvard & MIT

• Genotyping– Candidate genes

– Arrays

• Analysis– Risk prediction

– Response to therapy

27

Hazard Ratio 1.53

(95% CI 1.07-2.19)

P=0.014

8.0

12.1

1064 1009 999 980 870 755 542

Number at Risk:

Days After Randomization

Non-Carrier

395 364 360 348 306 270 181Carrier

CV

De

ath

, M

I, o

r S

tro

ke

(%

)

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

0 30 90 180 270 360 450

Non-carriers

CarriersCYP2C19 Reduced-Function

Allele Carriers

Non-carriers

HR 1.53(95% CI 1.07-2.19)

P=0.014

* Carriers ~30% of the population

CYP2C19 & Clinical Outcomes

Mega JL et al. & Sabatine MS. N Engl J Med 2009;360:354-62.

1477 Patients w/ ACS and planned PCI Rx’d w/ clopidogrel

Hazard Ratio 3.09

(95% CI 1.19-8.00)

P=0.015

0.8

2.6

1014 1004 1001 989 885 765 547

375 368 366 359 316 279 186

De

fin

ite o

r P

rob

ab

le S

ten

tT

hro

mb

os

is (

%)

0

1

2

3

4

0 30 90 180 270 360 450

Number at Risk:

Days After Randomization

Non-Carrier

Carrier

Non-carriers

Carriers

HR 3.09

(95% CI 1.19-8.00)P=0.015

CYP2C19 Reduced-FunctionAllele Carriers

Non-carriers

Plavix Prescribing Information, Revised May 2009

Value Added by ARO

• Internal validity of a clinical trial– Compliance with the protocol

– Data collection & adjudication

– Statistical analyses

• External validity or generalizability of a clinical trial– Hypothesis to be tested

– Study population (including location)

– Endpoints

• Answering additional questions– Well-characterized dataset

– Embedded mechanistic studies

30