baran kw august 28, 2000 kenneth w. baran md for the limit ami investigators st. paul heart clinic,...

Baran KW August 28, 2000

Kenneth W. Baran MDKenneth W. Baran MDfor the LIMIT AMI Investigatorsfor the LIMIT AMI Investigators

St. Paul Heart Clinic, St. Paul, MN, USASt. Paul Heart Clinic, St. Paul, MN, USA

Sponsor: Genentech Inc., South San Francisco, Sponsor: Genentech Inc., South San Francisco, USAUSA

LIMIT AMILIMIT AMI((LILImitation of mitation of MMyocardial yocardial IInjury following njury following

TThrombolysis in hrombolysis in AAcute cute MMyocardial yocardial IInfarction)nfarction)

An angiographic safety and efficacy trial of a An angiographic safety and efficacy trial of a novel anti-CD18 therapy in acute myocardial novel anti-CD18 therapy in acute myocardial infarction in conjunction with thrombolysisinfarction in conjunction with thrombolysis


rhuMAb CD18rhuMAb CD18

Antibody fragment [F(ab’)Antibody fragment [F(ab’)22]] Single dose administered as IV bolusSingle dose administered as IV bolus Plasma half-life 7 to 10 hoursPlasma half-life 7 to 10 hours 90% CD18-containing receptor 90% CD18-containing receptor

saturation maintained for ~ 24 hours saturation maintained for ~ 24 hours (0.5 mg/kg) and ~ 48 hours (2.0 mg/kg)(0.5 mg/kg) and ~ 48 hours (2.0 mg/kg)


The LIMIT AMI Trial of rhuMAb CD18The LIMIT AMI Trial of rhuMAb CD18

• ST elevation > 2 leads• Symptoms < 12 hrs• No prior coronary surgery• No cardiogenic shock• No thrombolytic exclusions• No major immune-related risks

ScreeningScreeningScreeningScreening





Randomization 1:1:1 with administration prior to full-dose tPARandomization 1:1:1 with administration prior to full-dose tPARandomization 1:1:1 with administration prior to full-dose tPARandomization 1:1:1 with administration prior to full-dose tPA

2 mg/kg 0.5 mg/kg Placebo+ usual care including aspirin, IV heparin





Coronary angiography 90 minutes from tPA initiationCoronary angiography 90 minutes from tPA initiationCoronary angiography 90 minutes from tPA initiationCoronary angiography 90 minutes from tPA initiation

Randomization 1:1:1 to study drug or placebo then full-dose tPARandomization 1:1:1 to study drug or placebo then full-dose tPARandomization 1:1:1 to study drug or placebo then full-dose tPARandomization 1:1:1 to study drug or placebo then full-dose tPA

2 mg/kg 0.5 mg/kg Placebo

• Corrected TIMI Frame Count, TIMI Flow Grade• TIMI Myocardial Perfusion Grade• Angioplasty ± Gp IIb/IIIa inhibitors as required

+ usual care including aspirin, IV heparin



• Infarct size• sestamibi at rest, day 6-9• CKMB 0-72 hours

• ECG ST segment resolution• 180 minutes

• Fever• Antibiotic use• General Safety

Other endpointsOther endpointsOther endpointsOther endpoints


Statistical AnalysisStatistical Analysis

Efficacy endpoint data analyzed by independent Efficacy endpoint data analyzed by independent and blinded Core Laboratoriesand blinded Core Laboratories

Time windows were used for efficacy endpoints Time windows were used for efficacy endpoints using imputation for missing data where possibleusing imputation for missing data where possible

““As treated” analysis of the evaluable cohortAs treated” analysis of the evaluable cohort Sensitivity analysesSensitivity analyses p values: non parametric testsp values: non parametric tests


ResultsResults

Enrollment from September 1998 to March 2000Enrollment from September 1998 to March 2000 413 subjects randomized413 subjects randomized 394 treated with rhuMAb CD18 or placebo394 treated with rhuMAb CD18 or placebo 19 randomized but not treated 19 randomized but not treated

mainly due to review of exclusion criteriamainly due to review of exclusion criteria

60 centers in US and Canada60 centers in US and Canada


Baseline characteristicsBaseline characteristics

Placebo 0.5 mg/kg 2.0 mg/kg

Age, mean 58.3 58.5 59.6

% Female 33 24 24

BMI, mean 29 28 29

% Previous MI 16 15 15

% Anterior MI 47 40 41

Time from pain onsetto tPA, mean (median)

3.6 (2.9) 3.3 (2.7) 3.4 (2.6)

% 0-6 hours 90 90 87


Concomitant Concomitant InterventionsInterventions


% Any PTCA 67 78 67

% PTCA with stent 60 71 61

% Any IIb/IIIa Day 1-2 27 29 30

% Plavix Day 1-2 58 61 55

% CABG 13 9 12


Change in peripheral Change in peripheral venous blood white cell venous blood white cell counts - mean valuescounts - mean values

8

10

12

14

16

18

0 24 48 72

Time (hours)

WB

C (

x100

0)



Primary Endpoint: Corrected Primary Endpoint: Corrected TIMI Frame Count @90 TIMI Frame Count @90

minutesminutesC

orr

ec

ted

TIM

I Fra

me

Co

un

t

10

20

30

40

50

60

70

80

90

100


Treatment Received

p = 0.2 p = 1.0

meanmeanmedianmedian


% TIMI Grade 3 flow% TIMI Grade 3 flow

0

10

20

30

40

50

60

70


% T

IMI

3 F

low

Expected per protocol: placebo 55%, treatment 70%

N=114 N=111 N=108

66%

58%63%


TIMI Flow Grades (all grades)TIMI Flow Grades (all grades)

0%10%20%30%40%50%60%70%80%90%

100%


% T

IMI

Flo

w

TIMI 3TIMI 2TIMI 1TIMI 0

N=114 N=111 N=108


TIMI Myocardial Perfusion TIMI Myocardial Perfusion GradeGrade

0%10%20%30%40%50%60%70%80%90%

100%


TIM

I P

erfu

sion

Gra

de

%

Grade 2,3Grade 0,1

N=107 N=101 N=102


ECG ST segment elevation ECG ST segment elevation resolutionresolution

at 180 minutesat 180 minutes

0%10%20%30%40%50%60%70%80%90%

100%


% E

CG

ST

Seg

men

t E

leva

tion

R

esol

utio

n

=>70%30 to <70%< 30%

N=109 N=103 N=106


Infarct Size by sestamibi Infarct Size by sestamibi scan Day 6-9scan Day 6-9

LV

de

fect

%

0

10

20

30

40

50

60

70

80


Treatment Received

meanmeanmedianmedian


Clinical outcomes at Day Clinical outcomes at Day 3030

Placebo(n=134)

0.5 mg/kg(n=129)

2.0 mg/kg(n=131)

Death 5.9% 3.1% 5.3%

Recurrent MI* 3.7% 2.3% 3.1%

CHF** 6.7% 7.8% 12.2%

Death/MI/CHF*** 11.9% 10.9% 15.3%

* Adverse Event report, complications CRF, or readmission diagnosis** CHF Killip III or IV, or CHF readmission, or CHF Adverse Event (serious or severe or cardiogenic shock)*** Death, CHF or recurrent AMI


Safety - fever and Safety - fever and antibiotic useantibiotic use

0

5

10

15

20

25

30


%

Fever all AE T => 101.5F Antibiotic Day 1-7

N=129 N=131N=134


Safety - Likely bacterial Safety - Likely bacterial infectionsinfections

02468

1012141618202224


%

Mild-moderate Severe

N=134 N=129 N=131

95% CI


General SafetyGeneral Safety

No effect on fibrinogen or d-dimer levelsNo effect on fibrinogen or d-dimer levels No increase in “serious and life-threatening No increase in “serious and life-threatening

bleeding”bleeding” Slight trend towards increases in overall bleeding Slight trend towards increases in overall bleeding

adverse events (adverse events ( 10%) and transfusions ( 10%) and transfusions ( 20%) 20%) Small number of mild thrombocytopenia cases Small number of mild thrombocytopenia cases

< 100,000/mm< 100,000/mm33: placebo 2 cases, 0.5 mg/kg 1 case, : placebo 2 cases, 0.5 mg/kg 1 case, 2.0 mg/kg 5 cases2.0 mg/kg 5 cases

No specific anti-rhuMAb CD18 antibody formation*No specific anti-rhuMAb CD18 antibody formation*

* Except for one 30 Day sample with possible low level anti-CDR activity still under investigation.


ConclusionsConclusions

rhuMAb CD18, in conjunction with rhuMAb CD18, in conjunction with thrombolysis, had no effect on coronary flow, thrombolysis, had no effect on coronary flow, infarct size or ECG ST segment resolutioninfarct size or ECG ST segment resolution

These results are consistent with the findings of These results are consistent with the findings of another Phase II study of an anti-CD18 antibody another Phase II study of an anti-CD18 antibody in Primary Angioplasty on infarct size (HALT in Primary Angioplasty on infarct size (HALT MI*)MI*)

There may be non CD18- dependent leukocyte There may be non CD18- dependent leukocyte binding and transmigration in AMIbinding and transmigration in AMI

Leukocytes may not be key to ischemia-Leukocytes may not be key to ischemia-reperfusion injury in human AMIreperfusion injury in human AMI

* Faxon D, Annual Meeting of the American Heart Association, Atlanta, November 1999

baran kw august 28, 2000 kenneth w. baran md for the limit ami investigators st. paul heart clinic,...

Documents

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cardiogenic shock

prior coronary surgery