Kenneth W. Baran MD
for the LIMIT AMI Investigators
St. Paul Heart Clinic, St. Paul, MN, USA
Sponsor: Genentech Inc., South San Francisco, USA
LIMIT AMI
(LImitation of Myocardial Injury following Thrombolysis in Acute Myocardial Infarction)
An angiographic safety and efficacy trial of a novel anti-CD18 therapy in acute myocardial infarction in conjunction with thrombolysis
rhuMAb CD18
Antibody fragment [F(ab’)2]
Single dose administered as IV bolus
Plasma half-life 7 to 10 hours
? 90% CD18-containing receptor saturation maintained for ~ 24 hours (0.5 mg/kg) and ~ 48 hours (2.0 mg/kg)
The 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
Screening
The 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
Screening
Randomization 1:1:1 with administration prior to full-dose tPA
+ usual care including aspirin, IV heparin
The 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
Screening
Coronary angiography 90 minutes from tPA initiation
Randomization 1:1:1 to study drug or placebo then full-dose tPA
Corrected TIMI Frame Count, TIMI Flow Grade
TIMI Myocardial Perfusion Grade
Angioplasty ± Gp IIb/IIIa inhibitors as required
+ usual care including aspirin, IV heparin
The LIMIT AMI Trial of rhuMAb CD18
Infarct size
sestamibi at rest, day 6-9
CKMB 0-72 hours
ECG ST segment resolution
180 minutes
Fever
Antibiotic use
General Safety
Other endpoints
Statistical Analysis
Efficacy endpoint data analyzed by independent and blinded Core Laboratories
Time windows were used for efficacy endpoints using imputation for missing data where possible
“As treated” analysis of the evaluable cohort
Sensitivity analyses
p values: non parametric tests
Results
Enrollment from September 1998 to March 2000
413 subjects randomized
394 treated with rhuMAb CD18 or placebo
19 randomized but not treated
mainly due to review of exclusion criteria
60 centers in US and Canada
Baseline characteristics
Concomitant Interventions
Change in peripheral venous blood white cell counts - mean values
Primary Endpoint: Corrected TIMI Frame Count @90 minutes
Corrected TIMI Frame Count
10
20
30
40
50
60
70
80
90
100
Placebo
0.5 mg/kg
2.0 mg/kg
Treatment Received
p = 0.2
p = 1.0
% TIMI Grade 3 flow
Expected per protocol: placebo 55%, treatment 70%
N=114
N=111
N=108
66%
58%
63%
TIMI Flow Grades (all grades)
N=114
N=111
N=108
TIMI Myocardial Perfusion Grade
N=107
N=101
N=102
ECG ST segment elevation resolution at 180 minutes
N=109
N=103
N=106
Infarct Size by sestamibi scan Day 6-9
LV defect %
0
10
20
30
40
50
60
70
80
Placebo
0.5 mg/kg
2.0 mg/kg
Treatment Received
Clinical outcomes at Day 30
* 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 antibiotic use
N=129
N=131
N=134
Safety - Likely bacterial infections
N=134
N=129
N=131
95% CI
General Safety
No effect on fibrinogen or d-dimer levels
No increase in “serious and life-threatening bleeding”
Slight trend towards increases in overall bleeding adverse events (? 10%) and transfusions (? 20%)
Small number of mild thrombocytopenia cases < 100,000/mm3: placebo 2 cases, 0.5 mg/kg 1 case, 2.0 mg/kg 5 cases
No specific anti-rhuMAb CD18 antibody formation*
* Except for one 30 Day sample with possible low level anti-CDR activity still under investigation.
Conclusions
rhuMAb CD18, in conjunction with thrombolysis, had no effect on coronary flow, infarct size or ECG ST segment resolution
These results are consistent with the findings of another Phase II study of an anti-CD18 antibody in Primary Angioplasty on infarct size (HALT MI*)
There may be non CD18- dependent leukocyte binding and transmigration in AMI
Leukocytes may not be key to ischemia-reperfusion injury in human AMI
* Faxon D, Annual Meeting of the American Heart Association, Atlanta, November 1999