Transcript Slide 1

Drotrecogin alfa (activated)
Randy Wax, MD, FRCP(C)
Staff Intensivist and Education Director
Mount Sinai Hospital
Department of Medicine
University of Toronto
Objectives
 Understand
trial design of PROWESS
 Evaluate the impact of the single protocol
amendment during the trial
 Evaluate the overall benefit of activated Protein
C for severe sepsis
 Consider the results of sub-group analyses
 Safety profile during PROWESS
 Some real case examples
A new understanding of sepsis pathophysiology
Sepsis
 Coagulation
 Fibrinolysis
Endothelial
injury
Organ failure
Death
 Inflammation
Study design
Randomized,
double-blind, placebo-controlled
study in adult patients with severe sepsis
 164 sites in 11 countries
 Planned 2280 patients
Single-dose study
 24 mg/kg/hr drotrecogin alfa (activated)
infusion or placebo for 96 hours
6510.01
Study design
 Primary
objective
 Effect on 28-day all-cause mortality
 Secondary objectives
 Safety
 Effect on organ function
 Pharmacokinetics and pharmacodynamics
Study Design
28-day all-cause mortality assessed
24 hr Start of study drug infusion
to meet
entry
criteria
Routine Patient Care
24 hr from
meeting entry
criteria to start
of drug
W. Macias, Eli Lilly
End of 96-hour infusion
of study drug
Study design

Inclusion criteria = Severe Sepsis
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Known or suspected infection
Evidence of a systemic response to infection
• Three or four of the criteria defining SIRS
One or more sepsis-induced organ dysfunctions
• Cardiovascular
• Respiratory
• Renal
• Hematologic
• Metabolic acidosis
Study design
 Exclusion
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criteria
High risk of bleeding - similar risk assessment as for
systemic heparin
Systemic heparin and anti-platelet agents (except
ASA)
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Platelet count <30,000/mm3
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End stage liver disease
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End stage renal disease (on RRT)
Study design
 Exclusion
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criteria
HIV with CD4 count <=50/mm3
Bone marrow, lung, liver, pancreas, or small bowel
transplantation
Organ failure >24 hours in duration at time all entry
criteria met
Study design
 Exclusion
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criteria
Moribund and where death is imminent
Not expected to survive 28 days due to underlying
non-sepsis related condition
Patient advance directive to withhold life-support
with the exception of CPR
Family not committed to aggressive management of
patient
Primary physician not committed to aggressive
management of patient
Prowess Study: Amendment
Minor Changes to Inclusion Criteria
 Original
protocol: Allowed respiratory organ failure
(PaO2/FiO2) to be calculated by % saturation
 Amended
protocol: Required respiratory organ failure
(PaO2/FiO2) to be calculated by blood gas
 Original
protocol: Allowed metabolic organ failure to be
either low pH or elevated lactic acid concentration
 Amended
protocol: Required metabolic organ failure to be
both low pH and elevated lactic acid concentration
W. Macias, Eli Lilly
Prowess Study: Changes to Exclusion Criteria
with Amended Protocol
 Original
protocol: "Patients with high probability of dying from
underlying non-sepsis condition within the 28-day study period were
excluded."
 Amended

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protocol: clarified the following exclusion criteria:
"Known or suspected portal hypertension" changed to include clinical
manifestations – esophageal varices, chronic jaundice, cirrhosis, or chronic
ascites
"Not expected to survive 28 days given preexisting medical condition"
changed to "… preexisting uncorrectable medical condition." Examples
were provided. Enrollment of patients with malignancy must have had prior
approval by coordinating center
W. Macias, Eli Lilly
Prowess Study: Changes to Exclusion Criteria
with Amended Protocol
 The
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following populations were excluded:
Patients with bone marrow, lung, liver, pancreas, or small bowel
transplantation
Patients who were moribund and death was imminent
Patients whose family had not committed to aggressive
management of patient
Patients whose 1st organ failure >24 hours in duration at time of
meeting all inclusion and exclusion criteria
W. Macias, Eli Lilly
Timeline of Study
Date
7/28/1998
3/05/1999
6/06/1999
10/ 08/1999
6/28/2000
7/26/2000
W. Macias, Eli Lilly
Event
First patient enrolled
Protocol amendment approved by Lilly
First patient enrolled under amendment
First interim analysis by independent DSMB
(Efficacy stopping rules based on method of
O’Brien -Fleming)
Recommendation: “Continue the trial”
Second interim analysis by independent
DSMB
Recommendation: “Stop trial for highly
statistically significant results”
Last patient enrolled completes study
http://www.fda.gov/ohrms/dockets/ac/01/slides/3797s1_02_Forsyth/
http://www.fda.gov/ohrms/dockets/ac/01/slides/3797s1_02_Forsyth/
http://www.fda.gov/ohrms/dockets/ac/01/slides/3797s1_02_Forsyth/
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28 day Mortality
2-Sided p-Value
Relative Risk Reduction
Absolute Risk Reduction
Primary Analysis Results
0.005
19.4%
6.1% (NNT=16)
35
30.8%
30
25
24.7%
20
15
10
5
0
Drotrecogin
Alfa
(activated)
(N=850)
Placebo
(N=840)
Survival Analysis (Intention to treat)
Percent Survivors
100
90
Drotrecogin Alfa (activated)
(N=850)
80
Placebo
(N=840)
70
p=0.006 (stratified log-rank test)
0
0
W. Macias, Eli Lilly
7
14
21
Days from Start of Infusion to Death
28
PROWESS: Mortality by APACHE II Quartile
Drotrecogin
Alfa
N (activated) Placebo
Overall
1690
24.7
30.8
1st Quartile
433
15.1
12.1
2nd Quartile
440
22.5
25.7
3rd Quartile
366
23.5
35.8
4th Quartile
451
38.1
49.0
1.25
0.5
1.67
0.6 0.7 0.8 0.9 1
2
Relative Risk of Death (Point Estimate and 95% CI)
W. Macias, Eli Lilly
from Baseline
Median Percent Change
PROWESS Study: D-Dimer
Percent Change from Baseline
15
10
5
0
-5
-10
-15
-20
-25
-30
Drotrecogin Alfa
(activated) (N=770)
*
Placebo (N=729)
2
*
6
7
*
p<0.05
*
*
Pre1
infusion
*
*
*
3
4
5
Study Day
Treatment groups compared using ranked ANOVA.
W. Macias, Eli Lilly
PROWESS Study: Thrombin-Antithrombin Complex –
Percent Change from Baseline
Treatment groups compared using ranked ANOVA
W. Macias, Eli Lilly
RPOWESS Study:
Plasminogen Activator Inhibitor-1 –
Percent Change from Baseline
Treatment groups compared using ranked ANOVA
W. Macias, Eli Lilly
PROWESS Study: Interleukin-6
Change from Baseline
Treatment groups compared using ranked ANOVA
W. Macias, Eli Lilly
Xigris (Drotrecogin Alfa (activated)) Approved in
United States with the Following
Indication Statement:
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Xigris is indicated for the reduction of mortality in adult patients with
severe sepsis (sepsis associated with acute organ dysfunction) who
have a high risk of death (e.g., as determined by APACHE II score,
see Clinical Trial Section).
Efficacy has not been established in adult patients with severe
sepsis and lower risk of death.
Safety and efficacy have not been established in pediatric patients
with severe sepsis.
W. Macias, Eli Lilly
Intensive DOCTOR care
 Time
to take a breath…
http://www.fda.gov/ohrms/dockets/ac/01/slides/3797s1_02_Forsyth/
http://www.fda.gov/ohrms/dockets/ac/01/slides/3797s1_02_Forsyth/
http://www.fda.gov/ohrms/dockets/ac/01/slides/3797s1_02_Forsyth/
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http://www.fda.gov/ohrms/dockets/ac/01/slides/3797s1_02_Forsyth/
Reference Diseases
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Incidence in US (cases per 100,000)
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Colon cancer
Breast cancer
AIDS
Congestive heart failure
Sepsis
50
110
17
~130
~300
Number of deaths in US each year
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Acute myocardial infarction
Severe sepsis
211,000
215,000
Slide presentation, D. Angus, SCCM 2001
Hospital costs associated with sepsis
 Average
hospital LOS - 19.6 d
 Average
hospital cost - $22,100
 National
costs - $16.7 billion
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Neonates - $1.1 billion
> 65 yrs - $8.7 billion
Slide presentation, D. Angus, SCCM 2001
Resolution of organ failure
 Patients
treated with APC had quicker resolution
of:
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Cardiovascular failure
Respiratory failure
 Patients
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treated with APC had more
vasopressor-free days (20.06 versus 18.78 days,
p=0.014)
ventilator-free days (14.33 versus 13.24 days,
p=0.049)
APC and organ failure
1 organ failure
2 or more organ failures
N=419
N=1271
Mean age 61
Mean age 58
Mean APACHE II = 26
22
RRR 0.92 (0.63-1.34)
RRR 0.78 (0.66-0.93)
Bleeding 2.8% vs 1%
Bleeding 3.8% vs 2.4%
Dhainaut et al. ESICM
http://www.fda.gov/ohrms/dockets/ac/01/slides/3797s1_02_Forsyth/
Functional status
 No
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difference in independent ADLs
Bathing
Dressing
Toilet care
Transferring
Continence
Feeding
Hospital costs/resources
 For
survivors and non-survivors, use of APC did
not increase:
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Hospital and ICU length of stay
TISS points
Estimated costs (not including drug)
Clermont et al., AJRCCM 163(5):A802
Cost effectiveness/utility
 $27,400/QALY
(High risk)—Angus
 $46,560/QALY vs. $32,872 (High risk)—Manns
 CDN$67,700/QALY vs. CDN$31,500/QALY
(High risk)--Coyle
Health economics
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Autologous BMT for
relapsed Hodgkins
Adjuvant tamoxifen in
premenopausal ERwomen
Dialysis for ESRD
ICD vs. amiodarone
Xigris vs. standard of
care (high risk)
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$421,000
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$57,000-$214,000
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$40,000
 $27,400-$32,900
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$23,000
Conclusions
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Long-term follow up?
 Cost-effectiveness analysis will have to take into
account:
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Money saved by health care system
Benefits to quality of life (cost-utility analysis)
Comparison to other public health problems/solutions
Compare/combine with other therapies? (e.g., steroids)
 Await results of randomized trial in severe sepsis
patients with low severity of illness scores