Drotrecogin alfa (activated) Randy Wax, MD, FRCP(C) Staff Intensivist and Education Director Mount Sinai Hospital Department of Medicine University of

Drotrecogin alfa (activated)Drotrecogin alfa (activated)

Randy Wax, MD, FRCP(C)Randy Wax, MD, FRCP(C)Staff Intensivist and Education DirectorStaff Intensivist and Education Director

Mount Sinai HospitalMount Sinai HospitalDepartment of MedicineDepartment of Medicine

University of TorontoUniversity of Toronto

ObjectivesObjectives

Understand trial design of PROWESSUnderstand trial design of PROWESS Evaluate the impact of the single protocol Evaluate the impact of the single protocol

amendment during the trialamendment during the trial Evaluate the overall benefit of activated Protein Evaluate the overall benefit of activated Protein

C for severe sepsisC for severe sepsis Consider the results of sub-group analysesConsider the results of sub-group analyses Safety profile during PROWESSSafety profile during PROWESS Some real case examplesSome real case examples

A new understanding of sepsis pathophysiologyA new understanding of sepsis pathophysiology

Organ failureOrgan failure

SepsisSepsis

CoagulationCoagulation Fibrinolysis Fibrinolysis InflammationInflammationEndothelial Endothelial

injuryinjury

DeathDeath

Study designStudy designRandomized, double-blind, placebo-controlled Randomized, double-blind, placebo-controlled

study in adult patients with severe sepsisstudy in adult patients with severe sepsis164 sites in 11 countries164 sites in 11 countriesPlanned 2280 patientsPlanned 2280 patients

Single-dose studySingle-dose study24 24 g/kg/hrg/kg/hr drotrecogin alfa (activated) drotrecogin alfa (activated)

infusion or placebo for 96 hours infusion or placebo for 96 hours

6510.01

Study designStudy design

Primary objectivePrimary objective Effect on 28-day all-cause mortalityEffect on 28-day all-cause mortality

Secondary objectivesSecondary objectives SafetySafety Effect on organ functionEffect on organ function Pharmacokinetics and pharmacodynamicsPharmacokinetics and pharmacodynamics

Study DesignStudy Design

Start of study drug infusion24 hr to meet

entry criteria

End of 96-hour infusion of study drug

28-day all-cause mortality assessed

Routine Patient Care

24 hr from meeting entry criteria to start

of drug

W. Macias, Eli Lilly


Inclusion criteria = Severe SepsisInclusion criteria = Severe Sepsis Known or suspected infectionKnown or suspected infection Evidence of a systemic response to infectionEvidence of a systemic response to infection

• Three or four of the criteria defining SIRS Three or four of the criteria defining SIRS One or more sepsis-induced organ dysfunctionsOne or more sepsis-induced organ dysfunctions

• CardiovascularCardiovascular• RespiratoryRespiratory• RenalRenal• HematologicHematologic• Metabolic acidosisMetabolic acidosis


Exclusion criteriaExclusion criteria High risk of bleeding - similar risk assessment as for High risk of bleeding - similar risk assessment as for

systemic heparinsystemic heparin Systemic heparin and anti-platelet agents (except Systemic heparin and anti-platelet agents (except

ASA)ASA) Platelet count <30,000/mmPlatelet count <30,000/mm33

End stage liver diseaseEnd stage liver disease End stage renal disease (on RRT)End stage renal disease (on RRT)


Exclusion criteriaExclusion criteria HIV with CDHIV with CD44 count <=50/mm count <=50/mm33

Bone marrow, lung, liver, pancreas, or small bowel Bone marrow, lung, liver, pancreas, or small bowel transplantationtransplantation

Organ failure >24 hours in duration at time all entry Organ failure >24 hours in duration at time all entry criteria metcriteria met


Exclusion criteriaExclusion criteria Moribund and where death is imminentMoribund and where death is imminent Not expected to survive 28 days due to underlying Not expected to survive 28 days due to underlying

non-sepsis related conditionnon-sepsis related condition Patient advance directive to withhold life-support Patient advance directive to withhold life-support

with the exception of CPRwith the exception of CPR Family not committed to aggressive management of Family not committed to aggressive management of

patientpatient Primary physician not committed to aggressive Primary physician not committed to aggressive

management of patientmanagement of patient

Prowess Study: Amendment Prowess Study: Amendment Minor Changes to Inclusion CriteriaMinor Changes to Inclusion Criteria

Original protocol:Original protocol: Allowed respiratory organ failure Allowed respiratory organ failure (PaO(PaO22/FiO/FiO22) to be calculated by % saturation) to be calculated by % saturation

Amended protocol: Amended protocol: Required respiratory organ failure Required respiratory organ failure (PaO(PaO22/FiO/FiO22) to be calculated by blood gas) to be calculated by blood gas

Original protocol:Original protocol: Allowed metabolic organ failure to be Allowed metabolic organ failure to be either low pH or elevated lactic acid concentrationeither low pH or elevated lactic acid concentration

Amended protocol: Amended protocol: Required metabolic organ failure to be Required metabolic organ failure to be both low pH both low pH andand elevated lactic acid concentration elevated lactic acid concentration


Prowess Study: Changes to Exclusion Criteria Prowess Study: Changes to Exclusion Criteria with Amended Protocolwith Amended Protocol

Original protocol:Original protocol: "Patients with high probability of dying from "Patients with high probability of dying from underlying non-sepsis condition within the 28-day study period were underlying non-sepsis condition within the 28-day study period were excluded."excluded."

Amended protocol:Amended protocol: clarified the following exclusion criteria: clarified the following exclusion criteria: "Known or suspected portal hypertension""Known or suspected portal hypertension" changed to include clinical changed to include clinical

manifestations – esophageal varices, chronic jaundice, cirrhosis, or chronic manifestations – esophageal varices, chronic jaundice, cirrhosis, or chronic ascitesascites

"Not expected to survive 28 days given preexisting medical condition" "Not expected to survive 28 days given preexisting medical condition" changed to "…changed to "… preexisting uncorrectable medical condition." Examples preexisting uncorrectable medical condition." Examples were provided. Enrollment of patients with malignancy must have had prior were provided. Enrollment of patients with malignancy must have had prior approval by coordinating centerapproval by coordinating center


Prowess Study: Changes to Exclusion Criteria Prowess Study: Changes to Exclusion Criteria with Amended Protocolwith Amended Protocol

The following populations were excluded:The following populations were excluded: Patients with bone marrow, lung, liver, pancreas, or small bowel Patients with bone marrow, lung, liver, pancreas, or small bowel

transplantationtransplantation

Patients who were moribund and death was imminent Patients who were moribund and death was imminent

Patients whose family had not committed to aggressive management Patients whose family had not committed to aggressive management of patientof patient

Patients whose 1st organ failure >24 hours in duration at time of Patients whose 1st organ failure >24 hours in duration at time of

meeting all inclusion and exclusion criteriameeting all inclusion and exclusion criteria


Timeline of StudyTimeline of StudyDate Event 7/28/1998 First patient enrolled 3/05/1999 Protocol amendment approved by Lilly 6/06/1999 First patient enrolled under amendment 10/ 08/1999 First interim analysis by independent DSMB

(Efficacy stopping rules based on method of O’Brien -Fleming) Recommendation: “Continue the trial”

6/28/2000 Second interim analysis by independent DSMB Recommendation: “Stop trial for highly statistically significant results”

7/26/2000 Last patient enrolled completes study


http://www.fda.gov/ohrms/dockets/ac/01/slides/3797s1_02_Forsyth/






28 day Mortality28 day Mortality

0

5

10

15

20

25

30

3530.8%

24.7%

Primary Analysis Results2-Sided p-Value 0.005Relative Risk Reduction 19.4%Absolute Risk Reduction 6.1% (NNT=16)

Placebo(N=840)

DrotrecoginAlfa

(activated)(N=850)


Survival Analysis (Intention to treat)Survival Analysis (Intention to treat)

0 7 14 21 28

70

80

90

100

Days from Start of Infusion to Death

Per

cen

t S

urv

ivo

rs

p=0.006 (stratified log-rank test)0

Placebo(N=840)

Drotrecogin Alfa (activated) (N=850)


PROWESS: Mortality by APACHE II QuartilePROWESS: Mortality by APACHE II Quartile

Overall

1st Quartile

2nd Quartile

3rd Quartile

4th Quartile

1690

433

440

366

451

30.8

12.1

25.7

35.8

49.0

24.7

15.1

22.5

23.5

38.1

Drotrecogin Alfa N (activated) Placebo

0.5 0.6 0.7 0.8 1 1.25 1.67 20.9Relative Risk of Death (Point Estimate and 95% CI)


PROWESS Study: D-DimerPROWESS Study: D-DimerPercent Change from BaselinePercent Change from Baseline

Treatment groups compared using ranked ANOVA.

-30

-25

-20

-15

-10

-5

0

5

10

15

Placebo (N=729)

Drotrecogin Alfa(activated) (N=770)

7654321Pre-infusion

Study Day

* p<0.05

*

***

*

**

Med

ian

Per

cen

t C

han

ge

fro

m B

asel

ine


PROWESS Study: Thrombin-Antithrombin Complex – PROWESS Study: Thrombin-Antithrombin Complex – Percent Change from BaselinePercent Change from Baseline

Treatment groups compared using ranked ANOVAW. Macias, Eli Lilly

RPOWESS Study: RPOWESS Study: Plasminogen Activator Inhibitor-1 – Plasminogen Activator Inhibitor-1 –

Percent Change from BaselinePercent Change from Baseline

Treatment groups compared using ranked ANOVA W. Macias, Eli Lilly

PROWESS Study: Interleukin-6 PROWESS Study: Interleukin-6 Change from BaselineChange from Baseline

Treatment groups compared using ranked ANOVA W. Macias, Eli Lilly

XigrisXigris (Drotrecogin Alfa (activated)) Approved in (Drotrecogin Alfa (activated)) Approved in United States with the Following United States with the Following

Indication Statement:Indication Statement:

Xigris is indicated for the reduction of mortality in adult patients with Xigris is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (e.g., as determined by APACHE II score, have a high risk of death (e.g., as determined by APACHE II score, see Clinical Trial Section). see Clinical Trial Section).

Efficacy has not been established in adult patients with severe Efficacy has not been established in adult patients with severe sepsis and lower risk of death. sepsis and lower risk of death.

Safety and efficacy have not been established in pediatric patients Safety and efficacy have not been established in pediatric patients with severe sepsis.with severe sepsis.


Intensive DOCTOR care Intensive DOCTOR care

Time to take a breath…Time to take a breath…






Reference DiseasesReference Diseases

Incidence in US (cases per 100,000)Incidence in US (cases per 100,000) Colon cancerColon cancer 50 50 Breast cancer Breast cancer 110 110 AIDS AIDS 17 17 Congestive heart failure Congestive heart failure ~130~130 Sepsis Sepsis ~300~300

Number of deaths in US each yearNumber of deaths in US each year Acute myocardial infarctionAcute myocardial infarction 211,000 211,000 Severe sepsisSevere sepsis 215,000 215,000

Slide presentation, D. Angus, SCCM 2001

Hospital costs Hospital costs associatedassociated with sepsis with sepsis

Average hospital LOS - 19.6 dAverage hospital LOS - 19.6 d

Average hospital cost - $22,100Average hospital cost - $22,100

National costs - $16.7 billionNational costs - $16.7 billion Neonates - $1.1 billionNeonates - $1.1 billion > 65 yrs - $8.7 billion> 65 yrs - $8.7 billion

Slide presentation, D. Angus, SCCM 2001

Resolution of organ failureResolution of organ failure

Patients treated with APC had quicker resolution Patients treated with APC had quicker resolution of:of: Cardiovascular failureCardiovascular failure Respiratory failureRespiratory failure

Patients treated with APC had more Patients treated with APC had more vasopressor-free days (20.06 versus 18.78 days, vasopressor-free days (20.06 versus 18.78 days,

p=0.014) p=0.014) ventilator-free days (14.33 versus 13.24 days, ventilator-free days (14.33 versus 13.24 days,

p=0.049)p=0.049)

APC and organ failureAPC and organ failure

1 organ failure1 organ failure 2 or more organ failures2 or more organ failures

N=419N=419 N=1271N=1271

Mean age 61Mean age 61 Mean age 58Mean age 58

Mean APACHE II = 26Mean APACHE II = 26 2222

RRR 0.92 (0.63-1.34)RRR 0.92 (0.63-1.34) RRR 0.78 (0.66-0.93)RRR 0.78 (0.66-0.93)

Bleeding 2.8% vs 1%Bleeding 2.8% vs 1% Bleeding 3.8% vs 2.4%Bleeding 3.8% vs 2.4%

Dhainaut et al. ESICMDhainaut et al. ESICM


Functional statusFunctional status

No difference in independent ADLsNo difference in independent ADLs BathingBathing DressingDressing Toilet careToilet care TransferringTransferring ContinenceContinence FeedingFeeding

Hospital costs/resourcesHospital costs/resources

For survivors and non-survivors, use of APC did For survivors and non-survivors, use of APC did not increase:not increase: Hospital and ICU length of stayHospital and ICU length of stay TISS pointsTISS points Estimated costs (not including drug)Estimated costs (not including drug)

Clermont et al., AJRCCM 163(5):A802

Cost effectiveness/utilityCost effectiveness/utility

$27,400/QALY (High risk)—Angus$27,400/QALY (High risk)—Angus $46,560/QALY vs. $32,872 (High risk)—Manns$46,560/QALY vs. $32,872 (High risk)—Manns CDN$67,700/QALY vs. CDN$31,500/QALY CDN$67,700/QALY vs. CDN$31,500/QALY

(High risk)--Coyle(High risk)--Coyle

Health economicsHealth economics

Autologous BMT for Autologous BMT for relapsed Hodgkinsrelapsed Hodgkins

Adjuvant tamoxifen in Adjuvant tamoxifen in premenopausal ER- premenopausal ER- womenwomen

Dialysis for ESRDDialysis for ESRD ICD vs. amiodaroneICD vs. amiodarone Xigris vs. standard of Xigris vs. standard of

care (high risk)care (high risk)

$421,000$421,000

$57,000-$214,000$57,000-$214,000

$40,000$40,000 $27,400-$32,900$27,400-$32,900

$23,000$23,000

ConclusionsConclusions

Long-term follow up?Long-term follow up? Cost-effectiveness analysis will have to take into Cost-effectiveness analysis will have to take into

account:account: Money saved by health care systemMoney saved by health care system Benefits to quality of life (cost-Benefits to quality of life (cost-utilityutility analysis) analysis) Comparison to other public health problems/solutionsComparison to other public health problems/solutions

Compare/combine with other therapies? (e.g., steroids)Compare/combine with other therapies? (e.g., steroids) Await results of randomized trial in severe sepsis Await results of randomized trial in severe sepsis

patients with low severity of illness scorespatients with low severity of illness scores

Documents

Drotrecogin alfa (activated) Randy Wax, MD, FRCP(C) Staff Intensivist and Education Director Mount Sinai Hospital Department of Medicine University of