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

2. 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

3. A new understanding of sepsis pathophysiology Organ failure Sepsis Coagulation Fibrinolysis  Coagulation  Fibrinolysis Inflammation  Inflammation Endothelial injury Death

4. Study design  Randomized, double-blind, placebo-controlled study in adult patients with severe sepsis 164 sites in 11 countries 164 sites in 11 countries Planned 2280 patients Planned 2280 patients  Single-dose study 24  g/kg/hr drotrecogin alfa (activated) infusion or placebo for 96 hours 24  g/kg/hr drotrecogin alfa (activated) infusion or placebo for 96 hours 6510.01

5. Study design  Primary objective Effect on 28-day all-cause mortality Effect on 28-day all-cause mortality  Secondary objectives Safety Safety Effect on organ function Effect on organ function Pharmacokinetics and pharmacodynamics Pharmacokinetics and pharmacodynamics

6. Study Design Start of study drug infusion 24 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

7. Study design  Inclusion criteria = Severe Sepsis Known or suspected infection Known or suspected infection Evidence of a systemic response to infection Evidence of a systemic response to infection Three or four of the criteria defining SIRSThree or four of the criteria defining SIRS One or more sepsis-induced organ dysfunctions One or more sepsis-induced organ dysfunctions CardiovascularCardiovascular RespiratoryRespiratory RenalRenal HematologicHematologic Metabolic acidosisMetabolic acidosis

8. Study design  Exclusion criteria High risk of bleeding - similar risk assessment as for systemic heparin High risk of bleeding - similar risk assessment as for systemic heparin Systemic heparin and anti-platelet agents (except ASA) Systemic heparin and anti-platelet agents (except ASA) Platelet count <30,000/mm 3 Platelet count <30,000/mm 3 End stage liver disease End stage liver disease End stage renal disease (on RRT) End stage renal disease (on RRT)

9. Study design  Exclusion criteria HIV with CD 4 count <=50/mm 3 HIV with CD 4 count <=50/mm 3 Bone marrow, lung, liver, pancreas, or small bowel transplantation Bone marrow, lung, liver, pancreas, or small bowel transplantation Organ failure >24 hours in duration at time all entry criteria met Organ failure >24 hours in duration at time all entry criteria met

10. Study design  Exclusion criteria Moribund and where death is imminent Moribund and where death is imminent Not expected to survive 28 days due to underlying non-sepsis related condition 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 Patient advance directive to withhold life-support with the exception of CPR Family not committed to aggressive management of patient Family not committed to aggressive management of patient Primary physician not committed to aggressive management of patient Primary physician not committed to aggressive management of patient

11. Prowess Study: Amendment Minor Changes to Inclusion Criteria  Original protocol: Allowed respiratory organ failure (PaO 2 /FiO 2 ) to be calculated by % saturation  Amended protocol: Required respiratory organ failure (PaO 2 /FiO 2 ) 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

12. 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 protocol: clarified the following exclusion criteria: "Known or suspected portal hypertension" changed to include clinical manifestations – esophageal varices, chronic jaundice, cirrhosis, or chronic ascites "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 "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

13. Prowess Study: Changes to Exclusion Criteria with Amended Protocol  The following populations were excluded: Patients with bone marrow, lung, liver, pancreas, or small bowel transplantation Patients with bone marrow, lung, liver, pancreas, or small bowel transplantation 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 of patient 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 Patients whose 1st organ failure >24 hours in duration at time of meeting all inclusion and exclusion criteria W. Macias, Eli Lilly

14. Timeline of Study Date 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 W. Macias, Eli Lilly

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

21. 28 day Mortality 0 5 10 15 20 25 30 35 30.8% 24.7% Primary Analysis Results 2-Sided p-Value 0.005 Relative Risk Reduction19.4% Absolute Risk Reduction 6.1% (NNT=16) Placebo (N=840) Drotrecogin Alfa (activated) (N=850) W. Macias, Eli Lilly

22. Survival Analysis (Intention to treat) 07142128 70 80 90 100 Days from Start of Infusion to Death Percent Survivors p=0.006 (stratified log-rank test) 0 Placebo (N=840) Drotrecogin Alfa (activated) (N=850) W. Macias, Eli Lilly

23. PROWESS: 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 2 0.9 Relative Risk of Death (Point Estimate and 95% CI) W. Macias, Eli Lilly

24. PROWESS Study: D-Dimer Percent 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 * * * * * * * Median Percent Change from Baseline W. Macias, Eli Lilly

25. PROWESS Study: Thrombin-Antithrombin Complex – Percent Change from Baseline Treatment groups compared using ranked ANOVA W. Macias, Eli Lilly

26. RPOWESS Study: Plasminogen Activator Inhibitor-1 – Percent Change from Baseline Treatment groups compared using ranked ANOVA W. Macias, Eli Lilly

27. PROWESS Study: Interleukin-6 Change from Baseline Treatment groups compared using ranked ANOVA W. Macias, Eli Lilly

29. Xigris  (Drotrecogin Alfa (activated)) Approved in United States with the Following Indication Statement: 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). 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. 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. Safety and efficacy have not been established in pediatric patients with severe sepsis. W. Macias, Eli Lilly

30. Intensive DOCTOR care  Time to take a breath…

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

36. Reference Diseases  Incidence in US (cases per 100,000) Colon cancer 50 Colon cancer 50 Breast cancer 110 Breast cancer 110 AIDS 17 AIDS 17 Congestive heart failure ~130 Congestive heart failure ~130 Sepsis ~300 Sepsis ~300  Number of deaths in US each year Acute myocardial infarction 211,000 Acute myocardial infarction 211,000 Severe sepsis 215,000 Severe sepsis 215,000 Slide presentation, D. Angus, SCCM 2001

37. Hospital costs associated with sepsis  Average hospital LOS - 19.6 d  Average hospital cost - $22,100  National costs - $16.7 billion Neonates - $1.1 billion Neonates - $1.1 billion > 65 yrs - $8.7 billion > 65 yrs - $8.7 billion Slide presentation, D. Angus, SCCM 2001

38. Resolution of organ failure  Patients treated with APC had quicker resolution of: Cardiovascular failure Cardiovascular failure Respiratory failure Respiratory failure  Patients treated with APC had more vasopressor-free days (20.06 versus 18.78 days, p=0.014) vasopressor-free days (20.06 versus 18.78 days, p=0.014) ventilator-free days (14.33 versus 13.24 days, p=0.049) ventilator-free days (14.33 versus 13.24 days, p=0.049)

39. APC and organ failure 1 organ failure 2 or more organ failures N=419N=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

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

41. Functional status  No difference in independent ADLs Bathing Bathing Dressing Dressing Toilet care Toilet care Transferring Transferring Continence Continence Feeding Feeding

42. Hospital costs/resources  For survivors and non-survivors, use of APC did not increase: Hospital and ICU length of stay Hospital and ICU length of stay TISS points TISS points Estimated costs (not including drug) Estimated costs (not including drug) Clermont et al., AJRCCM 163(5):A802

43. 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

44. Health economics  Autologous BMT for relapsed Hodgkins  Adjuvant tamoxifen in premenopausal ER- women  Dialysis for ESRD  ICD vs. amiodarone  Xigris vs. standard of care (high risk)  $421,000  $57,000-$214,000  $40,000  $27,400-$32,900  $23,000

45. Conclusions  Long-term follow up?  Cost-effectiveness analysis will have to take into account: Money saved by health care system Money saved by health care system Benefits to quality of life (cost-utility analysis) Benefits to quality of life (cost-utility analysis) Comparison to other public health problems/solutions 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