1 Study F1K-MC-EVAD: Relative Risk under Original and Amended Protocols Interaction P-Value Amended...

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Study F1K-MC-EVAD: Relative Risk under Study F1K-MC-EVAD: Relative Risk under Original and Amended ProtocolsOriginal and Amended Protocols

Interaction P-Value

Amended Protocol

Original ProtocolPatient Population

0.500.770.87Sites Enrolling under Both Protocols

0.080.710.94Entire Population

Relative Risk

6586.01

2

Study F1K-MC-EVAD: Relative Risk by Site Study F1K-MC-EVAD: Relative Risk by Site EnrollmentEnrollment

0.080.71 (970)0.94 (720)164 (1690)All Sites

0.240.72 (887)0.89 (664)105 (1551) 5

0.400.72 (718)0.86 (537)62 (1255) 10

38 (956)

20 (655)

11 (457)

No. of Sites(no. of patients)

Interaction P-Value

Amended Protocol (no. of patients)

Original Protocol (no. of patients)

Site Enrollment

0.520.69 (539)0.79 (417) 15

0.360.67 (364)0.84 (291) 20

0.750.83 (255)0.91 (202) 25

Relative Risk

6587.01

3

Study F1K-MC-EVAD: Mortality by Type of Study F1K-MC-EVAD: Mortality by Type of Clinical Trial MaterialClinical Trial Material

Number of PatientsDosed per Site No. of

No. ofPatients

Mortality RateN (%)

CT-BDS2 CT-BDS2+ Sites Dosed CT-BDS2 CT-BDS2+ Placebo

4 4 23 684 182 (24.7) 157 (24.2) 339 (30.1)

4* 3* 31 818 224 (22.8) 181 (22.1) 405 (30.6)

3 3 39 944 248 (24.2) 216 (19.9) 468 (29.7)

* This grouping of patients was selected to reflect the differential number of patients dosed with CT-BDS2 (N=471) compared with CT-BDS2+ (N=355).

6936.01

4

Study F1K-MC-EVAD: Cox Regression Analysis Study F1K-MC-EVAD: Cox Regression Analysis by Baseline and Any Heparin Exposure by Baseline and Any Heparin Exposure Placebo PatientsPlacebo Patients

Patient Group Other variables in model

Relative Rate of DeathHeparin versus

No Heparin Group(95% CI) p-Value

Baseline Heparin Exposure

None 0.94 (0.73 – 1.22) 0.64

APACHE II 0.89 (0.69 – 1.15) 0.36

Any Heparin Exposure(Time dependent covariate)

None 0.94 (0.71 – 1.26) 0.69

APACHE II 0.92 (0.69 – 1.22) 0.57

9270.01

5

Study F1K-MC-EVAD: Patient Populations Study F1K-MC-EVAD: Patient Populations within First APACHE II Quartile – IL-6 Levelwithin First APACHE II Quartile – IL-6 Level

6940.01

Drotrecogin Alfa(activated) Placebo

IL-6 LevelNo. of

PatientsDied

n (%)No. of

PatientsDied

n (%)Relative

Risk

Below Median(N=258)

131 14 (10.7) 127 17 (13.4) 0.80

Above Median(N=160)

82 17 (20.7) 78 9 (11.5) 1.80

Includes patients with available baseline measurements (N=418)

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Study F1K-MC-EVAD: Location and Functional Study F1K-MC-EVAD: Location and Functional Status – Original vs Amended ProtocolStatus – Original vs Amended Protocol

Original Protocol Amended ProtocolDrotrecogin

Alfa (activated)(N = 360)

Placebo(N = 360)

Drotrecogin Alfa(activated)(N = 490)

Placebo(N = 480)

Location Before Hospitalization (% of patients)

Home 78.9 79.2 82.7 78.8

Acute Care Hospital

9.2 8.9 9.4 9.6

Skilled Nursing Facility

7.5 8.6 4.3 8.3

Other 4.4 3.3 3.7 3.3

Functional Status (% of patients)

No Disabilities 68.0 65.3 78.2 74.3

6351.02

7

Study F1K-MC-EVAD: Safeguards to Maintain Study F1K-MC-EVAD: Safeguards to Maintain Study Blind during Conduct of Interim AnalysesStudy Blind during Conduct of Interim Analyses

Patient entered at investigative site

External CRO providesrandomized treatment code

to unblinded pharmacist at site

Unblinded pharmacist providesdrotrecogin alfa (activated) or

placebo to investigator

Patient receives study drug and up to 28 days of follow-up

Data management functions performed by Lilly blinded to

patient treatment codes

Blinded interim analysis data setsprepared by Lilly and sent to external statistical services organization (SSO)

SSO merged patient treatment codesprovided by CRO and prepared interim

analysis reports

SSO provided interim analysisreports to DSMB

DSMB provides recommendation to Lilly6452.01

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Study F1K-MC-EVAD: Mortality by Adequate Study F1K-MC-EVAD: Mortality by Adequate Use of Antibiotics (CEC)Use of Antibiotics (CEC)


No. ofPatients

Diedn (%)

No. ofPatients

Diedn (%)

Relative Risk(95% CI)

Yes 776 188 (24.2) 766 227 (29.6) 0.82 (0.69 – 0.96)

No 74 22 (29.7) 74 32 (43.2) 0.69 (0.44 – 1.06)

6718.01

9

Study F1K-MC-EVAD: Mortality by Culture or Study F1K-MC-EVAD: Mortality by Culture or Blood Culture (CEC)Blood Culture (CEC)


No. ofPatients

Diedn (%)

No. ofPatients

Diedn (%)

Relative Risk(95% CI)

CulturePositive

531 127 (23.9) 561 167 (29.8) 0.80 (0.66 – 0.98)

CultureNegative

319 83 (26.0) 279 92 (33.0) 0.79 (0.61 – 1.01)

Blood CulturePostive

266 73 (27.4) 275 93 (33.8) 0.81 (0.63 – 1.05)

Blood CultureNegative

584 137 (23.5) 565 166 (29.4) 0.80 (0.66 – 0.97)

6714.01

10

Study F1K-MC-EVAD: Stepwise Multiple Study F1K-MC-EVAD: Stepwise Multiple Logistic RegressionLogistic Regression

• Common approach to model selection

• Model provides probability of death estimates based on important covariates and treatment

• Intuitively, covariates are included based on their explanatory "value"

• Assess evidence of potential differential treatment effects with drotrecogin alfa (activated) accounting for the condition of the patient from multiple perspectives

6737.02

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21 variables considered for inclusion• Demographics: age, gender, origin, geographic

region• Patient location prior to hospitalization, co-

morbidity status, functional dependency status• Infection site and type, surgical status• Clinical markers: APACHE II, number of organ

failures, renal SOFA score, respiratory SOFA score, cardiovascular SOFA score, ventilation status, shock status

• Biochemical markers: Protein C activity, prothrombin time, APTT, log IL-6

6738.02

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• Treatment required in model

• All two-factor interactions (e.g., age by treatment, age by gender) included in stepwise procedure

• Schwartz criterion chosen as method to select terms

• Forward and backward steps

• Goodness-of-fit assessed using the Hosmer-Lemeshow chi-square statistic


6739.01

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• Following covariates retained in model• Age• APACHE II score• PT, log IL-6• Dependency status, urosepsis or not

• Goodness-of-fit statistic supports model's adequacy (p=0.50)

• Estimated constant 40.2% increase in the odds of survival with drotrecogin alfa (activated) across the population

• No interaction terms– no treatment-by-covariate interactions

Study F1K-MC-EVAD: Stepwise Multiple Study F1K-MC-EVAD: Stepwise Multiple Logistic Regression ResultsLogistic Regression Results

6740.01

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Study F1K-MC-EVAD: Data Safety Study F1K-MC-EVAD: Data Safety Monitoring Board MembersMonitoring Board Members

• Steven Opal, M.D. (Chairman)Professor of Medicine, Brown University

• Edward Abraham, M.D.Professor of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Science Center

• Steve Lowry, M.D.Chairman and Professor, University of Medicine and Dentistry of New Jersey.

• Janet Wittes, Ph.D.Statistician, Statistics Collaborative Incorporation, Washington, DC 20036

• Statistician resource- Pat O'Meara, PhD Pat O'Meara Associates, Inc, a Statistical Services Organization (SSO)

6722.01

15

Study F1K-MC-EVAD: Cumulative MortalityStudy F1K-MC-EVAD: Cumulative Mortality

6316.02

0.40

0.35

0.30

0.25

0.20

Over Time (by Covance Randomization Date)

1 Aug1998

1 Nov1998

1 Feb1999

1 May1999

1 Aug1999

1 Nov1999

1 Feb2000

1 May2000

1 Jul2000

Number of Sites = 164Number of Patients = 1690

Placebo

Drotrecogin Alfa(activated)

Last patient enrolled - original protocolFirst patient enrolled - amended protocol

28-D

ay M

ort

alit

y R

ate

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Study F1K-MC-EVAD: Cumulative MortalityStudy F1K-MC-EVAD: Cumulative MortalitySites Enrolling under Original and Amended Sites Enrolling under Original and Amended ProtocolsProtocols

6404.02

0.40

0.35

0.30

0.25

0.20

1 Aug1998

1 Nov1998

1 Feb1999

1 May1999

1 Aug1999

1 Feb2000

1 May2000

1 Jul2000

Over Time (by Covance Randomization Date)

Number of Sites = 99Number of Patients = 1463

1 Nov1999

Placebo


Last patient enrolled - original protocolFirst patient enrolled - amended protocol

28-D

ay M

ort

alit

y R

ate

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Why not a randomized controlled trial in kids?Why not a randomized controlled trial in kids?

• Assuming a 12.5% placebo mortality rate and 10% drotrecogin alfa (activated) mortality rate

• Using a 2-sided chi-square test for equality of proportions with an alpha level of 5%

• With 80% power need 5172 patients

• Largest pediatric trial ever was 396 patients

9040.01

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Controlled Trial Sample Size Estimates Controlled Trial Sample Size Estimates

Assumed PlaceboMortality Rate

12.5% 15% 20%

Active TreatmentMortality Rate

10% 12% 16%

Sample size 5172 4204 2994

Using a 2-sided chi-square test for equality of proportions with an alpha level of 5% and 80% power to detect a treatment effect

9191.01

19

Studies F1K-MC-EVAO/EVAD: Number of Organ Studies F1K-MC-EVAO/EVAD: Number of Organ Failures at Baseline – Pediatric versus Adult Failures at Baseline – Pediatric versus Adult PatientsPatients

0

10

20

30

40

50

One Two Three Four

Number of Organ Failures

Pe

rce

nt

of

Pa

tie

nts

Pediatric (N=83)

Adult (N=1690)

*Wilkinson JD et al, 1987 J. Pediatr. 111(3):325-3289303.01

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Studies F1K-MC-EVAO/EVAD: Type of Organ Studies F1K-MC-EVAO/EVAD: Type of Organ Failure at Baseline – Pediatric versus Adult Failure at Baseline – Pediatric versus Adult PatientsPatients

0

20

40

60

80

100

Cardiovascular Respiratory Hematologic Renal

Type of Organ Failure

Pe

rce

nt

of

Pa

tie

nts

Pediatric (N=83)

Adult (N=1690)

*Wilkinson JD et al, 1987 J. Pediatr. 111(3):325-3289304.01

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Studies F1K-MC-EVAO/EVAD: Percent of Studies F1K-MC-EVAO/EVAD: Percent of Patients with Positive Cultures at BaselinePatients with Positive Cultures at Baseline

9140.01

Per

cen

t o

f P

atie

nts

0

5

10

15

20

25

30

35

40

Adult Patients (N=1690)

Pediatric Patients (N=83)

ViralFungalGramMixed

GramNegative

GramPositive

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Reporting of Adverse Events – Study F1K-Reporting of Adverse Events – Study F1K-MC-EVAO versus Study F1K-MC-EVAD MC-EVAO versus Study F1K-MC-EVAD

• Study F1K-MC-EVAO: All clinical manifestations of severe sepsis were collected as adverse events

• Study F1K-MC-EVAD: Clinical manifestations of severe sepsis were not collected as adverse events unless considered drug related

9137.01

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Study F1K-MC-EVAO: Adverse Events Study F1K-MC-EVAO: Adverse Events Occurring in Occurring in 5% of Patients – Part 25% of Patients – Part 2

EventsPercentage of Patients

(N=62)

Generalized Edema 19.4Lung Edema 19.4Oliguria 17.7Bradycardia 16.1Hypokalemia 16.1Thrombocytopenia 16.1Pleural Effusion 14.5Vomiting 14.5Agitation 12.9Anemia 12.9Peripheral Edema 12.9Hyperglycemia 11.3Vesicullobullous Rash 11.3Ascites 9.7Atelectasis 9.7Diarrhea 9.7Fever 9.7Hypernatremia 9.7Infection 9.7

9031.01

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Study F1K-MC-EVAO: Baseline Organ Failures Study F1K-MC-EVAO: Baseline Organ Failures for Selected Safety Categories for Selected Safety Categories

All Patients (N =83)

Patients with Serious Adverse Events (N =20)

Patients with Bleeding Event

Reported as Serious Adverse Event

(N =4)

Patients who Died

(N =8)

Mean Organ Failures at Baseline

2.7 3.3 4.0 4.1

Type of Organ Failure (% of patients)

Cardiovascular 93 95 100 100

Respiratory 87 95 100 100

Neurological 14 26 25 63

Hematologic 49 60 75 75

Renal 16 35 50 38

Hepatic 9 15 50 38 PIM

9193.03

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Study F1K-MC-EVAO: Intracerebral Study F1K-MC-EVAO: Intracerebral Hemorrhage – Patient Scenario 1Hemorrhage – Patient Scenario 1

• 14 year-old enrolled with N. meningitidis in blood and cerebral spinal fluid, severe multi-organ dysfunction, shock requiring multiple inotropes, and coagulopathy. Anisocoria diagnosed and drotrecogin alfa (activated) stopped after 10.5 hours (platelet count 26x103/μL). Continuous veno-venous hemofiltration with heparin began about 10 hours post study drug and continued until the patient died. Clinical brain death diagnosed on Study Day 13. Postmortem CT scan revealed a right frontal parachymal hematoma, severe cerebral edema, and subarachnoid hemorrhage. The severe intracranial hemorrhage was considered possibly related to study drug infusion by the investigator.

6646.02

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Location


(N=218)n (%)

Placebo(N=215)n (%)

Home 182 (83.5%) 177 (82.3%)

Acute Care Hospital 22 (10.1%) 20 (9.3%)

Skilled Nursing Facility 5 (2.3%) 10 (4.7%)

Other 9 (4.1%) 8 (3.7%)

Study F1K-MC-EVAD: Location Prior to Study F1K-MC-EVAD: Location Prior to Hospitalization Hospitalization – – First APACHE II QuartileFirst APACHE II Quartile

6497.02

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