# Presentation: 727731

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

**Interaction P-Value**

**Amended Protocol**

**Original Protocol**

**Patient Population**

**0.50**

**0.77**

**0.87**

**Sites Enrolling under Both Protocols**

**0.08**

**0.71**

**0.94**

**Entire Population**

**Relative Risk**

**6586.01**

## Study F1K-MC-EVAD: Relative Risk by Site Enrollment

**6587.01**

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

**6936.01**

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

**9270.01**

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

**6940.01**

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

**6351.02**

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

- Patient entered at investigative site

- External CRO provides
- randomized treatment code
- to unblinded pharmacist at site

- Unblinded pharmacist provides
- drotrecogin 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 sets
- prepared by Lilly and sent to external statistical services organization (SSO)

- SSO merged patient treatment codes
- provided by CRO and prepared interim
- analysis reports

- SSO provided interim analysis
- reports to DSMB

- DSMB provides recommendation to Lilly

**6452.01**

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

**6718.01**

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

**6714.01**

## Study F1K-MC-EVAD: Stepwise Multiple Logistic 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**

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

**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**

## 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

**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**

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

**6739.01**

## 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 

**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 Logistic Regression Results**

**6740.01**

## Study F1K-MC-EVAD: Data Safety Monitoring 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**

## Study F1K-MC-EVAD: Cumulative Mortality

**6316.02**

## Study F1K-MC-EVAD: Cumulative MortalitySites Enrolling under Original and Amended Protocols

**6404.02**

## 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**

**Notes:**
The 10% comes from the observed mortality rate in EVAO .  The 12.5 placebo rate is just the mortality rate that equates to a 20% redution in death when Xigris is 10%.

## Controlled Trial Sample Size Estimates 

**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**

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

***Wilkinson JD et al, 1987 J. Pediatr. 111(3):325-328**

**9303.01**

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

***Wilkinson JD et al, 1987 J. Pediatr. 111(3):325-328**

**9304.01**

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

**9140.01**

## Reporting of Adverse Events – Study F1K-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**

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

**9031.01**

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

**9193.03**

## Study F1K-MC-EVAO: Intracerebral Hemorrhage – 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 26x10****3****/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**

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

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

**6497.02**