Secondary analysis for estimating heterogeneous treatment effects for the “Drotrecogin Alfa (Activated) in Adults with Septic Shock” trial

Lead Investigator: Ewan Goligher, University of Toronto
Title of Proposal Research: Secondary analysis for estimating heterogeneous treatment effects for the “Drotrecogin Alfa (Activated) in Adults with Septic Shock” trial
Vivli Data Request: 9093
Funding Source: This work is supported by a grant from the National Sanitarium Association
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Sepsis is a life-threatening condition arising when the body’s reaction to infection injures its own tissues and organs. It occurs when the immune system – which normally helps to protect us against infection – goes into overdrive. It can lead to shock, multiple organ failure and sometimes death.

In sepsis, increased inflammation and blood clotting are harmful and interrelated drivers of the disease process. Protein C, a substance occurring naturally in the body that promotes clot breakdown and inhibits inflammation, is depleted. In preliminary studies, administration of activated protein C led to dose-dependent reductions in markers of deranged blood clotting and inflammation. These promising results warranted conclusive studies of clinical efficacy. Several large randomized clinical trials have produced inconsistent information about efficacy of activated protein C in a form of Drotrecogin alfa (activated) in patients with severe sepsis.

In 2011, the Drotrecogin Alfa (Activated) in Adults with Septic Shock (PROWESS-SHOCK) study failed to confirm efficacy of activated protein C for reduction of mortality. In the subgroup analysis, a trend for benefit among more severely ill patients was observed. The negative results of the PROWESS-SHOCK study resulted in withdrawal of Drotrecogin Alfa (Activated) from the market.

Whilst the study results for all the total trial population suggest a drug is ineffective, the diversity of trial participants within the trial might be hiding the fact that it is relatively effective for some subgroups. Recent advances in research methodology allow for predicting treatment effect for individual patients by using all available information, such as baseline characteristics, comorbidities, severity of illness, etc. Discrepancies between predicted individual and observed overall treatment effects suggest heterogeneity of treatment effect (HTE) determined by patients’ characteristics.

In this secondary analysis of the PROWESS-SHOCK trial we will use novel analytical approaches to test for HTE in the study population. This will allow us to identify patients that might benefit from the intervention, which may inform future research aiming at reducing mortality among patients with severe sepsis

Requested Studies:

A Randomized, Double-blind, Placebo-controlled, Multicenter, Phase 3 Study of Drotrecogin Alfa (Activated) Administered as a Continuous 96-hr Infusion to Adult Patients With Septic Shock
Data Contributor: Lilly
Study ID: NCT00604214
Sponsor ID: 11940