Lead Investigator: Gus Slotman, Inspira Health Network
Title of Proposal Research: Identifying Patients in the PROWESS SHOCK Clinical Trial Among Whom Drotrecogin Alfa (DrottAA) Reduced Mortality
Vivli Data Request: 6710
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
For nearly 40 years, more than 100 randomized clinical trials (RCT), from the original Solu-Medrol RCT through the recent SCARLET RCT, have tested novel interventions targeting the host response to infection in sepsis, organ failure and septic shock on thousands of patients. (1, 2, 3) All of those molecules and regimens were grounded firmly in basic science, both in-vitro and in-vivo. After 40 years of sepsis clinical trials, worldwide sepsis still claims 11 million lives each year. Many new drugs targeting the detrimental effects of sepsis performed well in the laboratory but none reduced septic mortality in clinical trials. Hypothesis: Non-specific clinical sepsis definitions entry criteria enroll so many patients whose bodies cannot benefit from the study drug that the true treatment effects of effective drugs are masked. The present study proposes to determine whether or not it is possible to predict from pre-randomization RCT data which septic patients are able to benefit from Drotrecogin Alfa (DrotAA), a drug from Eli Lilly & Co. If this investigation identifies such patients within the PROWESS SHOCK RCT, then it may be possible to identify drug-responsive patients in other sepsis RCT’s, possibly facilitating new life-saving treatments for sepsis.
Statistical Analysis Plan:
We now propose to examine the PROWESS SHOCK RCT of DrotAA in septic shock (19), using the above described statistical approach (18) with the objective of determining whether or not, from pre-randomization data, cohorts of individuals among whom DrotAA reduced septic shock mortality can be identified and predicted. Since DrotAA did not improve survival in PROWESS SHOCK, logically the probability of successfully identifying in advance drug-responsive patients within this RCT may be low. However, considering that PROWESS demonstrated a significant treatment effect for DrotAA, especially in the highest two APACHE II quartiles, for many it has not made sense that a similar positive signal was not observed among essentially the same patients in PROWESS SHOCK. Therefore, from the PROWESS (2) results and our preliminary experience with the other RCT’s in sepsis, one might speculate that a cohort of drug-responsive patients within PROWESS SHOCK exists among whom DrotAA saved lives. This investigation proposes to explore that possibility. As described previously, survival treatment effects of DrotAA in PROWESS SHOCK will be evaluated separately among patients enrolled under consensus definitions and among patients predicted to respond to it. Mortality will be analyzed by Kaplan–Meier statistics. (20) Ideally, PROWESS SHOCK database should be received in SAS format and in flat files.
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
Sponsor: Eli Lilly and Company
Study ID: NCT00604214
Sponsor ID: 11940
Kelter, David MD; Slotman, Gus J MD, FACS. Smart Identifies Dichotomous Drotrecogin Alfa Activated Treatment Effects on Mortality in Prowess Shock. Journal of the American College of Surgeons: November 2022 – Volume 235 – Issue 5 – p S296. doi: 10.1097/01.XCS.0000895332.83940.b8