The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*.
OBJECTIVE
The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies.


METHODS
We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years.


METHODS
Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies.


METHODS
Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized.


RESULTS
After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis.


CONCLUSIONS
We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis.
1Infectious Disease Division, The Alpert Medical School of Brown University, Providence, RI. 2Critical Care Department, Robert Wood Johnson Medical School, Camden, NJ. 3Critical Care Department, Erasme University Hospital, Brussels, Belgium. 4Critical Care Department, National Institutes of Health, Bethesda, MD. 5Critical Care Department, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Steven M
SM
Opal
R Phillip
RP
Dellinger
Jean-Louis
JL
Vincent
Henry
H
Masur
Derek C
DC
Angus
D015415:Biomarkers; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012107:Research Design; D018805:Sepsis / Q000188:drug therapy*
D015415:Biomarkers; D005343:Fibrinolytic Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated