The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*

Abstract

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.

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

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

Data extraction: 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.

Data synthesis: 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.

Figure 1

A summary of the recent history of experimental agents tested in clinical trials for the treatment of sepsis S-soluble; rTLAF - human recombinant talactoferrin; PS - PROWESS/Shock; AT- antithrombin; TFPI - tissue factor pathway inhibitor; r-recombinant; NO-nitric oxide; NOS – nitric oxide synthase; PAF – platelet activating factor; R’- receptor; PAF-AH - PAF acetyl hydrolase ; IL-1ra- interleukin-1 receptor antagonist; mAb-monoclonal antibody; Ab-antibody; J5 sera - polyclonal antibodies in serum directed against the core glycolipid structure from the lipopolysaccharide of E. coli strain J5; PL’s – phospholipids to include phospholipid emulsions and high density lipoprotein; Pmx-polymyxin B hemoperfusion columns. The bars indicate the approximate start dates and finish dates of each intervention in clinical trials. The bars with a thick black line on the right side of the bar indicate current ongoing studies.