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The Next Generation of Sepsis Clinical Trial Designs: What Is Next After the Demise of Recombinant Human Activated Protein C?*

Opal, Steven M. MD1; Dellinger, R. Phillip MD2; Vincent, Jean-Louis MD, PhD3; Masur, Henry MD4; Angus, Derek C. MD, MPH5

doi: 10.1097/CCM.0000000000000325
Special Article

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.

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.

* See also p. 1743.

Presented, in part, at the 10th Stephen F. Lowry ISF Colloquium, Bethesda, MD, May 4–5, 2012.

Dr. Opal served as board member for Kenta biotech (advice on monoclonal antibody targets for bacterial infections) and Arsanis (advice on anti-LPS antibody targets), consulted for Medimmune (monoclonal antibody strategies), received royalties from Elsevier (book royalties for an infectious disease textbook), and disclosed DSMB for Tetraohase and DSMB for Achaogen (data review committee). His institution received grant support from Asahi Kasei, Sirtris, and GSK and he has patents with the University of Maryland (patent on a novel vaccine for endotoxin) and Prothera biologics (patent on a novel therapy for anthrax). Dr. Masur received support for article research from the National Institutes of Health. Dr. Angus consulted for Idaho Technology, Pfizer, Elsai, and Medimmune, LLC and disclosed that he has interest in Eli Lilly (member). His institution received grant support from Elsai Inc. (grant to the University of Pittsburgh Medical Center. Dr. Angus served as PI from 2006-2010 and served as co-investigator from 2010-2012). The remaining authors have disclosed that they do not have any potential conflicts of interest.

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© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins