Bactericidal/permeability-increasing protein - Lessons learned from the phase III, randomized, clinical trial of rBPI(21) for adjunctive treatment ofchildren with severe meningococcemia

Objectives: To review the scientific rationale for the clinical use of reco mbinant bactericidal permeability-increasing protein (rBPI(21)) and to disc uss the results, implications, and lessons learned during the clinical deve lopment of rBPI(21) for adjunctive treatment of children with severe mening ococcemia. Data Sources: The published medical literature. Study Selection: Of the phase I/II and phase III trials in humans, preclini cal experimental studies were selected. Data from these sources are present ed in the context of the authors' experiences as principal investigators in the phase I/II and/or phase III clinical trials, Data Extraction and Data Synthesis: Bactericidal permeability-increasing pr otein and N-terminal fragments of bactericidal permeability-increasing prot ein, such as rBPI(21), bind and neutralize endotoxin and are potently bacte ricidal against both smooth and rough forms of Gram-negative bacteria, incl uding Neisseria meningitidis, Based on these properties and compelling prec linical data indicating that administration of rBPI(21) reduced mortality i n several models of sepsis, we initiated clinical trials by using rBPI(21) as adjunctive therapy for children with severe meningococcemia, Data from t he phase III, randomized, placebo-controlled trial indicate that rBPI(21) r educes clinically significant morbidities and improves the functional outco me of children with severe meningococcemia, No statistically significant be nefit in mortality was demonstrated; however, because of the rare Incidence of disease and the rapidity of death in this study, the trial was substant ially underpowered to detect a statistically significant mortality advantag e. Before the completion of the trial, the probability that the study might have been underpowered to detect a significant reduction in mortality was recognized. An attempt at selecting a previously unvalidated composite end point to increase the meaningful event rate for the primary end point prove d unsuccessful, Significant improvements were seen in other prospectively d efined outcome variables that suggest an overall substantial benefit of the rapy with rBPI(21) in children with severe meningococcemia. Conclusions:As the largest therapeutic trial conducted in pediatric critica l care, the phase III trial of rBPI(21) demonstrates important principles t hat can influence the design of future trials targeting rare, life-threaten ing diseases.