Objectives: To review the scientific rationale for the clinical use of recombinant bactericidal permeability-increasing protein (rBPI21) and to discuss the results, implications, and lessons learned during the clinical development of rBPI21 for adjunctive treatment of children with severe meningococcemia.
Data sources: The published medical literature.
Study selection: Of the phase I/II and phase III trials in humans, preclinical experimental studies were selected. Data from these sources are presented 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 protein and N-terminal fragments of bactericidal permeability-increasing protein, such as rBPI21, bind and neutralize endotoxin and are potently bactericidal against both smooth and rough forms of Gram-negative bacteria, including Neisseria meningitidis. Based on these properties and compelling preclinical data indicating that administration of rBPI21 reduced mortality in several models of sepsis, we initiated clinical trials by using rBPI21 as adjunctive therapy for children with severe meningococcemia. Data from the phase III, randomized, placebo-controlled trial indicate that rBPI21 reduces clinically significant morbidities and improves the functional outcome of children with severe meningococcemia. No statistically significant benefit in mortality was demonstrated; however, because of the rare incidence of disease and the rapidity of death in this study, the trial was substantially underpowered to detect a statistically significant mortality advantage. 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 proved unsuccessful. Significant improvements were seen in other prospectively defined outcome variables that suggest an overall substantial benefit of therapy with rBPI21 in children with severe meningococcemia.
Conclusions: As the largest therapeutic trial conducted in pediatric critical care, the phase III trial of rBPI21 demonstrates important principles that can influence the design of future trials targeting rare, life-threatening diseases.