title: Bactericidal/permeability-increasing protein--lessons learned from the phase III, randomized, clinical trial of rBPI21 for adjunctive treatment of children with severe meningococcemia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The published medical literature.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Children's Meical Center, Dallas, TX 75235, USA. Bgiroi@childmed.dallas.tx.us
authors.forename: B P
authors.initials: BP
authors.lastname: Giroir
authors.forename: P J
authors.initials: PJ
authors.lastname: Scannon
authors.forename: M
authors.initials: M
authors.lastname: Levin
mesh_terms: D000203:Activities of Daily Living; D000818:Animals; D016470:Bacteremia / Q000145:classification / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D002648:Child; D017326:Clinical Trials, Phase III as Topic; D006233:Persons with Disabilities; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008565:Membrane Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D008589:Meningococcal Infections / Q000145:classification / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D008565:Membrane Proteins; C025357:endotoxin binding proteins