Bactericidal/permeability-increasing protein -: Lessons learned from the phase III, randomized, clinical trial of rBPI21 for adjunctive treatment of children with severe meningococcemia

被引:53
作者
Giroir, BP
Scannon, PJ
Levin, M
机构
[1] Childrens Med Ctr, Dallas, TX 75235 USA
[2] XOMA LLC, Berkeley, CA USA
[3] Univ London Imperial Coll Sci Technol & Med, Sch Med, London, England
关键词
sepsis; meningococcal infections; endotoxin; clinical trials; infection; pediatrics;
D O I
10.1097/00003246-200107001-00039
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Objectives: To review the scientific rationale for the clinical use of recombinant bactericidal permeability-increasing protein (rBPI(21)) and to discuss the results, implications, and lessons learned during the clinical development of rBPI(21) 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 rBPI(21), 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 rBPI(21) reduced mortality in several models of sepsis, we initiated clinical trials by using rBPI(21) as adjunctive therapy for children with severe meningococcemia, Data from the phase III, randomized, placebo-controlled trial indicate that rBPI(21) 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 rBPI(21) in children with severe meningococcemia. Conclusions:As the largest therapeutic trial conducted in pediatric critical care, the phase III trial of rBPI(21) demonstrates important principles that can influence the design of future trials targeting rare, life-threatening diseases.
引用
收藏
页码:S130 / S135
页数:6
相关论文
共 42 条
[1]  
AMMONS WS, 1996, NOVEL THERAPEUTIC ST, P55
[2]   RECOMBINANT HUMAN BACTERICIDAL PERMEABILITY-INCREASING PROTEIN (RBPI23) IS A UNIVERSAL LIPOPOLYSACCHARIDE-BINDING LIGAND [J].
APPELMELK, BJ ;
AN, YQ ;
THIJS, BG ;
MACLAREN, DM ;
DEGRAAFF, J .
INFECTION AND IMMUNITY, 1994, 62 (08) :3564-3567
[3]   BACTERICIDAL PERMEABILITY-INCREASING PROTEIN PROTECTS VASCULAR ENDOTHELIAL-CELLS FROM LIPOPOLYSACCHARIDE-INDUCED ACTIVATION AND INJURY [J].
ARDITI, M ;
ZHOU, J ;
HUANG, SH ;
LUCKETT, PM ;
MARRA, MN ;
KIM, KS .
INFECTION AND IMMUNITY, 1994, 62 (09) :3930-3936
[4]   Crystal structure of human BPI and two bound phospholipids at 2.4 angstrom resolution [J].
Beamer, LJ ;
Carroll, SF ;
Eisenberg, D .
SCIENCE, 1997, 276 (5320) :1861-1864
[5]   Endotoxin, toll-like receptor 4, and the afferent limb of innate immunity [J].
Beutler, B .
CURRENT OPINION IN MICROBIOLOGY, 2000, 3 (01) :23-28
[6]  
Brandtzaeg P., 1995, Meningococcal disease, P71
[7]   EFFECT OF LIPOPOLYSACCHARIDE (LPS) CHAIN-LENGTH ON INTERACTIONS OF BACTERICIDAL/PERMEABILITY-INCREASING PROTEIN AND ITS BIOACTIVE 23-KILODALTON NH2,-TERMINAL FRAGMENT WITH ISOLATED LPS AND INTACT PROTEUS-MIRABILIS AND ESCHERICHIA-COLI [J].
CAPODICI, C ;
CHEN, S ;
SIDORCZYK, Z ;
ELSBACH, P ;
WEISS, J .
INFECTION AND IMMUNITY, 1994, 62 (01) :259-265
[8]   BACTERICIDAL PERMEABILITY-INCREASING PROTEIN INHIBITS INDUCTION OF MACROPHAGE NITRIC-OXIDE PRODUCTION BY LIPOPOLYSACCHARIDE [J].
CORRADIN, SB ;
HEUMANN, D ;
GALLAY, P ;
SMITH, J ;
MAUEL, J ;
GLAUSER, MP .
JOURNAL OF INFECTIOUS DISEASES, 1994, 169 (01) :105-111
[9]   Pathophysiology of meningococcal sepsis in children [J].
de Kleijn, ED ;
Hazelzet, JA ;
Kornelisse, RF ;
de Groot, R .
EUROPEAN JOURNAL OF PEDIATRICS, 1998, 157 (11) :869-880
[10]  
FIJNVANDRAAT K, 1995, THROMB HAEMOSTASIS, V73, P15