Influence of Diagnostic Method on Outcomes in Phase 3 Clinical Trials of Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection: A Post Hoc Analysis of MODIFY I/II.
diagnosis
diarrhea
toxin
treatment outcome
Journal
Open forum infectious diseases
ISSN: 2328-8957
Titre abrégé: Open Forum Infect Dis
Pays: United States
ID NLM: 101637045
Informations de publication
Date de publication:
01 Aug 2019
01 Aug 2019
Historique:
received:
06
03
2019
accepted:
03
07
2019
entrez:
4
8
2019
pubmed:
4
8
2019
medline:
4
8
2019
Statut:
ppublish
Résumé
The optimum diagnostic test method for Clostridioides difficile infection (CDI) remains controversial due to variation in accuracy in identifying true CDI. This post hoc analysis examined the impact of CDI diagnostic testing methodology on efficacy outcomes in phase 3 MODIFY I/II trials. In MODIFY I/II (NCT01241552/NCT01513239), participants received bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment for primary/recurrent CDI (rCDI). Using MODIFY I/II pooled data, initial clinical cure (ICC) and rCDI were assessed in participants diagnosed at baseline using direct detection methods (enzyme immunoassay [EIA]/cell cytotoxicity assay [CCA]) or indirect methods to determine toxin-producing ability (toxin gene polymerase chain reaction [tgPCR]/toxigenic culture). Of 1554 participants who received bezlotoxumab or placebo in MODIFY I/II, 781 (50.3%) and 773 (49.7%) were diagnosed by tgPCR/toxigenic culture and toxin EIA/CCA, respectively. Participants diagnosed by toxin EIA/CCA were more likely to be inpatients, older, and have severe CDI. In bezlotoxumab recipients, ICC rates were slightly higher in the toxin EIA/CCA subgroup (81.7%) vs tgPCR/toxigenic culture (78.4%). Bezlotoxumab significantly reduced the rCDI rate vs placebo in both subgroups; however, the magnitude of reduction was substantially larger in participants diagnosed by toxin EIA/CCA (relative difference, -46.6%) vs tgPCR/toxigenic culture (-29.1%). In bezlotoxumab recipients, the rCDI rate was lower in the toxin EIA/CCA subgroup (17.6%) vs tgPCR/toxigenic culture (23.6%; absolute difference, -6.0%; 95% confidence interval, -12.4 to 0.3; relative difference, -25.4%). Diagnostic tests that detect fecal C. difficile toxins are of fundamental importance to accurately diagnosing CDI, including in clinical trial design, ensuring that therapeutic efficacy is not underestimated.
Sections du résumé
BACKGROUND
BACKGROUND
The optimum diagnostic test method for Clostridioides difficile infection (CDI) remains controversial due to variation in accuracy in identifying true CDI. This post hoc analysis examined the impact of CDI diagnostic testing methodology on efficacy outcomes in phase 3 MODIFY I/II trials.
METHODS
METHODS
In MODIFY I/II (NCT01241552/NCT01513239), participants received bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment for primary/recurrent CDI (rCDI). Using MODIFY I/II pooled data, initial clinical cure (ICC) and rCDI were assessed in participants diagnosed at baseline using direct detection methods (enzyme immunoassay [EIA]/cell cytotoxicity assay [CCA]) or indirect methods to determine toxin-producing ability (toxin gene polymerase chain reaction [tgPCR]/toxigenic culture).
RESULTS
RESULTS
Of 1554 participants who received bezlotoxumab or placebo in MODIFY I/II, 781 (50.3%) and 773 (49.7%) were diagnosed by tgPCR/toxigenic culture and toxin EIA/CCA, respectively. Participants diagnosed by toxin EIA/CCA were more likely to be inpatients, older, and have severe CDI. In bezlotoxumab recipients, ICC rates were slightly higher in the toxin EIA/CCA subgroup (81.7%) vs tgPCR/toxigenic culture (78.4%). Bezlotoxumab significantly reduced the rCDI rate vs placebo in both subgroups; however, the magnitude of reduction was substantially larger in participants diagnosed by toxin EIA/CCA (relative difference, -46.6%) vs tgPCR/toxigenic culture (-29.1%). In bezlotoxumab recipients, the rCDI rate was lower in the toxin EIA/CCA subgroup (17.6%) vs tgPCR/toxigenic culture (23.6%; absolute difference, -6.0%; 95% confidence interval, -12.4 to 0.3; relative difference, -25.4%).
CONCLUSIONS
CONCLUSIONS
Diagnostic tests that detect fecal C. difficile toxins are of fundamental importance to accurately diagnosing CDI, including in clinical trial design, ensuring that therapeutic efficacy is not underestimated.
Identifiants
pubmed: 31375837
pii: 5543265
doi: 10.1093/ofid/ofz293
pmc: PMC6677672
pii:
doi:
Types de publication
Journal Article
Langues
eng
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
Références
CMAJ. 2004 Jul 6;171(1):51-8
pubmed: 15238498
Nat Clin Pract Gastroenterol Hepatol. 2004 Nov;1(1):32-8
pubmed: 16265042
Clin Infect Dis. 2008 Jan 15;46 Suppl 1:S12-8
pubmed: 18177217
Clin Infect Dis. 2009 Mar 1;48(5):568-76
pubmed: 19191641
Infect Control Hosp Epidemiol. 2010 May;31(5):431-55
pubmed: 20307191
N Engl J Med. 2011 Feb 3;364(5):422-31
pubmed: 21288078
Infect Control Hosp Epidemiol. 2011 Sep;32(9):932-3
pubmed: 21828981
Eur J Clin Microbiol Infect Dis. 2012 Sep;31(9):2219-25
pubmed: 22327373
Clin Infect Dis. 2013 Jan;56(1):67-73
pubmed: 23011147
Am J Gastroenterol. 2013 Apr;108(4):478-98; quiz 499
pubmed: 23439232
Lancet Infect Dis. 2013 Nov;13(11):936-45
pubmed: 24007915
Clin Infect Dis. 2014 Aug 1;59(3):345-54
pubmed: 24799326
JAMA Intern Med. 2015 Nov;175(11):1792-801
pubmed: 26348734
BMC Infect Dis. 2015 Nov 14;15:516
pubmed: 26573915
Clin Infect Dis. 2016 Mar 1;62(5):574-580
pubmed: 26582748
BMC Infect Dis. 2016 Jun 18;16:303
pubmed: 27316794
Clin Microbiol Infect. 2016 Aug;22 Suppl 4:S63-81
pubmed: 27460910
Infect Control Hosp Epidemiol. 2017 Jan;38(1):109-111
pubmed: 27745553
N Engl J Med. 2017 Jan 26;376(4):305-317
pubmed: 28121498
Clin Infect Dis. 2018 Mar 19;66(7):e1-e48
pubmed: 29462280
Clin Infect Dis. 2018 Aug 16;67(5):649-656
pubmed: 29538686
Clin Infect Dis. 2017 Oct 1;65(7):1218-1221
pubmed: 30060024
Stat Med. 1985 Apr-Jun;4(2):213-26
pubmed: 4023479
Scand J Gastroenterol. 1997 Sep;32(9):920-4
pubmed: 9299672
J Hosp Infect. 1998 Sep;40(1):1-15
pubmed: 9777516