Design, conduct, and analysis of a multicenter, pharmacogenomic, biomarker study in matched patients with severe sepsis treated with or without drotrecogin Alfa (activated). - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Annals of Intensive Care Year : 2012

Design, conduct, and analysis of a multicenter, pharmacogenomic, biomarker study in matched patients with severe sepsis treated with or without drotrecogin Alfa (activated).

Jean Paul Mira
  • Function : Author
  • PersonId : 928244
Lorraine Ware
  • Function : Author
  • PersonId : 928245
Jonathan Sevransky
  • Function : Author
  • PersonId : 928247
Frank Stüber
  • Function : Author
  • PersonId : 928248
Patrick Heagerty
  • Function : Author
  • PersonId : 928249
Hugh Wellman
  • Function : Author
  • PersonId : 928250
Mauricio Neira
  • Function : Author
  • PersonId : 928251
Alexandra Mancini
  • Function : Author
  • PersonId : 928252
James Russell
  • Function : Author
  • PersonId : 928253

Abstract

ABSTRACT: BACKGROUND: A genomic biomarker identifying patients likely to benefit from drotrecogin alfa (activated) (DAA) may be clinically useful as a companion diagnostic. This trial was designed to validate biomarkers (improved response polymorphisms (IRPs)). Each IRP (A and B) contains two single nucleotide polymorphisms that were associated with a differential DAA treatment effect. METHODS: DAA is typically given to younger patients with greater disease severity; therefore, a well-matched control group is critical to this multicenter, retrospective, controlled, outcome-blinded, genotype-blinded trial. Within each center, DAA-treated patients will be matched to controls treated within 24 months of each other taking into account age, APACHE II, cardiovascular, respiratory, renal, and hematologic dysfunction, mechanical ventilation status, medical/surgical status, and infection site. A propensity score will estimate the probability that a patient would have received DAA given their baseline characteristics. Two-phase data transfer will ensure unbiased selection of matched controls. The first transfer will be for eligibility and matching data and the second transfer for outcomes and genotypic data. The primary analysis will compare the effect of DAA in IRP + and IRP - groups on in-hospital mortality through day 28. DISCUSSION: A design-based approach matching DAA-free to DAA-treated patients in a multicenter study of patients who have severe sepsis and high risk of death will directly compare control to DAA-treated groups for mortality by genotype. Results, which should be available in 2012, may help to identify the group of patients who would benefit from DAA and may provide a model for future investigation of sepsis therapies.
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inserm-00720878 , version 1 (26-07-2012)

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Djillali Annane, Jean Paul Mira, Lorraine Ware, Anthony Gordon, Jonathan Sevransky, et al.. Design, conduct, and analysis of a multicenter, pharmacogenomic, biomarker study in matched patients with severe sepsis treated with or without drotrecogin Alfa (activated).. Annals of Intensive Care, 2012, 2 (1), pp.15. ⟨10.1186/2110-5820-2-15⟩. ⟨inserm-00720878⟩

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