Open Access Research

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

Djillali Annane110*, Jean Paul Mira2, Lorraine B Ware3, Anthony C Gordon4, Jonathan Sevransky5, Frank Stüber6, Patrick J Heagerty7, Hugh F Wellman8, Mauricio Neira8, Alexandra DJ Mancini8 and James A Russell9

Author Affiliations

1 Service de reanimation medicale, CIC-IT805 (INSERM), Hopital R. Poincare (AP-HP), 104 Bd Raymond Poincare, 92380, Garches, France

2 Université Paris Descartes, Sorbonne Paris Cité, Cochin Hotel-Dieu University Hospital Medical Intensive Care Unit, AP-HP, 75014, Paris, France

3 Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, 1161 21st Avenue South T1218 MCN, Nashville, TN, 37232-2650, USA

4 Section of Anaesthetics, Pain Medicine, and Intensive Care, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, UK

5 MICU, John Hopkins BMC, 5501 Hopkins Bayview Circle, Suite 4B-73, Baltimore, MD, 21224, USA

6 Universitatsklinik fur Anasthesiologie und Schmerztherapie Inselspital, 3010, Bern, Switzerland

7 Department of Biostatistics, University of Washington, F-600, Health Sciences Building, Box 357232, Office: H-665D HSB, Seattle, WA, 98195-7232, USA

8 Sirius Genomics Inc, 603-1125 Howe St, Vancouver, BC, V6Z 2K8, Canada

9 Critical Care Research Laboratories, The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul’s Hospital and University of British Columbia, Burrard Building, Rm 166-1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada

10 Hospital Raymond Poincaré (AP-HP), University of Versailles SQY, 104 boulevard Raymond Poincaré, 92380, Garches, France

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Annals of Intensive Care 2012, 2:15  doi:10.1186/2110-5820-2-15

Published: 13 June 2012

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.

Keywords:
Drotrecogin alfa (activated); Pharmacogenomics biomarker; Predictive marker; Propensity score; Severe sepsis; Treatment selection; Sepsis; Drotrecogin alfa activated (DAA); Activated protein C; Genome wide association study; Survival