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Correspondence: djillali.annane@rpc.aphp.fr 1 Service de reanimation medicale, CIC-IT805 (INSERM), Hopital R. Poincare (AP-HP), 104 Bd Raymond Poincare, 92380, Garches, France 10 Hospital Raymond Poincaré (AP-HP), University of Versailles SQY, 104 boulevard Raymond Poincaré, 92380, Garches, France.

DA, AM, and JR contributed to the conception and design of the study and drafted this manuscript. JPM, LW, AG, JS, and FS contributed to the design of the study and helped drafting the manuscript.

PH, HW, MN contributed in the design of the study and developed the statistical plan.

All authors read and approved the final manuscript.

We thank all the patients who are part of this study and their families.

We also thank the caregivers of the patients in these centers.

We also thank Nicholas J. Schork, PhD, Director, Bioinformatics & Biostatistics, Scripps Translational Science Institute, Professor, The Scripps Research Institute, Adjunct Professor, Psychiatry, University of California, San Diego, and Robert F. Balshaw, PhD, Director, Biometrics, Syreon Corporation, Adjunct Professor, Statistics, University of British Columbia and Simon Fraser University, Vancouver, for their reviews of the statistical aspects of the protocol.

Dr Gordon is a U.K. National Institute for Health Research (NIHR) Clinician Scientist award holder and is grateful for funding from the NIHR comprehensive Biomedical Research Centre funding stream.

Dr. Russell reports holding stock in Sirius Genomics Incorporated, which has submitted patents owned by the University of British Columbia (UBC) and licensed to Sirius Genomics, which are related to the genetics of sepsis and its treatment.

The University of British Columbia also has submitted a patent related to the use of vasopressin in septic shock.

Drs. Russell and Gordon report being inventors on these patents.

Dr. Russell reports receiving consulting fees from Ferring Pharmaceuticals (which manufactures vasopressin and is developing a selective V1a agonist), from Astra Zeneca (which is developing an anti-TNFα), from BioCritica (which used to sell activated protein C in the United States), and from Sirius Genomics Inc.

Dr. Russell reports having received grant support from Sirius Genomics, Ferring Pharmaceuticals, Astra Zeneca, and Eli Lilly, which is provided to and administered by UBC.

Dr. Russell has received speaking honoraria from Pfizer and Eli Lilly.

Dr. Gordon has received consulting and speaker fees from Eli Lilly.

Dr. Gordon reports having previously been employed by Sirius Genomics and subsequently receiving consulting fees.

Subjects:

Research Funding:

This study is funded by Sirius Genomics Inc.

Dr Gordon is a U.K. National Institute for Health Research (NIHR) Clinician Scientist award holder and is grateful for funding from the NIHR comprehensive Biomedical Research Centre funding stream.

Dr. Ware is funded by an American Heart Association Established Investigator Award.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Critical Care Medicine
  • General & Internal Medicine
  • 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

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

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Journal Title:

Annals of Intensive Care

Volume:

Volume 2, Number 1

Publisher:

, Pages 1-17

Type of Work:

Article | Final Publisher PDF

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 wellmatched control group is critical to this multicenter, retrospective, controlled, outcomeblinded, 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. Twophase 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 inhospital 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.

Copyright information:

©2012 annane et al.; licensee Springer.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 2.0 Generic License (http://creativecommons.org/licenses/by/2.0/).

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