Septic Shock Clinical Trial
Official title:
A Multicenter Pharmacogenomic Biomarker Study in Matched Patients With Severe Sepsis Treated With or Without Recombinant Human Activated Protein C [Xigris®, Drotrecogin Alfa (Activated)]
The overall purpose of the study is to determine whether either of the Improved Response Polymorphisms (IRPs) individually predicts a differential DrotAA treatment effect in patients with severe sepsis and high risk of death. This will be an international, multicenter, "prospective-retrospective", nonrandomized, controlled, outcome-blinded, genotype-blinded, matched-patients study. No prospective enrollment or treatment of patients will occur under this protocol. Retrospectively collected clinical data and DNA samples will be analyzed for existing cohorts of patients with severe sepsis who were previously treated with DrotAA (treatment group) or not (control group) as part of their standard care in an ICU.
This will be a multicenter, "prospective-retrospective", controlled, matched-patients study.
Retrospective phenotypic data and DNA samples will be obtained from patient registries and
clinical trials where the study hypotheses were not related to DrotAA treatment. The
prospective aspect of this study will be the statistical testing of prespecified hypotheses
regarding the IRP genotype as a predictive biomarker for differential DrotAA treatment
effects.
To control for differences in standard of care in different countries and medical centers,
the selection of matched control patients will be performed within each cohort. Control
patients will be selected to match the DrotAA-treated patients using an algorithm that
matches on baseline demographic and disease characteristics that may have influenced the
decision to give DrotAA or that may impact survival. A propensity score (the likelihood for
having received DrotAA treatment) will be derived using the matching variables that are
common in all cohorts. The number of matched control patients for each treated patient will
be variable, up to a maximum of 3.
The selection of the control patients via the matching algorithm will be conducted by an
independent clinical research organization (CRO) in a blinded manner - specifically without
knowledge of survival outcome, other outcome data, and genotype. A two-phase transfer of
data from each center will be implemented to ensure that the selection of matched control
patients is implemented in a blinded manner. The first step will involve the transfer of the
baseline data for all variables needed to conduct the matching. Once the control patients
have been identified for each cohort, the outcomes data will be transferred to the CRO in
the second phase of data transfer.
Centralized genotyping using a validated Taqman®-based analytical method will be conducted
on the DNA samples for all matched patients. The genotyping laboratory will be blinded to
treatment and outcome.
The total number of patients in the available cohorts is >23,000, with approximately 800 who
have received DrotAA as part of their standard ICU-based care. After applying eligibility
criteria to all patients and selecting the matched control patients, it is expected that the
final analysis will include approximately 3000 patients.
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Time Perspective: Retrospective
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