Abstract
BackgroundA 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.MethodsDAA 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.DiscussionA 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.
Highlights
A genomic biomarker identifying patients likely to benefit from drotrecogin alfa (DAA) may be clinically useful as a companion diagnostic
The ADDRESS study in sepsis patients at low risk of death [7], and the RESOLVE trial, in children with sepsis-induced cardiovascular and respiratory failure [8], were both stopped for futility
A design-based approach matching Drotrecogin alfa activated (DAA)-free controls to DAA-treated patients in a multicenter study of patients who have severe sepsis and high risk of death decreases lack of balance between groups for variables associated with risk of death and response to DAA treatment
Summary
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)). The incidence of septic shock is increasing [3] and mortality from severe sepsis and septic shock is high, ranging from 30% to 60%, respectively. PROWESS, the first Phase III, randomized, controlled trial of drotrecogin alfa (activated) (DAA) (recombinant human activated protein C), demonstrated an absolute risk reduction (ARR) of 6.1% in the 28-day mortality rate (P = 0.005) in severe sepsis [4]. There are safety concerns, including increased incidence of serious bleeding after DAA compared to placebo (5.6% DAA; 2.0% placebo, P < 0.001) [9]
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