Two-stage randomization designs in drug development.

One challenge in oncology drug development is to determine whether a new agent to the care of patients should be added concurrently as a new component to standard of care (SOC) induction treatment, used sequentially as an extended maintenance treatment after SOC induction for patients responding to induction therapy, or used in both the induction and the maintenance settings. A two-stage randomization design (TSRD) addresses these questions simultaneously. In such trials patients are initially randomized to two induction therapies, followed by another randomization to maintenance therapy contingent upon disease remission under induction therapy.

Cox regression methods for two-stage randomization designs.

Two-stage randomization designs (TSRD) are becoming increasingly common in oncology and AIDS clinical trials as they make more efficient use of study participants to examine therapeutic regimens. In these designs patients are initially randomized to an induction treatment, followed by randomization to a maintenance treatment conditional on their induction response and consent to further study treatment. Broader acceptance of TSRDs in drug development may hinge on the ability to make appropriate intent-to-treat type inference within this design framework as to whether an experimental induction regimen is better than a standard induction regimen when maintenance treatment is fixed.

Decreased protein C, protein S, and antithrombin levels are predictive of poor outcome in Gram-negative sepsis caused by Burkholderia pseudomallei.

Background: Acute septicemic melioidosis is associated with systemic release of endotoxin and the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin-1, and interleukin-6. Excessive release of these cytokines may lead to endothelial injury, depletion of naturally occurring endothelial modulators, microvascular thrombosis, organ failure, and death.

Method: Plasma samples drawn at baseline and after initial antimicrobial therapy in 30 patients with suspected acute severe melioidosis were assayed for D-dimer levels, protein C and protein S antigen levels, and antithrombin functional activities.

Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.

Objective: To assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]).

Design: Univariate and multivariable analysis of prospectively defined subgroups from the PROWESS study.

Setting: A total of 164 medical centers in 11 countries.

Pharmacokinetic-pharmacodynamic analysis of drotrecogin alfa (activated) in patients with severe sepsis.

Objective: We aimed to characterize the pharmacokinetics and pharmacodynamics of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis.

Methods: Patients (N = 1690) in a randomized, double-blind, placebo-controlled phase 3 trial received a 96-hour infusion of placebo (n = 840) or drotrecogin alfa (activated) (n = 850), 24 microg x kg(-1) x h(-1). Plasma samples from 680 patients were collected for pharmacokinetic assessment.