Use of a screening authorization and randomization center for severe sepsis patient qualification and real-time enrollment in a phase 2 trial of eritoran tetrasodium (E5564), a TLR4 antagonist

Introduction

Trials of many promising sepsis modifiers have often failed to demonstrate benefits because of, among other reasons, poor characterization of enrolled patients.

Materials

Advantages of utilizing a screening authorization and randomization center (SAC) method to characterize patients in trials for sepsis modifiers are presented.

Methods

A central SAC on call 24 hours per day was employed in a phase 2, double-blind, randomized comparison of eritoran 45 and 105 mg versus placebo. SAC activities were conducted (January 2002 to April 2005) by six clinical pharmacists. Severe sepsis was defined with at least three systemic inflammatory response syndrome criteria within 12 hours before onset of ≥1 new organ dysfunction. Patients were randomized and treated within 8 to 12 hours. The 8-hour to 12-hour window for qualification and start of treatment was the primary challenge to the SAC and study sites. Each site used two sequences of drug assignment based on Acute Physiology and Chronic Health Evaluation (APACHE) II predicted mortality to yield a balanced allocation of high and low APACHE II predicted mortality within the three treatment groups: one sequence for subjects with APACHE II predicted mortality 20 to 50%, and another for subjects with predicted mortality 51 to 80% as calculated by the SAC.

Results

The SAC screened 1,025 patients from 78 sites; 300 patients from 54 sites were randomized, and 293 were treated. The Independent Clinical Evaluation Committee subsequently qualified 229/293 (78%). Calls to the SAC averaged 24 patients/month; eight patients/month were randomized (33%). Enrollments ranged from 0 to 39 patients/site; 35 sites randomized ≥3 patients; nine sites randomized ≥10 patients. Of 35 sites with ≥3 patients, 6 to 100% led to randomization.

Conclusion

Advantages of utilizing the SAC included a high evaluable rate of enrolled patients, correct Predicted Risk of Mortality calculations, timing of qualifying organ failures, drug preparation advice, verification of key clinical data, and eligibility with sponsor prior to enrollment. SAC activities ensured an informative phase 2 trial and will be utilized for the phase 3 trial.