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Sources of variability on the estimate of treatment effect in the PROWESS trial: Implications for the design and conduct of future studies in severe sepsis*

Objective:To elucidate sources of variability in the estimate of treatment effects in a successful phase 3 trial in severe sepsis and to assess their implications on the design of future clinical trials. Design:Retrospective evaluation of prospectively defined subgroups from a large phase 3, placebo-controlled clinical trial (PROWESS). Setting:The study involved 164 medical centers. Patients:Patients were 1,690 patients with severe sepsis. Interventions:Drotrecogin alfa (activated) (Xigris) 24 &mgr;g/kg/hr for 96 hrs, or placebo. Measurements and Main Results:All prospectively defined subgroups were examined to identify treatment effects that potentially differed across subgroup strata (assessed by Breslow-Day p < .10). Potential interactions were identified for subgroups defined by a) presence vs. absence of a significant protocol violation (p = .07); b) original vs. amended protocol (p = .08); and c) Acute Physiology and Chronic Health Evaluation (APACHE) II quartile at baseline (p = .09). No treatment benefit was observed in patients having a protocol violation, regardless of type. There appeared to be less treatment effect in patients enrolled under the original vs. amended protocol. The risk ratio exceeded 1.0 for patients in the lowest APACHE II score quartile. A highly significant correlation was observed between the sequence of enrollment at a site, the frequency of protocol violations, and the observed treatment effect. As enrollment increased, frequency of protocol violations decreased (p < .0001) and the treatment effect improved. The correlation between the sequence of enrollment and improvement in treatment effect remained even after removal of patients with protocol violations. Removal of the first block of patients at each site from the analysis reduced the extent of interaction by protocol version and APACHE II score. Conclusions:A learning curve appeared to be present within the PROWESS trial such that the ability to demonstrate efficacy improved with increasing site experience. This potential learning curve may have implications for design of future trials. Investigational sites may need to require a minimum level of protocol-specific experience to appropriately implement a given trial. This experience should be an important consideration in designing trials and analysis plans. Diligence by coordinating centers, site investigators, study coordinators, and sponsors is necessary to ensure that the protocol is executed as designed such that a treatment benefit, if present, will be evident.