Coenrollment of critically ill patients in PROSPECT: characteristics and association with treatment efficacy and safety.

Abstract

Introduction: Coenrollment is the enrollment of one participant into more than one study. While coenrollment can enhance research efficiency, it theoretically may result in treatment interactions that distort effect estimates. This study aimed to explore the sensitivity of safety and efficacy outcomes to coenrollment in an international, blinded randomized controlled trial evaluating probiotic use in critically ill patients (PROSPECT: Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial; [NCT02462590]).

Methods: In this planned secondary analysis of PROSPECT, we performed Cox proportional hazards analyses to assess the sensitivity of the treatment effect of probiotics to coenrollment on the primary outcome of ventilator-associated pneumonia. Secondarily, we examined the characteristics of coenrolled patients, studies, and centers using descriptive statistics, explored factors associated with coenrollment via a multilevel logistic regression model, and conducted Fisher's exact tests to evaluate the difference in adverse event rates (defined as Lactobacillus species from a sterile site or cultured as the sole or predominant organism from a nonsterile site) by coenrollment status.

Results: Of 2650 PROSPECT participants recruited across 44 centers, 568 patients (21.4%) were coenrolled a total of 680 times across 115 studies. Coenrollment did not modify the effect of probiotics on the primary outcome of ventilator-associated pneumonia (p = 0.630). Patients who were coenrolled in any other study had a higher rate of adverse events compared to non-coenrolled patients (p = 0.011); however, post hoc testing found no difference in adverse events between patients coenrolled specifically into at least one other randomized controlled trial and patients who were not coenrolled into another randomized controlled trial (i.e., coenrolled into an observational study or not coenrolled at all; p = 0.126). Multivariable analyses found more severely ill patients (p = 0.038) and patients from centers with a longer PROSPECT recruitment period (p = 0.047) were more likely to be coenrolled.

Conclusion: In this international, blinded trial, one-fifth of patients enrolled were coenrolled in at least one other study, which had no influence on the effect of probiotics on the primary outcome. Coenrolled patients were more likely to have higher disease severity, and to be recruited from a center with a longer history of participation in PROSPECT.

Trial registration: The PROSPECT trial was registered in ClinicalTrials.gov NCT02462590. Registered on June 2015.