Enrolment patterns in a randomized controlled trial of probiotics in critically ill patients: a retrospective analysis of the PROSPECT trial

Background

Projected patient enrolment rates in multicenter randomized clinical trials (RCTs) are often over-estimated, leading to delayed trial completion, cost over-runs, and applications for grant extensions. Furthermore, low patient recruitment is the one of the most frequent reasons for trial discontinuation [1, 2].

While site selection for multicenter trials often hinges on pragmatic considerations, including interest in participating, local case-mix alignment with eligibility criteria, and past collaborations with the coordinating team [3], identifying sites that may face enrollment challenges before commencement may allow trial methods centers to extend early support. This could include sharing recruitment strategies and providing individualized mentorship to enhance site capacity, ensuring success in the current trial and fostering future collaboration [4].

Site-level factors influencing patient enrollment are unclear, and published trials seldom report on enrolment patterns or their determinants. Our study addresses this gap using a retrospective analysis of a randomized trial testing the effects of probiotics on infectious outcomes during critical illness (PROSPECT: Probiotics to prevent Severe Pneumonia and Endotracheal Colonization Trial; NCT02462590) [5] aiming to (1) describe patient enrolment across sites over the course of the trial and (2) examine early site factors which may be associated with monthly enrolment.

Methods

PROSPECT trial summary

The PROSPECT trial was conducted between July 2015 and March 2019. We enrolled a total of 2653 patients across 44 sites (288 patients in the pilot and vanguard phases, [6, 7] and 2365 patients in the main phase of the trial, which is the focus of this report). There were 42 centers in Canada, 1 in the United States, and 1 in Saudi Arabia. In PROSPECT, we randomized invasively mechanically ventilated patients to receive the study product (1 × 10¹⁰ colony-forming units of Lactobacillus rhamnosus GG) or an identical enteral placebo for up to 60 days, until discharge from ICU [8]. We found that L. rhamnosus GG did not reduce the risk of ventilator-associated pneumonia, Clostridioides difficile or other infections, or any other clinically important endpoints [5]. We summarize the trial timeline in Fig. 1.

Fig. 1 [Images not available. See PDF.]

PROSPECT Timeline and Milestones. Timeline of the PROSPECT trial, including major milestones, beginning with pilot trial registration in June 2013 and completing with final manuscript published in...