The PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial) study, a multicenter randomized controlled trial (RCT) conducted across 44 sites in Canada, the United States, and Saudi Arabia between July 2015 and March 2019, investigated the efficacy of Lactobacillus rhamnosus GG in preventing ventilator-associated pneumonia (VAP) and other infections in critically ill patients. A recent retrospective analysis of the PROSPECT trial has shed light on factors influencing patient enrollment rates in such large-scale clinical trials.
The original PROSPECT trial randomized 2653 invasively mechanically ventilated patients to receive either L. rhamnosus GG (1 × 10^10 colony-forming units) or a placebo for up to 60 days. The primary outcome of the main trial indicated that L. rhamnosus GG did not significantly reduce the risk of VAP, Clostridioides difficile infection, or other clinically important endpoints.
Factors Influencing Enrollment Rates
The retrospective analysis, focusing on 41 sites, examined site-level data to identify predictors of enrollment. The primary outcome measure for this analysis was the average monthly enrollment rate per site, accounting for the number of ICU beds to mitigate confounding factors such as ICU size and duration of site engagement.
Key findings from the analysis include:
- Time to First Randomization: The time elapsed between regulatory approval and the enrollment of the first patient was a significant factor. A longer delay was associated with lower monthly enrollment rates.
- Quartile of Site Engagement: Sites that joined the trial later, specifically in the 2nd, 3rd, or 4th quartile of the overall trial recruitment period, exhibited lower enrollment rates compared to those that joined in the 1st quartile.
- Research Coordinator Experience: While not statistically significant, there was a trend suggesting that sites with more experienced lead research coordinators (≥10 years of ICU research experience) at the time of regulatory approval tended to have higher average monthly recruitment rates.
Statistical Analysis
Multivariable negative binomial regression was employed to estimate the association between predictor variables and site enrollment rate. The analysis revealed incident rate ratios (IRR) and 95% confidence intervals (CI) to quantify the impact of each factor. Although the experience of research coordinators did not reach statistical significance (p>0.05), the trends observed suggest its potential importance.
Implications for Clinical Trial Design
These findings underscore the importance of efficient site activation and early engagement in clinical trials. Minimizing delays between regulatory approval and patient enrollment can significantly impact overall trial success. While the study did not find L. rhamnosus GG to be effective in preventing VAP, understanding enrollment dynamics is crucial for designing and executing future clinical trials in critically ill patient populations. Further research may explore strategies to expedite site activation and leverage the experience of research coordinators to optimize patient recruitment.
