A randomized controlled trial of precision bezlotoxumab treatment for Clostridioides difficile infection

Abstract

Early risk recognition for organ dysfunction and death by Clostridioides difficile infection (CDI) is an unmet need. A prediction score is developed in the BEYOND study (ClinicalTrials.gov; NCT02573571, NCT04725123, and NCT05304715). At the first stage, using 153 patients and 150 comparators, the BEYOND score was developed integrating hemoglobin; blood urea; blood interleukin-8; carriage of G alleles of rs2091172; and presence of Terrisporobacter glycolicus, Enterococcus avium, and Anaerovorax odorimutans in the stool. The score had 84.6% sensitivity and 95.8% specificity for unfavorable outcomes. At the second stage, a double-blind randomized controlled trial was performed, and 44 patients at high-risk by BEYOND score were treated with standard-of-care plus Bezlotoxumab or placebo. The primary endpoint was the incidence of organ dysfunction, CDI relapse, and/or death. This endpoint was met in 72.7% of patients in the placebo arm and 31.8% in the Bezlotoxumab arm (p = 0.015). Results suggest that BEYOND score can detect early risk in patients with CDI.

Keywords: Clostridioides difficile; bezlotoxumab; microbiome; single-nucleotide polymorphisms.

Graphical abstract

Figure 1

Suggestive SNPs of susceptibility for CDI (A) Manhattan plot presenting the p values of comparisons of SNPs between patients (n = 134) and comparators (n = 134). The cutoffs of statistical significance (red line) and suggestive significance (blue line) are provided. (B) Final step of the stepwise logistic regression procedure with group (comparators vs. CDI) as the dependent variable; odds ratios less than 1 indicate protective alleles. Abbreviations: CDI, Clostridioides difficile infection; CI, confidence interval; OR, odds ratio; SNP, single-nucleotide polymorphism.

Figure 2

Development of the BEYOND score to predict the risk of progression into unfavorable outcomes within the first 40 days from the onset of infection by Clostridioides difficile (A) Stepwise logistic regression analysis that identifies four independent host variables associated with unfavorable outcome by CDI. (B) Stepwise logistic regression analysis that identifies three bacterial species in the stool that are independently associated with unfavorable outcomes by CDI. (C) Calculation of the BEYOND score. The score is calculated in two steps. At the first step, the presence of the host variables provides individual points per variable. If the sum is more than 9, then the patient is called high-risk for unfavorable outcome. If the first step is negative (i.e., sum ≤9), RT-PCR should run for three bacterial species, and the presence of each species provides separate points. If the sum is more than −3.5, then the patient is called high-risk. If this is less than or equal to −3.5, the patients is called low-risk. (D) Total prognostic performance of the BEYOND score for unfavorable CI outcome. Abbreviations: CI, confidence interval; n. number of patients; OR; odds ratio; NPV, negative predictive value; PPV, positive predictive value; RT-PCR, real-time PCR.

Figure 3

BEYOND trial flow chart Abbreviations: ITT, intent-to-treat; n, number of patients; SoC, standard of care.

Figure 4

Comparison of the family abundance in the gut microbiome during the two stages of the BEYOND project The relative abundances of the 20 most common families in stool are shown for participants of the first stage of the project (upper row (A), n = 61) and the second stage of the project (lower row (B), n = 81). Each row provides separate distribution for patients with favorable and unfavorable outcomes of the Clostridioides difficile infection. The analysis of the second stage contains patients who failed screening because of negative BEYOND score and patients who were enrolled in the study and randomized to placebo treatment. The distributions of species between patients with favorable outcome and patients with unfavorable outcome from each stage of the project are similar.