A Randomized, Double-Blind, Phase 3 Safety and Efficacy Study of Ridinilazole Versus Vancomycin for Treatment of Clostridioides difficile Infection: Clinical Outcomes With Microbiome and Metabolome Correlates of Response

Abstract

Background: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI.

Methods: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs.

Results: Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (∼3.5-fold), and increased the resistome.

Conclusions: Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566.

Keywords: Clostridioides difficile; bile acids; microbiome; ridinilazole; vancomycin.

Graphical Abstract

https://tidbitapp.io/tidbits/test-7e5035e4-ad1b-417a-bee9-788b33377fe0

Figure 1.

Participant enrollment, randomization, and follow-up. *Subjects could have more than 1 reason for exclusion from the mITT population. The ITT population consists of all randomized subjects and is summarized by randomized treatment assignment; the safety population consists of all subjects who took at least 1 dose of study treatment and is summarized by the actual treatment received by subjects; the mITT population consists of all randomized and treated subjects who had ≥3 UBMs 24 hours prior to randomization and had positive toxin test or CCNA test at baseline and is summarized by randomized treatment assignment. Abbreviations: CCNA, cell cytotoxicity neutralization assay; ITT, intent-to-treat; mITT, modified intent-to-treat; UBM, unformed bowel movement.

Figure 2.

Clinical efficacy outcomes in 745 patients with CDI randomized to ridinilazole or vancomycin. A, Depicts SCR, clinical response, and recurrence rate in the mITT population. B, Depicts CDI recurrence rate in prespecified subgroups. Numbers above the boxes indicate the median percentage of SCR, clinical response, and recurrence, as appropriate. The primary endpoint was SCR, defined as clinical response and no recurrent CDI through 30 days post–end of treatment. Abbreviations: CDI, Clostridioides difficile infection; COVID-19, coronavirus disease 2019; IDSA, Infectious Diseases Society of America; mITT, modified intent-to-treat; SCR, sustained clinical response; UBM, unformed bowel movement.

Figure 3.

Cox proportional hazards of developing a recurrence of CDI shown as a percentage of the study population experiencing a CDI recurrence during the 100 days of study. P values were obtained by log-rank test stratified by randomization stratification factors, age group (<65 years or ≥65 years) and history of CDI in the past 12 months (none or 1–3 previous occurrences). HRs and 95% CIs were estimated using a Cox proportional hazards model stratified by the 2 randomization stratification factors. Abbreviations: CDI, Clostridioides difficile infection; CI, confidence interval; HR, hazard ratio.

Figure 4.

A, Depicts SBAs per treatment group, at BSL, EOT, and D40 post-treatment for RDZ or VAN. B, Depicts SBAs per treatment group including sustained clinical response (left) and recurrence (right), regardless of treatment arm randomization. Circles show the means; horizontal bars show the medians. Numbers below the boxplots indicate the number of samples at each visit for time point in RDZ and VAN treatment groups (A). “N” indicates number of samples included in the analysis, irrespective of treatment group. Abbreviations: BSL, baseline; D40, day 40; EOT, end of treatment; RDZ/Rid, ridinilazole; SBA, secondary bile acid; VAN/Van, vancomycin.

Figure 5.

Gut microbiome differences in participants receiving RDZ or VAN as measured by richness and Shannon index (alpha-diversity). Richness refers to the total number of bacterial species present in participants receiving ridinilazole or vancomycin. The Shannon index assesses diversity by measuring the number and evenness of bacterial species between 2 groups. The higher the Shannon index, the greater the diversity in a group. Circles show the means; horizontal bars show the medians. Numbers below the boxplots indicate the number of samples at each visit for time point in RDZ and VAN treatment groups. Median richness values in RDZ and VAN groups were 45.0 vs 45.5 at BSL, 48.0 vs 25.0 at EOT, and 85.0 vs 68.0 at D40, respectively. Median Shannon index values in RDZ and VAN groups were 2.42 vs 2.41 at BSL, 2.55 vs 1.84 at EOT, and 3.16 vs 2.93 at D40, respectively. Abbreviations: BSL, baseline; D40, day 40; EOT, end of treatment; RDZ, ridinilazole; VAN, vancomycin.

Figure 6.

Gut microbiome differences at the phylum level in participants taking RDZ or VAN measured by metagenomic deep shotgun sequencing at BSL, EOT, or D40 post-treatment. “N” indicates numbers of samples at the indicated time points in RDZ and VAN treatment groups used for the Shannon index and phyla relative abundance analyses. Median Shannon index and median relative abundance of bacterial phyla >2% at any given time point are represented. Phyla with lower relative abundances are included in the “Other” category. Abbreviations: BSL, baseline; D40, day 40; EOT, end of treatment; FDR, false discovery rate; RDZ, ridinilazole; VAN, vancomycin. ⁺For the analysis of the relative abundance of bacterial phyla, 313 and 316 baseline samples for RDZ and VAN were used, respectively (vs 304 samples for Shannon index), and 338 EOT samples for VAN were used (vs 337 samples for Shannon index). *Significant change from baseline in Shannon index using Wilcoxon signed­ rank test comparing baseline with post-baseline visits, P < .05. ^#Significant change in the phylum relative abundance compared with baseline using the FDR-adjusted P value from the Wilcoxon signed-rank test comparing baseline with post-baseline visits.

Figure 7.

Presence of ARGs, carbapenem RGs, or third-generation cephalosporin RGs in the stool of participants taking RDZ or VAN at BSL, EOT, and D40. Circles show the means; horizontal bars show the medians. Numbers below the boxplots indicate the number of samples at each time point in RDZ and VAN treatment arms. P values from Wilcoxon rank-sum test to compare RDZ and VAN treatments. In RDZ and VAN groups, respectively, median relative abundances in total ARGs were 0.11% vs 0.11% at BSL, 0.10% vs 0.27% at EOT, and 0.051% vs 0.06% at D40; median relative abundances in carbapenem-RGs were 0.0031% vs 0.0029% at BSL, 0.0034% vs 0.024% at EOT, and 0.00055% vs 0.0011% at D40; median relative abundances in third-generation cephalosporin-RGs were 0.0082% vs 0.0083% at BSL, 0.0089% vs 0.056% at EOT, and 0.0025% vs 0.0039% at D40. Abbreviations: ARG, antibacterial resistance gene; BSL, baseline; D40, day 40; EOT, end of treatment; RDZ, ridinilazole; RG, resistance gene; VAN, vancomycin.