Durable reduction of Clostridioides difficile infection recurrence and microbiome restoration after treatment with RBX2660: results from an open-label phase 2 clinical trial

Abstract

Background: Effective treatment options for recurrent Clostridioides difficile infection (rCDI) are limited, with high recurrence rates associated with the current standard of care. Herein we report results from an open-label Phase 2 trial to evaluate the safety, efficacy, and durability of RBX2660-a standardized microbiota-based investigational live biotherapeutic-and a closely-matched historical control cohort.

Methods: This prospective, multicenter, open-label Phase 2 study enrolled patients who had experienced either ≥ 2 recurrences of CDI, treated by standard-of-care antibiotic therapy, after a primary CDI episode, or ≥ 2 episodes of severe CDI requiring hospitalization. Participants received up to 2 doses of RBX2660 rectally administered with doses 7 days apart. Treatment success was defined as the absence of CDI diarrhea without the need for retreatment for 8 weeks after completing study treatment. A historical control group with matched inclusion and exclusion criteria was identified from a retrospective chart review of participants treated with standard-of-care antibiotics for recurrent CDI who matched key criteria for the study. The primary objective was to compare treatment success of RBX2660 to the historical control group. A key secondary outcome was the safety profile of RBX2660, including adverse events and CDI occurrence through 24 months after treatment. In addition, fecal samples from RBX2660-treated participants were sequenced to evaluate microbiome composition and functional changes from before to after treatment.

Results: In this Phase 2 open-label clinical trial, RBX2660 demonstrated a 78.9% (112/142) treatment success rate compared to a 30.7% (23/75) for the historical control group (p < 0.0001; Chi-square test). Post-hoc analysis indicated that 91% (88/97) of evaluable RBX2660 responders remained CDI occurrence-free to 24 months after treatment demonstrating durability. RBX2660 was well-tolerated with mostly mild to moderate adverse events. The composition and diversity of RBX2660 responders' fecal microbiome significantly changed from before to after treatment to become more similar to RBX2660, and these changes were durable to 24 months after treatment.

Conclusions: In this Phase 2 trial, RBX2660 was safe and effective for reducing rCDI recurrence as compared to a historical control group. Microbiome changes are consistent with restorative changes implicated in resisting C. difficile recurrence. Clinical Trials Registration NCT02589847 (10/28/2015).

Keywords: Clinical trial; Clostridioides difficile; Durability; Microbiota-based therapy; Recurrence; Response.

Conflict of interest statement

ED, DG, GH, CL, and RO serve on the Rebiotix Physician Advisory Board and DG is Medical Director for Rebiotix, Inc. SK and HD received research support and consulting fees from Rebiotix, Inc. KB, AH, and SM are employees of Rebiotix, Inc. SJ and DY declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Consort diagram showing participant enrollment, allocation, follow up, and analysis

Fig. 2

Non-parametric multidimensional similarity analysis (NDMS) based on Bray–Curtis dissimilarity for microbiome compositions of RBX2660 and responder microbiome compositions before treatment (BL) and 1, 4, and 8 weeks after last received RBX2660 treatment. A Treatment responders. B Treatment non-responders

Fig. 3

Microbiome composition and alpha diversity for RBX2660 and responders before and after treatment. A Sample and group mean (π) relative abundances at the class level for classes comprising at least 3% relative abundance at one or more time points, denoted as before treatment (BL), 7, 30, 60 days after treatment (7D, 30D, 60D), or 6, 12, 24 months after last received RBX2660 treatment (6 M, 12 M, 24 M). Individual samples are represented as dots, and group means (π) with upper and lower confidence intervals (red boxes) were calculated based on maximum likelihood estimate using the Dirichlet multinomial. B Group mean relative abundances (π) with upper and lower confidence intervals for subset of participants who provided all four time points shown—a repeated measurements analysis. C Alpha diversity of RBX2660 and participant samples for each time point group, expressed as the mean and standard deviation of the Shannon indices. Lines with an asterisk (*) indicate statistically significant differences (p < 0.05, t-test) between two time point groups

Fig. 4

Microbiome composition and alpha diversity for non-responders before and after treatment. A Sample and group mean (π) relative abundances at the class level for classes comprising at least 3% relative abundance at one or more time points, denoted as before treatment (BL) and 7 and 30 days after last received RBX2660 treatment (7D, 30D). Class abbreviations refer to the taxonomic classes in Fig. 3. B Alpha diversity of non-responders for each time point group, expressed as the mean and standard deviation of the Shannon indices. There were no significant differences among the time points

Fig. 5

Effect size of each time point group of responders and non-responders compared with RBX2660. Effect size is expressed as a modified Cramer criterion, ϕ, for each pairwise comparison