Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection

Abstract

Background: Recurrent Clostridioides difficile infection, associated with dysbiosis of gut microbiota, has substantial disease burden in the USA. RBX2660 is a live biotherapeutic product consisting of a broad consortium of microbes prepared from human stool that is under investigation for the reduction of recurrent C. difficile infection.

Methods: A randomized, double-blind, placebo-controlled, phase III study, with a Bayesian primary analysis integrating data from a previous phase IIb study, was conducted. Adults who had one or more C. difficile infection recurrences with a positive stool assay for C. difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of C. difficile infection diarrhea within 8 weeks of study treatment.

Results: Of the 320 patients screened, 289 were randomly assigned and 267 received blinded treatment (n = 180, RBX2660; n = 87, placebo). Original model estimates of treatment success were 70.4% versus 58.1% with RBX2660 and placebo, respectively. However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo, with an estimated treatment effect of 13.1% and a posterior probability of superiority of 0.991. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the RBX2660 and the placebo groups. Overall, RBX2660 was well tolerated, with manageable adverse events. The incidence of treatment-emergent adverse events was higher in RBX2660 recipients compared with placebo and was mostly driven by a higher incidence of mild gastrointestinal events.

Conclusions: RBX2660 is a safe and effective treatment to reduce recurrent C. difficile infection following standard-of-care antibiotics with a sustained response through 6 months.

Clinical trial registration: NCT03244644; 9 August, 2017.

Conflict of interest statement

Sahil Khanna has received grants or contracts from Rebiotix (a Ferring company), Finch Therapeutics, Seres Therapeutics, and Vedanta BioSciences, consulting fees from Niche Pharmaceuticals and Immuron Limited, participated on advisory or data safety monitoring boards for Ferring Pharmaceuticals, and has stock options with Jetson Probiotics. Christine Lee has received grants or contracts from Rebiotix, Inc., Seres Therapeutics, and Summit Therapeutic and participated on advisory or data safety monitoring boards for Ferring Pharmaceuticals and Pfizer. Thomas Louie has received consulting fees from Crestone, MGB BioPharma, Rebiotix, Inc., and Seres Therapeutics and participated on advisory boards for Seres Therapeutics and Vedanta BioSciences. Scott M. Berry has ownership in Berry Consultants who received fees for trial design and analyses; Tricia Braun, Lindy Bancke, and Xin Su are employees of Rebiotix, Inc. or were during conduct of the study. Paul Feuerstadt has received consulting fees from Rebiotix, Inc. and Takeda Pharmaceuticals, honoraria from Ferring Pharmaceuticals, Seres Therapeutics, and Takeda Pharmaceuticals, and participated on advisory or data safety monitoring boards for Ferring Pharmaceuticals, Seres Therapeutics, and Takeda Pharmaceuticals. Humberto Aguilar, Maha Assi, Julia Garcia-Diaz, Whitfield Knapple, Gary P. Wang, and David Yoho have no conflicts of interest to declare.

© 2022. The Author(s).

Figures

Fig. 1

PUNCH CD3 study profile. aOnset of AE occurred prior to treatment administration. AE adverse event, ITT intent-to-treat, mITT modified intent-to-treat, PP per-protocol

Fig. 2

Kaplan–Meier analysis of time to Clostridioides difficile infection (CDI) recurrence through 6 months (modified intent-to-treat population)

Fig. 3

Incidence and severity of adverse events (AEs) from baseline through 6 months of blinded treatment. Most AEs occurred during the first 2 weeks and were predominantly mild to moderate in both groups, with differences between RBX2660 and placebo primarily attributable to mild events by maximum severity. Adverse events declined after the initial 2 weeks, with comparable rates of AEs between RBX2660 and placebo. Participants may be represented in more than one interval; treatment failures censored at Clostridioides difficile infection recurrence