Impact of RBX2660 on the Intestinal Microbiota of Patients With Recurrent Clostridium difficile Infection Enrolled in the Randomized Placebo-Controlled PUNCH CD 2 Trial

Abstract

Background. Perturbation of the intestinal microbiota, primarily by antibiotics, sets the stage for Clostridium difficile infection (CDI). Restoration of a variable intestinal microbiota protects against recurrence. The impact of RBX2660 on the gut micro‐biota of patients with recurrent CDI was evaluated in PUNCH CD 2, a multicenter, randomized, double‐blinded, placebo‐controlled, dose‐ranging, phase 2b study. Methods. Patients with recurrent CDI were randomized to receive either 2 doses of RBX2660 (Group A); 2 doses of placebo (Group B); or 1 dose of RBX2660 and 1 dose of placebo (Group C). RBX2660 is a microbiota‐based drug manufactured from live human‐derived microbes and targeted at the prevention of recurrent CDI. All therapies were administered via enema with doses 7 days apart. Success was defined as the absence of Clostridium difficile‐associated diarrhea at 56 days. Longitudinal 16s rRNA analysis was performed on stool samples (n = 120) from a total of 75 patients (Group A: n = 23; Group B: n = 22; Group C: n = 22) at baseline, 7 days and 30 days after the second dose of the blinded therapy sequence using the Illu‐mina MiSeq platform. The variable region V4 was targeted to identify the operational taxonomic units (OTUs) in each sample. Results. OTU analysis demonstrated higher diversity between baseline and follow‐up time points for all patients who responded successfully to their assigned treatment. This included Group B‐2 doses of placebo‐in which 12 patients did not experience recurrent CDI symptoms prior to 56 days. Specifically, successful Group A patients had an increase in Akkermansia and Bacteroides from baseline; successful Group B and C patients had a decreased abundance of Enterobacter. Of the 3 groups of patients, those in Group A (2 doses of active treatment) showed the greatest increase in bacterial diversity (number of OTUs) and abundance of taxa between baseline and all follow‐up points. Conclusion. In this randomized, controlled study of RBX2660 for recurrent CDI, 16s rRNA analysis found that patients who succeeded with their assigned therapy had a more diverse intestinal microbiota at 7 and 30 days compared with baseline.