Background: Antibiotics used to treat Clostridioides difficile infection (CDI) can predispose patients to recurrent CDI (rCDI). Gut microbiome restoration by fecal microbiota transplantation is recommended by multiple guidelines after ≥2 episodes of rCDI, with no guideline-recommended options to restore the microbiome earlier in the course of CDI. RBX2660 is a standardized, microbiota-based live biotherapeutic being investigated as a treatment option to reduce recurrence of CDI in adults. RBX2660 is administered as a single dose via rectal administration without the need for sedation, colonoscopy, or bowel preparation. A prespecified Bayesian analysis of the phase 3 PUNCH CD3 (NCT03244644) study, integrating data from the phase 2b PUNCH CD2 (NCT02299570) study, demonstrated that the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo. In this post hoc analysis, we report the efficacy and safety of RBX2660 in a subgroup of participants with only 1 episode of rCDI before enrollment.

Methods: Participants enrolled in PUNCH CD3 were ≥18 years old with ≥1 rCDI episode as determined by the treating physician and assessed with current standard-of-care (SOC) diagnostic methods. After completing SOC antibiotic therapy for the enrolling CDI episode, participants received a single blinded dose of RBX2660 or placebo. Treatment success was defined as the absence of CDI recurrence for 8 weeks after treatment. Participants were monitored for recurrence through 6 months after treatment. Treatment-emergent adverse events (TEAEs) were summarized for the double-blind treatment period within 8 weeks.

Results: In the modified intent-to-treat population, 86 of 262 participants (32.8%) were enrolled after 1 rCDI episode. Participants were mostly white (93.0%) and female (66.3%), with a mean age of 58 years. At week 8, 79.2% (42/53) of RBX2660-treated and 60.6% (20/33) of placebo-treated participants achieved treatment success. Of responders, 90.5% (38/42) treated with RBX2660 and 85.0% (17/20) treated with placebo remained recurrence-free at 6 months. TEAEs were reported by 54.7% (29/53) of RBX2660-treated and 33.3% (11/33) of placebo-treated participants; mild events, mostly gastrointestinal, accounted for the difference. Serious adverse events were reported by 5.7% (3/53) of RBX2660-treated and 6.1% (2/33) of placebo-treated participants. No potentially life-threatening TEAEs or TEAEs leading to discontinuation or death were reported.

Conclusions: After 1 rCDI episode, RBX2660-treated participants had numerically higher treatment success at week 8 and sustained response at 6 months compared with placebo. Overall, TEAEs were typically mild to moderate in severity and comprised mainly gastrointestinal events. These results support the efficacy and safety of RBX2660 in reducing rCDI at first recurrence.