Dubberke, Erik R.

Background: Fecal microbiota, live-jslm (RBL) is approved in the United States and Canada for prevention of recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment. Objectives: Provide an updated integrated safety analysis, incorporating final safety data from Punch CD3-OLS. Design: Safety data were combined from five RBL trials: three phase II and two phase III trials. Methods: Adult participants had documented rCDI and completed SOC therapy before receiving one or two doses of RBL or placebo, rectally administered as one treatment course. Treatment-emergent adverse events (TEAEs) were recorded for ⩽6 months. Results: TEAEs were reported in 70.9% (845/1192) of RBL recipients; most TEAEs were mild to moderate and gastrointestinal in nature. Most serious TEAEs were related to preexisting conditions or CDI. There was no clustering of serious TEAEs. Most TEAEs leading to death were related to preexisting conditions. Conclusion: Overall, data demonstrate RBL has a favorable 6-month safety profile. Trial registration: ClinicalTrials.gov: NCT01925417; NCT02299570; NCT02589847; NCT03244644; NCT03931941.

Abstract Background The aim of this study was to evaluate the safety and efficacy of fecal microbiota, live-jslm (RBL; REBYOTA)—the first single-dose, broad consortia microbiota-based live biotherapeutic approved by the US Food and Drug Administration for preventing recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment. Methods PUNCH CD3-OLS was a prospective, phase 3, open-label study, conducted across the US and Canada. Participants were aged ≥18 years with documented rCDI and confirmed use of SOC antibiotics. Participants with comorbidities including inflammatory bowel disease and mild-to-moderate immunocompromising conditions could be enrolled. A single dose of RBL was rectally administered within 24–72 hours of antibiotic completion. The primary endpoint was the number of participants with RBL- or administration-related treatment-emergent adverse events (TEAEs). Secondary endpoints included treatment success and sustained clinical response, at 8 weeks and 6 months after RBL administration, respectively. Results Overall, 793 participants were enrolled, of whom 697 received RBL. TEAEs through 8 weeks after administration were reported by 47.3% of participants; most events were mild or moderate gastrointestinal disorders. Serious TEAEs were reported by 3.9% of participants. The treatment success rate at 8 weeks was 73.8%; in participants who achieved treatment success, the sustained clinical response rate at 6 months was 91.0%. Safety and efficacy rates were similar across demographic and baseline characteristic subgroups. Conclusions RBL was safe and efficacious in participants with rCDI and common comorbidities. This is the largest microbiota-based live biotherapeutic study to date, and findings support use of RBL to prevent rCDI in a broad patient population. Clinical Trials Registration NCT03931941.

Background: Microbiota-based treatments reduce the incidence of recurrent Clostridioides difficile infections (rCDIs), but prospectively collected safety data needed to broaden patient access and protect public health have been limited. Objectives: We provide cumulative safety data from five prospective clinical trials evaluating fecal microbiota, live-jslm (RBL) – the first microbiota-based live biotherapeutic product approved by the US Food and Drug Administration – for preventing rCDI in adults. Design: Integrated safety analysis includes three phase II trials (PUNCH CD, PUNCH CD2, PUNCH Open-Label) and two phase III trials (PUNCH CD3, PUNCH CD3-OLS) of RBL. Methods: Trial participants were at least 18 years of age with documented rCDI who completed standard-of-care antibiotic therapy before treatment with RBL. Assigned study treatment regimen was one or two doses of RBL (or placebo) administered rectally, depending on the trial design. In four of the five trials, participants with CDI recurrence within 8 weeks after RBL or placebo administration were eligible for treatment with open-label RBL. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; in PUNCH CD2 and PUNCH Open-Label trials, TEAEs and serious TEAEs were collected through 12 and 24 months, respectively. Results: Among the five trials, 978 participants received at least one dose of RBL (assigned treatment or after recurrence) and 83 participants received placebo only. TEAEs were reported in 60.2% of Placebo Only participants and 66.4% of RBL Only participants. Only abdominal pain, nausea, and flatulence were significantly higher in the RBL Only group compared with the Placebo Only group. Most TEAEs were mild or moderate in severity and were most frequently related to preexisting conditions. There were no reported infections for which the causative pathogen was traced to RBL. Potentially life-threatening TEAEs were infrequent (3.0% of participants). Conclusion: Across five clinical trials, RBL was well tolerated in adults with rCDI. In aggregate, these data consistently demonstrated the safety of RBL.