Guthmueller, Beth

Background: Recurrent Clostridioides difficile infection (rCDI) disrupts health-related quality of life (HRQoL), often causing debilitating symptoms, emotional distress, and social withdrawal. Fecal microbiota, live-jslm (RBL; REBYOTA ® ) is approved by the FDA to reduce CDI recurrence. While the burden of rCDI is well established, less is known about the patient experience after RBL treatment and its impact on HRQoL. Objectives: To explore the burden of rCDI on HRQoL, and any improvements in symptoms and impacts after RBL administration by colonoscopy. Design: A qualitative sub-study embedded in the CDI-SCOPE phase IIIb clinical trial (NCT05831189). Methods: Qualitative interviews were conducted with 30 trial participants approximately 8 weeks after RBL treatment. Interviews were conducted using a semi-structured discussion guide; they were audio-recorded, transcribed verbatim, and thematically analyzed. Results: Thirty of 41 trial participants (73%) took part in the qualitative interviews (July 2023–September 2024). Participants (mean age 59 years; 87% female) had experienced multiple prior rCDI episodes. Before RBL treatment, participants reported severe symptoms, including diarrhea (30/30; 100%), abdominal pain (21/30; 70%), and fatigue (14/30; 47%), which negatively affected daily life, social interactions, and emotional health. Eight weeks after RBL treatment, no participants reported a recurrence. Diarrhea symptoms resolved (17/30; 57%) or improved (13/30; 43%) for all participants, typically within 1 month. Average severity scores for diarrhea declined markedly (from 8.9 to 1.3). Every participant (100%) reported improved ability to engage in daily activities; nearly all (29/30; 97%) described positive changes to social life/relationships, and 77% (23/30) reported improved emotional well-being. Conclusion: RBL administered via colonoscopy provided rapid, meaningful relief from rCDI symptoms, and due to symptom improvements, many participants reported that they were able to resume daily life. These findings highlight the broader value of RBL in restoring HRQoL and overall well-being. Trial registration: ClinicalTrials.gov: NCT05831189.

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.

Background: Fecal microbiota, live-jslm (RBL) is a microbiota-based product for the prevention of recurrent Clostridioides difficile infection (rCDI) in adults following antibiotic treatment. The safety and clinical effectiveness of RBL administered via colonoscopy in adults with rCDI were evaluated in CDI-SCOPE. An 8-week analysis showed 9.8% of participants had RBL-related treatment-emergent adverse events (TEAEs; primary endpoint) and 95.1% experienced treatment success (no CDI recurrence). Objectives: To evaluate long-term safety and clinical effectiveness of RBL through 6 months of follow-up in CDI-SCOPE. Design: Single-arm exploratory phase IIIb trial conducted at 12 sites in the United States. Methods: Eligible adults with rCDI received a single 150-mL dose of RBL to the right colon via colonoscopy. The primary endpoint was RBL-related TEAEs through 8 weeks after RBL administration or confirmed treatment failure. Secondary endpoints included safety up to 6 months after RBL administration. Exploratory analyses included assessment of further CDI episodes. Results: Of the 41 participants enrolled, 39 completed trial assessments through 6 months. From 8 weeks through 6 months after RBL administration, 36 TEAEs in 15 participants (36.6%) were reported, one of which (irritable bowel syndrome) was RBL-related; most TEAEs (97.2%) were of mild or moderate severity. Over the 6-month trial period, 23 participants (56.1%) experienced 69 TEAEs; 94.2% were of mild or moderate severity. Serious TEAEs occurred in three participants (7.3%), none of which were related to RBL or its administration, and no TEAEs led to discontinuation or death. Overall, 38 participants (92.7%) did not experience further CDI episodes, 1 (2.4%) did between 8 weeks and 6 months, and 2 (4.9%) had an indeterminate outcome due to trial withdrawal before 8 weeks. Conclusion: RBL administered via colonoscopy was safe and effective for preventing CDI recurrence in adults with rCDI in CDI-SCOPE. Trial registration: ClinicalTrials.gov: NCT05831189.

Background: Recurrent Clostridioides difficile infection (rCDI) occurs in up to 35% of patients with CDI, and further recurrence is common. Fecal microbiota, live-jslm (RBL) is safe and effective for preventing rCDI in adults following antibiotic treatment for rCDI when administered rectally. There is clinical interest in alternative routes of administration. Objectives: CDI-SCOPE assessed the safety and clinical effectiveness of RBL when administered via colonoscopy to adults with rCDI. Design: Single-arm, exploratory phase IIIb trial conducted at 12 sites in the United States. Methods: Eligible adults with rCDI received one administration of RBL consisting of one 150-mL dose of RBL, delivered via colonoscopy to the right side of the colon. The primary endpoint assessed RBL-related treatment-emergent adverse events (TEAEs) within 8 weeks of RBL administration or until confirmed treatment failure. Secondary endpoints included treatment success (absence of CDI recurrence for 8 weeks following RBL administration), physician experience administering RBL via colonoscopy, and physician perception of participant benefit. Results: Of 54 participants screened, 41 were enrolled and received RBL via colonoscopy; 39 participants completed the 8-week visit. Five TEAEs in four participants (9.8%) were assessed as related to RBL, all of which were gastrointestinal and mild in severity. Overall, 18 participants (43.9%) experienced 33 TEAEs within 8 weeks, most of which were of mild (25/33; 75.8%) or moderate (5/33; 15.2%) severity. No TEAEs led to intensive care unit admission or death. Overall, 39 participants (95.1%) experienced treatment success; 2 participants (4.9%) withdrew consent and had an indeterminate outcome. Among physicians, 90.2% of investigators indicated a “positive” or “very positive” experience administering RBL by colonoscopy. All physicians assessed participant benefit as “much” or “very much” improved. Conclusion: This single-arm study suggests RBL administered via colonoscopy is practical, safe, and effective for preventing CDI recurrence following antibiotic treatment in adults. Trial registration: ClinicalTrials.gov: NCT05831189.

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.