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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.

Introduction Effective treatments for recurrent Clostridioides difficile infection (rCDI) are urgently needed. RBX2660 is an investigational microbiota-based live biotherapeutic to reduce CDI recurrence following standard-of-care antibiotic treatment in individuals with rCDI. Here we report the final safety data through 24 months of follow-up as well as final efficacy data, reflecting alignment of the pre-specified statistical analysis plan definitions with the data presented. Methods The PUNCH CD2 clinical trial was a prospective, multicenter, randomized, double-blinded, placebo-controlled, three-arm phase 2b study conducted to evaluate the efficacy and safety of RBX2660 for the reduction of rCDI compared to placebo. Eligible patients were at least 18 years of age and had at least three episodes of CDI and at least two rounds of standard antibiotic treatment or had at least two episodes of severe CDI resulting in hospitalization. Patients were randomized 1:1:1 to group A, two doses of RBX2660; group B, two doses of placebo; or group C, one dose of RBX2660 and one dose of placebo; all administered 7 ± 2 days apart. Treatment success was prevention of recurrence, defined as absence of diarrhea and no re-treatment for CDI any time after the first dose until 8 weeks after the second dose of the study treatment. Safety was assessed by reports of adverse events and symptoms. The final efficacy and safety are reported for data available through 24 months. Results For the primary endpoint, treatment success at 8 weeks, 56.8% (25/45) of participants who received one dose of RBX2660 + one dose of placebo, 55.6% (25/45) of participants who received two doses of RBX2660, and 43.2% (19/44) of participants who received two doses of placebo in the final intention-to-treat (ITT) population were responders (both p  = 0.2 vs placebo). In the per-protocol population, 87.5% (21/24) of participants who received one dose of RBX2660 + one dose of placebo and 58.1% (18/31) of those who received two doses of placebo had treatment success ( p  = 0.017; treatment difference, 29.4 [95% CI 7.6, 51.3]); 75.0% (21/28) of participants in the PP population who received two doses of RBX2660 were responders ( p  = 0.17 vs placebo). The safety profile of RBX2660, whether delivered as one or two doses, was similar to the placebo group. Conclusion While the phase 2b PUNCH CD2 clinical trial did not meet its pre-defined primary endpoint of treatment success at 8 weeks after two doses of RBX2660 vs two doses of placebo, clinically meaningful data were obtained to justify proceeding with the single dose regimen in the phase 3 clinical trial, PUNCH CD3, now complete. To date, the cumulative data for RBX2660 demonstrate consistent efficacy and safety outcomes for reduction of CDI recurrence in adults. Clinical Trial Registration ClinicalTrials.gov: NCT02299570. Infographic Digital Features This article includes an infographic. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.22100540 .

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: 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. Plain language summary Safety and prevention of Clostridioides difficile reinfection by fecal microbiota, live-jslm (RBL) when given during a colonoscopy Some patients who have had Clostridioides difficile infection (CDI) keep being reinfected. Fecal microbiota, live-jslm (REBYOTA®, abbreviated here as RBL) is a microbiome-based product that prevents another CDI reinfection after antibiotic treatment. RBL is given via the rectum but can also be given during a colonoscopy. The CDI-SCOPE trial looked at how safe RBL was and how well it prevented more CDI reinfections. Forty-one adults who had CDI more than once were given one dose of RBL during a colonoscopy. Investigators then monitored participants for side effects or CDI reinfections. After 8 weeks, four people (9.8%) had mild gastrointestinal side effects considered related to RBL, and none had confirmed CDI reinfections. The trial showed that RBL is safe and effective at preventing CDI reinfection in adults when given during colonoscopy.

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. Infographic