Prevention of recurrent Clostridioides difficile infection by fecal microbiota, live-jslm (REBYOTA^®) administered via colonoscopy: 6-month data from the single-arm phase IIIb CDI-SCOPE trial

Abstract

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.

Introduction

Clostridioides difficile infection (CDI) is one of the leading causes of healthcare-associated infections and infective diarrhea in the United States.^1–3 Recurrence of CDI is common, with up to 35% of patients who develop CDI subsequently developing recurrent CDI (rCDI), and up to 60% of patients with rCDI developing further recurrence. ⁴ Standard-of-care antibiotics used to treat CDI can disrupt the gut microbiome, contributing to recurrence.^5–8

CDI symptoms, which range from mild to severe, have a detrimental impact on patients’ quality of life and are associated with morbidity and mortality. Symptoms include mild-to-severe diarrhea, and complications include pseudomembranous colitis, colonic perforation, toxic megacolon, sepsis, and death.^3,8,9 CDI symptoms impact the ability of patients to carry out daily and work activities, affecting patients’ physical, psychological, and social lives.^8,10,11 Furthermore, rCDI is associated with decreased quality of life, including increased anxiety, compared with no recurrence. ¹¹ Risk factors for rCDI include antibiotic use; advanced age (⩾65 years); hospitalization; underlying chronic comorbidities such as cardiac disease, kidney disease, or inflammatory bowel disease (IBD); immunosuppression; and proton pump inhibitor use.^12,13

Fecal microbiota, live-jslm (RBL; REBYOTA^®) is a microbiota-based product to prevent rCDI in adults after standard-of-care antibiotic treatment.^14,15 RBL is approved for rectal administration and has demonstrated safety and efficacy when administered via this route during the clinical development program.^{12,14,16–20}

CDI-SCOPE (NCT05831189), a single-arm exploratory phase IIIb trial conducted at 12 sites in the United States, assessed the safety and clinical effectiveness of RBL and explored the real-world feasibility of administering RBL by colonoscopy to adults with rCDI. An 8-week analysis found that 9.8% of participants (n = 4) experienced RBL-related treatment-emergent adverse events (TEAEs; the primary endpoint) through 8 weeks after RBL administration, and all were mild in severity and gastrointestinal in nature. ²¹ Through 8 weeks, 95.1% of participants experienced treatment success, defined as no CDI recurrence. Additionally, most physicians reported positive experiences administering RBL by colonoscopy. This manuscript reports 6-month follow-up safety and sustained effectiveness data from CDI-SCOPE.

Methods

Trial design and conduct

The methods for CDI-SCOPE have been previously published. ²¹ Adults aged 18 years or older with a diagnosis of rCDI (⩾1 recurrence or ⩾2 episodes and a positive stool test for C. difficile toxin or toxigenic C. difficile) who finished a standard-of-care antibiotic course were enrolled to receive RBL. Participants were ineligible for CDI-SCOPE if they were using systemic antibiotics for an indication other than for the qualifying episode of rCDI, had symptoms caused by a confirmed intestinal pathogen other than C. difficile, had current uncontrolled diarrhea unrelated to CDI, had CDI unresponsive to antibiotic therapy, had active/fulminant colitis, or had received any microbiota-based therapies within 6 months before screening or between screening and baseline.

All eligible participants received a single 150-mL dose of RBL to the right side of the colon between the ileocecal valve and the hepatic flexure of the colon via colonoscopy, following a 24- to 72-hour antibiotic washout period and bowel preparation. A single dose of RBL consists of 1 × 10⁸ to 5 × 10¹⁰ colony-forming units/mL of a microbiota suspension derived from human stool supplied by prescreened healthy donors. Bowel preparation methods and logistics of colonoscopy procedures were determined at the investigator’s discretion. Follow-up visits occurred at 1, 2, 4, and 8 weeks, and 3 and 6 months after RBL administration. The protocol was approved by the relevant institutional review boards, and the trial was conducted in accordance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and requirements for publicly registered clinical trials. All participants provided written informed consent prior to trial commencement. CONSORT guidelines were followed while developing this report (Supplemental Material). ²²

Trial endpoints

The primary endpoint of the trial assessed RBL-related TEAEs after RBL administration through 8 weeks or confirmed treatment failure. Treatment failure (i.e., recurrence) was defined as the presence of CDI-associated diarrhea and a positive test for C. difficile toxin (per the site’s standard practice) within 8 weeks after RBL administration, while treatment success was defined as the absence of CDI-associated diarrhea for 8 weeks after RBL administration. Additional secondary endpoints included safety up to 6 months after RBL administration, physician experience, and physician perception of participant benefit. Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities version 25.1. A TEAE was defined as any new AE or worsening of a pretreatment AE or preexisting medical condition that occurred after the start of RBL administration through the end of trial participation. AEs of special interest included septic shock, toxic megacolon, colonic perforation, emergency colectomy, and new onset of obesity, glucose intolerance, metabolic syndrome, or autoimmune conditions. Further CDI episodes occurring between 8 weeks and 6 months after RBL administration were also assessed as an exploratory analysis.

Statistical analysis

Due to the exploratory nature of the trial and no prespecified statistical hypotheses, the planned enrollment of approximately 40 participants was deemed sufficient for descriptive characterization of safety and effectiveness. Safety and effectiveness analyses were conducted for all participants who received RBL. Data were reported using descriptive statistics, and categorical data were summarized using counts and percentages. In cases of treatment failure (i.e., recurrence) or an indeterminate treatment outcome, TEAEs were included if the time of onset occurred after RBL administration and before the time of onset of CDI symptoms.

Results

There were 54 participants screened for eligibility between May 2023 and June 2024, and 41 participants were enrolled to receive RBL via colonoscopy. Of these, 39 participants (95.1%) completed trial assessments through 6 months, and two participants (4.9%) withdrew from the trial prior to week 8 (one participant experienced a serious AE of a brain neoplasm, unrelated to RBL, and one participant was lost to follow-up). ²¹ Baseline characteristics of CDI-SCOPE trial participants have been previously described; most participants were White (95.1%) and female (87.8%) and had a mean (SD) age of 61.2 (14.9) years. ²¹ Eighteen participants (43.9%) received RBL following their first CDI recurrence, while 13 (31.7%) had two and 10 (24.4%) had three or more CDI recurrences prior to receiving RBL. ²¹

Safety from 8 weeks through 6 months after RBL administration

From 8 weeks through 6 months after RBL administration, 36 TEAEs in 15 participants (36.6%) were reported. Most TEAEs reported during the 8-week through 6-month period (97.2%) were of mild or moderate severity and gastrointestinal in nature (Table 1). The most common gastrointestinal TEAE reported was diarrhea in four participants (9.8%); no other TEAEs had an incidence of ⩾5% during this period. Of the TEAEs reported between 8 weeks and 6 months following RBL administration, one (irritable bowel syndrome) was RBL-related and considered mild (Tables 1 and 2). None of the serious TEAEs, life-threatening TEAEs, or TEAEs leading to intensive care unit admission during the 8-week through 6-month period were considered related to RBL, and no TEAEs leading to death were reported.

Table 1.

Safety summary.

TEAE	RBL N = 41
	8 weeks–6 months		Overall trial period (6 months)
	n (%)	Events	n (%)	Events
TEAEs	15 (36.6)	36	23 (56.1)	69
Mild	12 (29.3)	22	17 (41.5)	47
Moderate	7 (17.1)	13	8 (19.5)	18
Severe	0	0	2 (4.9)	2
Potentially life-threatening	1 (2.4)	1 a	2 (4.9)	2
TEAEs of special interest	0	0	2 (4.9)	2 b
Serious TEAEs	1 (2.4)	1 a	3 (7.3)	3 c
Adverse drug reactions	1 (2.4)	1	4 (9.8)	6
TEAEs leading to discontinuation	0	0	0	0
TEAEs leading to death	0	0	0	0

^aSerious, potentially life-threatening TEAE (abdominal pain) was considered unrelated to RBL.

^bTEAEs of special interest were ulcerative colitis and inflammatory bowel disease, both unrelated to RBL.

^cSerious TEAEs were abdominal pain, ulcerative colitis, and brain neoplasm, all unrelated to RBL.

RBL, fecal microbiota, live-jslm; TEAE, treatment-emergent adverse event.

Table 2.

TEAEs considered related to RBL.

System organ class	RBL N = 41
Preferred term	8 weeks–6 months		Overall trial period (6 months)
	n (%)	Events	n (%)	Events
TEAEs	1 (2.4)	1	4 (9.8)	6
Mild	1 (2.4)	1	4 (9.8)	6
Gastrointestinal disorders	1 (2.4)	1	4 (9.8)	6
Abdominal distension	0	0	2 (4.9)	2
Constipation	0	0	1 (2.4)	1
Diarrhea	0	0	1 (2.4)	1
Flatulence	0	0	1 (2.4)	1
Irritable bowel syndrome	1 (2.4)	1	1 (2.4)	1

RBL, fecal microbiota, live-jslm; TEAE, treatment-emergent adverse event.

Safety during the overall trial period

Over the full 6-month trial period, six TEAEs in four participants (9.8%) were considered related to RBL, all of which were mild in severity and gastrointestinal in nature (Table 2). Overall, 69 TEAEs were experienced by 23 participants (56.1%); 94.2% were of mild or moderate severity (Table 1). During the overall trial period, TEAEs in the categories of gastrointestinal disorders and infections were most common, occurring in >5% of participants (Table 3). Potentially life-threatening TEAEs were reported in two participants (4.9%) and were not related to RBL. Serious TEAEs occurred in three participants (7.3%), none of which were related to RBL or its administration. TEAEs of special interest were reported in two participants (4.9%) and were not related to RBL. There were no TEAEs leading to discontinuation or death during the 6-month trial period (Table 1).

Table 3.

TEAEs occurring in ⩾5% of participants during the overall trial period (6 months).

System organ class	RBL N = 41
Preferred term	TEAEs unrelated to RBL		All TEAEs
	n (%)	Events	n (%)	Events
Gastrointestinal disorders	10 (24.4)	28	12 (29.3)	34
Diarrhea	5 (12.2)	7	5 (12.2)	8
Abdominal distension	2 (4.9)	2	4 (9.8)	4
Constipation	2 (4.9)	4	3 (7.3)	5
Irritable bowel syndrome	2 (4.9)	2	3 (7.3)	3
Infections	11 (26.8)	21	11 (26.8)	21
COVID-19	4 (9.8)	4	4 (9.8)	4

RBL, fecal microbiota, live-jslm; TEAE, treatment-emergent adverse event.

Sustained effectiveness at 6 months

Of the 41 participants who received RBL, 38 (92.7%) did not experience another episode of CDI within 6 months after RBL administration. One participant (2.4%) experienced a further CDI episode between 8 weeks and 6 months, and two participants (4.9%) had an indeterminate outcome due to trial withdrawal before 8 weeks (Figure 1). As previously reported, neither participant who withdrew reported CDI symptoms up to the time of withdrawal from the trial. ²¹

Figure 1.

Further CDI episodes within 6 months after RBL administration.

CDI, Clostridioides difficile infection; RBL, fecal microbiota, live-jslm.

Discussion

This updated analysis of CDI-SCOPE demonstrates long-term safety and 6-month sustained effectiveness of RBL for preventing CDI recurrence when given by colonoscopy. During this analysis, no new safety signals were identified within 6 months of RBL administration, and only one additional RBL-related TEAE was reported in the 8-week to 6-month follow-up period. The 6-month follow-up period of CDI-SCOPE exceeds the average follow-up period of 8–12 weeks for clinical trials evaluating the safety of fecal microbiota transplantation (FMT) for the prevention of rCDI, ²³ and therefore provides important long-term safety findings to support the use of microbiota-based products administered via colonoscopy as a safe and effective option for prevention of CDI recurrence in adults.

When administered via colonoscopy, the safety profile of RBL was consistent with that observed in previous trials involving rectal administration.^12,17,19,20 Across trials of RBL to date and regardless of administration route, the majority of TEAEs in participants who received RBL have been mild or moderate in severity and gastrointestinal in nature. In a safety analysis of five clinical studies of RBL administered rectally, the most common TEAE categories (reported in ⩾5% of participants) were gastrointestinal disorders, general disorders and administration site conditions, infections, and metabolism and nutrition disorders, ²⁴ similar to the most commonly observed TEAE categories in CDI-SCOPE.

As previously reported in the 8-week analysis of CDI-SCOPE, 90.2% of physicians who administered RBL via colonoscopy regarded the procedure either positively or very positively overall. ²¹ Furthermore, all physicians evaluated participants as either “very much improved” or “much improved.” Physicians may choose to administer microbiota-based products via colonoscopy rather than rectally, as it allows assessment of colonic mucosa, which may be of importance for patients with gastrointestinal comorbidities (e.g., IBD), and incidental findings of IBD, benign polyps, precancerous lesions, and colon cancer. ²⁵

The colonoscopic route of RBL administration in CDI-SCOPE aligns with historical approaches of administration of nonstandardized FMT via colonoscopy. In 2017, a randomized controlled trial evaluating the safety and efficacy of FMT via colonoscopy reported 96.2% of participants achieved treatment success at 12 weeks and 12.5% of participants reported AEs ²⁶ ; however, no direct comparisons can be made with RBL because FMT does not involve standardized stool donors, stool screening and testing, or a standardized amount of bacterial colony-forming units. ²³ Given the lack of standardization in manufacturing and the limited oversight of FMT, safety remains a concern. ²³ RBL is manufactured in accordance with good manufacturing practices, standardized screening procedures, and pathogen testing in alignment with Food and Drug Administration requirements. ²⁴

As previously discussed in the 8-week analysis of CDI-SCOPE, limitations include its small sample size and single-arm design. ²¹ The absence of a control group introduces potential bias in both treatment administration and outcome assessment and prevents the ability to draw definitive conclusions regarding the relative efficacy of RBL compared with alternative treatment options. In addition, analyses of TEAE relatedness to preexisting conditions were not performed, somewhat restricting the safety conclusions that can be drawn, the generalizability of the findings of CDI-SCOPE to a wider demographic might be limited due to a somewhat homogeneous trial population in terms of sex and race (comparable to previous RBL trials), despite efforts to be more inclusive. ²¹

Conclusion

The long-term safety profile of RBL when administered via colonoscopy is consistent with previous RBL trials that administered RBL rectally. These findings support the use of RBL administered via colonoscopy as a safe and effective option for preventing CDI recurrence in adults.