A real-world study of persistence and adherence to prescription medications in patients with chronic idiopathic constipation in the United States.

BACKGROUND: At present, 4 prescription therapies have been approved by the US Food and Drug Administration for the treatment of chronic idiopathic constipation (CIC) in adults. OBJECTIVES: To compare persistence with and adherence to prucalopride vs 3 other prescription medications for CIC in a US population. METHODS: This retrospective, observational cohort study used data from the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental Databases (January 2015-June 2020). Inclusion criteria were patients (aged ≥18 years) with at least 1 prescription fill for prucalopride, lubiprostone, linaclotide, or plecanatide on or after April 2, 2019 (commercial availability of prucalopride), and at least 1 constipation-related diagnosis code. Persistence was assessed by time to discontinuation, and adherence was assessed by the proportion of days covered (PDC) and the proportion of patients who achieved PDC of at least 80%. Adjusted hazard ratios (HRs) for discontinuation and odds ratios for adherence were calculated. RESULTS: A total of 14,700 patients (mean age = 48.3 years; female = 81.9%) were included (prucalopride, n = 675; lubiprostone, n = 1,591; linaclotide, n = 11,105; plecanatide, n = 1,329). After adjusting for confounding factors, the HRs for discontinuation were significantly higher for all comparator medications compared with prucalopride after 2 months (HR [95% CI]: lubiprostone, 1.70 [1.48-1.95]; linaclotide, 1.25 [1.10-1.41]; plecanatide, 1.31 [1.13-1.51], all P < 0.001). The unadjusted mean (SD) PDC was 0.53 (0.32) with prucalopride compared with 0.41 (0.31); P less than 0.001 with lubiprostone, 0.48 (0.31), P less than 0.05 with linaclotide, and 0.48 (0.29), P = 0.98 with plecanatide. The comparator medications were all associated with lower odds of achieving PDC of at least 80% relative to prucalopride (odds ratio [95% CI]: lubiprostone, 0.52 [0.40-0.69], P < 0.001; linaclotide, 0.73 [0.58-0.93], P = 0.009; plecanatide, 0.70 [0.53-0.93], P = 0.015). CONCLUSIONS: The findings of this study indicate that prucalopride has higher treatment persistence and adherence compared with other CIC prescription medications. This research represents the first instance of a real-world claims study showcasing such outcomes.

The 3 Ds: Depression, Dysbiosis, and Clostridiodes difficile.

This paper explores the intricate relationship between depression, gut dysbiosis, and Clostridioides difficile infections, collectively termed "The 3 Ds". Depression is a widespread mental disorder increasing in prevalence. It is recognized for its societal burden and complex pathophysiology, encompassing genetic, environmental, and microbiome-related factors. The consequent increased use of antidepressants has led to growing concerns about their effects on the gut microbiome. Various classes of antidepressants and antipsychotics show antimicrobial activity, potentially leading to shifts in the gut microbiome and contributing to the development of dysbiosis. Dysbiosis, in turn, can predispose individuals to opportunistic infections like C. difficile, a significant healthcare concern due to its high recurrence rates and severe impact on patients' quality of life. Further, the link between antidepressant use and an increased risk of C. difficile infection (CDI) is explored and, finally, the emergence of live biotherapeutic products as novel treatment options for recurrent CDI is discussed.

PUNCH CD3-OLS: a phase 3 prospective observational cohort study to evaluate the safety and efficacy of fecal microbiota, live-jslm (REBYOTA) in adults with recurrent Clostridioides difficile infection.

OBJECTIVE: 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 United States (US) Food and Drug Administration for preventing recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment. DESIGN: 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 24-72h 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 TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov (NCT03931941).

Frailty is a predictor for worse outcomes in patients hospitalized with Clostridioides difficile infection.

Background: Frailty has major health implications for affected patients and is widely used in the perioperative risk assessment. The Hospital Frailty Risk Score (HFRS) is a validated score that utilizes administrative billing data to identify patients at higher risk because of frailty. We investigated the utility of the HFRS in patients with Clostridioides difficile infection (CDI) to determine whether they were at risk for worse outcomes and higher healthcare resource utilization. Methods: Using the 2017 National Inpatient Sample, we identified all adults with a primary diagnosis of CDI. We classified patients into 2 groups: those who had an HFRS <5 (NonFrailCDI) and those with a score ≥5 (FrailCDI). We assessed differences in hospital outcomes and healthcare resource utilization based on frailty status. Results: We identified 93,810 hospitalizations, of which 54,300 (57.88%) were FrailCDI. FrailCDI patients were at higher risk for fulminant CDI (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.6-2.3), requiring colectomy (OR 4.1, 95%CI 1.5-11.2), and inpatient mortality (OR 4.5, 95%CI 2.8-7.1). Furthermore, FrailCDI patients had higher odds of requiring Intensive Care Unit admission (OR 13.7, 95%CI 6.3-29.9) or transfer to another facility on discharge (OR 2.2, 95%CI 2.0-2.4), and had longer hospital stays and higher total charges when compared with NonFrailCDI. Conclusions: Frailty as defined by the HFRS is an independent factor for worse outcomes and higher healthcare utilization in adults admitted for CDI. Risk stratifying patients by frailty may improve outcomes.

Integrated Safety and Efficacy Analyses of Phase 3 Trials of a Microbiome Therapeutic for Recurrent CDI.

INTRODUCTION: Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI. OBJECTIVE, DESIGN, AND PATIENTS: To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities. METHODS: VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24. RESULTS: TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week 8 was 9.5% (95% CI 6.6-13.0) and remained low through 24 weeks (15.2%; 95% CI 11.6-19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression. CONCLUSIONS: VOS was well tolerated and rates of rCDI remained low through week 24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03183128 and NCT03183141.

The Progression of Microbiome Therapeutics for the Management of Gastrointestinal Diseases and Beyond.

There has been an increased ability to investigate the human microbiota through next-generation sequencing and functional assessment. This advancement has rapidly expanded our ability to study and manipulate the gastrointestinal microbiome to mitigate disease. Fecal microbiota transplantation, a therapy that broadly transfers the entire intestinal ecosystem, has been explored as a potential therapeutic in a variety of gastrointestinal, hepatic, and extraintestinal conditions. The field, however, continues to evolve, with a movement toward precision microbiome therapeutics, individualizing care for various disorders. This review will describe the use of fecal microbiota transplantation, microbiota restoration, and precision microbiome therapeutics, focusing on gastrointestinal and hepatic diseases.

Retrospective subgroup analysis of fecal microbiota, live-jslm (REBYOTA®) administered by colonoscopy under enforcement discretion for the prevention of recurrent Clostridioides difficile infection.

Background: Fecal microbiota, live-jslm (RBL; REBYOTA®), is the first Food and Drug Administration (FDA)-approved, single-dose, rectally administered, microbiota-based live biotherapeutic product for preventing Clostridioides difficile infection (CDI) recurrence. Alternative routes of administration are of clinical interest. Objectives: Evaluate the safety and efficacy of RBL administration via colonoscopy. Design: Retrospective analysis of electronic medical records of participants administered RBL via colonoscopy under FDA enforcement discretion. Methods: The number of participants with treatment and/or procedure-emergent adverse events (TEAEs) was evaluated. Treatment success and sustained clinical response, defined as the absence of CDI recurrence within 8 weeks and 6 months, respectively, were evaluated. Results: TEAEs were experienced by 75% (6/8) of participants; most were mild to moderate in severity, and none due to RBL or its administration. Most participants had treatment success (80%; 8/10); 75% (6/8) had sustained clinical response. Conclusion: Real-world safety and efficacy of RBL administered via colonoscopy were consistent with clinical trials of rectally administered RBL.

Clinical Outcomes Before and After Prucalopride Treatment: An Observational Study in Patients With Chronic Idiopathic Constipation in the United States.

INTRODUCTION: This real-world US-based claims study compared constipation-related symptoms and complications 6 months before and after prucalopride initiation in adults with chronic idiopathic constipation (CIC). METHODS: This observational, retrospective cohort analysis used the IBM MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental Database (January 2015-June 2020). Prucalopride-treated patients (≥18 years old) who had ≥1 constipation-related International Classification of Diseases, Tenth Revision, Clinical Modification ( ICD-10-CM ) diagnosis code during the baseline or study period were included. The proportions of patients with constipation-related symptoms (abdominal pain, abdominal distension [gaseous], incomplete defecation, and nausea) and constipation-related complications (anal fissure and fistula, intestinal obstruction, rectal prolapse, hemorrhoids, perianal venous thrombosis, perianal/perirectal abscess, and rectal bleeding) were examined. Constipation-related symptoms and complications were identified using ICD-10-CM , ICD-10 - Procedure Coding System , or Current Procedural Terminology codes. Data were stratified by age (overall, 18-64 years, and ≥65 years). RESULTS: This study included 690 patients: The mean (SD) patient age was 48.0 (14.7) years, and 87.5% were women. The proportions of patients overall with constipation-related symptoms decreased 6 months after prucalopride initiation (abdominal pain [50.4% vs 33.3%, P < 0.001]; abdominal distension [gaseous] [23.9% vs 13.3%, P < 0.001]; and nausea [22.6% vs 17.7%, P < 0.01]; no improvements observed for incomplete defecation). Similarly, the proportions of patients overall with constipation-related complications decreased 6 months after prucalopride initiation (intestinal obstruction [4.9% vs 2.0%, P < 0.001]; hemorrhoids [10.7% vs 7.0%, P < 0.05]; and rectal bleeding [4.1% vs 1.7%, P < 0.05]). DISCUSSION: This study suggests that prucalopride may be associated with improved constipation-related symptoms and complications 6 months after treatment initiation.

Efficacy and Health-Related Quality of Life Impact of Fecal Microbiota, Live-jslm: A Post Hoc Analysis of PUNCH CD3 Patients at First Recurrence of Clostridioides difficile Infection.

INTRODUCTION: Clostridioides difficile infection (CDI) causes symptoms of varying severity and negatively impacts patients' health-related quality of life (HRQL). Despite antibiotic treatment, recurrence of CDI (rCDI) is common and imposes clinical and economic burdens on patients. Fecal microbiota, live-jslm (REBYOTA [RBL]) is newly approved in the USA for prevention of rCDI following antibiotic treatments. We analyzed efficacy and HRQL impact of RBL vs. placebo in patients at first rCDI using data from the phase 3 randomized, double-blind placebo-controlled clinical trial, PUNCH CD3. METHODS: This post hoc analysis included patients at first rCDI fromPUNCH CD3. Treatment success (i.e., absence of diarrhea within 8 weeks post-treatment) was analyzed adjusting for baseline patient characteristics. HRQL was measured using the Clostridioides difficile Quality of Life Survey (Cdiff32); absolute scores and change from baseline in total and domain (physical, mental, and social) scores were summarized and compared between arms. Analyses were conducted for the trial's blinded phase only. RESULTS: Among 86 eligible patients (32.8% of the overall trial population, RBL 53 [61.6%], placebo 33 [38.4%]), RBL-treated patients had significantly lower odds of recurrence (i.e., greater probability of treatment success) at week 8 vs. placebo (odds ratio 0.35 [95% confidence interval 0.13, 0.98]). Probability of treatment success at week 8 was 81% for RBL and 60% for placebo, representing 21% absolute and 35% relative increases for RBL (crude proportions 79.2% vs. 60.6%; relative risk 0.53, p = 0.06). Additionally, RBL was associated with significantly higher Cdiff32 total (change score difference 13.5 [standard deviation 5.7], p < 0.05) and mental domain (16.2 [6.0], p < 0.01) scores vs. placebo from baseline to week 8. CONCLUSION: Compared to placebo, RBL demonstrated a significantly higher treatment success in preventing further rCDI and enhanced HRQL among patients at first recurrence, establishing RBL as an effective treatment to prevent further recurrences in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03244644.

Fecal Microbiota, Live-jslm for the Prevention of Recurrent Clostridioides difficile Infection : Subgroup Analysis of PUNCH CD2 and PUNCH CD3.

GOALS: To assess fecal microbiota, live-jslm (REBYOTA, abbreviated as RBL, formerly RBX2660) efficacy and safety in participants grouped by recurrent Clostridioides difficile infection (rCDI) risk factors and treatment-related variables. BACKGROUND: RBL is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration for the prevention of rCDI in adults after antibiotic treatment for rCDI. STUDY: Treatment success rates across subgroups for PUNCH CD3 (NCT03244644) were estimated using a Bayesian hierarchical model, borrowing data from PUNCH CD2 (NCT02299570). Treatment-emergent adverse events were summarized for the double-blind treatment period within 8 weeks. RESULTS: Treatment differences between RBL and placebo at 8 weeks were similar to the total population for most subgroups. Treatment effect sizes were similar between CDI tests, higher for oral vancomycin courses >14 days versus ≤14 days and higher for antibiotic washout periods of 3 days versus ≤2 days. The largest reductions in the rate of rCDI with RBL versus placebo were observed for participants with a 3-day CDI antibiotic washout period and participants with ≥4 previous CDI episodes. Most RBL-treated participants experienced TEAEs that were mild or moderate in severity and related to preexisting conditions. CONCLUSION: This analysis provides further evidence of RBL efficacy and safety across subgroups, including those at high risk for rCDI.

Patient Perception of Route of Rectal Administration of Live Biotherapeutic Product for Recurrent Clostridioides difficile Infection.

Introduction: CDI is a recurrent disease that is treated with antibiotics, but patients commonly experience repeat infections with significant impacts on hospital budgets and patient health quality. Standard of care management includes the antibiotics, vancomycin and fidaxomicin, which frequently provide clinical response, but do not avoid recurrence of Clostridioides difficile infection (rCDI). These recurrent infections occur due to dysbiosis of the colonic microbiota. One adjunctive therapeutic approach is to restore the deficient gastrointestinal flora using fecal microbiota transplantation (FMT) or live biotherapeutic products (LBP) when given after standard of care antimicrobials, which have been successful in reducing repeat infections with success rates up to 88%. FMT or LBP can be given by various routes. Methods: Two groups of subjects aged ≥18 years with at least one previous CDI episode within the previous 36 months completed self-administered online surveys to assess the acceptability of an LBP administered rectally. Group 1 consisted of LBP-recipients who had received RBL (REBYOTA) rectally as part of the Phase III PUNCH CD3 clinical trial. Group 2 consisted of LBP-naïve subjects who volunteered to participate and had experienced CDI within the prior 36 months but had no history of receiving FMT or LBP therapy. Results: LBP-recipients considered rectal administration easy (96%) and quick (94%), while 98% of respondents considered the lack of need for bowel preparation appealing. Most LBP-recipients (96%) wished they had earlier access to RBL. Most LBP-naïve subjects (87%) were likely or somewhat likely to consider a rectally administered treatment and 80% preferred a treatment option that does not require bowel preparation. Many of these subjects (76%) expressed interest in finding out about new treatment options for rCDI. Discussion: LBP-recipients and LBP-naïve subjects alike felt that rectal delivery of microbiome therapy is not only acceptable but highly interesting as a treatment avenue.

First Clostridioides difficile Recurrence Is Highest Following Concomitant Antimicrobial Administration During and Within 30 Days of Treatment.

BACKGROUND: Clostridioides difficile infection (CDI) is an epidemic with the strongest risk factor being antibiotic usage. Patients who get CDI frequently require concomitant antibiotics for other indications around the time of their infection. AIMS: To assess the recurrence of CDI (rCDI) in patients receiving concomitant antibiotics at the same time or shortly thereafter treatment of CDI. METHODS: We retrospectively reviewed records for patients with their first inpatient CDI episode. Patients were grouped into those who didn't receive concomitant antibiotics (noABx), those receiving antibiotics at the same time as treatment of CDI (ABxDURING), those receiving antibiotics within 30-days of completion of CDI therapy (ABxAFTER) and those who received antibiotics both during and after CDI treatment (ABxDuringAfter). Our primary outcome was recurrence within 14-90 days; other outcomes included ICU stay at the time of diagnosis, 30-day ICU transfer, 30-day colectomy, and readmission. RESULTS: 457 patients had CDI during admission (mean age: 66.4 years, 51.9% female). 64.1% were exposed to concomitant antibiotics. Recurrence rates were 4.3%, 6.1%, 13.8% and 19.1%, for noABx, ABxDURING, ABxAFTER and ABxDuringAfter, respectively. Patients with ABxDuringAfter had the highest rates of rCDI when compared to noABx [OR 5.67, 95% CI (2.18-14.72)]. CONCLUSIONS: There is a high rate of utilization of non-CDI antibiotics during or shortly after completing CDI treatment with high rates of recurrence within 90-days. Concomitant antimicrobials alter the opportunity for the microbiota to re-grow and worsens dysbiosis leading to increases in recurrence. Concomitant antimicrobial stewardship remains important in patients being treated for CDI and shortly after treatment.

Effect of Fecal Microbiota, Live-Jslm (REBYOTA [RBL]) on Health-Related Quality of Life in Patients With Recurrent Clostridioides difficile Infection: Results From the PUNCH CD3 Clinical Trial.

Background: Recurrence of Clostridioides difficile infection (rCDI) is common, prolonging disease morbidity and leading to poor quality of life. We evaluated disease-specific health-related quality of life (HRQL) in patients with rCDI treated with fecal microbiota, live-jslm (REBYOTA [RBL]; Rebiotix) versus placebo. Methods: This was a secondary analysis of a randomized, double-blind, placebo-controlled phase 3 study (PUNCH CD3). The disease-specific Clostridioides difficile Quality of Life Survey (Cdiff32) was administered at baseline and at weeks 1, 4, and 8. Changes in Cdiff32 total and domain (physical, mental, social) scores from baseline to week 8 were compared between RBL and placebo and for responders and nonresponders. Results: Findings were analyzed in a total of 185 patients (RBL, n = 128 [69.2%]; placebo, n = 57 [30.8%]) with available Cdiff32 data. Patients from both arms showed significant improvements in Cdiff32 scores relative to baseline across all outcomes and at all time points (all P < .001); RBL-treated patients showed significantly greater improvements in mental domain than those receiving placebo. In adjusted analyses, RBL-treated patients showed greater improvements than placebo in total score and physical and mental domains (all P < .05). Similar improvement in mental domain was observed among responders, while nonresponders showed numerical improvements with RBL but not placebo. Conclusions: In a phase 3 double-blinded clinical trial, RBL-treated patients reported more substantial and sustained disease-specific HRQL improvements than placebo-treated patients. Clinical Trials Registration: ClinicalTrials.gov NCT03244644 (https://clinicaltrials.gov/ct2/show/NCT03244644).

Prevalence of Comorbid Factors in Patients With Recurrent Clostridioides difficile Infection in ECOSPOR III, a Randomized Trial of an Oral Microbiota-Based Therapeutic.

BACKGROUND: Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. METHODS: Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (<30, 30-50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. RESULTS: Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. CONCLUSIONS: In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.

Safety of fecal microbiota, live-jslm (REBYOTA™) in individuals with recurrent Clostridioides difficile infection: data from five prospective clinical trials.

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.