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Background Fecal microbiota, live-jslm (RBL; REBYOTA™), the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent Clostridioides difficile infection (rCDI) in adults, has been evaluated in 5 prospective clinical trials. A retrospective analysis considered the safety and efficacy of RBL administered under US Food and Drug Administration enforcement discretion to patients with rCDI and broad eligibility criteria mimicking real-world practice. Methods We retrospectively identified adults with rCDI treated with RBL under enforcement discretion between November 1, 2015, and September 30, 2019, across 5 study sites. CDI diagnosis was based on site-specific practice. The primary safety set (PSS) included all patients who were naïve to previous RBL treatment and had continuously comprehensive medical records for 6 months following treatment. Results The primary treatment cohort had 94 patients; the PSS included 64 patients with common comorbidities receiving diverse chronic therapeutics. Most treatment-emergent adverse events were mild to moderate in severity and comparable between comorbidity subgroups and the overall population. There were no serious adverse events related to RBL or the administration procedure. In the PSS, 82.8% of RBL-treated patients responded at 8 weeks, of whom 88.7% had sustained response through 6 months. The number of RBL doses administered had no marked effect on outcome. Conclusions Together with prospective clinical trial outcomes, these findings support the efficacy and safety of RBL to prevent rCDI, with diagnostics and comorbidities representative of real-world clinical practice.

Background Advanced age and underlying comorbidities are associated with greater rates of recurrence in patients with Clostridioides difficile infection (CDI). Reducing the likelihood of recurrence through treatment with an antimicrobial followed by a microbiota replacement therapy can decrease the burden of this infection and improve patient outcomes. We report the efficacy and safety of RBX2660, a microbiota-based live biotherapeutic, in older adults with recurrent CDI, grouped by comorbidities. Methods In this post hoc subgroup analysis of the PUNCH CD3 trial, we assessed outcomes in older adults (age ≥65 years) grouped by Charlson Comorbidity Index severity scores at screening (moderate [3–4] and severe [≥5]) and by the presence of underlying cardiac, renal, or gastrointestinal disorders. Results RBX2660 treatment success rates in older adults with comorbidities were consistent across subgroups and similar to those in the total RBX2660-treated population. A greater percentage of RBX2660-treated older adults remained free of CDI recurrence through 8 weeks following treatment compared with placebo-treated participants in all but 2 subgroups assessed. Across all subgroups, most treatment-emergent adverse events (TEAEs) were mild or moderate in severity and related to a preexisting condition. None of the serious or life-threatening TEAEs that occurred were related to RBX2660 or its administration. Occurrence of TEAEs did not cluster in any subgroup. Conclusions RBX2660 is efficacious and safe in older adults with recurrent CDI and underlying comorbidities.

Background Disruptions to gut microbiota composition can result in dysbiosis and subsequent intestinal colonization by opportunistic pathogens such as Clostridioides difficile.1,2 The incidence of Clostridioides difficile infection (CDI) in persons ≥ 65 years old is greater than in those < 65 years old,3 with 1 in 11 CDI patients ≥ 65 years old dying within 1 month of diagnosis.4 We report the efficacy and safety of RBX2660, a microbiota-based live biotherapeutic, in patients with recurrent CDI (rCDI) who were ≥ 65 years old with comorbidities. This is a subgroup analysis of the PUNCH CD3 trial (NCT03244644), a prospective, multicenter, randomized, double-blind, placebo-controlled phase 3 trial. Methods Participants enrolled in PUNCH CD3 were ≥ 18 years old with documented rCDI who completed standard-of-care antibiotic therapy prior to treatment with RBX2660 or placebo. Treatment success was defined as remaining recurrence-free 8 weeks after intervention. In this subgroup analysis, we assessed outcomes of participants ≥ 65 years old with underlying cardiac disorders, chronic kidney disease (CKD), and gastrointestinal (GI) disorders. The treatment-emergent adverse events (TEAEs) were summarized for the double-blind treatment period within 8 weeks and censored if a patient received open-label RBX2660 after CDI recurrence. Results In the modified intent-to-treat population, 119 of 262 participants (45%) were ≥ 65 years old. Of these 119 participants, 42% had a cardiac disorder, 19% had CKD, and 61% had a GI disorder; the respective RBX2660 treatment success rates were 69%, 68%, and 67% (Figure 1). In the total safety population, the overall incidence of TEAEs was 52% with RBX2660 treatment compared to 44% with placebo treatment; mild events accounted for most of the difference (40% vs 30%) (Table 1). The overall incidence of TEAEs was 51% in RBX2660-treated participants ≥ 65 years old and 61%, 68%, and 51% in those participants with a cardiac disorder, CKD, or GI disorder, respectively. Most TEAEs were mild or moderate in severity and related to a pre-existing condition. Conclusion RBX2660 is safe and efficacious across a range of medically complex patients and consistently reduced rCDI in adults ≥ 65 years old, regardless of baseline comorbidities. Disclosures Glenn S. Tillotson, PhD, Ferring Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support|Spero Pharmaceuticals: Advisor/Consultant|Taro Pharmaceuticals: Advisor/Consultant Paul Feuerstadt, MD, FACG, AGAF, Ferring/Rebiotix Pharmaceuticals: Advisor/Consultant|Ferring/Rebiotix Pharmaceuticals: Grant/Research Support|Merck and Co: Advisor/Consultant|SERES Therapeutics: Advisor/Consultant|SERES Therapeutics: Grant/Research Support|Takeda Pharmaceuticals: Advisor/Consultant Stuart Johnson, M.D., Ferring Pharmaceuticals: Membership on Ferring Publication Steering Committee|Ferring Pharmaceuticals: Employee|Summit Plc: Advisor/Consultant Adam Harvey, PhD, Ferring Pharmaceuticals: Employment.

Background Recurrence of Clostridioides difficile infection (rCDI) is common - up to 35% of patients may recur. RBX2660 is a microbiota restoration therapy to reduce rCDI. Here we report 8 weeks HRQL results using the Clostridioides difficile Health-related Quality-of-Life Questionnaire (Cdiff32), a disease-specific instrument, from PUNCH CD3 (a randomized, double-blinded, placebo-controlled RBX2660 Phase 3 trial, NCT03244644). Methods Cdiff32 includes three domains (physical, mental, and social) and a total score (all range from 0 to 100 [100 best possible]). Changes in Cdiff32 from baseline to week 8 were compared between RBX2660 and placebo (PBO) using unadjusted and adjusted analyses controlling for baseline score, demographic and disease characteristics. Per trial protocol, missing data were imputed via last observation carried forward (LOCF); as-observed data were also analyzed. Patients experiencing recurrence after blinded treatment received open-label RBX2660 per physician discretion; these participants were excluded unless, per LOCF, data were available from the blinded period for week 8 use. Results A total of 206 patients (140 RBX2660, 66 PBO) were included, with similar age (mean±SD) 61.1±16.9 yrs (RBX2660) and 57.3±16.4 yrs (PBO) and baseline Cdiff32 scores. More than half of the patients had multiple comorbidities. Cdiff32 scores improved significantly from baseline to weeks 1, 4, and 8 for both arms, with greater improvements for RBX2660 through week 8 (Figs. 1 & 2). At week 8, statistical differences were found for mental domain (unadjusted: 8.01±3.64; adjusted: 7.07, 95% confidence interval: [0.28, 13.86], both P< 0.05) and total score (adjusted: 6.11, [0.14, 12.08], P< 0.05), all favoring RBX2660. Results were similar for the as-observed analyses, with the adjusted physical domain also statistically favoring RBX2660. Conclusion Most patients in this study reported improved HRQL. Improvements were observed in both arms, but RBX2660-treated patients had more robust and sustained improvements with statistically significant differences in Cdiff32 scores. This study suggests that microbiome restoration therapy might positively affect HRQL; future research may link these improvements directly with microbiota changes. Disclosures Paul Feuerstadt, MD, FACG, AGAF, Ferring/Rebiotix Pharmaceuticals: Advisor/Consultant|Ferring/Rebiotix Pharmaceuticals: Grant/Research Support|Merck and Co: Advisor/Consultant|SERES Therapeutics: Advisor/Consultant|SERES Therapeutics: Grant/Research Support|Takeda Pharmaceuticals: Advisor/Consultant Erik R. Dubberke, MD, MSPH, Abbott: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Grant/Research Support|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Seres: Advisor/Consultant|Summit: Advisor/Consultant|Synthetic Biologics: Grant/Research Support Amy Guo, PhD, Ferring Pharmaceuticals: Employee Adam Harvey, PhD, Ferring Pharmaceuticals: Employment Min Yang, MD, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Viviana García-Horton, PhD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received consulting fees from Ferring for the conduct of this study. Mirko Fillbrunn, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Glenn S. Tillotson, PhD, Ferring Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support|Spero Pharmaceuticals: Advisor/Consultant|Taro Pharmaceuticals: Advisor/Consultant Lindy Bancke, PharmD, Rebiotix, a Ferring Company: Employee Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support.

Colon ischemia is the most common form of intestinal ischemic injury and is seen frequently in an elderly population. This disease is usually self-limited, and many causes have been identified. The recent literature has focused on estimates of prognosis, triaging appropriate level of care, and identification of optimal treatments. In this review, we will address our current understanding of colon ischemia including epidemiology, pathophysiology, segmental distribution, presentation, diagnosis, and management.Research has recently been focused on factors associated with poor outcome. The medical comorbidities identified include chronic obstructive pulmonary disease (COPD), hepatic cirrhosis, and chronic aspirin use. Serological markers are noninvasive tools that can triage severity. Recent studies have shown procalcitonin, C-reactive protein, D-dimer, and neutrophil counts can help predict those at greatest risk for poor outcome. The timing of colonoscopy relative to symptomatic onset also can help predict severity. Early colonoscopy allows for quicker identification of ischemic stigmata, reducing the chance of misdiagnosis and potentially unnecessary and harmful treatment. The treatment of colon ischemia has classically been conservative with antimicrobials reserved for those with moderate or severe disease. Recent retrospective analysis calls into question the utility of antibiotics in the treatment of colon ischemia, although the data is not convincing enough to advise against antimicrobial treatment in patients with severe and fulminant disease.It is an exciting time for research focused on colon ischemia. With an improved knowledge, awareness of associated risk factors and predictors of severity, clinicians now have enhanced clinical tools to diagnose and triage patients earlier in the disease. This should help institute prompt and appropriate therapies ultimately improving outcomes.

Recurrent Clostridioides difficile infection, associated with dysbiosis of gut microbiota, has substantial disease burden in the USA. RBX2660 is a live biotherapeutic product consisting of a broad consortium of microbes prepared from human stool that is under investigation for the reduction of recurrent C. difficile infection.A randomized, double-blind, placebo-controlled, phase III study, with a Bayesian primary analysis integrating data from a previous phase IIb study, was conducted. Adults who had one or more C. difficile infection recurrences with a positive stool assay for C. difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of C. difficile infection diarrhea within 8 weeks of study treatment.Of the 320 patients screened, 289 were randomly assigned and 267 received blinded treatment (n = 180, RBX2660; n = 87, placebo). Original model estimates of treatment success were 70.4% versus 58.1% with RBX2660 and placebo, respectively. However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo, with an estimated treatment effect of 13.1% and a posterior probability of superiority of 0.991. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the RBX2660 and the placebo groups. Overall, RBX2660 was well tolerated, with manageable adverse events. The incidence of treatment-emergent adverse events was higher in RBX2660 recipients compared with placebo and was mostly driven by a higher incidence of mild gastrointestinal events.RBX2660 is a safe and effective treatment to reduce recurrent C. difficile infection following standard-of-care antibiotics with a sustained response through 6 months.NCT03244644; 9 August, 2017.Clostridioides difficile is a diarrhea-causing bacterium that is associated with potentially serious and fatal consequences. Antibiotics used to treat or prevent infections have a side effect of damaging the healthy protective gut bacteria (microbiota). Damage to the gut microbiota can allow C. difficile to over-grow and produce toxins that injure the colon. Paradoxically, the standard of care treatment of C. difficile infection (CDI) is antibiotics. Although initially effective for the control of diarrhea, antibiotics can leave a patient at risk for CDI recurrence after antibiotic treatment is stopped. Live biotherapeutic products are microbiota-based treatments used to repair the gut microbiota. These products have been shown to reduce the recurrence of CDI. RBX2660 is an investigational microbiota-based live biotherapeutic. RBX2660 contains a diverse set of microorganisms. RBX2660 has been developed to reduce CDI recurrence in adults following antibiotic treatment for recurrent CDI. This study was conducted to demonstrate that RBX2660 is effective and safe in treating patients with recurrent CDI. Treatment was considered successful in participants who did not experience CDI recurrence within 8 weeks after administration. Overall, statistical modeling demonstrated that 70.6% of participants treated with RBX2660 and 57.5% of participants treated with placebo remained free of CDI recurrence through 8 weeks. A 13.1 percentage point increase in treatment success was observed with RBX2660 treatment compared with placebo. In participants who achieved treatment success at 8 weeks, more than 90% remained free of CDI recurrence through 6 months. The most common side effects with RBX2660 treatment were abdominal pain and diarrhea. No serious treatment-related side effects were reported. The current data from the comprehensive clinical development program support a positive benefit-risk profile for RBX2660 in the reduction of CDI recurrence in adults following antibiotic therapy for recurrent CDI.

Clinical trials have demonstrated the efficacy of FMT for reduction in CDI recurrences (rCDI), but this treatment and its reporting in the literature has significant heterogeneity. Recent publications (e.g., Ramai et al. in Dig Dis Sci 2020. https://doi.org/10.1007/s10620-020-06185-7 ) present the clinical outcomes for different FMT methodologies. However, to understand, compare, and contextualize outcomes, this heterogeneity in methods and reporting must be understood. We performed a literature review of randomized controlled trials (RCTs) of FMT for rCDI to evaluate heterogeneity among trials. A methodical search between January 2010 and May 2019 of Medline, Embase, and Cochrane was conducted for studies investigating FMT in adults with rCDI. RCTs were evaluated for a variety of methodological and reporting criteria. Eight RCTs were identified, wherein 14 different FMT preparations were considered (each with distinct protocols for processing, storage, administration, and dosing). Sample sizes were generally small, with only two studies performing FMT in more than 100 patients. Three studies used non-FMT controls (vancomycin), while the remaining compared FMT with differing routes of administration or formulations. Across the identified studies, there was no standardized manner for reporting the timing of the FMT procedure. All studies tracked adverse events; however, follow-up periods were limited. Considerable variability exists among RCTs, with marked differences in study design, control groups, and outcome assessment. Lack of a standard-of-care control in many trials may impact reproducibility of FMT trial outcomes in patients with rCDI. Widespread use of FMT for rCDI is still investigational; therefore, these foundational studies provide opportunities to optimize future trials.

BACKGROUND: Clostridioides difficile infection (CDI) affected an estimated 365,000 persons in the United States in 2017. Despite a nationally decreasing trend of CDI cases, the population incidence...

Aims: This study aimed to evaluate all-cause economic outcomes, healthcare resource utilization (HRU), and costs in patients with Clostridioides difficile infection (CDI) and recurrent CDI (rCDI) u...

Background Although the incidence, severity and mortality of Clostridioides (Clostridium) difficile infection (CDI) have been increasing, patients’ quality of life changes resulting from CDI have not been studied thoroughly. This study aimed at exploring the consequences of CDI on quality of life through patients’ perspective. Methods An observational, cross-sectional study involving 350 participants with a self-reported CDI diagnosis was conducted through an online self-administered survey. Participants were grouped into those who had active disease (“Current CDI”) and those who had a history of CDI (“Past CDI”). Results One hundred fifteen participants (33%) reported Current CDI and 235 (67%) reported Past CDI. A large majority of participants admitted that their daily activities were impacted by the infection (93.9% and 64.7% of Current and Past CDI respondents respectively, p p = 0.08; psychological consequences p = 0.21). After the infection, 56.6% of respondents noted that post-CDI symptoms remained; 40.9% believed they would never get rid of them. Conclusions While the societal burden of CDI is well described in the literature, our study is one of the first aimed at understanding the major burden of CDI on quality of life. Our results highlight the long-lasting nature of CDI and further reinforce the need for enhanced therapeutics in the prevention and treatment of this devastating infection.

BACKGROUND & AIMS Disease activity and severity of eosinophilic esophagitis (EoE) dictate therapeutic options and management, but the decision-making process for determining severity varies among practitioners. To reduce variability in practice patterns and help clinicians monitor the clinical course of the disease in an office setting, we aimed to create an international consensus severity scoring index for EoE. METHODS A multidisciplinary international group of adult and pediatric EoE researchers and clinicians, as well as non-EoE allergy immunology and gastroenterology experts, formed 3 teams to review the existing literature on histology, endoscopy, and symptoms of EoE in the context of progression and severity. A steering committee convened a 1-day virtual meeting to reach consensus on each team's opinion on salient features of severity across key clinicopathologic domains and distill features that would allow providers to categorize disease severity. RESULTS Symptom features and complications and inflammatory and fibrostenotic features on both endoscopic and histologic examination were collated into a simplified scoring system-the Index of Severity for Eosinophilic Esophagitis (I-SEE)-that can be completed at routine clinic visits to assess disease severity using a point scale of 0-6 for mild, 7-14 for moderate, and ≥15 for severe EoE. CONCLUSIONS A multidisciplinary team of experts iteratively created a clinically usable EoE severity scoring system denominated "I-SEE" to guide practitioners in EoE management by standardizing disease components reflecting disease severity beyond eosinophil counts. I-SEE should be validated and refined using data from future clinical trials and routine clinical practice to increase its utilization and functionality.

ImportanceRecurrent Clostridioides difficile infection (CDI) is a debilitating disease leading to poor health-related quality of life (HRQOL), loss of productivity, anxiety, and depression. The potential association of treatment with HRQOL has not been well evaluated.ObjectivesTo explore the association of SER-109 compared with placebo on HRQOL in patients with recurrent CDI up to week 8.Design, Setting, and ParticipantsThis study was a secondary analysis of a randomized, double-blind, placebo-controlled trial that took place at 56 sites in the US and Canada from July 2017 to April 2020 and included 182 patients randomized to SER-109 or placebo groups.InterventionsSER-109 or placebo (4 capsules once daily for 3 days) following antibiotics for CDI.Main Outcomes and MeasuresExploratory analysis of HRQOL using the disease specific Clostridioides difficile Quality of Life Survey (Cdiff32) assessed at baseline, week 1, and week 8.ResultsIn this study, 182 patients (109 [59.9%] female; mean age, 65.5 [16.5] years) were randomized to SER-109 (89 [48.9%]) or placebo (93 [51.1%]) groups and were included in the primary and exploratory analyses. Baseline Cdiff32 scores were similar between patients in the SER-109 and placebo groups (52.0 [18.3] vs 52.8 [18.7], respectively). The proportion of patients with overall improvement from baseline in the Cdiff32 total score was higher in the SER-109 arm than placebo at week 1 (49.4% vs 26.9%; P = .012) and week 8 (66.3% vs 48.4%; P = .001).Greater improvements in total and physical domain and subdomain scores were observed in patients in the SER-109 group compared with placebo as early as week 1, with continued improvements observed at week 8. Among patients in the placebo group, improvements in HRQOL were primarily observed in patients with nonrecurrent CDI while patients in the SER-109 group reported improvements in HRQOL, regardless of clinical outcome.Conclusions and RelevanceIn this secondary analysis of a phase 3 clinical trial, SER-109, an investigational microbiome therapeutic was associated with rapid and steady improvement in HRQOL compared with placebo through 8 weeks, an important patient-reported outcome.Trial RegistrationClinicalTrials.gov Identifier: NCT03183128

Estimate mortality, cost, and health care resource utilization for Medicare beneficiaries aged ≥65 years who suffered a primary Clostridioides difficile infection (CDI) episode only or any recurrent CDI, and understand how outcomes covary with death.Retrospective observational claims analysis.Patients aged ≥65 years who had an inpatient or outpatient CDI diagnosis claim to Medicare and continuous enrollment in Medicare parts A, B, and D during the 12-month pre- and post-index periods.Using 100% Medicare Fee-for-Service claims data for 2009-2017, primary (pCDI, n = 345,893) and recurrent (rCDI: n = 151,596) CDI episodes were identified. Demographic and clinical characteristics, mortality, health care resource utilization, and costs (per patient per month) were summarized for 12 months before and up to 12 months after episode start. Regression models were estimated for hospitalization risk, hospital length of stay (LOS), and cost to adjust for comorbidities.CDI-associated deaths were almost 10 times higher after recurrent CDI (25.4%) than primary CDI (2.7%). Compared with survivors, decedents were older, had higher Charlson Comorbidity Index scores, and were more likely Black. Adjusting for comorbidities, during follow-up, decedents had higher hospitalization rates [pCDI: odds ratio (OR) = 1.83, P.001; rCDI: OR = 2.58, P.001], and recurrent CDI decedents had more intensive care unit use (OR = 2.34, P.001) compared with survivors. Decedents also had a longer length of stay (pCDI: +3.2 days, P.001; rCDI: +2.6 days, P.001), and higher total cost (pCDI: +303%, P.001; rCDI: +297%, P.001).CDI is an important contributing diagnosis to all-cause mortality, particularly for recurrences. Prior to death, older Medicare beneficiaries who experienced CDI received longer, more intensive, and more costly care compared with survivors. Clinicians should be particularly attentive to prevention, identification, and appropriate treatment of CDI in older adults. Better treatments to reduce primary C difficile infection and recurrences in this vulnerable population can lower both mortality and economic burden.

To describe 12-month outcomes for beneficiaries in the 100% Medicare Fee-for-Service (FFS) population with primary and recurrentA retrospective, descriptive, cohort study of CDI claims from the 100% Medicare FFS population, with a first CDI diagnosis between January 1, 2010, and December 31, 2016.Any US-based provider that submitted inpatient or outpatient CDI diagnosis claims to Medicare FFS.The study included patients aged ≥65 years with continuous enrollment in Medicare Parts A, B, and D during 12 months before and 12 months after the index period.The number of CDI and recurrent (rCDI) episodes, healthcare resource utilization, treatments, complications, and procedures were calculated for pre-index and follow-up periods. The data were stratified by number of rCDI episodes (ie, no rCDI, 1 rCDI, 2 rCDI, and ≥3 rCDI).Of 268,762 patients with an index CDI, 34.7% had at least 1 recurrence. Of those who had 1 recurrence, 59.1% had a second recurrence and of those who had 2 recurrences, 58.4% had ≥3 recurrences. Incident psychiatric conditions occurred in 11.3%-18.2% of each rCDI cohort; 6.0% of patients with rCDI underwent subtotal colectomy, and 1.1% of patients underwent diverting loop ileostomy. After each CDI episode, ∼1 in 5 patients had a documented sepsis event. Over the 12-month follow-up, 30% of patients experienced sepsis, and sepsis occurred in 27.0% of the cohort with no rCDI, compared to 35.5% of patients in the rCDI cohorts.Elderly patients with CDI and rCDI experienced a significant clinical burden and complications.

Summary Background Faecal microbiota transplantation (FMT) has shown promise in alleviating the symptoms of irritable bowel syndrome (IBS); however, controlled data on this technique are scarce. The aim of this clinical trial was to assess the efficacy of FMT in alleviating diarrhoea-predominant IBS (IBS-D). Methods We did a double-blind, randomised, placebo-controlled crossover trial in patients aged 18–65 years with moderate-to-severe IBS-D defined by an IBS-Symptom Severity Score (IBS-SSS) of more than 175, recruited from three US centres. Patients were randomly assigned (1:1) in blocks of four with a computer-generated randomisation sequence to receive FMT capsules followed by identical-appearing placebo capsules, or placebo capsules followed by FMT capsules. All participants and study team members were masked to randomisation. An independent staff member assigned the treatments according to consecutive numbers. Patients received either 75 FMT capsules (each capsule contained approximately 0·38 g of minimally processed donor stool) or 75 placebo capsules over 3 days (25 capsules per day). All patients crossed over to the alternate treatment at 12 weeks. The primary outcome was difference in IBS-SSS between the groups at 12 weeks. Intention-to-treat analyses were done and all patients who received study drug were included in an adverse events analysis. The trial was terminated during recruitment because results from an interim analysis revealed futility. The study is registered with ClinicalTrials.gov , number NCT02328547 . Findings From May 28, 2015, to April 21, 2017, 48 patients were randomly assigned to receive FMT first (n=25) or placebo first (n=23). Three participants were lost to follow-up in the FMT group. IBS-SSS did not differ between FMT recipients (mean 221 [SD 105]) and placebo recipients (236 [95]) at 12 weeks (p=0·65), after adjustment for baseline scores. The most common drug-related adverse events included abdominal pain (five [10%] of the 48 participants while receiving FMT capsules vs four [8%] while receiving placebo), nausea (four [8%] vs two [4%]), and exacerbation of diarrhoea (three [6%] vs eight [17%]). One serious adverse event that was unrelated to study drug (acute cholecystitis) was reported in a patient while receiving placebo capsules. Interpretation FMT was safe, but did not induce symptom relief at 12 weeks compared with placebo. Additional studies are needed to determine the efficacy of FMT for IBS-D. Funding National Institutes of Health.