2829 Patients Eligible for Trials of Microbiota-Based Therapeutics Do Not Represent the Population With Recurrent Clostridioides difficile Infection

Abstract

INTRODUCTION: Industry-funded trials of microbiota-based therapeutics for treatment of Clostridioides difficile are ongoing, however due to strict enrollment criteria, not all patients are eligible. Furthermore, given the widespread availability of fecal microbiota transplantation (FMT) and overwhelming evidence supporting its efficacy, patients may refuse enrollment in trials with a placebo-arm. METHODS: This is a retrospective study performed at four tertiary referral centers for FMT. The electronic medical record at each was reviewed to capture patients referred for recurrent CDI over a 6- month time period. FMT eligibility was determined based on current CDI treatment guidelines.3 Inclusion and exclusion criteria for a clinical trial of an oral microbiota-based therapeutic were applied to determine eligibility, based on current enrolling trials at these centers. RESULTS: Of 199 patients referred for a diagnosis of recurrent CDI, 130 (65%) were deemed to be eligible for FMT based on the number and severity of episodes. Of the patients in whom FMT was determined to be an appropriate option, 94 (72%) met inclusion criteria for an RCT of a microbiota-based therapeutic drug, however 62 (66%) of those meeting inclusion criteria had one or more exclusion criteria (Table 1) precluding participation and 16 (17%) were eligible but refused to enroll. Only 16 (12%) of FMT-eligible patients were enrolled in the drug trial. Conventional FMT using stool-bank donor material was performed in 96 patients (74%) of those deemed eligible to undergo the procedure (Figure 1). Most patients (79%) met a single exclusion criterion, 14.5% met two criteria and 6.5% met three criteria. The most common reason for study exclusion was immunocompromise (17; 27%). Other common exclusions were inflammatory bowel disease (13; 21%), having already received more than 21 days of vancomycin (11; 18%) and diarrhea-predominant irritable bowel syndrome (10; 16%). CONCLUSION: Less than half of patients deemed eligible for FMT based on clinical history of recurrent CDI met eligibility criteria for a clinical trial of an encapsulated microbiota product. A smaller but relevant proportion of eligible patients refused to participate. Restrictions on stool banks would have detrimental effects on patient access to FMT. Furthermore, these results demonstrate that a relevant number of patients affected by recurrent CDI are currently being excluded from industry-funded trials.

Immune-Microbiota Interplay and Colonization Resistance in Infection

“…Of note, both cases were linked to the same stool donor. Moreover, it has been criticized that patient cohorts in existing RCTs are not sufficiently reflective of real-life CDI patients eligible for FMT (Kelly et al, 2019;Tariq et al, 2017). The mechanisms mediating FMT efficacy are elusive, as recent studies suggest that, rather than engraftment of complete live microbiota, transfer of specific bacterial consortia or even bacteria-free filtrates containing phages or secondary bile acids may suffice to achieve a treatment effect ll (Buffie et al, 2015;Lee et al, 2016;Ott et al, 2017;Staley et al, 2016;Zuo et al, 2018).…”

The Efficacy and Safety of Fecal Microbiota Transplant for Recurrent Clostridiumdifficile Infection: Current Understanding and Gap Analysis

“…A few FMT proponents have argued that some patient subgroups, such as immunocompromised hosts, often do not qualify for placebo-controlled trials and need open access to FMT [40]. However, implicit in this statement is the implication that FMT has been shown to be efficacious and safe in this patient population when there are no controlled trials to support such assumptions.…”