Data from a randomized controlled trial show that capsule-delivered fecal microbiota transplantation (FMT) was safe but failed to reduce recurrence of Clostridioides difficile infection (CDI), researchers reported today in Clinical Infectious Diseases.
The trial, which was led by investigators with the Minneapolis Veterans Affairs (VA) Health Care System and involved patients from 47 VA facilities in 40 states, aimed to assess the efficacy of capsule-delivered FMT versus placebo in reducing recurrent CDI, which is the leading cause of infectious diarrhea in the United States. While antibiotic treatment for initial CDI episodes is successful in most cases, recurrence occurs in 15% to 30% of CDI patients after an initial episode and 40% to 50% of those with subsequent episodes.
"Recurrent CDI is a challenging dilemma for clinicians and a trying illness for patients," the study authors wrote
The disturbance of the gut microbiome by antibiotics is thought to play a significant role in recurrent CDI and has led to efforts to find alternative treatments. One of the alternatives is FMT, which involves the transfer of healthy stool from screened donors to help restore the gut microbiome.
FMT has been found to be highly effective at reducing CDI recurrence in several observational studies and is recommended by clinical guidelines for patients who've had two or more CDI recurrences. But the investigators say more evidence is needed, given that there is a lack of large placebo-controlled trials on FMT and the results from existing trials have been inconsistent.
Trial stopped due to futility
From October 2018 through July 2022, investigators enrolled 153 participants (average age, 66.6 years; 86.2% male; 94.6% White) with one or more CDI episode who previously been treated with antibiotics and randomized them 1:1 to receive oral, donor-derived FMT or placebo capsules. The primary end point was possible or definite CDI recurrence or death within 56 days of randomization.
At the first interim analysis, 25 (32.9%) of 76 patients in the FMT group and 23 (29.9%) of 77 in the placebo group experienced the primary end point, for an absolute difference of 3.0% (95% confidence interval [CI], - 11.7% to 17.7%). Similar results were seen for each component of the primary end point (possible recurrence, definite recurrence, and death). Stratification by number of recurrences revealed no statistically significant differences.
There were no clinically important differences in serious adverse events (SAEs), with 22.4% of participants in the FMT arm and 27.3% in the placebo experiencing SAEs, only one of which was treatment-related.
"FMT was well-tolerated and safe, but did not lead to a reduction in recurrent CDI," the authors wrote.
Because the pre-specified criteria for stopping the trial was a between-group difference of less than 4%, investigators stopped the trial early.
FMT was well-tolerated and safe, but did not lead to a reduction in recurrent CDI.
The authors say the observed lack of benefit for FMT has several potential explanations, including the definitions for study inclusion and end points, number of episodes of recurrent CDI, FMT composition, and dose or route of administration. Another potential reason is the time between when patients ended antibiotic treatment and when FMT or placebo was administered (an average of 6 days for FMT and 6.3 days for placebo).
"Whether there is a difference in efficacy in patients receiving FMT one or two days after stopping antibiotics vs. receiving it several days later, assuming no signs of clinical recurrence, is unknown," they wrote. "Current guidance for administering FDA-approved stool-derived products is that they be given one to four days after cessation of antibiotics, although residual stool antimicrobials that could interfere with FMT are a concern."
Findings raise important questions
In an accompanying editorial, experts from the University of Toronto also note that 78% of participants had only one CDI recurrence prior to randomization, while most previous FMT trials have targeted patients with two or more recurrences.
"After a single recurrence, the risk for further recurrence is expected to be lower compared with subsequence recurrences, potentially because the colon is in a less dysbiotic state," Susan Poutanen, MD, MPH, and Susy Hota, MD, MSc, wrote. "The effect of FMT on recurrence risk for patients who have experienced a single recurrence of CDI is less studied."
Poutanen and Hota say that although the weight of evidence still appears to favor FMT for treatment of recurrent CDI, the study "should not be dismissed as an aberrancy" and presents important questions about optimal timing, dosage, donor profile, and patient population for FMT.
"Ongoing research into answering these questions should continue in order to optimize manufacturing and delivery of FMT to produce the best patient outcomes," they wrote.
