Left: Dimitri Drekonja, MD, MS serves as the chief of the infectious diseases section at the Minneapolis VA and is an associate professor of medicine at the University of Minnesota.
Image credit: US Dept. of Veterans Affairs
Right: Asma Shaukat, MD, MPH, Robert M and Mary H Glickman professor of medicine and population health, director of GI outcomes research at NYU and Harbor VA.
Image credit: NYU
To tackle the problem of 15% to 30% of patients getting sick again from Clostridioides difficile infections (CDI), researchers conducted a clinical trial to test the effectiveness of capsule-delivered fecal microbiota transplantation (FMT) compared to a placebo. The trial also aimed to assess the safety of FMT as a secondary objective. Overall, FMT therapy did not lead to a decrease in CDI recurrence or death at 56 days compared to placebo, and there were no significant differences in adverse events between the treatment groups.
The study was stopped early for futility after reaching pre-defined criteria. Among the 153 participants, 76 received FMT and 77 received a placebo. Of these, 25 participants (32.9%) in the FMT group and 23 (29.9%) in the placebo group experienced diarrhea, CDI recurrence, or death within 56 days. Dividing the groups by how many times they had infections showed no important differences, and there were no significant changes in side effects.
From 2018 to 2022, veterans within the Veterans Health Administration system who had recurrent CDI and responded to antibiotic treatment were randomly assigned in a 1:1 ratio in this trial. Randomization was stratified based on the number of previous CDI recurrences (1 or ≥2). The primary endpoint was clinical recurrence by day 56, defined as having more than three unformed stools daily for two or more days, with or without laboratory confirmation of C difficile, or death within 56 days.
Main Takeaways
- The trial found that capsule-delivered FMT did not significantly reduce CDI recurrence or mortality compared to placebo, leading to its early termination for futility.
- Researchers highlighted limitations in the study design, including participant selection and the interpretation of C difficile test results, which may have impacted the efficacy findings.
- Future research will focus on the long-term efficacy and safety of FMT, particularly for patients with multiple recurrences, to refine treatment strategies.
In an exclusive email interview with Contagion, researchers, Aasma Shaukat, MD, MPH and Dimitri Drekonja, MD, MS discussed limitations in the study design or execution that may have influenced the findings of futility regarding FMT’s effectiveness, “We can only guess at the reasons for the results we observed. Some possibilities include how we defined who could join the study and what we considered a successful outcome, the number of prior infections participants had, the makeup of the FMT, and the dose or method of giving it. One key point is that most participants tested positive for C difficile using a PCR test, which might indicate the presence of the bacteria rather than an active infection.”
They go on to discuss at the time of the study’s design and even currently, PCR and toxin tests are commonly used and accepted in the US for diagnosing CDIs. The primary outcome was chosen to reflect real-world conditions, focusing on symptom recurrence with or without laboratory confirmation. They continue, “This approach could have led to enrolling some people with other gastrointestinal issues that show similar symptoms. We also included participants with one or more recurrences of infection, and it’s possible FMT may work better for those with multiple recurrences. Lastly, while we used a well-established FMT product, there is no agreed-upon standard for the composition, dosage, or how it’s given. Other factors that could have affected results include the time between participants finishing antibiotics and receiving FMT or placebo (about 6 days for both groups) and allowing the use of certain medications like proton pump inhibitors, which are linked to higher recurrence rates.”
Shaukat and Drekonja discussed notable trends observed in the subgroup analysis based on the number of prior CDI recurrences, despite the lack of statistically significant differences, “The subgroups are small, so we can’t make any definite conclusions, but we did notice a trend where FMT seemed more effective in people with more previous recurrences and when it was given sooner after finishing antibiotics for the latest recurrence.”
In terms of the future, plans to assess the long-term efficacy and safety of FMT beyond the 56-day endpoint to better understand recurrence rates, “The study was set up to track outcomes for six months to evaluate both how well FMT works and its safety. We’ve completed the analysis and are reviewing the results,” Shaukat and Drekonja said. While this study suggests that FMT may not yet be a standard treatment for CDI, the findings offer valuable insights that could shape future research and improve treatment strategies.
