Fecal microbiota transplantation demonstrated noninferiority to standard vancomycin therapy for treating primary Clostridioides difficile infection in a phase 3 randomized controlled trial.
Researchers in the Norwegian multicenter study of 104 patients found that 66.7% of those who received fecal microbiota transplantation (FMT) achieved clinical cure at day 14 with no disease recurrence within 60 days using assigned treatment alone, compared with 61.2% in the vancomycin group—a difference of 5.4 percentage points (95.2% confidence interval [CI] = −13.5 to 24.4; P for noninferiority < .001). The primary end point was clinical cure, defined as fewer than 3 stools per day or firm stools (Bristol Stool Chart type up tp 4) for at least 48 hours at day 14, with no Clostridioides difficile infection (CDI) recurrence within 60 days on assigned treatment alone.
Recurrence Rates Favor FMT
Initial clinical cure rates at day 14 were similar: 70.6% (36 of 51) in the FMT group and 77.6% (38 of 49) in the vancomycin group. However, recurrence patterns differed substantially. Among patients who achieved initial cure, only 2 (5.6%) in the FMT group had disease recurrence compared with 8 (21.1%) in the vancomycin group between days 15 and 60.
When additional treatments were included, 40 of 51 patients (78.4%) in the FMT group achieved clinical cure at day 14 with no recurrence by day 60, compared with 30 of 49 (61.2%) in the vancomycin group (difference = 17.2 percentage points [95.2% CI = 0.7–35.1]).
In an accompanying editorial, Elizabeth Hohmann, MD, of Massachusetts General Hospital, noted that the confidence intervals overlap: "FMT is clearly not inferior and might be considered superior." She also observed, "although there are no quality of life surveys in Juul and colleagues’ study, had they been done, I suspect quality of life might have been higher in the FMT group; in my experience, people feel better after microbiome restoration."
Study Design and Patient Characteristics
The open-label, noninferiority trial randomized patients 1:1 to receive either 1 FMT enema within 24 hours of randomization or standard treatment with 125 mg of oral vancomycin 4 times daily for 10 days. Notably, patients in the FMT group did not receive any antibiotic pretreatment.
The study population was typical for CDI: median age was 70 to 71 years and approximately one-third of patients met the criteria for severe disease based on fever, leukocyte count of more than 15 × 10⁹/L, or creatinine of more than 1.5 mg/dL. Most participants (85.7%–90.2%) had received antibiotics within the previous 3 months.
Clinical Context and FDA-Approved Products
Dr. Hohmann's editorial highlighted that this trial should be considered within the context of current treatment options. In the U.S., FMT must be evaluated alongside two FDA-approved stool-derived products that have been studied in placebo-controlled trials: an enema (fecal microbiota, live-jslm; REBYOTA) and an oral capsule (fecal microbiota spores, live-brpk; VOWST).
However, "currently approved options are expensive and are not available to many who might benefit for various reasons, primarily cost," Dr Hohmann noted. Two recent developments have further complicated the treatment landscape: the cessation of bezlotoxumab manufacture in January 2025 and the discontinuation of OpenBiome’s provision of screened FMT inocula to many U.S. sites.
Safety Profile and Mortality
Adverse events occurred at similar rates between groups, with no significant differences in the number or severity of events. None were deemed related to the study treatment.
Seven patients died during the 60-day follow-up: 2 in the FMT group and 5 in the vancomycin group. One death in each group was attributed to CDI recurrence. None of the deaths were considered treatment related. The editorial noted that this mortality rate "is lower than the all-cause 30-day mortality of about 10% after C difficile infection in a previous study, highlighting this illness as a marker of age and comorbidities in many patients."
Clinical Implications and Future Questions
The trial used a 25–percentage point noninferiority margin which was justified by 3 potential advantages of FMT over first-line antibiotic therapy: 1) reduced antibiotic use supports antimicrobial stewardship; 2) FMT via enema is minimally invasive and completed in a single procedure; and 3) vancomycin carries risks for adverse effects and drug interactions.
Dr Hohmann noted the study "emphasizes the importance of a healthy gut microbiome in preventing and treating this common nosocomial and community-acquired infection. It supports antibacterial stewardship in general and greater use of, access to, and insurance coverage for the FDA-approved stool-derived biologic products."
She raised several key questions: "When should we use microbial products—at a first, second, or third episode of C difficile infection? How long after antibacterial treatment should they be used? Does this vary by preparation?" She added the need for "a fast and inexpensive test for gut dysbiosis (perhaps based on a gut metabolomic readout) that could help direct us, independent of episode number."
Study Limitations and Context of Previous Research
The trial was terminated early following recommendation by the Data and Safety Monitoring Board after interim analysis met the noninferiority criterion for the primary end point (P = .001).
Limitations included the open-label design and reliance on clinical outcomes without stool testing for C difficile or FMT engraftment posttreatment. The editorial noted that “there is little to criticize about Juul and colleagues’ study in terms of design and execution except for the fact that it is not a double-blinded study,” adding that such a design "would be complex and expensive, requiring a double-dummy design with both placebo enema and placebo vancomycin, and would be very logistically challenging."
These findings are consistent with previous research, including a recent postmarketing observational study of 676 patients with recurrent CDI who received an FDA-approved stool-derived enema after fidaxomicin or vancomycin, with a reported 74% cure rate at 8 weeks.
Dr Hohmann concluded, “I do not believe that we in the U.S. will see FMT as a primary treatment of C difficile infection anytime soon,” but emphasized that it should remain available for care and research: “we still have much to learn about how our microbial communities affect human health.”
The researchers concluded that this randomized phase 3 trial suggests a potential role for FMT in primary CDI and supports a paradigm shift toward microbiome restoration as first-line therapy for this increasingly common health care-associated infection.
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Source: Annals of Internal Medicine and Editorial