Summary
Background
Faecal microbiota transplantation (FMT) is highly effective in preventing recurrent Clostridioides difficile infection. However, it is not known whether live microbes are necessary in mediating FMT efficacy. This study aims to determine whether lyophilised sterile faecal filtrate (LSFF), free of live bacteria, is non-inferior to lyophilised donor stool (LFMT) in efficacy.
Methods
This multicentre, randomised, double-blinded, non-inferiority trial was done at four academic centres in Canada. Eligible patients were adults aged 18 years or older with recurrent C difficile infection (at least two recurrences). Eligible patients were randomly assigned (1:1 using a prespecified computer-generated randomisation list with permutation blocks of 2 and 4, stratified by age >65 years or <65 years) to receive oral LSFF or LFMT. Each treatment dose consisted of 15 capsules that appeared identical. Participants and investigators were masked to treatment allocation. The primary outcome was the proportion of participants without recurrent C difficile infection (absence of more than three Bristol type 6 or 7 bowel movements per 24 h persisting more than 2 consecutive days) at 8 weeks. Analysis was done in the per protocol population, in which participants with unknown outcome status at 8 weeks due to death or loss to follow-up were excluded. Non-inferiority was established if the lower bound of the one-sided 95% CI for the difference in proportions of participants without recurrent C difficile between the LSFF and LFMT groups was above the non-inferiority margin of –10%. This trial was registered at ClinicalTrials.gov, NCT03806803, and is complete.
Findings
Between March 27, 2019, and Nov 6, 2023, we assessed 409 patients for eligibility. 271 were excluded and the remaining 138 were enrolled and randomly assigned to receive LSFF (n=72) or LFMT (n=66). Participants' mean age was 61·2 years (SD 18·6); 91 (66%) of 138 patients were women and 47 (34%) were male. 127 participants (92%) were White. 130 (94%) of 138 participants completed the trial. At the planned interim analysis, 47 (65%) of 72 participants in the LSFF group and 57 (88%) of 65 participants in the LFMT group did not have C difficile recurrence at 8 weeks (difference –23%, one-sided 95% CI –33·8% to infinity; p=0·96). Given the pre-specified non-inferiority margin of –10%, non-inferiority of LSFF to LFMT could not be established and the study was terminated at the recommendation of the data safety monitoring board. Serious adverse events included one death (LFMT group) and five hospitalisations (four unrelated, one possibly related to interventions [LSFF group]). One event occurred before treatment and all others 2–20 weeks after study intervention. The most common adverse events were abdominal discomfort (48 [67%] of 72 patients in the LSFF group and 36 (55%) of 66 patients in the LFMT group) and nausea (13 [18%] in the LSFF group and 21 [32%] in LFMT group).
Interpretation
Among adults with recurrent C difficile infection, non-inferiority of LSFF to LFMT was not established for the prevention of recurrent C difficile infection over 8 weeks, supporting the crucial role of live microbes in mediating clinical efficacy.
Funding
Canadian Institutes of Health Research; University of Alberta Hospital Foundation; Alberta Health Services; Weston Foundation.
