Effects of lyophilized fecal filtrate compared with lyophilized donor stool on Clostridioides difficile recurrence: a multi-center, randomized, double-blinded trial

Kao, Dina; Wong, Karen; Lee, Christine; Steiner, Theodor; Franz, Rose; McDougall, Chelsea; Silva, Marisela; Schmidt, Thomas S.B.; Walter, Jens; Loebenberg, Raimar; Monaghan, Tanya M.; Giebelhaus, Ryland T.; Harynuk, James J.; Xu, Huiping; Yaskina, Maryna; MacDonald, Karen V.; Marshall, Deborah A.; Louie, Thomas

Abstract

Background Fecal microbiota transplantation (FMT) is highly effective in preventing recurrent Clostridioides difficile infection (rCDI). However, it is not known whether live microbes are necessary in mediating FMT efficacy. This study aims to determine whether lyophilized sterile fecal filtrate (LSFF), free of live bacteria, is non-inferior to lyophilized donor stool (LFMT) in efficacy.

Methods This multi-center, non-inferiority (margin=10%), double blinded trial randomized 138 adult rCDI participants (at least 2 recurrences) to either LSFF or LFMT (1:1 ratio using a prespecified computer-generated randomization list with permutation blocks of 2 and 4, stratified by age of >65 or <65) between March 27, 2019 and November 6, 2023, with follow-up to March 22, 2024. Each treatment dose consisted of 15 oral capsules which appeared identical. Participants and investigators were not aware of treatment allocation. The primary outcome was proportion of participants without rCDI (absence of more than 3 Bristol type 6 or 7 bowel movements per 24 hours persisting more than 2 consecutive days) at 8 weeks. Secondary outcomes included: (1) proportion of participants without rCDI at 24 weeks and (2) safety of interventions. Per protocol analysis was performed on primary and secondary outcomes.

Exploratory outcomes included changes at week 24 in (1) patient-reported health-related quality-of-life (EQ-5D-5L, CDIFF32) and work productivity and activity impairment (WPAI:SHP); and (2) fecal microbial composition. This completed trial was registered at clinicaltrials.gov (NCT03806803).

Findings Among 138 participants with at least 2 CDI recurrences (mean age [SD]: 61.2 [18.6] years; 91 women [65.9%]), 130 (94.2%) completed the trial, with 72 randomized to LSFF and 66 to LFMT. In per-protocol analysis, prevention of rCDI after 8 weeks occurred in 47/72 (65.3%) in LSFF and 57/65 (87.7%) in LFMT (difference, -22.4%, 1-sided 95% CI, -33.8% to ∞; P=0.96). Given the pre-specified non-inferiority margin of -10%, the non-inferiority of LSFF to LFMT could not be established. Serious adverse events included 1 death and 5 hospitalizations (4 unrelated, 1 possibly related to interventions). The most common adverse events were abdominal discomfort and nausea, reported by 48/72 and 13/72 in LSFF and 36/66 and 21/66 in LFMT group, respectively (p>0.05).

Interpretation Among adults with rCDI, LSFF was less efficacious than LFMT in preventing rCDI 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

Citation

Kao, D., Wong, K., Lee, C., Steiner, T., Franz, R., McDougall, C., Silva, M., Schmidt, T. S., Walter, J., Loebenberg, R., Monaghan, T. M., Giebelhaus, R. T., Harynuk, J. J., Xu, H., Yaskina, M., MacDonald, K. V., Marshall, D. A., & Louie, T. (in press). Effects of lyophilized fecal filtrate compared with lyophilized donor stool on Clostridioides difficile recurrence: a multi-center, randomized, double-blinded trial. The Lancet Gastroenterology & Hepatology,

• Journal Article Type: Article
• Acceptance Date: Jun 5, 2025
• Deposit Date: Jun 5, 2025
• Journal: The Lancet Gastroenterology & Hepatology
• Electronic ISSN: 2468-1253
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Public URL: https://nottingham-repository.worktribe.com/output/49910120