FMT Rigorous Donor Selection for Fecal Microbiota Transplantation in Active Ulcerative Colitis: Key Lessons From a Randomized Controlled Trial Halted for Futility (May 2024, n=72)

[Michael Harrop]

https://www.cghjournal.org/article/S1542-3565(24)00492-0/fulltext

A group from Belgium.

Abstract​

Background & Aims​

Rigorous donor preselection on microbiota level, strict anaerobic processing, and repeated fecal microbiota transplantation (FMT) administration were hypothesized to improve FMT induction of remission in ulcerative colitis (UC).

Methods​

The RESTORE-UC trial was a multi-centric, double-blind, sham-controlled, randomized trial. Patients with moderate to severe UC (defined by total Mayo 4–10) were randomly allocated to receive 4 anaerobic-prepared allogenic or autologous donor FMTs. Allogenic donor material was selected after a rigorous screening based on microbial cell count, enterotype, and the abundance of specific genera. The primary endpoint was steroid-free clinical remission (total Mayo ≤2, no sub-score >1) at week 8. A pre-planned futility analysis was performed after 66% (n = 72) of intended inclusions (n = 108). Quantitative microbiome profiling (n = 44) was performed at weeks 0 and 8.

Results​

In total, 72 patients were included, of which 66 received at least 1 FMT (allogenic FMT, n = 30 and autologous FMT, n = 36). At week 8, respectively, 3 and 5 patients reached the primary endpoint of steroid-free clinical remission (P = .72), indicating no treatment difference of at least 5% in favor of allogenic FMT. Hence, the study was stopped due to futility. Microbiome analysis showed numerically more enterotype transitions upon allogenic FMT compared with autologous FMT, and more transitions were observed when patients were treated with a different enterotype than their own at baseline (P = .01). Primary response was associated with lower total Mayo scores, lower bacterial cell counts, and higher Bacteroides 2 prevalence at baseline.

Conclusion​

The RESTORE-UC trial did not meet its primary endpoint of increased steroid-free clinical remission at week 8. Further research should additionally consider patient selection, sterilized sham-control, increased frequency, density, and viability of FMT prior to administration.
ClinicalTrials.gov, Number: NCT03110289.

Graphical abstract​

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Their donors:

Eligible donors were recruited locally, according to international consensus guidelines, based on a general health questionnaire and blood and fecal parameters (Supplementary Table 1). All potential donors were tested for transmittable diseases by blood and fecal examination (Supplementary Table 2), maximum 4 weeks before donation started and a second time at the end of the donation period. Potential ‘superdonors’ were further selected based on 3 criteria: microbial cell counts (>1.75 × 1011 cells/g), enterotype and the abundance (>1%) of the genera Fusobacterium, Escherichia/Shigella, and Veillonella. Also, samples belonging to the Bact2 enterotype were excluded, even if they were not low in bacterial cell count.

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This is the second trial that I recall that tried to select donors this way and failed. The previous one:

Fecal Microbiota Transplantation engraftment after budesonide or placebo in patients with active ulcerative colitis using pre-selected donors: a randomized pilot study (Apr 2024, n=24) "Clinical response appeared donor-dependent. These findings also suggest that selecting FMT donors based on in vitro, microbiome community, or animal model data alone may be insufficient to predict FMT clinical response"

This is not a valid donor-selection method. I've found observable stool characteristics to be one of the best tools.

Furthermore, they are likely attempting to select "super-donors" from a pool of low-quality donors. They need to run these tests on my top donors and compare them to lower-ranked donors.