Rigorous donor selection for fmt in active ulcerative colitis: key lessons from a randomized controlled trial halted for futility

Background and aims Rigorous donor preselection on microbiota level, strict anaerobic processing, and repeated FMT administration were hypothesized to improve FMT induction of remission in 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 four 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 one 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=0.72), indicating no treatment difference of at least 5% in favour of allogenic-FMT. Hence, the study was stopped due to futility. Microbiome analysis showed numerically more enterotype transitions upon allogenic-FMT compared to autologous-FMT and more transitions were observed when patients were treated with a different enterotype than their own at baseline (p=0.01). 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.