FAECAL MICROBIOTA TRANSPLANTATION IN ACTIVE ULCERATIVE COLITIS: INSIGHTS FROM A RANDOMIZED CONTROLLED TRIAL HALTED FOR FUTILITY

Intro/background Rigorous donor preselection on microbiota level, strict anaerobic processing, and repeated FMT administration were hypothesized to improve FMT outcomes for induction of remission in UC in the RESTORE-UC trial, for which we here report on the clinical results and observed microbial changes.
Methods The RESTORE-UC trial was a multi-centric double-blind, sham-controlled randomized trial. Patients with moderate to severe UC (total Mayo 4-10, endoscopic subscore ≥2) were randomly allocated to receive 4 weekly anaerobic-prepared allogenic or autologous donor FMT. Allogenic healthy donors were selected after a rigorous screening by microbial cell count, enterotype, and the abundance of specific genera. The primary endpoint was steroid-free clinical remission (total Mayo ≤2, no subscore >1) at week 8. A pre-planned futility analysis was performed after 66% (n=72) of intended inclusions (n=108). Quantitative microbiota 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, Fig. A). At week 8, resp. 3 and 5 patients reached the primary endpoint (p=0.72), indicating no treatment difference of at least 5% in favour of allogenic-FMT. Hence, the study was stopped due to futility. The procedure was well tolerated, and only 2 SAE were observed.
Microbial analysis showed no significant differences in baseline microbiome composition between treatment groups. However, numerically more enterotype transitions upon allogenic-FMT compared to autologous-FMT (Fig. B), 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 (Fig. C,D) and a tendency to more Bact 2 prevalence at baseline, independently from FMT origin. At the allogenic donor side, a positive association was suggested between stool moisture and treatment success (Wilcoxon test, p=0.057; Fig. F). However, no indications pointed towards a highly effective ‘superdonor’ profile.
Conclusion The RESTORE-UC trial comparing preselected allogenic to autologous FMT did not meet its primary endpoint of steroid-free clinical remission at week 8. Notably, participants exhibited more severe disease, aligning with recent guidelines recommending FMT for mild to moderate cases (Lopetuso & Deleu et al., 2023). In addition, our findings support adding microbial load and dysbiosis to the patient inclusion criteria based on a pre-treatment microbiome screening. Next to patient-selection, further research should additionally consider sterilized sham-control, increased frequency, density, and viability of FMT prior to administration.