Transfer of FRozen Encapsulated multi-donor Stool filtrate for active ulcerative Colitis (FRESCO): study protocol for a prospective, multicenter, double-blind, randomized, controlled trial

Abstract

Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease with significant morbidity and mortality. Although the precise cause remains unknown, disturbances in the intestinal microbial community have been linked to its pathogenesis. Randomized controlled trials in UC and relapsing Clostridioides difficile infection (CDI) have established fecal microbiota (FM) transfer (FMT) as an effective therapy. In this context, preliminary results indicated that the transfer of sterile fecal microbiota filtrates (<0.2 μm; FMF, FMFT) of donor stool also drives gastrointestinal microbiota changes and eliminates symptoms in CDI patients. However, along with the success of FMT, regulatory agencies issued safety alerts following reports of serious adverse events due to transmission of enteric pathogens through FMT. To reduce this risk, we established an extensive test protocol for our donors and quarantine regulations for the produced capsules, but alternative concepts are desirable. Methods Our project is a randomized, controlled, longitudinal, prospective, three-arm, multicenter, double-blind study to determine the safety and efficacy of repeated long-term, multi-donor FM or FMF transfers compared to placebo using oral, frozen capsules in 174 randomized patients with mild to moderate active UC. The primary outcome will be clinical remission at week 12. Discussion This proposal aims to examine (a) the efficacy of encapsulated transfer of FM and FMF as a therapy for mild to moderate UC, (b) the short- and long-term safety of FMT and FMFT in patients with UC, and (c) the microbial and immunologic changes that occur after FMT and FMFT to help understand how and why it affects inflammatory bowel disease. Trial registration ClinicalTrials.govNCT03843385. DRKS (Deutsches Register für Klinische Studien) DRKS00020471

Murine sterile fecal filtrate is a potent pharmacological agent that exerts age-independent immunomodulatory effects in RAW264.7 macrophages

“…In addition, the beneficial effects of FMT therapy have been related to the modulation of macrophage effector functions [ 27 , 28 ]. However, considering the limitations and challenges associated with FMT, the use of SFF is recently being recognized as an alternate approach for managing gut inflammatory disorders [ 14 , 29 ]. The present study thus evaluated whether SFF has the potency to stimulate as well as modulate macrophage functions that may be useful for maintaining cellular immune homeostasis and resisting inflammatory disorders respectively.…”

The practice of fecal microbiota transplantation in inflammatory bowel disease

“…Another technique fecal filtrate transplantation instead removes intact bacteria and only transfers bacterial debris, metabolites, and oligonucleotides [ 58 ]. It has been utilized successfully in CDI and is also being evaluated in UC in a clinical trial [ 59 ].…”

“…58 It has been utilized successfully in CDI and is also being evaluated in UC in a clinical trial. 59…”

Questions to consider when caring for patients with ulcerative colitis

“…Interestingly, it was shown that sterile stool filtrate also eliminated symptoms in chronic Clostridioides difficile infection [48]. The ongoing FRESCO trial currently addresses the question of whether transfer of sterile stool filtrate may also be sufficient to treat UC [49]. However, FMT as a therapeutic option for UC should be reserved for well-controlled clinical trials until more evidence on its efficacy and safety will be available.…”