A randomised controlled trial comparing FECal Microbiota Transplantation after BUDesonide or placebo induction in patients with ulcerative colitis; the FECBUD trial

Despite an increasing number of active drugs against Inflammatory Bowel Disease
(IBD) (ulcerative colitis and Crohn*s disease), treatment results are
disappointing for a subset of patients. In general, patients with ulcerative
colitis are treated with with mesalazine (with or without prednisolone as
induction). If mesalazine alone appears insufficient, a thiopurine
(azathioprine or purinethol) is added as maintenance treatment. In a subset of
patients, treatment with biologicals is required. Investigations of dysbiosis
of the gut microbiota in patients with IBD may guide the development of new
therapeutic strategies. IBD is characterized by a disturbed gut microbiota.
Importantly, fecal microbiota transplantation (FMT) is able to induce remission
in a small subset of patients with active ulcerative colitis (1-4).
Interestingly, certain donors may be more effective, and patients with a
response after FMT showed a change of their microbiota profile towards that of
their donor, pointing to the potential benefit of careful donor selection (1).
So far, FMT was been studied as induction therapy in patients with
active inflammation without pre-treatment with anti-inflammatory medication.
The active inflammation may in part explain the side effects of FMT described
in IBD patients, such as fever, increased CRP and bacteraemia. Furthermore, the
active inflammation may negatively influence engraftment of donor microbiota,
which could possibly explain the limited efficacy of FMT in IBD patients.

Our hypothesis is that the efficacy of FMT in patients with active ulcerative
colitis can be increased by:

1. Pre treatment with budesonide (cortiment, which is a standard treatment
approach in patients with activity of ulcerative colitis) to enhance
engraftment of donor microbiota in the recipient
2. Rational donor selection increases the effectiveness of FMT in patients with
FMT

To study the effect size of FMT after a 3 weeks course of budesonide as
induction therapy in patients with active ulcerative colitis despite previous
therapy. The purpose of the pre-treatment is to reduce active inflammation
prior to donor feces infusion, possibly enhancing engraftment of donor
microbiota. The initiation of budesonide is a standard treatment approach in
patients with activity of ulcerative colitis.
Donor selection is based on the microbiota profile of the donor and in vivo
assessment of the capacity of donor derived bacteria to induce regulatory T
cells in germ free mice as performed by Vedanta Biosciences.
The study is designed as a pilot study and the results may guide the
initiation of a larger randomized study investigating the effects of FMT after
pre-treatment with budesonide in combination with rational donor selection as
therapy in patients with IBD.

Multi center double-blind randomized placebo-controlled pilot study
investigating different strategies with regard to timing of FMT (before or
after initiation of standard induction therapy)

Intervention
Patients with active ulcerative colitis (n=24) will be randomized to a 3 weeks
course of budesonide 9 mg once a day or placebo, followed by 4 infusions of a
donor feces solution produced by the NDFB. The first FMT will be scheduled
immediately after cessation of budesonide or placebo (t=3 weeks) and is
delivered by a nasoduodenal tube. Three subsequent FMTs are scheduled weekly.
Each individual patient receives donor feces infusion of one donor. Patients
are treated with bowel lavage one day prior to the first FMT. Bowel lavage is
not given prior to the 2nd, 3rd and 4th FMT. Sigmoidoscopy will be performed 8
weeks after the 4th FMT, or earlier in case of clinical suspicion of persistent
or recurrent activity.

Randomized studies suggest a donor dependent effect of FMT. Initially, two
donors will be selected (donor A and donor B), and patients are randomized to
receive donor feces suspensions from either donor A or donor B. Previous
randomized controlled trials have shown modest effectivity of FMT in patients
with active ulcerative colitis using different treatment schedules with 3; 6
and 40 (repeated) infusions of donor feces suspensions (1-3). The study which
offered only three infusions of donor feces did not show a statistically
significant improvement (2). Therefore, the current study protocol consists of
4 infusions of donor feces suspensions after short induction treatment with
budesonide

Donor selection:
Donors are healthy volunteers, carefully selected by the Netherlands Donor
Feces Bank (5). Donor screening consists of questionnaires addressing potential
risk factors for transmittable diseases, and risk factors for diseases
associated with a disturbed gut microbiota. Subsequently, extensive blood and
stool testing for the presence of pathogens is performed (5). Donor stool is
diluted in isotonic NaCl with the addition of glycerol as cryoprotectant and
stored in -80 * Celsius. After negative results during retesting of the donor,
the donor feces solution can be used for FMT.

Donor feces of several potential donors will pre-screened by conducting
metagenomic sequencing to determine the nature and abundance of Clostridia
cluster IV, XIVa and XVIII organisms in the donor microbiota. In addition,
culturable bacteria isolated from each donor will be evaluated for their
capacity to induce regulatory T cells in inoculated germ-free mice.

- participants need to collect their stools at home and deliver the feces to
the hospital.
- Lack of effectivity of FMT, causing delay of initiation of other therapies
- Progression of activity during placebo treatment. Patients continue
maintenance treatment. In case of serious progression, patients will not
continue the study treatment.
- Theoretical long term and unknown side effects of FMT
- FMT is delivered through a nasoduodenal tube, which is placed by endoscopy.
The risks for bleeding or perforation are neglectable. In general, local
anesthesia is offered.
- Subjects will be seen in the hospital for 8 study visits (outpatient).
- sigmoidoscopy is performed to assess treatment outcome. Sedation and
analgesia will be offered using midazolam and/or fentanyl according to local
(standard) procedures. Complications of colonoscopy are perforation and
bleeding, which occur in about 0.1 % of patients undergoing diagnostic
colonoscopies. Substantially fewer complications occur after sigmoidoscopy.
- additional blood sampling will be performed.