Clinical trial NCT04997733: Fecal Microbiota Transplantation in Crohn's Disease as Relay After Anti-TNF Withdrawal
Official title: Fecal Microbiota Transplantation in Crohn's Disease as Relay After Anti-TNF Withdrawal
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Crohn Disease
Keywords: Crohn disease
Inflammatory bowel disease
Fecal microbiota transplantation
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: CRB-HUEP
name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2021-08-10
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Crohn's disease (CD) is a chronic inflammatory bowel disease. CD pathogenesis remains poorly understood but involves an inappropriate immune response toward an unbalanced gut microbiota in predisposed hosts.

The purpose of this study is to evaluate de clinical efficacy of the fecal microbiota transplantation (FMT) as a maintenance treatment following anti-TNF agent withdrawal in CD's patient.

Detailed description: Crohn's disease (CD) is a chronic inflammatory bowel disease affecting approximately 120000 patients in France, mostly at young age, and altering their quality of life.

Immunosuppressive treatments in CD are expensive and associated with potentially severe complications.

Alternative treatment strategies are thus required. This is particularly the case for CD patients in remission under anti-TNF agents for which no specific recommendation are available.

CD pathogenesis remains poorly understood but involves an inappropriate immune response toward an unbalanced gut microbiota in predisposed hosts.

Fecal microbiota transplantation (FMT) is currently recommended for treating recurrent Clostridium difficile infection. Although the pathogenesis involved in CD differs, FMT is a potential therapeutic strategy that could restore the appropriate host-microbiota crosstalk by transferring a healthy microbiota in a CD patient. However, as the gut microbiota is dramatically altered by intestinal inflammation, transferring a massive amount of microbes in an inflamed gut with epithelial barrier disruption might be a suboptimal strategy and could even have detrimental effects by allowing bacterial translocation.

Results of randomized controlled trial (RCT) in CD are lacking to date. We performed a pilot RCT (NCT02097797), evaluating the impact of a single FMT in 18 CD patients who achieved remission by corticosteroid treatment. A higher rate of steroid free clinical remission was observed in the FMT arm at 24 weeks (57.1% vs 33.3% in FMT and control arm respectively). CD Endoscopic Index of Severity was also improved at 6 weeks in FMT (median 8.5 vs 3.5 p=0.03) but not in sham group (median 2.4 vs 2.7 p=0.8). Moreover, the only 2 patients who early relapsed in the FMT group were those who did not show any engraftment of donor microbiota at week 6. These promising data, currently submitted for publication, suggest that using FMT as a maintenance treatment in CD can be effective. However, these promising findings need to be confirmed by a Phase III RCT.

Eligibility criteria: Inclusion Criteria for patients :

* Age ≥ 18 years and \< 75 years
* Crohn's disease (according to the Lennard-Jones criteria) for at least 6 months
* Patient in steroid-free clinical remission for at least 6 months under anti-TNF agent (no clinical evidence of flare nor change in Crohn's disease specific treatment (anti-TNF, immunosuppressive, ...) within 6 months before inclusion) and CDAI \<150 the week before inclusion) and willing to withdraw anti-TNF treatment
* Female of child-bearing age with an active contraception and this during at least the period of treatment (week 52)
* Patient with health insurance
* Informed Written consent

Inclusion Criteria for healthy volunteer donor :

* Age ≥ 18 years and \< 50 years
* 17 kg/m² \< body mass index \< 30 kg/m²
* Regular bowel movement defined as at least 1 stool every other day and maximum 2 stools per day
* Subject with health insurance (AME excepted)
* Informed written consent

Exclusion Criteria for patients :

* Crohn's Disease complication requiring surgical treatment
* Contraindication to colonoscopy or anesthesia
* Pregnancy or breastfeeding during the study (Cf. Addendum 4)
* Diagnosis of Crohn's disease restricted to the upper gastrointestinal tract (oesophagus, stomach, duodenum, jejunum)
* Patient with active perineal disease (defined as evidence of perineal abscess or active draining fistula or presence of seton or presence of perineal ulceration)
* History of more than one small bowel resection or small intestine resection \> 1 meter
* Current stoma (Ileostomy or a colostomy) or stoma in the last 6 months or any other intra-abdominal surgery within 3 months prior to inclusion
* Participation in any other interventional study
* Patient under legal protection

Exclusion Criteria for healthy volunteer donor :

- For details, please see protocol

Primary outcomes:
measure: Evaluate the clinical efficacy of FMT versus sham transplantation as a maintenance treatment following anti-TNF agent withdrawal in patients with Crohn's disease in steroid-free clinical remission for at least 6 months under anti-TNF agent
timeFrame: 52 weeks after FMT or sham-transplantation
Secondary outcomes:
measure: Relapse free survival
timeFrame: 52 weeks after FMT or sham-transplantation
Other outcomes:
measure: Mucosal healing
timeFrame: 52 weeks after FMT or sham-transplantation
measure: Clinical remission
timeFrame: 52 weeks after FMT or sham-transplantation
measure: Endoscopic remission
timeFrame: 52 weeks after FMT or sham-transplantation
measure: Changes in inflammation 1
timeFrame: 6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation
measure: Changes in inflammation 2
timeFrame: 6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation
measure: Changes in inflammation 3
timeFrame: 6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation
measure: Changes in intestinal microbiota composition
timeFrame: 6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation
Locations:
city: Paris
country: France
facility: Gastroenterology Department of Saint Antoine Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Harry SOKOL, PU-PH
role: PRINCIPAL_INVESTIGATOR
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