Fecal Microbiota Transplantation in Crohn's Disease as Relay After Anti-TNF Withdrawal (MIRACLE)

Assistance Publique - Hôpitaux de Paris

Status and phase: Enrolling; Phase 3

Conditions: Crohn Disease

Treatments: Drug: Fecal Microbiota Transplantation (FMT); Drug: Sham-transplantation (placebo)

Study type: Interventional

Funder types: Other

Identifiers

NCT04997733

APHP190183

2019-003816-29 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 150 estimated patients

Sex: All

Ages: 18 to 74 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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150 participants in 2 patient groups

Fecal microbiota

Experimental group

Description:

Patients receiving the fecal microbiota transplantation (FMT) in 3 times after inclusion and randomisation (endoscopic and oral)

Treatment:

Drug: Fecal Microbiota Transplantation (FMT)

Sham-transplantation

Sham Comparator group

Description:

Patients receiving the sham-transplantation in 3 times after inclusion and randomisation (endoscopic and oral)

Treatment:

Drug: Sham-transplantation (placebo)