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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Fecal Microbiota Transplantation in Crohn's Disease as Relay After Anti-TNF Withdrawal

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: Fecal Microbiota Transplantation (FMT)
* Drug: Sham-transplantation (placebo)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fecal microbiota<br>Patients receiving the fecal microbiota transplantation (FMT) in 3 times after inclusion and randomisation (endoscopic and oral) | Drug: Fecal Microbiota Transplantation (FMT)<br>* The colonoscopy for FMT will be planned between 7 and 14 days after the last adalimumab or sub-cutaneous infliximab administration and 6 weeks +/- 7 days after the last intravenous infliximab administration 14 and 28 days following the last sub-cutaneous golimumab administration. After colon cleansing using polyethylene glycol, the patient will have a colonoscopy under general anesthesia. The patient will then receive either FMT (frozen preparation of 50g of stools in 300ml of saline (NaCl 0.9%), (FMT vehicle in the terminal ileum or the colon. At W12 and W24 after first colonoscopy, the patient receives treatment by capsule (15 capsules contain 0.8g of stools by visit).<br>|
| Sham Comparator: Sham-transplantation<br>Patients receiving the sham-transplantation in 3 times after inclusion and randomisation (endoscopic and oral) | Drug: Sham-transplantation (placebo)<br>* The colonoscopy for sham-transplantation will be planned between 7 and 14 days after the last adalimumab or sub-cutaneous infliximab administration and 6 weeks +/- 7 days after the last intravenous infliximab administration, 14 and 28 days following the last sub-cutaneous golimumab administration. After colon cleansing using polyethylene glycol, the patient will have a colonoscopy under general anesthesia. The patient will then receive either sham transplantation (frozen preparation of NaCl 0.9% with 10% glycerol) in the terminal ileum or the colon. At S12 and S24 after first colonoscopy, the patient receives treatment by capsule (15 capsules contain placebo).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Clinical remission (defined by a Crohn's disease activity index (CDAI) <150) at week 52 (V8) without any flare between week 0 (colonoscopy (V2)) and week 52 (V8). Flare is defined by a CDAI (Addendum 2) above 250 or between 150 points and 250 points with a 70-point increase from baseline over 2 consecutive weeks and the need | 52 weeks after FMT or sham-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse free survival | Relapse free survival rate from week 0 (V2) to week 52 (V8) | 52 weeks after FMT or sham-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn disease, Inflammatory bowel disease, Fecal microbiota transplantation