Impact of Fecal Microbiota Transplantation in Ulcerative Colitis

Study Overview
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Brief Summary
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Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease. UC pathogenesis remains poorly understood but involves an inappropriate immune response toward an unbalanced gut microbiota (called dysbiosis) in predisposed hosts. The purpose of this study is to determine the effect of the fecal microbiota transplantation on UC.

Detailed Description
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Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease affecting approximately 90 000 patients in France, mostly at young age, and altering their quality of life. Conventional Immunosuppressive treatment (ie azathioprine, anti-TNF (tumor necrosis factor ), vedolizumab) used in UC are expensive and associated with potentially severe complications such as infections and cancers. UC pathogenesis remains poorly understood but involves an inappropriate immune response toward an unbalanced gut microbiota (called dysbiosis) in predisposed hosts. Fecal microbiota transplantation (FMT) is now recommended in guidelines for treating recurrent Clostridium difficile infection. Although the pathogenesis involved in UC is different, FMT is a potential therapeutic strategy as transferring a healthy microbiota in an UC patient could restore the appropriate host-microbiota crosstalk. As the gut microbiota is dramatically altered by intestinal inflammation, transferring a massive amount of microbial organisms in an inflamed gut with epithelial barrier disruption might be a suboptimal strategy and could even have detrimental effects by allowing bacterial translocation. Thus, it's possible that performing FMT in UC patients who achieved remission after conventional treatment might be associated with better clinical outcome than in patients with active disease.

Official Title
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Impact of Fecal Microbiota Transplantation in Ulcerative Colitis: a Randomized, Sham Controlled Trial

Conditions
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Ulcerative Colitis

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: Inclusion Criteria for patients : Age ≥ 18 years and < 75 years Ulcerative colitis (according to the Lennard Jones criteria) diagnosed for at least 3 months and : Currently active (PMC > 1) and planned to be treated by systemic corticosteroids (minimum 40mg prednisone equivalent daily) Or Currently treated by systemic corticosteroid (minimum 40 mg prednisone equivalent daily) within max 3 weeks Or Steroid dependent patients (at least one unsuccessful attempt to discontinue steroid within the last 6 months before inclusion) Patient with health insurance (AME excepted) Informed written consent Female of child-bearing age with an active contraception and this during at least period of treatment until the end of active follow-up period (week 24) Inclusion Criteria for healthy volunteers donors : 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: Exclusion Criteria for patients : UC complication requiring surgical treatment Patient treated with high dose corticosteroid more than three weeks before inclusion (≥ 40 mg prednisone equivalent daily) except in case of steroid-dependence Contraindication to colonoscopy or anesthesia Pregnancy or breastfeeding during the study Treatment preceding the colonoscopy with: intravenous infliximab and/or vedolizumab and/or ustekinumab (< 6 weeks before the planned date of the colonoscopy) and/or subcutaneous infliximab (<2 weeks before the planned date of the colonoscopy), and /or adalimumab (<2 weeks before the planned date of the colonoscopy) and/or golimumab and/or tofacitinib (<4 weeks before the planned date of the colonoscopy) immunosuppressant (thiopurine, methotrexate, tacrolimus or other classical immunosuppressant) started or stopped < 3 months before the planned date of the colonoscopy Antibiotics, antifungic or probiotics treatment < 4 weeks before the planned date of the colonoscopy participation in any other interventional study patient under legal protection Exclusion Criteria for healthy volunteers donors : - 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group B - fecal microbiota transplantation<br>Patients receiving the fecal microbiota transplantation (FMT) in 3 times after inclusion and randomisation | Drug: Fecal Microbiota Transplantation (FMT)<br>* The colonoscopy for FMT will be planned as soon as possible and never more than 5 weeks after inclusion visit. After colon cleansing using Polyethylen 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 physio, see donor section for details) or sham transplantation (FMT vehicle) in the cecum.<br>|
| Placebo Comparator: Group A- Sham-transplantation<br>Patients receiving the sham-transplantation in 3 times after inclusion and randomisation | Drug: Sham-transplantation Placebo<br>* The sham-transplantation will be planned as soon as possible and never more than 5 weeks after inclusion visit. After colon cleansing using Polyethylen glycol, the patient will have a colonoscopy under general anesthesia. The patient will then sham transplantation (FMT vehicle) in the cecum.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steroid-free clinical and endoscopic remission | Steroid-free clinical and endoscopic remission defined as a total Mayo score of 2 or lower and no subscore higher than 1 and mucosal healing defined as an endoscopic subscore of 0 or 1 (Sigmoidoscopy). | 12 weeks after FMT or sham-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steroid-free clinical remission | Steroid-free clinical remission defined as a Partial Mayo Clinic score of 0 or 1 | 12 weeks after FMT or sham-transplantation | 
| Steroid-free clinical remission | Steroid-free clinical remission defined as a Partial Mayo Clinic score of 0 or 1 | 24 weeks after FMT or sham-transplantation | 
| Steroid-free endoscopic response | Steroid-free endoscopic response defined as a Mayo endoscopy subscore of 1 or less, with a reduction of at least 1 point from baseline | 12 weeks after FMTor sham-transplantation | 
| Steroid-free endoscopic remission | Steroid-free endoscopic remission defined as an Endoscopic Mayo Clinic score of 0 | 12 weeks after FMT or sham-transplantation | 
| Microbiota composition and diversity | Microbiota composition and diversity assessed by 16s sequencing compared to baseline and to donor's microbiota. | 12 and 24 weeks after FMT or sham-transplantation | 
| Proportion of adverse events in each group | abdominal pain, nausea, vomiting, fever, modified intestinal transit and episode of infection | Through study completion, up to 25 months and one week | 
| Inflammatory biological parameter 1 | CRP | up to 24 weeks | 
| Inflammatory biological parameter 2 | fecal calprotectin | up to 24 weeks | 
| Inflammatory biological parameter 3 | platelet number | up to 24 weeks | 
| Endoscopic lesions | Endoscopic lesions at coloscopy and sigmoidoscopy by endoscopic Mayo score | 12 weeks after FMT or sham-transplantation | 
| Endoscopic lesions | Endoscopic lesions at coloscopy (baseline) and sigmoidoscopy by UCEIS score | 12 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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Ulcerative colitis, Inflammatory bowel disease, Fecal microbiota transplantation