Oral Fecal Microbiota Transplantation in Pediatric Ulcerative Colitis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate whether FMT by frozen stool capsules in pediatric UC patients in remission after corticosteroid treatment, can modify their dysbiotic gut microbiota by increasing the richness of their microbiota at 6 months.

Detailed Description
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Ulcerative colitis (UC) is characterized by chronic inflammation of the colon of undetermined origin. Their incidence is increasing dramatically in the paediatric population. Pediatric-onset inflammatory bowel disease (IBD) is characterized by a greater severity than adult IBD. Although great progress has been made in recent years, the pathogenesis of IBD is not fully elucidated. During UC, an imbalance in the composition of gut microbiota, called dysbiosis, has been identified. This dysbiosis is notably characterized by an increased proportion of pro-inflammatory microorganisms and a decreased proportion of anti-inflammatory microorganisms. The current treatments used in IBD mainly target the immune system through immunosuppressants, and help to shorten flairs and prevent recurrences, but there is no curative treatment. From a therapeutic point of view, the correction of this dysbiosis is thus an attractive approach. Until now, efficacy of microbiome-based therapies such as probiotics or antibiotics has been disappointing in IBD. Fecal microbiota transplantation (FMT) consists of the administration of fecal material from a donor into the intestinal tract of a recipient to change their microbiota composition and restore healthy conditions. FMT has been successfully used for many years for the treatment of Clostridioides difficile infection. Recent studies seem to show a benefit of FMT in UC. The investigator's main hypothesis is that the replacement of a dysbiotic microbiota by a 'healthy' microbiota by FMT can modify the richness of UC patient's microbiota and has a positive impact on the disease course. For the Receiver: Once steroid-induced remission will be achieved, patients will be included and randomised to receive either FMT by frozen stool capsules or enemas. They will receive 3 doses at 0, 1 and 2 months. They will be followed for one year with stool samples collected every 3 months. Clinical and laboratory data will be collected. For the Donor: Healthy donors will be recruited by advertising poster. During the inclusion visit, a complete physical examination, and blood and stool screening for pathogens will be performed before being selected to donate stool.

Official Title
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Pilot Study of a New Technique of Oral Fecal Transplantation Using Frozen Stool Capsules for the Maintenance Treatment of Pediatric Ulcerative Colitis.

Conditions
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Pediatric Ulcerative Colitis in Remission

Intervention / Treatment
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* Drug: Fecal Microbiota Transplantation by Stool capsules
* Drug: Fecal Microbiota Transplantation by Intra-rectal enemas


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for patients: - Patient aged 8 to 17 years old Ulcerative colitis (UC), whatever the extent, except isolated proctitis (<5 cm), diagnosed for more than 3 months according to the usual clinical, biological and endoscopic criteria Moderate active UC defined by a PUCAI score > 35 and responding to corticosteroid treatment with a PUCAI score <10 at enrollment Treatment of UC (5-ASA, immunosuppressants, biotherapies) stable for more than 3 months Patient able to swallow test capsules For girls of childbearing age: To have a negative blood (or urine) pregnancy test To agree to use a reliable contraceptive method from visit 1 until the end of the research Patient with health insurance Informed written consent form signed by both parents or by the person (s) with parental authority Inclusion Criteria for healthy volunteers donors: Aged between 20 and 50 years Body mass index (BMI) between 17 kg / m² and 27 kg / m² Usually regular transit defined as at least one stool per day, usually issued in the morning For women of childbearing age: o have a negative pregnancy (or urine) blood test Subject with health insurance Informed Written consent Exclusion Criteria for patients: isolated proctitis (<5 cm) severe colitis defined by a PUCAI score> 65 Being on enteral nutrition Have received antibiotic or antifungal treatment in the 4 weeks prior to enrollment Having a Clostridioides difficile infection in the 4 weeks prior to enrollment; Being pregnant or breastfeeding, or have a positive pregnancy test; Have a contraindication to colonoscopy or general anaesthesia Exclusion Criteria for healthy volunteers donors: - For details, please see protocol

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fecal Microbiota Transplantation by Stool capsules<br>Patients receiving fecal microbiota transplantation from a healthy donor in 3 times after inclusion and randomisation (Month 0 - Month 1 - Month 2) using frozen stool capsules | Drug: Fecal Microbiota Transplantation by Stool capsules<br>* After colon cleansing using PolyEthylen glycol, the patient will have a colonoscopy under general anaesthesia. The patient will then receive orally FMT (frozen stools capsules prepared from healthy donor feces).<br>* Other names: UC treatment;|
| Experimental: Fecal Microbiota Transplantation by enema<br>Patients receiving fecal microbiota transplantation from a healthy donor in 3 times after inclusion and randomisation (Month 0 - Month 1 - Month 2) using frozen stool enemas. | Drug: Fecal Microbiota Transplantation by Intra-rectal enemas<br>* After colon cleansing using Polyethylen glycol, the patient will have a colonoscopy under general anaesthesia. The patient will then receive first FMT (frozen preparation of stools) by infusion in caecum during colonoscopy and the second and third doses by enemas.<br>* Other names: UC Treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success of FMT with frozen stool capsules defined by an increase in the richness of the recipient's microbiota at 6 months. | Success of FMT is defined by an increase in the richness of the recipient's microbiota at 6 months. Microbiota richness will be evaluated by measuring the alpha diversity of the microbiota using Shannon index. The success of the FMT will be defined by an increase in the Shannon index of 0.5 points between the recipient microbiota at M0 and the recipient microbiota at M6. | 6 months after the first Fecal Microbiota Transplantation (FMT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success of FMT with frozen stool capsules defined by an increase in the richness of the recipient's microbiota at 12 months | The success of the FMT will be defined by an increase in the Shannon index of 0.5 points between the recipient microbiota at M0 and the recipient microbiota at M12. | 12 months after the first FMT | 
| Success of FMT by stool enema defined by an increase in the richness of the recipient's microbiota at 6 and 12 months | The success of the FMT will be defined by an increase in the Shannon index of 0.5 points between the recipient microbiota at M0 and the recipient microbiota at M6 and M12 | 6 and 12 months after the first FMT | 
| Success of FMT with frozen stool capsules on the change of recipient dysbiotic microbiota at 6 and 12 months | The success of the FMT will be defined by a Bray Curtis (BC) Index [recipient after FMT vs donnor] greater than a BC Index [recipient after FMT vs recipient before FMT], with a BC Index [recipient after FMT vs donnor] ≥ 0.6. | 6 and 12 months after the first FMT | 
| Success of FMT by enema on the change of recipient dysbiotic microbiota at 6 and 12 months | The success of the FMT will be defined by a Bray Curtis (BC) Index [recipient after FMT vs donnor] greater than a BC Index [recipient after FMT vs recipient before FMT], with a BC Index [recipient after FMT vs donnor] ≥ 0.6. | 6 and 12 months after the first FMT | 
| Success of FMT with frozen stool capsules on the richness and change of mucosal microbiota at 12 months | The success of the FMT will be defined by an increase in the Shannon index of 0.5 points between the mucosal recipient microbiota at M0 and the mucosal recipient microbiota at M12 | 12 months | 
| Success of FMT by enema on the richness and change of mucosal microbiota at 12 months | The success of the FMT will be defined by an increase in the Shannon index of 0.5 points between the mucosal recipient microbiota at M0 and the mucosal recipient microbiota at M12 | 12 months | 
| Success of FMT with frozen stool capsules on the change of mucosal recipient dysbiotic microbiota at 6 and 12 months | The success of the FMT will be defined by a Bray Curtis (BC) Index [recipient after FMT vs donnor] greater than a BC Index [recipient after FMT vs recipient before FMT], with a BC Index [recipient after FMT vs donnor] ≥ 0.6. | 6 and 12 months after the first FMT | 
| Success of FMT by enema on the change of mucosal recipient dysbiotic microbiota at 6 and 12 months | The success of the FMT will be defined by a Bray Curtis Index [recipient after FMT vs donnor] greater than a BC Index [recipient after FMT vs recipient before FMT], with a BC Index [recipient after FMT vs donnor] ≥ 0.6. | 6 and 12 months after the first FMT | 
| FMT with frozen stool capsules Feasibility | Number of capsules intake, facility of capsules intake, tolerance, intake duration | At inclusion, 1 and 2 months after each FMT | 
| FMT by enema Feasibility | Number of enemas, tolerance , enemas duration, difficulties related to the application of enemas | At inclusion, 1 and 2 months after each FMT | 
| Ulcerative colitis clinical relapse | Defined as a Pediatric Ulcerative Colitis Activity Index (PUCAI) > 35, number of relapses during the follow-up, treatments received during the follow-up | 6 and 12 months | 
| Ulcerative colitis Endoscopic relapse | Defined as an Ulcerative Colitis Endoscopic Index of Severity (UCEIS) ≥ 2 | 12 months | 
| Change of inflammatory blood markers from baseline to 12 months | CRP, VS, Leucocytes levels | At inclusion, 6, 9 and 12 months | 
| Change of faecal calprotectin from baseline to 12 months | Calprotectin level | At inclusion, 6, 9 and 12 months | 
| Change of patient's quality of life evaluated with IMPACT-3 questionnaire from inclusion until 12 months | IMPACT-3 questionnaire of 35 closed questions - scale ranging from 1 to 5 for all answers - higher score suggesting better quality of life | At inclusion 2, 6, 9 and 12 months | 
| Incidence of adverse events |  | 26 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ulcerative Colitis, Pediatric Onset Inflammatory Bowel Disease, Microbiota, Fecal Microbiota Transplantation, Stool capsule, Intra-rectal enemas