Manipulating the Microbiome in IBD by Antibiotics and FMT

Study Overview
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Brief Summary
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the etiology of Inflammatory Bowel Diseases (IBD) is closely associated with the gut microbiome. The results of previous studies on the effectiveness of antibiotics and fecal macrobiota transplantation (FMT) are contradicting. Aims: to evaluate the effectiveness of wide-spectrum antibiotic regimens in acute severe colitis in an addition to standard corticosteroid therapy (UC and isolated UC-like Crohn's colitis). The secondary aim is to assess the outcome of FMT in those not responding to five days of therapy (in either arm). As an exploratory aim, any IBD patient with a resistant disease to at least two immunosuppressive medications, may be treated with either interventions.

Official Title
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Manipulating the Microbiome in IBD by Antibiotics and Fecal Microbiota Transplantation (FMT): a Randomized Controlled Trial

Conditions
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Exacerbation of Ulcerative Colitis, Ulcerative Colitis, Active Severe, Crohn's Colitis

Intervention / Treatment
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* Drug: AB (antibiotics)
* Drug: CS (corticosteroids) Only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children over the age the 2 years and adults of all ages with established diagnosis of UC using standard criteria (26, 27). Admission for IV steroid therapy PUCAI of at least 65 points at admission (i.e. severe attack) PUCAI>45 at enrollment Ability to swallow antibiotics (pills or syrup) Exclusion Criteria: Change in dose or intervals of anti-TNF within the past 2 months prior to admission. Disease confined to the rectum (Proctitis). Antibiotic use in the past 4 weeks. Any known erosive inflammation anywhere in the small bowel or esophagus. Any proven infection such as positive stool culture, parasite or C. difficile, urinary tract infection, cellulitis, abscess, pneumonia, line-infections etc. Fever >38.5, or >38.0c thought to be unrelated to the inflammatory process of active UC. The probable need for second line medical therapy (infliximab, cyclosporine, tacrolimus) or colectomy within 5 days of enrollment, as judged by the caring physician. Known allergy to more than one antibiotic regimen from the list below. Pregnancy.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Antibiotics in addition to steroids<br>methylprednisolone-1.5mg/kg up to 60mg daily in two divided doses and in addition the following antibiotics: PO Vancomycin 250mg 4 times a day for 3 weeks (children under age 8 125mgX4/d for 3 weeks) PO Amoxycillin 50mg per Kg divided by 3 (up to 500mg 3 times a day) - for 3 weeks PO Metronidazole 5mg per Kg 3 times a day (up to 250mg 3 times a day) - for 3 weeks PO Doxycycline 2mg per kg twice a day (up to 100mg twice a day) - for 3 weeks; OR- For children younger than 7 years: PO Ciprofloxacin 10mg per Kg twice a day (up to 250mg twice a day) for 3 weeks | Drug: AB (antibiotics)<br>* PO Vancomycin 250mgX4/d for 3 weeks PO Amoxycillin 50mg/Kg divided by 3 (up to 500mgX3/d) - for 3 weeks PO Doxycycline 2mg/kg X2/d (up to 100mgX2/d) - for 3 weeks; OR- For children younger than 8 years: PO Ciprofloxacin 10mg/Kg X2/2 (up to 250mgX2/d) for 3 weeks Patients with known allergy to one of the drugs may be treated with oral Gentamycin (2.5mg/KgX3/d) for 3 weeks instead of the allergenic drug.<br>* Other names: Vancomycin-Vanco-Teva®;|
| Active Comparator: Steroids only<br>methylprednisolone-1.5mg/kg up to 60mg daily in two divided doses | Drug: CS (corticosteroids) Only<br>* methylprednisolone (1.5mg/kg up to 60mg daily in two divided doses) PO Metronidazole 5mg/Kg X3/d (up to 250mgX3/d) - for 3 weeks<br>* Other names: Metronidazole-Flagyl®;|
| Other: Open arm<br>either the antibiotics and/or FMT (fecal microbiome transplant) may be administered in a non-randomized, uncontrolled open-label arm to any resistant IBD patients | Drug: AB (antibiotics)<br>* PO Vancomycin 250mgX4/d for 3 weeks PO Amoxycillin 50mg/Kg divided by 3 (up to 500mgX3/d) - for 3 weeks PO Doxycycline 2mg/kg X2/d (up to 100mgX2/d) - for 3 weeks; OR- For children younger than 8 years: PO Ciprofloxacin 10mg/Kg X2/2 (up to 250mgX2/d) for 3 weeks Patients with known allergy to one of the drugs may be treated with oral Gentamycin (2.5mg/KgX3/d) for 3 weeks instead of the allergenic drug.<br>* Other names: Vancomycin-Vanco-Teva®;Drug: CS (corticosteroids) Only<br>* methylprednisolone (1.5mg/kg up to 60mg daily in two divided doses) PO Metronidazole 5mg/Kg X3/d (up to 250mgX3/d) - for 3 weeks<br>* Other names: Metronidazole-Flagyl®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total PUCAI (Pediatric Ulcerative Colitis Activity Index) score |  | at day 5 after treatment (compared between the two treatment groups). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission rates | defined by PUCAI<10 without the need for second line therapy (anti TNF (Tumor Necrosis Factor), cyclosporine or tacrolimus) or colectomy. | at days 7, separately at discharge, separately at day 14, and separately at 90 days. | 
| Number of patients with PUCAI<35 points | without the need for second line therapy (anti TNF, cyclosporine or tacrolimus) or colectomy. | at day 5 | 
| The need for second line therapy or colectomy by discharge |  | by 90 days and at 1 year | 
| Rate of steroid | defined as a course longer than 3 month with an unsuccessful attempt to wean steroids or cumulative steroid treatment months of 4 months, during the year. | dependency at 1 year | 
| Need for subsequent admission |  | by 1 year | 
| Calprotectin levels |  | at 5 and 14 days after treatment. | 
| Rate of gastrointestinal carriage of resistant organisms (VRE, ESBL) |  | at days 5 and 14 after treatment. | 
| Change in microbiome pattern. |  | 3 years from baseline | 
| Rate of C. difficile infection |  | at days 5 and 14 after treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IBD: Inflammatory Bowel Diseases, CD: Crohn's Disease, UC: Ulcerative Colitis, ASC: Acute Severe Colitis, FMT: Fecal Microbiota Transplantation, PUCAI: Pediatric Ulcerative Colitis Activity Index, Ciprofloxacin, Doxycycline, Gentamycin, amoxicillin, vancomycin, metronidazole,ciprofloxacin