Manipulating the Microbiome in IBD by Antibiotics and FMT (FMT)

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

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.

Study Overview

• Status: Completed
• Conditions: Exacerbation of Ulcerative Colitis; Ulcerative Colitis, Active Severe; Crohn's Colitis
• Intervention / Treatment: Drug: AB (antibiotics); Drug: CS (corticosteroids) Only

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Toronto, Canada
    • The Hospital for Sick Children (SickKids)
• Finland
  • Helsinki, Finland
    • Hospital for Children and Adolescents Helsinki University Hospital
• Israel
  • Beer Sheva, Israel
    • Soroka Medical Center
  • Haifa, Israel
    • Rambam Medical Cener
  • Holon, Israel
    • Wolfson Medical Center
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center
  • Petach Tikva, Israel
    • Schneider Medical Center
  • Ramat Gan, Israel
    • Sheba Medical Center
• Italy
  • Napoli, Italy
    • Università degli Studi di Napoli "Federico II"
  • Rome, Italy
    • Sapienza University of Rome
• Poland
  • Krakow, Poland
    • Univeristy Children's Hospital in Krakow
• Spain
  • Malaga, Spain
    • Hospital Regional Universitario Carlos Haya Málaga

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Antibiotics in addition to steroids; 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); 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.; Other Names: Ciprofloxacin-Ciprodex®; Doxycycline-Doxylin®; Gentamycin-Gentamicin®; Amoxicillin-Amoxyclav®; Vancomycin-Vanco-Teva®
Active Comparator: Steroids only; methylprednisolone-1.5mg/kg up to 60mg daily in two divided doses	Drug: CS (corticosteroids) Only; 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; Other Names: Metronidazole-Flagyl®
Other: Open arm; 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); 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.; Other Names: Ciprofloxacin-Ciprodex®; Doxycycline-Doxylin®; Gentamycin-Gentamicin®; Amoxicillin-Amoxyclav®; Vancomycin-Vanco-Teva®; Drug: CS (corticosteroids) Only; 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; Other Names: Metronidazole-Flagyl®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.

Collaborators and Investigators

• Sponsor: Shaare Zedek Medical Center
• Investigators: Principal Investigator: Dan Turner, MD, Shaare Zedek Medical Center

Publications and helpful links

General Publications

• Turner D, Bishai J, Reshef L, Abitbol G, Focht G, Marcus D, Ledder O, Lev-Tzion R, Orlanski-Meyer E, Yerushalmi B, Aloi M, Griffiths AM, Albenberg L, Kolho KL, Assa A, Cohen S, Gophna U, Vlamakis H, Lurz E, Levine A. Antibiotic Cocktail for Pediatric Acute Severe Colitis and the Microbiome: The PRASCO Randomized Controlled Trial. Inflamm Bowel Dis. 2020 Oct 23;26(11):1733-1742. doi: 10.1093/ibd/izz298.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): January 1, 2021

Study Registration Dates

• First Submitted: December 3, 2013
• First Submitted That Met QC Criteria: January 9, 2014
• First Posted (Estimate): January 10, 2014

Study Record Updates

• Last Update Posted (Actual): October 8, 2021
• Last Update Submitted That Met QC Criteria: September 30, 2021
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: 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
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Cytochrome P-450 CYP1A2 Inhibitors; Vancomycin; Metronidazole; Anti-Bacterial Agents; Doxycycline; Gentamicins; Ciprofloxacin; Amoxicillin
• Other Study ID Numbers: ABCS-FMT-01