Fecal Microbial Transplantation in Treatment of Irritable Bowel Syndrome; a Double Blinded Placebo Controlled Trial. (REFIT)

Recalibrating Intestinal Microflora in IBS by Fecal Transplantation

Fecal Microbial Transplantation in Treatment of Irritable Bowel Syndrome; a Double Blinded Placebo Controlled Trial - the REFIT project

Irritable bowel syndrome (IBS) is a condition characterized by variable complaints like diarrhoea, bloating and abdominal pain, and may result in considerably reduced quality of life and increased sickness absence. The prevalence of IBS in the general population may be as high as 15 per cent depending on the diagnostic criteria used. The pathophysiology of IBS is poorly understood and theories of visceral hypersensitivity, micro-inflammation and other less well founded theories have been stated. So far, no measurement or test can affirm diagnosis, but exclusion of organic diseases in combination with a typical symptom pattern according to the Rome classification can set the diagnosis.

Earlier non-controlled case reports have shown a convincing effect of fecal microbial transplantation (FMT) in IBS patients. However, no placebo controlled trial has been performed in this condition. Changes in the gut microbiome may be an important factor in IBS pathogenesis. Microbiome analysis has revealed changes in microbiome composition that may trigger changes in visceral sensibility and pain perception.

The fecal microbial transplantation (FMT) procedure has been used primarily to treat clostridium difficile infections. Few minor side effects have been reported.

Hypothesis: IBS is caused by an imbalance of the gut microbiome that may be reset by transplanting a microbiome sample from a healthy donor.

Aim of study:

• To test the clinical effect of FMT in patients with IBS
• To describe the fecal microbiome in IBS patients
• To describe changes in the fecal microbiome of IBS patients following FMT

The REFIT study will perform a randomized placebo-controlled double blinded trial of FMT on IBS according to the Rome 3 criteria. A study group of 60 IBS (diarrhoea variant) patients will recruited from general practice and allocated to active (30) or placebo (30) by block randomization. Donors will be 15 healthy volunteers with no risk behaviour and a pre-screening for communicable diseases will be performed.

Outcome measures will be clinical assessment by IBS-severity scoring system (IBS-SSS) at 0, 1, 3, 6, and 12 months. Microbiome analysis will be performed by metagenomic sequencing (University of Tromsø) at 0, 3, and 12 months for patients, and at inclusion for donors.

Study Overview

• Status: Completed
• Conditions: Irritable Bowel Syndrome
• Intervention / Treatment: Biological: Fecal transplantation; Other: Placebo fecal transplant

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Harstad, Norway, 9406
    • University Hospital of North Norway

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for patients:

• Patients with IBS-D according to Roma 3 criteria

Exclusion Criteria for patients:

• Immunomodulating medication
• Nocturnal abdominal pain
• Constant abdominal pain
• Alarm symptoms like rectal bleeding, weight loss, nightsweats
• Symptomatic heart/vascular/lung disease
• Renal failure
• Known food allergy
• Microscopic/collagenous colitis
• non-compliant
• BMI <18

Inclusion criteria for donors:

• healthy volunteers

Exclusion criteria for donors

• Tattoos, imprisoning or piercing last 3 months
• Any history of chronic diarrhoea, constipation, inflammatory bowel disease, irritable bowel disease, colorectal polyps or cancer, immunosuppression, morbid obesity, metabolic syndrome, atopica, or fatigue
• positive test for hepatitis B, C, HIV, treponema pallidum
• sexual high risk habits
• antibiotic treatment in the past 3 months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fecal transplantation; Fecal transplantation of freshly prepared feces from healthy donor. Application by colonoscope in proximal half of colon.	Biological: Fecal transplantation; Preparation of flesh feces by blending in 0.9 % saline and crude filtering. The solution is applied in proximal colon of IBS patient by colonoscopy after standard bowel preparation.; Other Names: Fecal microbial transplantation
Placebo Comparator: Placebo fecal transplantation; Sham transplant subject's own feces. Application by colonoscope in proximal part of colon.	Other: Placebo fecal transplant; Fecal transplantation with own feces

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in subjective symptom score	Comparison of Irritable bowel syndrome severity scoring system (IBS-SSS) grade assessment before and after fecal transplantation	at 0 and 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiome profile change	Characterization of fecal microbiome by metagenomic analysis before and after intervention	at 0, 3 and 12 months
Long term effects of fecal transplantation	Assessment of symptom burden by IBS-SSS	at 12 months
Safety of fecal transplantation in IBS	Registration of any adverse events. If any serious adverse events are encountered, the study group and local ethics committee will evaluate if study should be terminated.	during study period (0-12 months)

Collaborators and Investigators

• Sponsor: University Hospital of North Norway
• Investigators: Principal Investigator: Rasmus Goll, PhD, University Hospital of North Norway; Study Director: Per C Valle, PhD, University Hospital of North Norway

Publications and helpful links

General Publications

• Goll R, Johnsen PH, Hjerde E, Diab J, Valle PC, Hilpusch F, Cavanagh JP. Effects of fecal microbiota transplantation in subjects with irritable bowel syndrome are mirrored by changes in gut microbiome. Gut Microbes. 2020 Nov 9;12(1):1794263. doi: 10.1080/19490976.2020.1794263.
• Johnsen PH, Hilpusch F, Cavanagh JP, Leikanger IS, Kolstad C, Valle PC, Goll R. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol. 2018 Jan;3(1):17-24. doi: 10.1016/S2468-1253(17)30338-2. Epub 2017 Nov 1.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: April 10, 2014
• First Submitted That Met QC Criteria: May 30, 2014
• First Posted (Estimate): June 3, 2014

Study Record Updates

• Last Update Posted (Estimate): January 13, 2017
• Last Update Submitted That Met QC Criteria: January 12, 2017
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: gut microbiome; FMT; metagenomics; IBS-D
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Syndrome; Irritable Bowel Syndrome
• Other Study ID Numbers: 2013/971/REK