Faecal Microbiota Transplantation in Irritable Bowel Syndrome

Study Overview
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Brief Summary
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Irritable bowel syndrome (IBS) is the most common functional bowel disorder, being present in approximately 10% of adult Europoid population. The etiology of IBS is elusive. Literature indicates that modification of patients´colonic microbiota might ameliorate the condition. Here we test an intervention by faecal microbiota transplantation of artificially inflated microbiome diversity, versus autoclaved placebo.

Detailed Description
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Three-groups, double-blind, placebo-controlled, randomised, cross-over study in adult patients diagnosed with IBS (diarrhoeal or mixed form) according to Rome IV criteria. Each study subject will undergo two pairs of faecal microbiota transplantation (a total of four enemas for each patient), with the pairs of transfers being eight weeks apart. The active intervention substance is a mixed stool microbiota derived from healthy individuals, screened for infectious diseases according to European consensus conference on faecal microbiota transplantation guidelines, and who were preselected for high alpha diversity of their microbiome and distance in community ordination from IBS patients microbiota. Placebo is the same mixture, inactivated by autoclaving.

Official Title
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Faecal Microbiota Transplantation in Irritable Bowel Syndrome: a Randomised, Double-blind Cross-over Study Utilising Mixed Microbiota From Healthy Donors

Conditions
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Irritable Bowel Syndrome With Diarrhea, Irritable Bowel Syndrome Mixed

Intervention / Treatment
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* Other: Faecal microbiota transplantation with active study microbiota first
* Other: Faecal microbiota transplantation with inactive autoclaved study microbiota first
* Other: Faecal microbiota transplantation with inactive autoclaved study microbiota only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diarrhea Predominant Irritable Bowel Syndrome (IBS-D) or Irritable Bowel Syndrome with mixed bowel habits (IBS-M) according to the Rome IV criteria Exclusion Criteria: The use of antibiotics within one month prior to faecal microbiota transplantation The use of probiotics within one month prior to faecal microbiota transplantation History of inflammatory bowel disease or gastrointestinal malignancy, systemic autoimmune diseases (ongoing or in history) Previous abdominal surgery (other than appendectomy or cholecystectomy or hernioplasty or cesarean section) HIV infection or other active infection Renal or hepatic disease (both defined by biochemistry workup) Diabetes mellitus, abnormal thyroid functions not controlled by thyroid medications Bipolar disorder or schizophrenia (ongoing or history thereof), moderately severe depression defined by Patient Health Questionnaire-9 (PHQ-9) score > 15 Anxiety defined by a Generalised Anxiety Disorder 7 (GAD7) score > 10 Current pregnancy and lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Crossover Assignment
Interventional Model Description: Each study subject will undergo two pairs of faecal microbiota transplantation eight weeks apart (a total of four enemas for each patient). Our study design has several specific features: (a) Two consecutive transfers were designed to improve study microbiota engraftment. Before the first of every transfer pairs, the subjects will receive a reduced dose of oral polyethylene glycol for partial bowel preparation. (b) To help discern potential carry-over effects, a placebo-only group was included; this also enables us to assess long-term effects of the intervention. (c) The transferred microbiota is identical throughout the study, having been mixed beforehand, aliquoted and deep frozen. Its alpha diversity was artificially increased by mixing stools from several donors. (d) Placebo is made of the same mixture by careful autoclaving.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group A (active microbiota first)<br>Patients will first receive two enemas of active study microbiota mixture (deep-frozen stored stool microbiota mixed from eight donors in order to increase its diversity), then after eight weeks they will receive two enemas with placebo. | Other: Faecal microbiota transplantation with active study microbiota first<br>* 2x enema with active study microbiota; after 8 wks 2x enema with inactive autoclaved study microbiota<br>|
| Other: Group B (inactive microbiota first)<br>Patients will first receive placebo, then the active study microbiota mixture. | Other: Faecal microbiota transplantation with inactive autoclaved study microbiota first<br>* 2x enema with inactive autoclaved study microbiota; after 8 wks 2x enema with active study microbiota<br>|
| Other: Group C (inactive microbiota only)<br>Patients will receive similarly timed enemas with placebos only. | Other: Faecal microbiota transplantation with inactive autoclaved study microbiota only<br>* 2x enema with inactive autoclaved study microbiota; after 8 wks 2x enema with inactive autoclaved study microbiota<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the IBS severity symptom score (IBS-SSS) | Change in the IBS severity symptom score (IBS-SSS) in the active microbiota group relative to the placebo group. | The difference between the score at four weeks after the intervention (study weeks 5 or 13, respectively) and the baseline score (week -1 in 'Active microbiota first' group or week 8 in 'Inactive microbiota first' group) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The acute change in the IBS severity symptom score (IBS-SSS) | IBS-SSS between baseline and two weeks after intervention | study weeks 3 and 11, respectively | 
| The long-term change in the IBS severity symptom score (IBS-SSS) | IBS-SSS between baseline (week -1) and week 32. The long term change will compare placebo group to merged active study microbiota groups. | baseline and study week 32 | 
| Change in number of loose stools per day | Change in number of loose stools per day in the active microbiota group relative to the placebo group | baseline and study week 32 | 
| Change in stool consistency | Change in stool consistency evaluated by Bristol stool scale (type 3 and 4 - normal; types 1,2,5,6 and 7 - abnormal) in the active microbiota group relative to the placebo group | baseline and study week 32 | 
| Change in abdominal pain | Change in abdominal pain measured by Visual Analogue Scale (VAS) (0 - no pain, 10 - worst pain) in the active microbiota group relative to the placebo group | baseline and study week 32 | 
| Change in frequency of bloating per week | Change in frequency of bloating per week (as there is no standardised measurement, it will be reported as number of episodes per time unit, where the possible answers could be: no bloating, bloating once a week, twice a week, three times a week, four times a week, five times a week, six times a week, bloating daily, bloating daily and sometimes at night, bloating more than half of days, bloating continuously) in the active microbiota group relative to the placebo group | baseline and study week 32 | 
| Change in Body Mass Index | Change in Body Mass Index (BMI in kg/m^2) in the active microbiota group relative to the placebo group | baseline and study week 32 | 
| Change in waist circumference | Change in waist circumference (in centimeters) in the active microbiota group relative to the placebo group | baseline and study week 32 | 
| Change in body fat mass estimated by skinfold thickness measuring | Change in body fat mass estimated by measuring combined skinfold thickness at given locations (biceps, triceps, subscapular, suprailiac) in millimetres in the active microbiota group relative to the placebo group | baseline and study week 32 | 
| Change in body fat mass measured by bioelectrical impedance analysis | Change in body fat mass in the active microbiota group relative to the placebo group measured by bioelectrical impedance analysis (in %) | baseline and study week 32 | 
| Change in faecal microbiome's alpha (within-sample) diversity | Change in faecal microbiome's alpha (within-sample) diversity in the active microbiota group relative to the placebo group measured by Chao index of alpha diversity (higher value means higher alpha-diversity) | baseline and study week 32 | 
| Change in faecal microbiome's beta (between samples) diversity | Change in faecal microbiome's beta (between samples) diversity in the active microbiota group relative to the placebo group assessed by the quantitative Bray-Curtis index (more distant means more different bacterial composition) ordinated by nonmetric multidimensional scaling (NMDS) | baseline and study week 32 | 
| Change in the quantity of single-cell protist Blastocystis | Change in the quantity of single-cell protist Blastocystis in the active microbiota group relative to the placebo group assessed by a specific quantitative polymerase chain reaction assay measured in genomic equivalents per microlitre DNA (the higher concentration means more of Blastocystis) | baseline and study week 32 | 
| The psychological and well-being effects of the therapy (IBS-QoL) | The psychological and well-being effects of the therapy scored by IBS-QoL questionnaires | baseline and study week 32 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IBS - D, IBS - M