Fecal Microbiota Transplantation for the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome

Study Overview
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Brief Summary
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The objectives of this study are (1) to determine the efficacy of fecal microbiota transplantation (FMT), given as oral capsules, compared with placebo for the treatment of refractory diarrhea-predominant irritable bowel syndrome (IBS-D); (2) determine the impact of FMT on the intestinal microbiome of patients with IBS-D; and (3) assess the safety, feasibility, and tolerability of FMT for patients with IBS-D.

Detailed Description
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This is a multicenter study including Montefiore Medical Center, Concorde Medical Group PLLC and the Medical Research Center of Connecticut/Yale-New Haven Hospital Langone Medical Center. Patients with IBS-D will be recruited from outpatient gastroenterology clinics at these institutions and referrals from the medical community. FMT capsules and placebo capsules, provided by OpenBiome, Medford, MA, will be used for this study. Patients will be randomized to undergo FMT using fecal capsules (experimental group) or placebo capsules (control group) via a computer-generated program. All patients will cross-over into the alternate arm of the study at 12 weeks. Therefore, all patients enrolled will receive the experimental drug during the course of the study. Each patient will be enrolled in the study for a total of 6 months. Intestinal microbiome analyses using DNA sequencing and non-cultivation-based approaches (16S DNA technology) will be performed in all patients in the experimental and control groups to assess stability of the microbiome over time.

Official Title
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Randomized, Double-blinded, Placebo-controlled Trial of Fecal Microbiota Transplantation (FMT) for Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D)

Conditions
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Irritable Bowel Syndrome

Intervention / Treatment
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* Drug: Fecal microbiota transplantation capsules
* Drug: Placebo capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 19-65 years established diagnosis of IBS-D as determined by Rome III Criteria moderate-severe disease activity (as determined by an IBS-Symptom Severity Score ≥175) persistent symptoms despite conventional therapy normal colonoscopy with biopsies in the past for work-up of IBS symptoms negative work-up for celiac disease either by duodenal biopsies or negative serologies Exclusion Criteria: pregnancy nursing cognitive impairment or severe neuropsychiatric comorbidities who are incapable of providing their own informed consent severely immunocompromised or immunosuppressed patients (e.g., organ transplant recipients, severe neutropenia with an absolute neutrophil count of <500cells/mL, current treatment or treatment within 3 months with anti-neoplastic agents and HIV-positive patients with CD4 counts <200cells/mm^3) treated with any antibiotics in the 3 months prior to FMT GI symptoms can be explained by the presence of an underlying organic disease including, underlying inflammatory bowel disease, infectious enteritis, previously established and untreated small intestinal bacterial overgrowth or known motility disorder previous FMT severe (anaphylactic) food allergy unable to comply with protocol requirements American Society of Anesthesiologists (ASA) Physical Status classification IV and V acute illness or fever on the day of planned FMT will be excluded (not randomized) with the option of including that subject at a future date new antidepressant started or dose of antidepressant change <3 months prior to enrollment elevated ESR or CRP within the past 3 months baseline laboratory abnormalities on CBC, chemistry or liver tests pain score >75 on IBS-SSS

Ages Eligible for Study
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Minimum Age: 19 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FMT capsules<br>Intervention: Fecal microbiota transplantation capsules containing extensively screened donor stool, prepared by OpenBiome, Medford, MA. 25 FMT capsules will be take on three consecutive days. | Drug: Fecal microbiota transplantation capsules<br>* Fecal microbiota transplantation capsules contain extensively screened donor stool and are prepared by OpenBiome, Medford, MA.<br>* Other names: FMT oral capsules;|
| Placebo Comparator: Placebo capsules<br>Intervention: Placebo capsules that do not contain donor stool or any active drug, prepared by OpenBiome, Medford, MA. 25 placebo capsules will be taken on three consecutive days. | Drug: Placebo capsules<br>* Placebo capsules prepared by OpenBiome, Medford, MA<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Within and Between Group Comparisons of Disease Severity as Determined by Irritable Bowel Syndrome-Symptom Severity Score (IBS-SSS) | Within and between group comparisons of changes (from baseline) in Irritable Bowel Syndrome-Symptom Severity Score (IBS-SSS), obtained via administration of a Questionnaire, for each of the two arms/groups (FMT capsules first, and placebo capsules first). The scale range was 0-500 (min-max). Scores were averaged among time points to yield an overall mean score. Higher scores were indicative of greater disease severity (worse outcome). Subjects were categorized as having mild (75-175), moderate (175-300), or severe (>300) irritable bowel syndrome (IBS) based on symptomology. Only the following time points were analyzed: Baseline vs Week 12 and Week 24. | Baseline, Week 12 (before cross-over), Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Within and Between Group Comparisons of Quality of Life as Determined by the Irritable Bowel Syndrome-Quality of Life (IBS-QOL) Score | Within and between group comparisons of changes (from baseline) in Irritable Bowel Syndrome-Quality of Life (IBS-QOL), obtained via administration of a Questionnaire, for each of the two arms/groups (FMT capsules first, and placebo capsules first). Irritable Bowel Syndrome-Quality of Life (IBS-QOL) is administered via a questionnaire of 34 items each with an individual five-point response scale. The responses to these items are summed and averaged for a total score and then transformed to a 100-point scale for ease of interpretation based on a validated method. IBS-QOL is measured on a scale range of 0-100. Higher IBS-QOL scores are indicative of a better IBS-specific quality of life. Only the following time points were analyzed: Baseline vs Week 12 | Baseline, Week 12 (before cross-over), Week 24 | 
| Intestinal Microbiota Composition Pre- and Post-FMT (Fecal Microbiota Transplantation) | Microbiota composition before and after FMT were assessed among FMT responders and FMT non-responders. Only patients who received FMT capsules at the start of this clinical trial were included. Placebo capsule recipients were not included in these analyses. Data were analyzed up to 12 weeks and not beyond. Microbiome data following cross-over were not analyzed because of the potential for carry-over and order effects in the second half of the trial. Outcomes assessed included alpha and beta diversity (Jensen-Shannon divergence) and abundance of Bacteroidetes, Firmicutes and Prevotella. All of the microbiome data that were analyzed are included in the table below. No additional microbiome data from this clinical trial were analyzed. | Baseline, Week 1, Week 4 and Week 12 | 
| Anxiety as Measured by the Hospital Anxiety and Depression Scale (HADS). HADS-A (Anxiety) | Anxiety at baseline and at the time of cross-over (Week 12) as measured by Hospital Anxiety and Depression Scale (HADS). HADS-A (Anxiety) The Hospital Anxiety and Depression Scale (HADS) is a fourteen item scale which was administered via questionnaire. Seven of the items relate to anxiety (HADS-A) and seven relate to depression (HADS-D). Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. The HADS uses a scale and therefore the data returned from the HADS is ordinal. Higher HADS scores are indicative of more severe depression and anxiety. Only the following time points were analyzed: Baseline vs Week 12 | Baseline, Week 12 (before cross-over), Week 24 | 
| Depression as Measured by the Hospital Anxiety and Depression Scale (HADS). HADS-D (Depression) | Depression at baseline and at the time of cross-over (Week 12) as measured by Hospital Anxiety and Depression Scale (HADS). HADS-D (Depression) The Hospital Anxiety and Depression Scale (HADS) is a fourteen item scale which was administered via questionnaire. Seven of the items relate to anxiety (HADS-A) and seven relate to depression (HADS-D). Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. The HADS uses a scale and therefore the data returned from the HADS is ordinal. Higher HADS scores are indicative of more severe depression and anxiety. Only the following time points were analyzed: Baseline vs Week 12 | Baseline, Week 12 (before cross-over), Week 24 | 
| Bowel Consistency as Measured by the Bristol Stool Form Scale (BSFS) | Bowel consistency as measured by the Bristol Stool Form Scale on a daily basis. The Bristol Stool Form Scale was administered via questionnaire. This scale is a diagnostic medical tool designed to classify the form of human feces into seven categories. Assigned categories range from 1-7 based on appearance of the stool. Type 1 and 2 stools indicate constipation. Type 4 are the ideal stools as they are easy to defecate while not containing excess liquid, Type 5 tends towards diarrhea, and Types 6 and 7 indicate diarrhea. Only the following time points were analyzed: Baseline vs Week 12 | Baseline, Week 12 (before cross-over), Week 24 | 
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | The total number of participants in each of the arms/groups (FMT and Placebo) who experienced at least one adverse event (AE) as recorded in patient diaries. | All AEs over 24 weeks | 
| Satisfaction With Fecal Microbiota Transplantation (FMT) | Weekly assessments of satisfaction with the Fecal Microbiota Transplantation (FMT) will be recorded in patient diaries. | Week 12 following administration of FMT | 
| Change in Bowel Habits and Abdominal Pain After Fecal Microbiota Transplantation (FMT) | Degree of improvement in bowel habits and abdominal pain will be recorded in patient diaries. | Week 12 following administration of FMT | 
| Number of Doctor or Emergency Department (ED) Visits Post-Fecal Microbiota Transplantation (Post-FMT) for Irritable Bowel Syndrome-D (IBS-D) Related Symptoms | The number of doctor or ED visits post-Fecal Microbiota Transplantation for Irritable Bowel Syndrome-D (IBS-D) related symptoms will be recorded in patient diaries. | Week 12 following administration of FMT | 
| Initiation of New Medications Post-FMT for the Treatment of IBS-D Symptoms | Initiation of new medications post-FMT for the treatment of IBS-D symptoms will be recorded in patient diaries. | Week 12 following administration of FMT | 
| Patient Attitudes Towards Fecal Microbiota Transplantation (FMT) | Patient attitudes towards Fecal Microbiota Transplantation (FMT) will be recorded in patient diaries. | Week 12 following administration of FMT | 
| Tolerability of Fecal Microbiota Transplantation (FMT) | Tolerability of Fecal Microbiota Transplantation (FMT) will be maintained in patient diaries. | Week 12 following administration of FMT | 
| Intestinal Microbiota Composition Pre- and Post-FMT (Fecal Microbiota Transplantation) | Microbiota composition before and after FMT were assessed among FMT responders and FMT non-responders. Only patients who received FMT capsules at the start of this clinical trial were included. Placebo capsule recipients were not included in these analyses. Data were analyzed up to 12 weeks and not beyond. Microbiome data following cross-over were not analyzed because of the potential for carry-over and order effects in the second half of the trial. Outcomes assessed included alpha and beta diversity (Jensen-Shannon divergence) and abundance of Bacteroidetes, Firmicutes and Prevotella. All of the microbiome data that were analyzed are included in the table below. No additional microbiome data from this clinical trial were analyzed. The Alpha Diversity Index is a quantitative measure that reflects the diversity of bacterial species in a sample. The greater the index, the more diverse the intestinal microbiota. | Baseline, Week 1, Week 4 and Week 12 | 
| Intestinal Microbiota Composition Pre- and Post-FMT (Fecal Microbiota Transplantation) | Microbiota composition before and after FMT were assessed among FMT responders and FMT non-responders. Only patients who received FMT capsules at the start of this clinical trial were included. Placebo capsule recipients were not included in these analyses. Data were analyzed up to 12 weeks and not beyond. Microbiome data following cross-over were not analyzed because of the potential for carry-over and order effects in the second half of the trial. Outcomes assessed included alpha and beta diversity (Jensen-Shannon divergence) and abundance of Bacteroidetes, Firmicutes and Prevotella. All of the microbiome data that were analyzed are included in the table below. No additional microbiome data from this clinical trial were analyzed. The Beta Diversity Index or Jensen-Shannon divergence is a quantitative measure that reflects the diversity of bacterial species between two different regions. The greater the index, the more diverse the intestinal microbiota between the two regions. | Baseline, Week 1, Week 4 and Week 12 | 
| Intestinal Microbiota Composition Pre- and Post-FMT (Fecal Microbiota Transplantation) | Microbiota composition before and after FMT were assessed among FMT responders and FMT non-responders. Only patients who received FMT capsules at the start of this clinical trial were included. Placebo capsule recipients were not included in these analyses. Data were analyzed up to 12 weeks and not beyond. Microbiome data following cross-over were not analyzed because of the potential for carry-over and order effects in the second half of the trial. Outcomes assessed included alpha and beta diversity (Jensen-Shannon divergence) and abundance of Bacteroidetes, Firmicutes and Prevotella. All of the microbiome data that were analyzed are included in the table below. No additional microbiome data from this clinical trial were analyzed. Information on abundance of Prevotella was only available at baseline and week 1. | Baseline and Week 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fecal microbiota transplantation, diarrhea-predominant