Brief Summary
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.
Brief Title
Fecal Microbiota Transplantation for the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome
Detailed Description
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Irritable Bowel Syndrome
Eligibility Criteria
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
* 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
Inclusion Criteria
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
* 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
Gender
All
Gender Based
false
Keywords
fecal microbiota transplantation
diarrhea-predominant
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
65 Years
Minimum Age
19 Years
NCT Id
NCT02328547
Org Class
Other
Org Full Name
Montefiore Medical Center
Org Study Id
2014-3941
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Randomized, Double-blinded, Placebo-controlled Trial of Fecal Microbiota Transplantation (FMT) for Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D)
Primary Outcomes
Outcome Description
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.
Only the following time points were analyzed: Baseline vs Week 12 and Week 24.
Outcome Measure
Within and Between Group Comparisons of Disease Severity as Determined by Irritable Bowel Syndrome-Symptom Severity Score (IBS-SSS)
Outcome Time Frame
Baseline, Week 12 (before cross-over), Week 24
Secondary Outcomes
Outcome Description
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
Only the following time points were analyzed: Baseline vs Week 12
Outcome Time Frame
Baseline, Week 12 (before cross-over), Week 24
Outcome Measure
Within and Between Group Comparisons of Quality of Life as Determined by the Irritable Bowel Syndrome-Quality of Life (IBS-QOL) Score
Outcome Description
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.
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.
Outcome Time Frame
Baseline, Week 1, Week 4 and Week 12
Outcome Measure
Intestinal Microbiota Composition Pre- and Post-FMT (Fecal Microbiota Transplantation)
Outcome Description
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
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
Outcome Time Frame
Baseline, Week 12 (before cross-over), Week 24
Outcome Measure
Anxiety as Measured by the Hospital Anxiety and Depression Scale (HADS). HADS-A (Anxiety)
Outcome Description
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
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
Outcome Time Frame
Baseline, Week 12 (before cross-over), Week 24
Outcome Measure
Depression as Measured by the Hospital Anxiety and Depression Scale (HADS). HADS-D (Depression)
Outcome Description
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
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
Outcome Time Frame
Baseline, Week 12 (before cross-over), Week 24
Outcome Measure
Bowel Consistency as Measured by the Bristol Stool Form Scale (BSFS)
Outcome Description
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.
Outcome Time Frame
All AEs over 24 weeks
Outcome Measure
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Outcome Description
Weekly assessments of satisfaction with the Fecal Microbiota Transplantation (FMT) will be recorded in patient diaries.
Outcome Time Frame
Week 12 following administration of FMT
Outcome Measure
Satisfaction With Fecal Microbiota Transplantation (FMT)
Outcome Description
Degree of improvement in bowel habits and abdominal pain will be recorded in patient diaries.
Outcome Time Frame
Week 12 following administration of FMT
Outcome Measure
Change in Bowel Habits and Abdominal Pain After Fecal Microbiota Transplantation (FMT)
Outcome Description
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.
Outcome Time Frame
Week 12 following administration of FMT
Outcome Measure
Number of Doctor or Emergency Department (ED) Visits Post-Fecal Microbiota Transplantation (Post-FMT) for Irritable Bowel Syndrome-D (IBS-D) Related Symptoms
Outcome Description
Initiation of new medications post-FMT for the treatment of IBS-D symptoms will be recorded in patient diaries.
Outcome Time Frame
Week 12 following administration of FMT
Outcome Measure
Initiation of New Medications Post-FMT for the Treatment of IBS-D Symptoms
Outcome Description
Patient attitudes towards Fecal Microbiota Transplantation (FMT) will be recorded in patient diaries.
Outcome Time Frame
Week 12 following administration of FMT
Outcome Measure
Patient Attitudes Towards Fecal Microbiota Transplantation (FMT)
Outcome Description
Tolerability of Fecal Microbiota Transplantation (FMT) will be maintained in patient diaries.
Outcome Time Frame
Week 12 following administration of FMT
Outcome Measure
Tolerability of Fecal Microbiota Transplantation (FMT)
Outcome Description
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.
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.
Outcome Time Frame
Baseline, Week 1, Week 4 and Week 12
Outcome Measure
Intestinal Microbiota Composition Pre- and Post-FMT (Fecal Microbiota Transplantation)
Outcome Description
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.
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.
Outcome Time Frame
Baseline, Week 1, Week 4 and Week 12
Outcome Measure
Intestinal Microbiota Composition Pre- and Post-FMT (Fecal Microbiota Transplantation)
Outcome Description
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.
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.
Outcome Time Frame
Baseline and Week 1
Outcome Measure
Intestinal Microbiota Composition Pre- and Post-FMT (Fecal Microbiota Transplantation)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
65
Minimum Age Number (converted to Years and rounded down)
19
Investigators
Investigator Type
Principal Investigator
Investigator Name
Olga Aroniadis
Investigator Email
oaroniad@montefiore.org
Investigator Phone
Categories Mesh Debug
Gastrointestinal (GI) Cancers --- COLONIC DISEASES
Digestive System --- COLONIC DISEASES
Gastrointestinal (GI) Cancers --- INTESTINAL DISEASES
Digestive System --- INTESTINAL DISEASES
Gastrointestinal (GI) Cancers --- GASTROINTESTINAL DISEASES
Digestive System --- GASTROINTESTINAL DISEASES
Gastrointestinal (GI) Cancers --- DIGESTIVE SYSTEM DISEASES
Digestive System --- DIGESTIVE SYSTEM DISEASES
Liver --- DIGESTIVE SYSTEM DISEASES
MeSH Terms
IRRITABLE BOWEL SYNDROME
COLONIC DISEASES, FUNCTIONAL
COLONIC DISEASES
INTESTINAL DISEASES
GASTROINTESTINAL DISEASES
DIGESTIVE SYSTEM DISEASES
FECAL MICROBIOTA TRANSPLANTATION
COUNTERFEIT DRUGS
BIOLOGICAL THERAPY
THERAPEUTICS
SUBSTANDARD DRUGS
PHARMACEUTICAL PREPARATIONS